Method for producing cyano heterocyclic compound

Abstract

To provide methods for producing cyano derivatives of heterocyclic compounds with sulfur-containing substituents, which act as valuable synthetic intermediates in the production of heterocyclic compounds with sulfur-containing substituents having pest control activity.SOLUTION: The present invention provides a method for producing a cyano heterocyclic compound represented by formula (2) by reacting a heterocyclic compound represented by formula (1) with a cyanating agent (3) and an iodide salt (4). The inventive method enables the high-yield production of the cyano heterocyclic compound, which is the target product, while suppressing the formation of by-products.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a cyano heterocyclic compound. [Background technology]

[0002] Heterocyclic compounds having a sulfur-containing substituent that function as a pesticide for harmful arthropods are known. For example, Patent Documents 1 to 4 disclose amidine compounds having a heterocyclic group with a sulfur-containing substituent. Patent Document 5 discloses an amide compound having a heterocyclic group with a sulfur-containing substituent. The production of these amidine compounds and amide compounds can be achieved by using cyano derivatives of heterocyclic compounds having a sulfur-containing substituent, and it is desirable to establish an efficient method for producing them. Patent Document 6 describes a method for synthesizing 2-cyano-3-ethylsulfonylpyridines. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2020 / 054712 [Patent Document 2] International Publication No. 2021 / 177410 [Patent Document 3] International Publication No. 2022 / 259985 [Patent Document 4] JP 2023-031268 A [Patent Document 5] International Publication No. 2014 / 021468 [Patent Document 6] JP 2015-196668 A Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention aims to provide a method for producing a cyano derivative of a heterocyclic compound having a sulfur-containing substituent, which is a useful synthetic intermediate in the production of a heterocyclic compound having a sulfur-containing substituent and having pesticidal activity. Specifically, the present invention aims to provide a production method in which the production of by-products is reduced in the cyanation reaction of a heterocyclic compound having a sulfur-containing substituent with a cyanating agent. [Means for solving the problem]

[0005] The present invention relates to the following [1] to [7]. [1] A method for producing a cyano heterocyclic compound represented by formula (2) by reacting a heterocyclic compound represented by formula (1) with a cyanating agent (3) and an iodide salt (4).

[0006] [ka]

[0007] [In formula (1) and formula (2), R a may have a substituent (C 1 ~C 6 ) alkyl group, and optionally substituted (C 3 ~C 6 ) a group selected from the group consisting of cycloalkyl groups, n represents 0, 1, or 2; X 1 may have a halogen atom or a substituent (C 1 ~C 6 ) a group selected from the group consisting of an alkylsulfonyloxy group and an optionally substituted phenylsulfonyloxy group; G 1 is a nitrogen atom or C(R 1 ), G 2 is a nitrogen atom or C(R 2 ), G 3 is a nitrogen atom or C(R 3 ), R 1 , R 2 , and R 3 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C 3 ~C 6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, a phenoxy group which may be substituted, a pyridyloxy group which may be substituted, NY 1 Y 2 Base, C(O)NY 1 Y 2 Group, C(=NY 2 )Y 3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 represents a group selected from the group consisting of The above Y 1 When a plurality of groups are present, each group independently has a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl groups, The above Y 2 When a plurality of groups are present, each group independently may have a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6) a group selected from the group consisting of an alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, a cyano group, and a hydroxy group; The above Y 3 When a plurality of groups are present, each group independently may have a hydrogen atom, a halogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 3 ~C 6 ) a cycloalkyl group, an optionally substituted phenyl group, and NY 1 Y 2 A group (Y 1 and Y 2 has the same meaning as above), ]

[0008] [2] Cyanating agent (3) is HCN, LiCN, NaCN, KCN, BrCN, CuCN, Zn(CN) 2 The method according to [1], wherein the compound is one or more compounds selected from the group consisting of acetone cyanohydrin and trimethylsilyl cyanide. [3] Iodide salts (4) are HI, LiI, NaI, KI, and MgI 2 , N.H. 4 I, CsI, N(Y 4 ) 4 One or more compounds selected from the group consisting of I [Y 4 may each independently have a hydrogen atom or a substituent (C 1 ~C 6 ) is a group selected from the group consisting of an alkyl group, an optionally substituted phenyl group, and an optionally substituted heterocyclic group. The method for producing a compound according to [1] or [2], [4] In formula (1), G1 , G 2 and G 3 are respectively C(R 1 ), C(R 2 ), and C(R 3 The method for producing a semiconductor device according to any one of [1] to [3],

[0009] [5] A cyano heterocyclic compound represented by formula (2) produced by the method according to any one of [1] to [4].

[0010] [ka]

[0011] [In formula (2), R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above.] to an amide compound represented by formula (5):

[0012] [ka]

[0013] [In formula (5), R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above; R b may have a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) a group selected from the group consisting of an alkoxycarbonyl group, and a phenyl group which may have a substituent; G 4 is a nitrogen atom or C(R 4 ), G 5 is a nitrogen atom or C(R 5 ), G 6 is a nitrogen atom or C(R 6 ), G 7 is a nitrogen atom or C(R 7 ), G 8 is a nitrogen atom or C(R 8 ), R 4 , R 5 , R 6 , R 7 , and R 8 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C3 ~C 6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY 1 Y 2 Base, C(O)NY 1 Y 2 Group, C(=NY 2 )Y 3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 A group (Y1 , Y 2 , and Y 3 has the same meaning as above), It is.] The present invention relates to a method for producing an amide compound.

[0014] [6] A cyano heterocyclic compound represented by formula (2) produced by the method according to any one of [1] to [4].

[0015] [ka]

[0016] [In formula (2), R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above.] to an amidine compound represented by formula (6):

[0017] [ka]

[0018] [(In formula (6), R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above; R b may have a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) a group selected from the group consisting of an alkoxycarbonyl group, and a phenyl group which may have a substituent; G 4 is a nitrogen atom or C(R 4 ), G 5 is a nitrogen atom or C(R 5 ), G 6 is a nitrogen atom or C(R 6 ), G 7 is a nitrogen atom or C(R 7 ), G 8 is a nitrogen atom or C(R 8 ), R 4 , R 5 , R 6 , R 7 , and R 8 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C 3 ~C6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY 1 Y 2 Base, C(O)NY 1 Y 2 Group, C(=NY 2 )Y 3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 A group (Y 1 , Y2 , and Y 3 has the same meaning as above), R c may have a hydrogen atom, a hydroxyl group, an amino group, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyloxy group, an optionally substituted phenyl group, and NY 1 Y 2 A group (Y 1 , and Y 2 has the same meaning as above) It is.] A method for producing an amidine compound, comprising the steps of:

[0019] [7] A cyano heterocyclic compound represented by formula (2) produced by the method according to any one of [1] to [4].

[0020] [ka]

[0021] [In formula (2), R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y3 and n are as defined above.] from the cyclic group-linked heterocyclic compound represented by formula (7):

[0022] [ka]

[0023] [In formula (7), R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above; G 4 is a nitrogen atom or C(R 4 ), G 5 is a nitrogen atom or C(R 5 ), G 6 is a nitrogen atom or C(R 6 ), G 7 is a nitrogen atom or C(R 7 ), G 8 is a nitrogen atom or C(R 8 ), R 4 , R 5 , R 6 , R 7 , and R 8 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C1 ~C 6 ) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C 3 ~C 6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY 1 Y 2 Base, C(O)NY 1 Y2 Group, C(=NY 2 )Y 3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 A group (Y 1 , Y 2 , and Y 3 has the same meaning as above), m represents 0, 1, or 2; J 1 , J 2 , J 3 and J 4 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, a hydroxy group, or J 1 and J 2 , J 3 and J 4 The two bonds taken together form a group selected from the group consisting of a carbonyl group and a thiocarbonyl group. The present invention relates to a method for producing a cyclic group-linked heterocyclic compound. Effect of the Invention

[0024] According to the present invention, the cyano heterocyclic compound represented by formula (2) can be produced in a high yield. Preferably, the production of the cyano heterocyclic compound can be highly selectively produced while suppressing the production of by-products in the cyanation reaction step. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] <Method for Producing a Cyano Heterocyclic Compound of Formula (2); from a Heterocyclic Compound of Formula (1);> The present invention relates to a method for producing a cyano heterocyclic compound represented by formula (2) by reacting a heterocyclic compound represented by formula (1) with a cyanating agent (3) and an iodide salt (4).

[0026] [ka]

[0027] The heterocyclic compound represented by formula (1) and the cyano heterocyclic compound represented by formula (2) in the production method of the present invention will be described below.

[0028] In the heterocyclic compound represented by formula (1) and the cyano heterocyclic compound represented by formula (2), R a may have a substituent (C 1 ~C 6 ) alkyl group, and optionally substituted (C 3 ~C 6 ) a group selected from the group consisting of cycloalkyl groups. Preferably, R a may have a substituent (C 1 ~C 6 ) alkyl group, more preferably a methyl group, an ethyl group, or a trifluoromethyl group, and even more preferably an ethyl group. R a The substituents that the group may have include a halogen atom, a NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 has the same meaning as above. When two or more substituents are present, the respective substituents may be the same or different. Preferred are a halogen atom and a cyano group.

[0029] In formula (1) and formula (2), n is 0, 1, or 2. Preferably, n is 1 or 2. More preferably, n is 2, i.e., S(O) n R aPreferred embodiments of the group include a methylsulfonyl group, an ethylsulfonyl group, and a trifluoromethylsulfonyl group.

