Method for producing 2-heteroarylpyridine compounds

Abstract

The present invention provides a method for producing a compound represented by formula (3) (in the formula, Q, R1, and R2 represent the same as in formula (1) and formula (2)) that includes chemically reacting a compound represented by formula (1) (in the formula, Q represents a substituted or unsubstituted 5- to 6-membered or 9- to 10-membered heteroaryl group, R1 represents a C1-6 alkyl group) with a compound represented by formula (2) (in the formula, R2 represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group) in the presence of a metal alkoxide or a base and a method for producing a compound represented by formula (4) (in the formula, Q, R1, and R2 represent the same as in formula (3)) that includes chemically reacting a compound represented by formula (3) with hydroxylamine or a salt thereof and dehydrating the product of the chemical reaction.

Description

Technical Field

[0001] The present invention relates to a method for producing a 2-heteroaryl pyridine compound.

Background Art

[0002] The nitrogen-containing heterocycle is a main substructure (building block) constituting compounds that serve as the origin of pharmaceuticals and agricultural chemicals. In recent years, the development of harmful arthropod control agents having a pyridine ring has been actively carried out. For example, Patent Documents 1 to 5 describe pyridine compounds having a 5-member heteroaryl group and a sulfur-containing hydrocarbon group.

[0003] Non-Patent Document 1 also discloses that 3-phenyl-5-chloro-2-pyridone (4g) and 3-hydroxycarbonyl-5-chloro-2-pyridone (4h) were produced by reacting 2-chloro-N,N-dimethylaminotrimethinium hexafluorophosphate with methyl phenylacetate and 3-methoxy-3-oxopropanoic acid.

[0004]

Chemical Formula

[0005]

Chemical Formula

[0006] Patent Document 6 discloses a method for constructing a pyridine ring according to the following scheme.

[0007]

Chemical Formula

[0008] In the above scheme, Q represents a pyridyl group or the like, and R 1 represents a C1-C6 alkyl group which may have one or more halogen atoms, and R 2R represents a C1-C6 alkyl group, which may have one or more halogen atoms, 3 , R 4 and R 5 represents a hydrogen atom, etc., and n represents 0, etc. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] WO 2017 / 016910 A [Patent Document 2] WO 2017 / 050685 A [Patent Document 3] WO 2020 / 050212 A [Patent Document 4] WO 2020 / 071304 A [Patent Document 5] WO 2020 / 090585 A [Patent Document 6] WO 2018 / 194077 A [Non-patent literature]

[0010] [Non-Patent Document 1] Jean-Francuois Marcoux et al. "A General Preparation of Pyridines and Pyridones via the Annulation of Ketones and Esters" J. Org. Chem., Vol. 66, No. 12, 2001, 4194-4199 [Overview of the project] [Problems that the invention aims to solve]

[0011] The objective of the present invention is to provide a method for producing a 2-heteroarylpyridine compound having a sulfur-containing functional group, which is one of the building blocks of the present invention. [Means for solving the problem]

[0012] As a result of repeated studies to achieve the above object, the present invention including the following aspects has been completed.

[0013] [1] A method for producing a compound represented by formula (3) (hereinafter sometimes referred to as compound (3)), which includes subjecting a compound represented by formula (1) (hereinafter sometimes referred to as compound (1)) and a compound represented by formula (2) (hereinafter sometimes referred to as compound (2)) to a chemical reaction in the presence of a metal alkoxide or a base.

[0014] [Chemical formula]

[0015] (In formula (1), Q represents a substituted or unsubstituted 5- to 6-membered or 9- to 10-membered heteroaryl group, and R 1 represents a C1-6 alkyl group.)

[0016] [Chemical formula]

[0017] (In formula (2), R 2 represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group.)

[0018] [Chemical formula]

[0019] (In formula (3), Q, R 1 , and R 2 represent the same as those in formula (1) and formula (2).)

[0020] [2] The manufacturing method according to [1], wherein Q in formulas (1) and (3) is a group represented by formula (5).