[0030] In formula (1), X 1 may have a halogen atom or a substituent (C 1 ~C 6 ) represents a group selected from the group consisting of an alkylsulfonyloxy group, and a phenylsulfonyloxy group which may have a substituent. X 1 preferably represents a halogen atom, and a group selected from a methylsulfonyloxy group, a 4-methylbenzenesulfonyloxy group, and a trifluoromethylsulfonyloxy group. 1 is a halogen atom, and a bromo group or an iodine group is particularly preferred. X 1 The substituents that the group may have include a halogen atom, an alkyl group, a cyano group, and a nitro group. When two or more substituents are present, the respective substituents may be the same or different. Preferred are a halogen atom, an alkyl group, and a nitro group.

[0031] In formula (1) and formula (2), G 1 is a nitrogen atom or C(R 1 ), and G 2 is a nitrogen atom or C(R 2 ), and G 3 is a nitrogen atom or C(R 3 ) Preferably, G 1 , G 2 , G 3 is C(R 1 ), C(R 2 ), C(R 3 That is, preferred embodiments of the formula (1) and the formula (2) are pyridine compounds.

[0032] In formula (1) and formula (2), R 1 , R 2 , and R 3 may each independently have a hydrogen atom, a halogen atom, or a substituent (C1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C 3 ~C 6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY 1 Y 2 Base, C(O)NY 1 Y 2 Group, C(=NY 2 )Y 3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 It should be noted that the Y 1 When a plurality of groups are present, each group independently has a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl groups, The above Y 2 When a plurality of groups are present, each group independently may have a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) a group selected from the group consisting of an alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, a cyano group, and a hydroxy group; The above Y 3 When a plurality of groups are present, each group independently may have a hydrogen atom, a halogen atom or a substituent (C 1 ~C 6) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 3 ~C 6 ) a cycloalkyl group, an optionally substituted phenyl group, and NY 1 Y 2 A group (Y 1 and Y 2 has the same meaning as above),

[0033] R 1 , R 2 , and R 3Examples of the "heterocyclic group" in the above formula include thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isoxazolin-3-yl, isoxazolin-4-yl, isoxazolin-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol 3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-1-yl , 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-2-yl, 1,2,3,4-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl -yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, benzothiophen-2-yl, benzothiophen-3-yl, benzothiophen-4-yl, benzothiophen-5-yl, benzothiophen-6-yl, benzothiophen-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl,Benzofuran-7-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, Benzisoxazol-3-yl, Benzisoxazol-4-yl, Benzisoxazol-5-yl, Benzisoxazol-6-yl, Benzisoxazol-7-yl, Benzisothiazol-3-yl, Benzisothiazol-4-yl, Benzisothiazol-5-yl, Benzisothiazol-6-yl, Benzisothiazol-7-yl, Indazol-1-yl, Indazol-3-yl, Indazol-4-yl, Indazol-5-yl, Indazol-6-yl, Indazol-7-yl, Benzoxazol-2-yl benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl Specific examples include quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, phthalazin-1-yl, phthalazin-4-yl, phthalazin-5-yl, phthalazin-6-yl, phthalazin-7-yl, phthalazin-8-yl, cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, cinnolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl.

[0034] R 1 Group, R 2 Groups and R 3 The substituents that the group may have include a halogen atom, a NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, the respective substituents may be the same or different. Preferable are a halogen atom, a cyano group, a nitro group, and SF 5 It is based on In addition, R 1 Group, R 2 Groups and R 3 In the case where the group is a phenyl group which may have a substituent, a heterocyclic group which may have a substituent, a phenoxy group which may have a substituent, or a pyridyloxy group which may have a substituent, examples of the substituent that may be present include a halogen atom, (C 1 ~C 6 ) alkyl group, halo(C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, halo(C 3 ~C 6 ) cycloalkyl group, (C 1 ~C 6 ) alkoxy group, halo(C 1 ~C 6 ) alkoxy group, halo(C 3 ~C 6 ) cycloalkoxy group, (C 1 ~C 6 ) alkylthio group, halo(C 1 ~C 6 ) alkylthio group, (C 1 ~C 6 ) alkylsulfinyl group, halo(C 1 ~C 6) alkylsulfinyl group, (C 1 ~C 6 ) alkylsulfonyl group, halo(C 1 ~C 6 ) alkylsulfinyl group, NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, each substituent may be the same or different. Preferred are a halogen atom, (C 1 ~C 6 ) alkyl group, halo(C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, halo(C 3 ~C 6 ) cycloalkyl group, (C 1 ~C 6 ) alkoxy group, halo(C 1 ~C 6 ) alkoxy group, halo(C 3 ~C 6 ) cycloalkoxy group, (C 1 ~C 6 ) alkylthio group, halo(C 1 ~C 6 ) Alkylthio group, cyano group, nitro group, and SF 5 It is based on

[0035] Preferably, R 1 , R 2、 and R 3 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C6 ) an alkoxy group, optionally having a substituent (C 3 ~C 6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) represents a group selected from the group consisting of an alkylsulfonyl group, an optionally substituted phenyl group, and an optionally substituted heterocyclic group. More preferably, R 1 , and R 3 is a hydrogen atom, and R 2 may have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 3 ~C 6 ) a group selected from the group consisting of a cycloalkoxy group, an optionally substituted phenyl group, and an optionally substituted heterocyclic group. More preferably, R 1 , and R 3 is a hydrogen atom, and R 2 may have a hydrogen atom or a substituent (C 3 ~C 6 ) a group selected from the group consisting of a cycloalkyl group, an optionally substituted phenyl group, and an optionally substituted heterocyclic group. R 1 , R 2 , and R 3In the above, preferred embodiments of the phenyl group which may have a substituent include a 3-fluorophenyl group, a 3-chlorophenyl group, a 3-bromophenyl group, a 3-iodophenyl group, a 3-cyanophenyl group, a 3-(trifluoromethyl)phenyl group, a 3-(trifluoromethoxy)phenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-iodophenyl group, a 4-cyanophenyl group, a 4-(trifluoromethyl)phenyl group, a 4-(trifluoromethoxy)phenyl group, a 4-cyclopropylphenyl group, a 4-(1-cyanocyclopropyl)phenyl group, a 2,4-difluorophenyl group, a 2,4,6-trifluorophenyl group, and a 3,5-difluorophenyl group.

[0036] Preferred embodiments of the heterocyclic compound of formula (1) include the following compounds. 2-Bromo-3-(ethylsulfonyl)pyridine, 2-Bromo-3-(ethylsulfonyl)-5-fluoropyridine, 2-Bromo-5-chloro-3-(ethylsulfonyl)pyridine, 2,5-dibromo-3-(ethylsulfonyl)pyridine, 2-Bromo-3-(ethylsulfonyl)-5-iodopyridine, 2-Bromo-3-(ethylsulfonyl)-5-(trifluoromethyl)pyridine, 2-Bromo-3-(ethylsulfonyl)-5-(trifluoromethoxy)pyridine, 2-Bromo-5-cyclopropyl-3-(ethylsulfonyl)pyridine, 1-(6-Bromo-5-(ethylsulfonyl)pyridin-3-yl)cyclopropane-1-carbonitrile, 2-Bromo-3-(ethylsulfonyl)-5-(4-fluorophenyl)pyridine, 2-Bromo-5-(4-chlorophenyl)-3-(ethylsulfonyl)pyridine 2-bromo-3-(ethylsulfonyl)-5-(4-iodophenyl)pyridine, 2-bromo-3-(ethylsulfonyl)-5-(4-(trifluoromethyl)phenyl)pyridine, 2-bromo-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridine, 2-bromo-5-(2,4-difluorophenyl)-3-(ethylsulfonyl)pyridine, 2-bromo-5-(3,5-difluorophenyl)-3-(ethylsulfonyl)pyridine, 2-bromo-3-(ethylsulfonyl)-5-(2,4,6-trifluorophenyl)pyridine, 4-(6-bromo-5-(ethylsulfonyl)pyridin-3-yl)benzonitrile, 6'-bromo-5'-(ethylsulfonyl)-2,3'-bipyridine, 3-(ethylsulfonyl)-2-fluoropyridine, 3-(ethylsulfonyl)-2,5-Difluoropyridine, 5-chloro-3-(ethylsulfonyl)-2-fluoropyridine, 3-(ethylsulfonyl)-2-fluoro-5-iodopyridine, 5-cyclopropyl-3-(ethylsulfonyl)-2-fluoropyridine, 1-(5-(ethylsulfonyl)-6-fluoropyridin-3-yl)cyclopropane-1-carbonitrile, 3-(ethylsulfonyl)-2-fluoro-5-(trifluoromethyl)pyridine, 3-(ethylsulfonyl)-2-fluoro-5-(trifluoromethoxy)pyridine, 3-(ethylsulfonyl)-2-fluoro-5-(4-fluorophenyl)pyridine, 5-(4-chlorophenyl)-3-(ethylsulfonyl)-2-fluoropyridine, 5-(4-bromophenyl)-3-(ethylsulfonyl)-2-fluoropyridine, 3-(ethylsulfonyl)-2-fluoro -5-(4-iodophenyl)pyridine, 3-(ethylsulfonyl)-2-fluoro-5-(4-(trifluoromethyl)phenyl)pyridine, 3-(ethylsulfonyl)-2-fluoro-5-(4-(trifluoromethoxy)phenyl)pyridine, 5-(2,4-difluorophenyl)-3-(ethylsulfonyl)-2-fluoropyridine, 3-(ethylsulfonyl)-2-fluoro-5-(2,4,6-trifluorophenyl)pyridine, 5-(3,5-difluorophenyl)-3-(ethylsulfonyl)-2-fluoropyridine, 4-(5-(ethylsulfonyl)-6-fluoropyridin-3-yl)benzonitrile, 5'-(ethylsulfonyl)-6'-fluoro-2,3-bipyridine, 2-chloro-3-(ethylsulfonyl)pyridine, 2-chloro-3-(ethylsulfonyl)-5-fluoropyridine, 2,5-Dichloro-3-(ethylsulfonyl)pyridine, 2-Chloro-3-(ethylsulfonyl)-5-iodopyridine, 2-Chloro-5-cyclopropane-3-(ethylsulfonyl)pyridine, 1-(6-chloro-5-(ethylsulfonyl)pyridin-3-yl)cyclopropane-1-carbonitrile, 2-Chloro-3-(ethylsulfonyl)-5-(trifluoromethyl)pyridine, 2-Chloro-3-(ethylsulfonyl)-5-(trifluoromethoxy)pyridine, 2-Chloro-3-(ethylsulfonyl)-5-(4-fluorophenyl)-pyridine, 2-Chloro-5-(4-chlorophenyl)-3-(ethylsulfonyl)-pyridine, 5-(4-bromophenyl)-2-chloro-3-(ethylsulfonyl)-pyridine , 2-chloro-3-(ethylsulfonyl)-5-(4-iodophenyl)pyridine, 2-chloro-3-(ethylsulfonyl)-5-(4-trifluoromethyl)phenyl)pyridine, 2-chloro-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridine, 2-chloro-5-(2,4-difluorophenyl)-3-(ethylsulfonyl)pyridine, 2-chloro-3-(ethylsulfonyl)-5-(2,4,6-trifluorophenyl)pyridine, 2-chloro-5-(3,5-difluorophenyl)-3-(ethylsulfonyl)pyridine, 4-(6-chloro-5-(ethylsulfonyl)pyridin-3-yl)benzonitrile, 6'-chloro-5'-(ethylsulfonyl)-2,3'-bipyridine. ,

[0037] Preferred embodiments of the cyano heterocyclic compound (2) of the formula (2) include the following compounds. 3-(ethylsulfonyl)-5-fluoropicolinonitrile, 5-chloro-3-(3-ethylsulfonyl)picolinonitrile, 5-bromo-3-(ethylsulfonyl)picolinonitrile, 3-(ethylsulfonyl)-5-iodopicolinonitrile, 3-(ethylsulfonyl)-5-(trifluoromethyl)picolinonitrile, 3-(ethylsulfonyl)-5-(trifluoromethoxy)picolinonitrile, 3-(ethylsulfonyl)picolinonitrile, 5-cyclopropyl-3-(ethylsulfonyl)picolinonitrile, 5-(1-cyanocyclopropyl)-3-(ethylsulfonyl)picolinonitrile, 3-(ethylsulfonyl)-5-(4-fluorophenyl)picolinonitrile, 5-(4-chlorophenyl)-3-(ethylsulfonyl)picolinonitrile, 5-( 4-bromophenyl)-3-(ethylsulfonyl)picolinonitrile, 3-(ethylsulfonyl)-5-(4-iodophenyl)picolinonitrile, 3-(ethylsulfonyl)-5-(4-(trifluoromethyl)phenyl)picolinonitrile, 3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)picolinonitrile, 5-(2,4-difluorophenyl)-3-(ethylsulfonyl)picolinonitrile, 3-(ethylsulfonyl)-5-(2,4,6-trifluorophenyl)picolinonitrile, 5-(3,5-difluorophenyl)-3-(ethylsulfonyl)picolinonitrile, 5-(4-cyanophenyl)-3-(ethylsulfonyl)picolinonitrile, 5'-(ethylsulfonyl)-[2,3'-bipyridine]-6'-carbonitrile.

[0038] The cyanating agent (3) and iodide salt (4) in the production method of the present invention, as well as the production method of the cyano heterocyclic compound represented by formula (2) from the heterocyclic compound represented by formula (1) using them will be described below.

[0039] Examples of the cyanating agent (3) include alkali metal cyanide salts such as lithium cyanide, sodium cyanide, and potassium cyanide, copper cyanide (CuCN), zinc cyanide (Zn(CN) 2), organic cyanating agents such as trimethylsilyl cyanide and acetone cyanohydrin, cyanogen bromide, and hydrogen cyanide, but are not limited thereto. The cyanating agent (3) is preferably copper cyanide (CuCN), zinc cyanide (Zn(CN) 2 ), more preferably copper cyanide (CuCN). The amount of the cyanating agent (3) used is usually 1 to 10 mol, preferably 1 to 5 mol, and more preferably 1 to 2 mol, per mol of compound (1).

[0040] Examples of the iodide salt (4) include, but are not limited to, alkali metal iodide salts such as lithium iodide, sodium iodide, potassium iodide, and cesium iodide; alkaline earth metal iodide salts such as magnesium iodide and calcium iodide; quaternary ammonium iodide salts such as ammonium iodide and tetrabutylammonium iodide; and hydrogen iodide. The iodide salt (4) is preferably an alkali metal iodide, such as lithium iodide, sodium iodide, potassium iodide, or cesium iodide, and more preferably sodium iodide or potassium iodide. The amount of the iodide salt (4) used is usually 0.01 to 5 mol, and preferably 0.1 to 2.0 mol, per 1 mol of compound (1).

[0041] The reaction of the heterocyclic compound of formula (1) with the cyanating agent (3) and the iodide salt (4) may be carried out in the presence of a solvent. Examples of the solvent include water; aromatic hydrocarbon solvents such as benzene, chlorobenzene, and toluene; halogen-containing aliphatic hydrocarbon solvents such as chloroform and dichloromethane; alcohol solvents such as methanol, ethanol, and normal butanol; nitrile solvents such as acetonitrile and propylnitrile; aromatic heterocyclic solvents such as pyridine; sulfoxide solvents such as dimethyl sulfoxide and sulfolane; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, and mixtures thereof. The solvent is preferably a sulfoxide solvent or an amide solvent, more preferably an amide solvent, and further preferably N,N-dimethylacetamide. The amount of the solvent used is usually 1 to 100 parts by mass, preferably 1 to 20 parts by mass, per part by weight of the heterocyclic compound of formula (1). Usually, the heterocyclic compound (1) is mixed with a cyanating agent (3) and an iodide salt (4).

[0042] The reaction temperature for the reaction of the heterocyclic compound (1) of the formula (1) with the cyanating agent (3) and the iodide salt (4) is usually 20 to 200°C, preferably 50 to 150°C, and more preferably 50 to 130°C. The reaction is preferably carried out under a nitrogen atmosphere. The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 24 hours.

[0043] The reaction of the heterocyclic compound of formula (1) with the cyanating agent (3) and the iodide salt (4) may be carried out in the presence of a base. Examples of the base include, but are not limited to, pyridine compounds such as pyridine and 4-dimethylaminopyridine; tertiary amine compounds such as triethylamine and ethyldiisopropylamine; and carbonates such as sodium hydrogen carbonate, sodium carbonate, and potassium carbonate. The base is preferably a pyridine compound. The amount of the base used is usually 1 to 10 mol, preferably 1 to 5 mol, per mol of the heterocyclic compound (1).

[0044] The reaction of the heterocyclic compound of formula (1) with the cyanating agent (2) and the iodide salt (4) may be carried out in the presence of a transition metal catalyst, such as palladium, rhodium, nickel, etc., preferably palladium. The amount of the transition metal catalyst used is usually 0.01 to 10 mol %, and preferably 0.1 to 5 mol %, based on 1 mol of the heterocyclic compound (1).

[0045] The heterocyclic compound (1) of formula (1) can be reacted with a cyanating agent (3) and an iodide salt (4) to obtain a cyano heterocyclic compound of formula (2). The reaction mixture obtained can be concentrated to obtain the cyano heterocyclic compound (2). Alternatively, the cyano heterocyclic compound (2) can be obtained by extracting and washing the cyano heterocyclic compound from the reaction mixture obtained. The isolated cyano heterocyclic compound (2) can be purified by a conventional purification method such as washing, column chromatography, or recrystallization.

[0046] In the present invention, the cyano heterocyclic compound of formula (2) obtained by reacting the heterocyclic compound of formula (1) with the cyanating agent (3) and the iodide salt (4) can be a reaction substrate for the amide compound of formula (5), the amidine compound of formula (6), and the cyclic group-linked heterocyclic compound of formula (7). The following describes the method for producing the compounds of formula (5), formula (6), and formula (7) using the cyano heterocyclic compound of formula (2) as a reaction substrate.

[0047] <Method for producing an amide compound of formula (5); from a cyano heterocyclic compound of formula (2);> The present invention includes a method for producing an amide compound according to formula (5), which uses a cyano heterocyclic compound of formula (2) obtained by reacting a heterocyclic compound of formula (1) with a cyanating agent (3) and an iodide salt (4) as a reaction substrate. The production method can be prepared from a cyano compound by a commonly used method for producing an amide.

[0048] The amide compound represented by formula (5) in the present invention is R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above, and are the following compounds.

[0049] [ka]

[0050] In formula (5), R b may have a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 A group selected from the group consisting of an alkoxycarbonyl group and a phenyl group which may have a substituent. 1 ~C 6 ) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, which may have a hydrogen atom or a substituent (C 1 ~C 6 ) Alkyl groups are more preferred. R b The substituents that the group may have include halogen atoms, (C 1 ~C 6 ) alkoxy group, NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2(has the same meaning as above). When two or more substituents are present, each substituent may be the same or different. Preferred are a halogen atom, (C 1 ~C 6 ) an alkoxy group, and a cyano group.

[0051] In formula (5), G 4 is a nitrogen atom or C(R 4 ), and G 5 is a nitrogen atom or C(R 5 ), and G 6 is a nitrogen atom or C(R 6 ), and G 7 is a nitrogen atom or C(R 7 ), and G 8 is a nitrogen atom or C(R 8 ) is preferably G 4 is a nitrogen atom, and G 5 ~G 8 are nitrogen atoms or C(R 5 )~C(R 8 ) is preferred. 4 is a nitrogen atom, and G 5 ~G 8 C(R 5 )~C(R 8 ) is preferred.

[0052] In formula (5), R 4 , R 5 , R 6 , R 7 , and R 8 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C 3 ~C 6 ) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY 1 Y 2 Base, C(O)NY 1 Y 2 Group, C(=NY 2 )Y3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 A group (Y 1 , Y 2 , and Y 3 has the same meaning as above).

[0053] R 4 , R 5 , R 6 , R 7 , and R 8Examples of the "heterocyclic group" in the above formula include thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isoxazolin-3-yl, isoxazolin-4-yl, isoxazolin-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol 3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-1-yl , 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-2-yl, 1,2,3,4-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl -yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, benzothiophen-2-yl, benzothiophen-3-yl, benzothiophen-4-yl, benzothiophen-5-yl, benzothiophen-6-yl, benzothiophen-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl,Benzofuran-7-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, Benzisoxazol-3-yl, Benzisoxazol-4-yl, Benzisoxazol-5-yl, Benzisoxazol-6-yl, Benzisoxazol-7-yl, Benzisothiazol-3-yl, Benzisothiazol-4-yl, Benzisothiazol-5-yl, Benzisothiazol-6-yl, Benzisothiazol-7-yl, Indazol-1-yl, Indazol-3-yl, Indazol-4-yl, Indazol-5-yl, Indazol-6-yl, Indazol-7-yl, Benzoxazol-2-yl benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl Specific examples include quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl, phthalazin-1-yl, phthalazin-4-yl, phthalazin-5-yl, phthalazin-6-yl, phthalazin-7-yl, phthalazin-8-yl, cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, cinnolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl.

[0054] R 4 Group, R 5 Group, R 6 Group, R 7 Groups and R 8 The substituents that the group may have include a halogen atom, a NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, the respective substituents may be the same or different. Preferable are a halogen atom, a cyano group, a nitro group, and SF 5 It is based on In addition, R 4 Group, R 5 Group, R 6 Group, R 7 Groups and R 8 In the case where the group is a phenyl group which may have a substituent, a heterocyclic group which may have a substituent, a phenoxy group which may have a substituent, or a pyridyloxy group which may have a substituent, examples of the substituent that may be present include a halogen atom, (C 1 ~C 6 ) alkyl group, halo(C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, halo(C 3 ~C 6 ) cycloalkyl group, (C 1 ~C 6 ) alkoxy group, halo(C 1 ~C 6 ) alkoxy group, halo(C 3 ~C 6 ) cycloalkoxy group, (C 1 ~C 6 ) alkylthio group, halo(C 1 ~C 6 ) alkylthio group, (C1 ~C 6 ) alkylsulfinyl group, halo(C 1 ~C 6 ) alkylsulfinyl group, (C 1 ~C 6 ) alkylsulfonyl group, halo(C 1 ~C 6 ) alkylsulfinyl group, NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, each substituent may be the same or different. Preferred are a halogen atom, (C 1 ~C 6 ) alkyl group, halo(C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, halo(C 3 ~C 6 ) cycloalkyl group, (C 1 ~C 6 ) alkoxy group, halo(C 1 ~C 6 ) alkoxy group, halo(C 3 ~C 6 ) cycloalkoxy group, (C 1 ~C 6 ) alkylthio group, halo(C 1 ~C 6 ) Alkylthio group, cyano group, nitro group, and SF 5 It is based on

[0055] R 4 , R 5 , R 6 , R 7 and R 8 is preferably a hydrogen atom, a halogen atom, or a group which may have a substituent (C 1 ~C 6) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, a cyano group, a nitro group, and SF 5 More preferably, it is a hydrogen atom, a halogen atom, or a group optionally having a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) alkylsulfonyl groups.

[0056] The amide compound of formula (5) can be produced from the cyano heterocyclic compound of formula (2) by, for example, the methods shown in steps a-1 to a-4, or steps b and c below. That is, the process includes a step (step a-1) of preparing a carboxy heterocyclic compound according to formula (8) from a cyano heterocyclic compound of formula (2), and a step (step a-2) of reacting a carboxy heterocyclic compound according to formula (8) with an amino compound according to formula (10) to produce an amide compound according to formula (5). Alternatively, after the above (step a-1), the process includes a step (step a-3) of preparing a carbonyl heterocyclic compound according to formula (9) from a carboxy heterocyclic compound according to formula (8), and a step (step a-4) of reacting a carbonyl heterocyclic compound according to formula (9) with an amino compound according to formula (10) to produce an amide compound according to formula (5).

[0057] <Formula (5); Amide compound production steps a-1 to a-4>

[0058] [ka]

[0059] <Process a-1> A cyano heterocyclic compound represented by formula (2) is reacted with a reactant in the presence of an inert solvent and, optionally, a base to produce a carboxy heterocyclic compound represented by formula (8). a , G 1 , G 2 , and G 3 has the same meaning as above, and n is 0 to 2.

[0060] The reaction agent usable in step a-1 may be a base, and examples of the base include alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium carbonate. The amount of the base used may be appropriately selected usually within a range of about 0.5 to 10 times the molar amount of the heterocyclic compound represented by formula (2).

[0061] The reactant usable in step a-1 may be an acid, and examples of the acid include inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid, organic acids such as acetic acid and p-tosylic acid, and Lewis acids such as trimethylaluminum, aluminum chloride, etc. The amount of the acid usable in this reaction may be appropriately selected usually within the range of about 1 to 10 times the molar amount of the heterocyclic compound represented by formula (2).

[0062] The solvent that can be used in step a-1 may be any solvent that does not significantly inhibit the reaction, and examples of such solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, ethers such as tetrahydrofuran and 1,4-dioxane, polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and 1,3-dimethyl-2-imidazolinone, H 2 These inert solvents can be used alone or in combination of two or more.

[0063] The reaction temperature in step a-1 may usually be within the range of about -78°C to the boiling point of the solvent used, and the reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc. For example, it may be appropriately selected within the range of several minutes to 48 hours. This reaction can also be carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation.

[0064] <Process a-2> The amide compound represented by formula (5) is produced by reacting the carboxy heterocyclic compound represented by formula (8) with the amino compound represented by formula (10) and a reactant in an inert solvent, optionally in the presence of a base. a , R b , G 1 , G 2 , G 3 , G 4 , G5 , G 6 , G 7 , and G 8 has the same meaning as above, and n is 0 to 2.

[0065] Examples of the reactant that can be used in step a-2 include condensation agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, HATU, PyBOP, and Mukaiyama reagent. The amount of the reaction accelerator used may be appropriately selected usually within the range of about 1 to 3 times the molar amount of the compound represented by formula (8) or (10).

[0066] Examples of the base that can be used in step a-2 include triethylamine, N,N-diisopropylethylamine, pyridine, and the like. The amount of the base used may be appropriately selected usually within the range of about 1 to 5 moles per mole of the compound represented by formula (8) or (10).

[0067] The inert solvent that can be used in step a-2 may be any solvent that does not significantly inhibit the reaction, and examples of such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc., and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolinone, etc. These inert solvents can be used alone or in combination of two or more kinds.

[0068] The reaction temperature in step a-2 may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc., and may be appropriately selected within the range of, for example, several minutes to 48 hours. This step may also be carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation.

[0069] 〈Process a-3〉 The carbonyl heterocyclic compound represented by formula (9) is produced by reacting the carboxy heterocyclic compound represented by formula (8) with a reactant in an inert solvent, optionally in the presence of a base. a , R b , G 1 , G 2 , and G 3 And n and X 2 has the same meaning as above.

[0070] Examples of the reactant that can be used in step a-3 include thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, triphosgene, and the like. The amount of the reactant used may be appropriately selected usually within the range of about 1 to 10 times the molar amount of the compound represented by formula (8). In step a-3, a base may be present. Examples of the base include alkali metal salts such as sodium hydride, sodium carbonate, and potassium carbonate, tertiary amines such as triethylamine and N,N-diisopropylethylamine, and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine. The amount of the base used may be appropriately selected usually within the range of about 1 to 5 moles relative to the amount of the compound represented by formula (8).

[0071] The inert solvent that can be used in step a-3 may be any solvent that does not significantly inhibit the reaction, and examples of the inert solvent include ethers such as tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc., polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolinone, etc. These inert solvents can be used alone or in combination of two or more kinds.

[0072] The reaction temperature in step a-3 may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc., and may be appropriately selected within the range of, for example, several minutes to 48 hours. Alternatively, the reaction may be carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas. After the reaction is completed, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product may be produced by purifying the product by recrystallization, column chromatography, etc., as necessary. The composition containing the target product may be used in the next step without isolation. Alternatively, the next step may be carried out without isolation.

[0073] <Step a-4> The amide compound represented by formula (5) can be produced by reacting the carbonyl heterocyclic compound represented by formula (9) with the amino compound represented by formula (10) in an inert solvent with any reactant, optionally in the presence of a base. a , R b , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , and n and X 2 has the same meaning as above.

[0074] Examples of the base that can be used in step a-4 include alkali metal salts such as sodium hydride, sodium carbonate, and potassium carbonate; tertiary amines such as triethylamine and N,N-diisopropylethylamine; and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine. The amount of the compound used may be appropriately selected usually within the range of about 1 to 5 times the molar amount of the compound represented by formula (9) or (10).

[0075] The inert solvent that can be used in step a-4 may be any solvent that does not significantly inhibit the reaction, and examples of the inert solvent include ethers such as tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc., polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolinone, etc. These inert solvents can be used alone or in combination of two or more kinds.

[0076] The reaction temperature in step a-4 may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc., and may be appropriately selected within the range of, for example, several minutes to 48 hours. The reaction can also be carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation.

[0077] <Production method of amide compound of formula (5); from cyano heterocyclic compound of formula (2); via amidine compound of formula (6);> The present invention encompasses a method for producing an amide compound represented by formula (5) by using a cyano heterocyclic compound represented by formula (2), obtained by reacting a heterocyclic compound represented by formula (1) with a cyanating agent (3) and an iodide salt (4), as a reaction substrate, via an amidine compound represented by formula (6). The production method can be carried out by a conventional production method of amidinating a cyano compound and subsequently producing an amide.

[0078] The method for producing the amide compound represented by formula (5) of the present invention also includes a method for producing the amide compound represented by formula (5) (step c) via an amidine compound represented by formula (6) described below (step b). That is, the process includes a step (step b) of reacting a cyano heterocyclic compound of formula (2) with an amino compound of formula (10) to prepare an amidine compound of formula (6), and a step (step c) of producing an amide compound of formula (5) from the amidine compound of formula (6). Step b will be described later, and here step c will be described.

[0079] <Formula (5); Amide compound production steps b and c>

[0080] [ka]

[0081] <Process c> From the cyano heterocyclic compound represented by formula (2), an amidine compound represented by formula (6) is prepared in step b, and the amidine compound is reacted with a reactant in an inert solvent to produce an amide compound represented by formula (5). a , R b , R c , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , and n and G 8The amidine compound represented by formula (6) produced in step b may be subjected to step c in the same reaction system without being isolated.

[0082] The reactant usable in step c may be a base, and examples thereof include alkali metal salts such as sodium hydride, sodium hydroxide, sodium carbonate, and potassium carbonate; tertiary amines such as triethylamine and N,N-diisopropylethylamine; and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine. The amount of the base used may be appropriately selected usually within the range of about 1 to 5 times the molar amount of the amidine compound represented by formula (6).

[0083] The reactant usable in step c may be an acid, and examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid, organic acids such as acetic acid and p-tosylic acid, and Lewis acids such as trimethylaluminum and aluminum chloride. The amount of the reactant used in this reaction may be appropriately selected usually within the range of about 1 to 10 times the molar amount of the amidine compound represented by formula (6).

[0084] The inert solvent that can be used in step c may be any solvent that does not significantly inhibit the reaction, and examples of such solvents include ethers such as tetrahydrofuran, ethylene glycol dimethyl ether, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and 1,3-dimethyl-2-imidazolinone; 2 These inert solvents can be used alone or in combination of two or more.

[0085] The reaction temperature in step c may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc., and may be appropriately selected within the range of, for example, several minutes to 48 hours. The reaction can also be carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation.

[0086] <Method for producing amidine compound of formula (6); from cyano heterocyclic compound of formula (2);> The present invention includes a method for producing an amidine compound according to formula (6), which uses a cyano heterocyclic compound of formula (2) obtained by reacting a heterocyclic compound of formula (1) with a cyanating agent (3) and an iodide salt (4) as a reaction substrate. The method for producing the amidine compound can be carried out by a commonly used method for producing an amidine from a cyano compound.

[0087] The amidine compound represented by formula (6) in the present invention is R a , G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and n are as defined above, and are the following compounds.

[0088] [ka]

[0089] In formula (6), R b may have a hydrogen atom or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 1 ~C 6) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 A group selected from the group consisting of an alkoxycarbonyl group and a phenyl group which may have a substituent. 1 ~C 6 ) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, which may have a hydrogen atom or a substituent (C 1 ~C 6 ) Alkyl groups are more preferred. R b The substituents that the group may have include a halogen atom, a NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, each substituent may be the same or different. Preferred are a halogen atom, (C 1 ~C 6 ) an alkoxy group, and a cyano group.

[0090] In formula (6), R c may have a hydrogen atom, a hydroxyl group, an amino group, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyloxy group, an optionally substituted phenyl group, and NY 1 Y 2 A group (Y 1 , and Y 2 is the same as defined above). Preferably, it is a hydroxy group, a group which may have a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) alkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyloxy group. More preferably, it is a hydroxy group, an optionally substituted (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) alkylcarbonyloxy groups. R c The substituents that the group may have include a halogen atom, a NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 has the same meaning as above. When two or more substituents are present, the respective substituents may be the same or different. Preferred are a halogen atom, a cyano group, and a nitro group.

[0091] In equation (6), G 4 is a nitrogen atom or C(R 4 ), and G 5 is a nitrogen atom or C(R 5 ), and G 6 is a nitrogen atom or C(R 6 ), and G 7 is a nitrogen atom or C(R 7 ), and G 8 is a nitrogen atom or C(R 8 ) is preferably G 4 is a nitrogen atom, and G 5 ~G 8 are nitrogen atoms or C(R 5 )~C(R 8 ) is preferred. 4 is a nitrogen atom, and G 5 ~G 8 C(R 5 )~C(R 8 ) is preferred.

[0092] In formula (6), R 4 , R 5 , R 6 , R 7 , and R 8 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxy group, optionally having a substituent (C 3 ~C 6) a cycloalkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkenyloxycarbonyl group, optionally having a substituent (C 2 ~C 6 ) an alkynyloxycarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkenylcarbonyloxy group, optionally having a substituent (C 2 ~C 6 ) an alkynylcarbonyloxy group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY 1 Y 2 Base, C(O)NY 1 Y 2 Group, C(=NY 2 )Y 3 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH 2 Group, and SF 5 A group (Y 1 , Y 2 , and Y3 has the same meaning as above). R 4 Base~R 8 The substituents that the group may have include a halogen atom, a NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, the respective substituents may be the same or different. Preferable are a halogen atom, a cyano group, a nitro group, and SF 5 It is based on In addition, R 4 Group, R 5 Group, R 6 Group, R 7 Groups and R 8 In the case where the group is a phenyl group which may have a substituent, a heterocyclic group which may have a substituent, a phenoxy group which may have a substituent, or a pyridyloxy group which may have a substituent, examples of the substituent that may be present include a halogen atom, (C 1 ~C 6 ) alkyl group, halo(C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, halo(C 3 ~C 6 ) cycloalkyl group, (C 1 ~C 6 ) alkoxy group, halo(C 1 ~C 6 ) alkoxy group, halo(C 3 ~C 6 ) cycloalkoxy group, (C 1 ~C 6 ) alkylthio group, halo(C 1 ~C 6 ) alkylthio group, (C 1 ~C 6 ) alkylsulfinyl group, halo(C 1~C 6 ) alkylsulfinyl group, (C 1 ~C 6 ) alkylsulfonyl group, halo(C 1 ~C 6 ) alkylsulfinyl group, NY 1 Y 2 Base, C(O)NY 1 Y 2 group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, C(O)NH 2 group, trimethylsilyl group, and SF 5 Group(Y 1 and Y 2 (has the same meaning as above). When two or more substituents are present, each substituent may be the same or different. Preferred are a halogen atom, (C 1 ~C 6 ) alkyl group, halo(C 1 ~C 6 ) alkyl group, (C 3 ~C 6 ) cycloalkyl group, halo(C 3 ~C 6 ) cycloalkyl group, (C 1 ~C 6 ) alkoxy group, halo(C 1 ~C 6 ) alkoxy group, halo(C 3 ~C 6 ) cycloalkoxy group, (C 1 ~C 6 ) alkylthio group, halo(C 1 ~C 6 ) Alkylthio group, cyano group, nitro group, and SF 5 It is based on

[0093] R 4 , R 5 , R 6 , R 7 and R 8 is preferably a hydrogen atom, a halogen atom, or a group which may have a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylcarbonyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkylcarbonyl group, optionally having a substituent (C 1 ~C 6 ) an alkylthio group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfinyl group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, a cyano group, a nitro group, and SF 5 More preferably, it is a hydrogen atom, a halogen atom, or a group optionally having a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 3 ~C 6 ) Cycloalkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, optionally having a substituent (C 1 ~C 6 ) an alkylsulfonyl group, an optionally substituted phenoxy group, a cyano group, a nitro group, and SF 5 is a group selected from the group consisting of groups.

[0094] The amidine compound of formula (6) can be produced from the cyano heterocyclic compound of formula (2) by, for example, the method shown in the following step b.

[0095] In the present invention, the method for producing amidine compound (6) using formula (2) obtained by reacting compound (1) with cyanating agent (3) and iodide salt (4) as a reaction substrate can be, but is not limited to, the method shown in step b. That is, this is a method for producing an amidine compound represented by formula (6) by reacting a cyano heterocyclic compound represented by formula (2) with an amino compound represented by formula (10).

[0096] <Formula (6); Amidine compound manufacturing process b>

[0097] [ka]

[0098] <Step b> The amidine compound represented by formula (6) can be produced by reacting the cyano heterocyclic compound represented by formula (2) with the amino compound represented by formula (10) in an inert solvent with a reactant, optionally in the presence of a base. a , R b , R c , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , and n and G 8 has the same meaning as above.

[0099] The reactant that can be used in step b includes, for example, Lewis acids such as trimethylaluminum and aluminum chloride. The amount of the reactant used is usually within a range of 1 mole to 10 moles based on the compound represented by formula (10) or (2).

[0100] Examples of the base that can be used in step b include alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, and calcium hydride; and organometallic amides such as n-butyllithium, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium diisopropylamide. The amount of the base used is usually within a range of about 1 mole to 10 moles relative to the compound represented by formula (10) or (2).

[0101] The inert solvent that can be used in step b may be any solvent that does not significantly inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc., ethers such as tetrahydrofuran, 1,4-dioxane, etc., polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolinone, etc. These inert solvents can be used alone or in combination of two or more kinds.

[0102] The reaction temperature in step b may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc., and may be appropriately selected within the range of, for example, several minutes to 48 hours. The reaction can also be carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation.

[0103] The amidine compound represented by formula (6) can also be produced via the amide compound represented by formula (5). Here, the method for producing the amide compound represented by formula (5) can be carried out according to the above-mentioned step a or step c. That is, the process includes a step of producing an amide compound represented by formula (5) from a cyano heterocyclic compound represented by formula (2), and then a step (step d) of producing an amidine compound represented by formula (6) by reacting the amide compound represented by formula (5) with an amine compound represented by formula (12).

[0104] <Formula (6); Amidine compound manufacturing process d>

[0105] [ka]

[0106] <Process d> The amidine compound represented by formula (6) can be produced by reacting the amide compound represented by formula (6), which can be produced from the cyano heterocyclic compound represented by formula (2) by the method described in the above <Steps a-1 to a-4> or <Step c>, with the amine compound represented by formula (12) in an inert solvent. a , R b , R c , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , and n and G 8 has the same meaning as above. The amine compound represented by formula (12) may form a salt with any acid.

[0107] Examples of the reactant that can be used in step d include Lewis acids such as trimethylaluminum and aluminum chloride, and chlorinating agents such as phosphorus oxychloride, phosphorus pentachloride, and carbon tetrachloride-triphenylphosphine. The amount of the reactant used may be appropriately selected from the range of about 1 to 10 times the molar amount of the compound represented by formula (5). In addition, the reactant such as phosphorus oxychloride can be reacted without a solvent by adding an excess amount of the reactant. In step d, a base may be applied, for example, alkali metal salts such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, etc., tertiary amines such as triethylamine, N,N-diisopropylethylamine, etc., and nitrogen-containing aromatic compounds such as pyridine, 4-dimethylaminopyridine, etc. The amount of the base used may be appropriately selected from the range of about 1 to 5 moles based on the amount of the compound represented by formula (5).

[0108] The inert solvent that can be used in step d may be any solvent that does not significantly inhibit the reaction, and examples of such solvents include ethers such as tetrahydrofuran, ethylene glycol dimethyl ether, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and 1,3-dimethyl-2-imidazolinone; 2 These inert solvents can be used alone or in combination of two or more.

[0109] The reaction temperature in step d may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time may be appropriately selected depending on the reaction scale, reaction temperature, etc., and may be appropriately selected within the range of, for example, several minutes to 48 hours. The reaction can also be carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation.

[0110] <Method for Producing a Cyclic Group-Linked Heterocyclic Compound of Formula (7); from a Cyano Heterocyclic Compound of Formula (2)> The present invention encompasses a method for producing a cyclic group-linked heterocyclic compound according to formula (7), which uses a cyano heterocyclic compound of formula (2) obtained by reacting a heterocyclic compound of formula (1) with a cyanating agent (3) and an iodide salt (4) as a reaction substrate. The production method can be a conventional method for producing a cyclized product from a cyano compound (2) via an amidine compound (6).

[0111] The cyclic group-linked heterocyclic compound represented by formula (7) in the present invention is R a , G 1 , G 2 , G 3 , R 1 , R2 , R 3 , Y 1 , Y 2 , Y 3 , n, G 4 , G 5 , G 6 , G 7 is the following compound, which has the same meaning as above.

[0112] [ka]

[0113] In formula (7), m is 0, 1 or 2. m is preferably 0.

[0114] In equation (7), J 1 , J 2 , J 3 and J 4 may each independently have a hydrogen atom, a halogen atom, or a substituent (C 1 ~C 6 ) alkyl group, optionally having a substituent (C 1 ~C 6 ) an alkoxy group, a hydroxy group, or J 1 and J 2 , J 3 and J 4 The two bonds taken together form a group selected from the group consisting of a carbonyl group and a thiocarbonyl group. 1 and J 2 , J 3 and J 4 It is preferable that the two bonds taken together form a group selected from the group consisting of a carbonyl group and a thiocarbonyl group.

[0115] The cyclic group-linked heterocyclic compound of formula (7) can be produced from the cyano heterocyclic compound of formula (2) by, for example, the method shown in step b or step d below.

[0116] In the present invention, the method for producing amidine compound (6) using formula (2) obtained by reacting compound (1) with cyanating agent (3) and iodide salt (4) as a reaction substrate can be, but is not limited to, the method shown in step e. That is, the process includes a step of producing an amidine compound represented by formula (6) from a cyano heterocyclic compound represented by formula (2) (step b or d), and then a step of producing a cyclic group-linked heterocyclic compound represented by formula (7) from the amidine compound represented by formula (6) (step e).

[0117] <Formula (7); Cyclic group-linked heterocyclic compound production process e>

[0118] [ka]

[0119] <Process e> The cyclic group-linked heterocyclic compound represented by formula (7) can be produced by reacting the amidine compound represented by formula (6), which can be produced from the cyano heterocyclic compound represented by formula (2) by the method described in the above step b) or step d, with a reactant in an inert solvent. a , G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , G 7 , G 8 , n, J 1 ,J 2 ,J 3 ,J 4 and m are as defined above. In formula (6), R c is a hydroxy group.

[0120] Examples of reactants that can be used in step e include 1,1-carbonyldiimidazole, 1,1-thiocarbonyldiimidazole, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, 4-nitrophenyl chloroformate, dibromomethane, bromochloromethane, 1,2-dichloroethane, 1,2-dibromoethane, chloroacetyl chloride, and bromoacetyl chloride. The amount of the reactant used may be appropriately selected usually within the range of about 1 to 20 times the molar amount of the amidine compound represented by the formula (6). In step e, a base may be used, for example, alkali metal salts such as sodium hydroxide and lithium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine and N,N-diisopropylethylamine, and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine. The amount of the base used may be appropriately selected usually within the range of about 1 to 20 times the molar amount of the amidine compound represented by formula (6).

[0121] The inert solvent that can be used in step e may be any solvent that does not significantly inhibit the reaction, and examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and 1,3-dimethyl-2-imidazolinone; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; alcohols such as methanol, ethanol, and isopropanol; 2 These inert solvents can be used alone or in combination of two or more.

[0122] The reaction temperature in step e may usually be within the range of about -78°C to the boiling point of the solvent used. The reaction time varies depending on the reaction scale, reaction temperature, etc., but may be appropriately selected within the range of several minutes to 48 hours. The reaction can also be carried out under an atmosphere of an inert gas such as nitrogen gas or argon gas. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it, if necessary, by recrystallization, column chromatography, etc. The composition containing the target product may be used in the next step without isolation. EXAMPLES

[0123] Example 1: Method for the preparation of 2-bromo-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridine 2-Bromo-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridine (250 mg, 0.61 mmol) was dissolved in N,N-dimethylacetamide (DMAc 1 mL), and the cyanating agent and additives were added thereto. After replacing the atmosphere in the reaction system with nitrogen, the reaction vessel was sealed and stirred at 110°C for 5 hours. After 5 hours of reaction, the reaction solution was subjected to high performance liquid chromatography to analyze the compounds in the reaction system. The cyanating agent, additives, and components (area ratio) in the reaction solution are summarized in Table 1. The high performance liquid chromatography analysis conditions in Table 1 are shown in Table 2.

[0124] [ka]

[0125] [Table 1]

[0126] [Table 2]

[0127] Example 9: Preparation of 3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)picolinonitrile using the iodide salt 2-Bromo-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridine (3 g, 7.31 mmol), copper(I) cyanide (760 mg, 8.49 mmol), and sodium iodide (1.18 g, 7.87 mmol) were dissolved in N,N-dimethylacetamide (12 mL), and the reaction system was replaced with nitrogen. After reacting at 110°C for 6 hours, the mixture was stirred at room temperature overnight. The reaction solution was distilled under reduced pressure at 110°C to remove N,N-dimethylacetamide (8mL). Dichloromethane (30mL) was added thereto, and the mixture was washed three times with 10% aqueous ammonia solution (20mL), separated, and washed twice with 10% aqueous ammonium chloride solution, separated. The reaction solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 2.56g of a crude product. The results of high performance liquid chromatography analysis of the crude product (area ratio) were as follows: target product: 96.3%, by-product 1: 0.5%, by-product 2: 0.2%. This crude product was purified by silica gel column chromatography to obtain the target compound (2.30 g, 6.45 mmol, yield 88.2%). 1 H NMR (CDCl 3 ) δ9.13(1H, d, J=2.1Hz), 8.58(1H, d, J=2.4Hz), 7.74-7.70(2H, m), 7.43(2H, d, J=7.43Hz), 3.52(2H, q, J=7.5Hz), 1.41(3H, t, J= 7.5Hz)

[0128] Comparative Example 5: Preparation of 3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)picolinonitrile without using iodide salt 2-Bromo-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridine (3 g, 7.31 mmol) and copper(I) cyanide (760 mg, 8.49 mmol) were dissolved in N,N-dimethylacetamide (12 mL), and the reaction system was replaced with nitrogen. After reacting at 110°C for 6 hours, the mixture was stirred at room temperature overnight. The reaction solution was distilled under reduced pressure at 110°C to remove N,N-dimethylacetamide (8mL). Dichloromethane (30mL) was added thereto, and the mixture was washed three times with 10% aqueous ammonia solution (20mL) and separated, and then washed twice with 10% aqueous ammonium chloride solution and separated. The reaction solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 2.67g of crude product. The results of high performance liquid chromatography analysis of the crude product (area ratio) were as follows: target product: 39.2%, by-product 1: 45.6%, by-product 2: 2.2%. This crude product was purified by silica gel column chromatography to obtain the target compound (1.13 g, 3.17 mmol, yield 43.4%).

[0129] Example 10-1: Preparation of 3-(ethylthio)-5-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picoline imidamide

[0130] [ka]

[0131] 5-(trifluoromethyl)pyridin-2-amine (106 mg, 0.65 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (content 55%, 31 mg, 0.71 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. 3-Ethylthio-5-(4-(trifluoromethyl)phenyl)picolinonitrile (200 mg, 6.49 mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. Water was then added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and then distilled under reduced pressure using a rotary evaporator. The resulting crude product was purified by silica gel column chromatography, and then suspended in a mixture of ethyl acetate and hexane, and filtered to obtain the target product. 1 H NMR (CDCl 3) δ10.07(1H, br), 8.65(1H, s), 8.55(1H, d, J=1.8Hz), 7.86(1H, dd, J=8.4Hz, 2.4Hz), 7.84(1H, d, J=2.1Hz), 7.78(2H, d, J=8.1H z), 7.72(2H, d, J=8.1Hz), 7.46 (1H, d, J=8.4Hz), 2.97(2H, q, J=7.5Hz), 1.46(3H, t, J=7.5Hz)

[0132] Example 10-2: Preparation of 3-(ethylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picoline imidamide

[0133] [ka]

[0134] 3-(ethylthio)-5-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picoline imidamide (270 mg, 0.57 mmol) prepared in Synthesis Example 10-1 was dissolved in dichloromethane (2.5 mL), 3-chloroperbenzoic acid (65%, 0.31 g, 1.15 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then distilled under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography to obtain the target product (260 mg, 91.5%). 1 H NMR (CDCl 3 ) δ10.17(1H, br), 9.05(1H, d, J=2.1Hz), 8.71(1H, d, J=1.5Hz), 8.69(1H, s), 7.95-7.75(6H, m), 7.20(1H, d, J=2.4Hz), 4.05(2H, q, J=7.5Hz), 1.42(3H, t, J=7.5Hz)

[0135] Example 11-1: Preparation of 3-(ethylthio)-5-(4-(trifluoromethoxy)phenyl)-picolinic acid

[0136] [ka]

[0137] The product 3-(ethylthio)-5-(4-(trifluoromethoxy)phenyl)picolinonitrile (2.00 g, 6.17 mmol) was dissolved in ethanol (60 mL) and dioxane (20 mL), and a 25% aqueous sodium hydroxide solution (50.0 g, 308 mmol) was added thereto and stirred under reflux for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was diluted with water and 1N hydrochloric acid, and then extracted three times with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting composition was suspended in a mixture of ethyl acetate and hexane, and the suspension was filtered to obtain the target product (2.18 g, quant.) as a residue. 1 H NMR (CDCl 3 )δ10.07(1H, br), 8.65(1H, s), 8.55(1H, d, J=1.8Hz), 7.86(1H, dd, J= 8.4Hz, 2.4Hz), 7.84(1H, d, J=2.1Hz), 7.78(2H, d, J=8.1Hz), 7.72(2H, d, J=8.1Hz), 7.46(1H, d, J=8.4Hz), 2.97(2H, q, J=7.5Hz), 1.46(3H, t, J=7.5Hz)

[0138] Example 11-2: Preparation of 3-(ethylthio)-5-(4-(trifluoromethoxy)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picolinamide

[0139] [ka]

[0140] The product of Example 11-1 (5.22 g, 15.2 mmol) was dissolved in dichloromethane (140 mL), and oxalyl chloride (2.61 mL, 30.4 mmol) and dimethylformamide (500 μL) were added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (120 mL). 2-amino-5-trifluoromethylpyridine (3.20 g, 19.7 mmol) and triethylamine (11 mL, 78.9 mmol) were added thereto, and the mixture was stirred at room temperature for 4.5 hours. Water and saturated saline were added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure, and the crude product was purified by silica gel chromatography to obtain the target compound (3.46 g, 46.7%). 1 H NMR (CDCl 3 )δ10.17(1H, br), 9.05(1H, d, J=2.1Hz), 8.71(1H, d, J=1.5Hz), 8.69(1 H, s), 7.95-7.75(6H, m), 7.20(1H, d, J=2.4Hz), 4.05(2H, q, J=7.5Hz), 1.42(3H, t, J=7.5Hz)

[0141] Example 11-3: Preparation of 3-(ethylsulfonyl)-5-(4-(trifluoromethoxyphenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picolinamide

[0142] [ka]

[0143] The product of Example 11-2 (190 mg, 0.390 mmol) was dissolved in dichloromethane (7 mL), and 3-chloroperbenzoic acid (65%, 208 mg, 0.783 mmol) was added thereto, followed by stirring at room temperature for 7 hours. Aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain the target compound (177 mg, 87.4%). 1 H NMR (CDCl 3 )δ10.17(1H, broad), 9.05(1H, d, J=2.1Hz), 8.71(1H, d, J=1.5Hz), 8.6 9(1H, s), 7.95-7.75(6H, m), 7.20(1H, d, J=2.4Hz), 4.05(2H, q, J=7.5Hz), 1.42(3H, t, J=7.5Hz)

[0144] Example 12: Preparation of 3-(ethylsulfonyl)-N'-hydroxy-5-(4-(trifluoromethoxy)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picoline imidamide

[0145] [ka]

[0146] 3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picolinamide (218 mg, 0.42 mmol) prepared in Example 11-3 was dissolved in acetonitrile (7 mL), carbon tetrachloride (122 μL, 1.25 mmol) and triphenylphosphine (0.66 g, 2.52 mmol) were added, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 50% aqueous hydroxylamine solution (1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Most of the acetonitrile in the reaction mixture was distilled off, and the residue was purified by silica gel chromatography to obtain the desired product (185 mg, 87.7%). 1 H NMR (CDCl 3) δ8.97(1H, d, J=2.4Hz), 8.57(1H, d, J=2.1Hz), 8.14(1H, s), 7.76-7.6 9(2H, m), 7.65(1H, dd, J=8.7, 2.4Hz), 7.40(2H, d, J=8.1Hz), 6.63(1H, d, J=8.7Hz), 3.60(2H, q, J=7.5Hz), 1.36(3H, t, J=7.5Hz)

[0147] Example 13: Preparation of N'-acetoxy-3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picoline imidamide

[0148] [ka]

[0149] 3-(ethylsulfonyl)-N'-hydroxy-5-(4-(trifluoromethoxy)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)picoline imidamide (80 mg, 0.15 mmol) prepared in Example 12 was dissolved in pyridine (2 mL), acetic anhydride (21 μL, 0.23 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Most of the pyridine in the reaction solution was distilled off, and the product was purified by silica gel column chromatography to obtain the target product (37 mg, 42.6%). 1 H NMR (CDCl 3 )δ8.95(1H, d, J=2.1Hz), 8.58(1H, d, J=2.1Hz), 8.24(1H, d, J=4.8Hz), 7.72(2H, d, J=8.7Hz), 7.64(1H, dd, J=2.1, 8.7Hz), 7.41(2H, d, J=8.4Hz), 6.63(1H, d, J=8.7Hz), 3.81(2H, q, J=7.2Hz), 2.30(3H, s), 1.40(3H, t, J=7.2Hz)

[0150] Example 14: Preparation of 3-(3-(ethylsulfonyl)-5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-(4H)-one)

[0151] [ka]

[0152] 3-(ethylsulfonyl)-N'-hydroxy-5-(4-(trifluoromethoxy)phenyl)-N-(6-(trifluoromethyl)pyridin-3-yl)picoline imidamide (110 mg, 0.21 mmol) prepared in Example 12 was dissolved in tetrahydrofuran (13 mL), 1,1'-carbonylimidazole (52 mg, 0.31 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Most of the tetrahydrofuran in the reaction mixture was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product (85 mg, 73.4%). 1 H NMR (CDCl 3 )δ9.05(1H, d, J=2.1Hz), 8.58(1H, d, J=2.1Hz), 8.26(2H, d, J=9.3Hz), 8.08(1H, dd, J=2.4, 7.9Hz), 7.78-7.74(2H, m), 7.45(2H, d, J=7.8Hz), 3.51(2H, q, J=7.5Hz), 1.39(3H, t, J=7.5Hz)

Claims

1. A method for producing a cyano heterocyclic compound represented by formula (2) by reacting a heterocyclic compound represented by formula (1) with a cyanating agent (3) and an iodide salt (4). 【Chemistry 1】 [In formula (1) and formula (2), R ａ may have a substituent (C １ ~C ６ ) an alkyl group, and (C ３ ~C ６ ) a group selected from the group consisting of cycloalkyl groups, n represents 0, 1, or 2; X １ may have a halogen atom or a substituent (C １ ~C ６ ) a group selected from the group consisting of an alkylsulfonyloxy group and an optionally substituted phenylsulfonyloxy group; G １ is a nitrogen atom or C(R １ ) G ２ is a nitrogen atom or C(R ２ ) G ３ is a nitrogen atom or C(R ３ ) R １ , R ２ , and R ３ may each independently have a hydrogen atom, a halogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxy group, optionally having a substituent (C ３ ~C ６ ) a cycloalkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkoxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxycarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkenylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) an alkylthio group, optionally having a substituent (C １ ~C ６ ) an alkylsulfinyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY １ Y ２ Group, C(O)NY １ Y ２ Group, C(=NY ２ ) Y ３ group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH ２ group, and SF ５ represents a group selected from the group consisting of The Y １ When a plurality of groups are present, each group independently has a hydrogen atom or a substituent (C １ ~C ６ ) alkyl groups, The Y ２ When a plurality of groups are present, each group independently may have a hydrogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) a group selected from the group consisting of an alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, a cyano group, and a hydroxy group; The Y ３ When a plurality of groups are present, each group independently may have a hydrogen atom, a halogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylthio group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, an optionally substituted phenyl group, and NY １ Y ２ A group (Y １ and Y ２ has the same meaning as above), indicates.]

2. Cyanating agent (3) is HCN, LiCN, NaCN, KCN, BrCN, CuCN, Zn(CN) ２ 2. The method according to claim 1, wherein the compound is one or more compounds selected from the group consisting of acetone cyanohydrin and trimethylsilyl cyanide.

3. Iodide salt (4) is HI, LiI, NaI, KI, MgI ２ , N.H. ４ I, CsI, N(Y ４ ) ４ One or more compounds selected from the group consisting of I [Y ４ may each independently have a hydrogen atom or a substituent (C １ ~C ６ ) is a group selected from the group consisting of an alkyl group, an optionally substituted phenyl group, and an optionally substituted heterocyclic group. The method according to claim 1,

4. In formula (1), G １ , G ２ and G ３ are respectively C(R １ ), C(R ２ ), and C(R ３ 2. The method according to claim 1 , wherein

5. A cyano heterocyclic compound represented by formula (2) produced by the method according to any one of claims 1 to 4. 【Chemistry 2】 [In formula (2), R ａ , G １ , G ２ , G ３ , R １ , R ２ , R ３ , Y １ , Y ２ , Y ３ and n are as defined above. to an amide compound represented by formula (5): 【Chemistry 3】 [In formula (5), R ａ , G １ , G ２ , G ３ , R １ , R ２ , R ３ , Y １ , Y ２ , Y ３ and n are as defined above; R ｂ may have a hydrogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) a group selected from the group consisting of an alkoxycarbonyl group, and a phenyl group which may have a substituent; G ４ is a nitrogen atom or C(R ４ ) G ５ is a nitrogen atom or C(R ５ ) G ６ is a nitrogen atom or C(R ６ ) G ７ is a nitrogen atom or C(R ７ ) G ８ is a nitrogen atom or C(R ８ ) R ４ , R ５ , R ６ , R ７ , and R ８ may each independently have a hydrogen atom, a halogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxy group, optionally having a substituent (C ３ ~C ６ ) a cycloalkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkoxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxycarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkenylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) an alkylthio group, optionally having a substituent (C １ ~C ６ ) an alkylsulfinyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY １ Y ２ Group, C(O)NY １ Y ２ Group, C(=NY ２ ) Y ３ group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH ２ group, and SF ５ A group (Y １ , Y ２ , and Y ３ has the same meaning as above), It is.] The present invention relates to a method for producing an amide compound.

6. A cyano heterocyclic compound represented by formula (2) produced by the method according to any one of claims 1 to 4. 【Chemistry 4】 [In formula (2), R ａ , G １ , G ２ , G ３ , R １ , R ２ , R ３ , Y １ , Y ２ , Y ３ and n are as defined above. to an amidine compound represented by formula (6): 【Chemistry 5】 [In formula (6), R ａ , G １ , G ２ , G ３ , R １ , R ２ , R ３ , Y １ , Y ２ , Y ３ and n are as defined above; R ｂ may have a hydrogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) a group selected from the group consisting of an alkoxycarbonyl group, and a phenyl group which may have a substituent; G ４ is a nitrogen atom or C(R ４ ) G ５ is a nitrogen atom or C(R ５ ) G ６ is a nitrogen atom or C(R ６ ) G ７ is a nitrogen atom or C(R ７ ) G ８ is a nitrogen atom or C(R ８ ) R ４ , R ５ , R ６ , R ７ , and R ８ may each independently have a hydrogen atom, a halogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxy group, optionally having a substituent (C ３ ~C ６ ) a cycloalkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkoxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxycarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkenylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) an alkylthio group, optionally having a substituent (C １ ~C ６ ) an alkylsulfinyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY １ Y ２ Group, C(O)NY １ Y ２ Group, C(=NY ２ ) Y ３ group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH ２ group, and SF ５ A group (Y １ , Y ２ , and Y ３ has the same meaning as above), R ｃ may have a hydrogen atom, a hydroxyl group, an amino group, or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkoxycarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) an alkoxycarbonyloxy group, an optionally substituted phenyl group, and NY １ Y ２ A group (Y １ , and Y ２ has the same meaning as above) It is.] A method for producing an amidine compound, comprising the steps of:

7. A cyano heterocyclic compound represented by formula (2) produced by the method according to any one of claims 1 to 4. 【Chemistry 6】 [In formula (2), R ａ , G １ , G ２ , G ３ , R １ , R ２ , R ３ , Y １ , Y ２ , Y ３ and n are as defined above. from a cyclic group-linked heterocyclic compound represented by formula (7): 【Chemistry 7】 [In formula (7), R ａ , G １ , G ２ , G ３ , R １ , R ２ , R ３ , Y １ , Y ２ , Y ３ and n are as defined above; G ４ is a nitrogen atom or C(R ４ ) G ５ is a nitrogen atom or C(R ５ ) G ６ is a nitrogen atom or C(R ６ ) G ７ is a nitrogen atom or C(R ７ ) G ８ is a nitrogen atom or C(R ８ ) R ４ , R ５ , R ６ , R ７ , and R ８ may each independently have a hydrogen atom, a halogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxy group, optionally having a substituent (C ３ ~C ６ ) a cycloalkoxy group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyl group, optionally having a substituent (C ３ ~C ６ ) a cycloalkylcarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkoxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkenyloxycarbonyl group, optionally having a substituent (C ２ ~C ６ ) an alkynyloxycarbonyl group, optionally having a substituent (C １ ~C ６ ) an alkylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkenylcarbonyloxy group, optionally having a substituent (C ２ ~C ６ ) an alkynylcarbonyloxy group, optionally having a substituent (C １ ~C ６ ) an alkylthio group, optionally having a substituent (C １ ~C ６ ) an alkylsulfinyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyl group, optionally having a substituent (C １ ~C ６ ) an alkylsulfonyloxy group, an optionally substituted phenyl group, an optionally substituted heterocyclic group, an optionally substituted phenoxy group, an optionally substituted pyridyloxy group, NY １ Y ２ Group, C(O)NY １ Y ２ Group, C(=NY ２ ) Y ３ group, cyano group, nitro group, hydroxy group, mercapto group, amino group, formyl group, carboxy group, trimethylsilyl group, C(O)NH ２ group, and SF ５ A group (Y １ , Y ２ , and Y ３ has the same meaning as above), m represents 0, 1, or 2; J １ , J ２ , J ３ and J. ４ may each independently have a hydrogen atom, a halogen atom or a substituent (C １ ~C ６ ) an alkyl group, optionally having a substituent (C １ ~C ６ ) an alkoxy group, a hydroxy group, or J １ and J. ２ , J ３ and J. ４ The two bonds taken together form a group selected from the group consisting of a carbonyl group and a thiocarbonyl group. The present invention relates to a method for producing a cyclic group-linked heterocyclic compound.

Images