[0021] [ka]

[0022] (In equation (5), * indicates a bonding site, R 3 R represents a C1-6 alkyl group, 4 (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.)

[0023] [3] A method for producing a compound represented by formula (4) (hereinafter sometimes referred to as compound (4)), comprising chemically reacting a compound represented by formula (3) (hereinafter sometimes referred to as compound (3)) with hydroxylamine or a salt thereof, and dehydrating the product of the chemical reaction.

[0024] [ka]

[0025] (In formula (3), Q represents a substituted or unsubstituted 5-6 membered or 9-10 membered heteroaryl group, R 1 R represents a C1-6 alkyl group, 2 (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group.)

[0026] [ka] (In formula (4), Q, R 1 , and R 2 The terms in formula (3) represent the same terms as those in formula (3). A method for manufacturing ).

[0027] [4] A method for producing a compound represented by formula (4), comprising: chemically reacting a compound represented by formula (3) with ammonia or an ammonium salt in the presence of an alcohol; and oxidizing the product of the chemical reaction in the presence of an organic oxidizing agent.

[0028] [ka]

[0029] (In formula (3), Q represents a substituted or unsubstituted 5-6 membered or 9-10 membered heteroaryl group, R 1 R represents a C1-6 alkyl group, 2 (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group.)

[0030] [ka]

[0031] (In formula (4), Q, R 1 , and R 2 These represent the same things as those in equation (3).

[0032] [5] The manufacturing method according to [3] or [4], wherein Q in formulas (3) and (4) is the group represented by formula (5).

[0033] [ka]

[0034] (In equation (5), * indicates a bonding site, R 3 R represents a C1-6 alkyl group, 4 (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.)

[0035] [6] A compound represented by formula (3a).

[0036] [ka]

[0037] (In formula (3a), R 1 R represents a C1-6 alkyl group, 2 R represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. 3 R represents a C1-6 alkyl group, 4 (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.) [Effects of the Invention]

[0038] According to the manufacturing method of the present invention, compounds represented by formula (3) and compounds represented by formula (4) can be obtained in high yield. [Modes for carrying out the invention]

[0039] In this invention, the term "unsubstituted" means that only the core group is present. When the term "substituted" is not used and only the name of the core group is given, it means "unsubstituted" unless otherwise specified. On the other hand, the term "substitution" means that one of the hydrogen atoms of the core group is substituted by a group (substituent) that has the same or a different structure as the core group. Therefore, a "substituent" is another group bonded to the core group. There may be one substituent or two or more substituents. The two or more substituents may be the same or different. Terms such as "C1-6" indicate that the parent group has 1 to 6 carbon atoms. This number of carbon atoms does not include the number of carbon atoms in substituents. For example, a butyl group with an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. The "substituents" are chemically acceptable and not particularly limited insofar as they have the effects of the present invention.

[0040] The following are examples of groups that can act as "substituents". C1-6 alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, and n-hexyl group; C2-6 alkenyl groups such as vinyl group, 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, and 2-methyl-2-propenyl group; C2-6 alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, and 1-methyl-2-propynyl group;

[0041] C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; Phenyl group; A heterocyclyl group with 3 to 6 members;

[0042] C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C6-10 aryloxy groups such as phenoxy and naphthoxy groups; Five- to six-membered heteroaryloxy groups such as thiazolyloxy and pyridyloxy groups;

[0043] C1-6 alkoxycarbonyl groups such as methoxycarbonyl groups, ethoxycarbonyl groups, n-propoxycarbonyl groups, i-propoxycarbonyl groups, n-butoxycarbonyl groups, and t-butoxycarbonyl groups;

[0044] Halogeno groups such as fluoro groups, chloro groups, bromo groups, and iod groups; C1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1,2-dichloro-n-propyl, 1-fluoro-n-butyl, and perfluoro-n-pentyl groups; C1-6 haloalkoxy groups such as trifluoromethoxy, 2-chloro-n-propoxy, and 2,3-dichlorobutoxy;

[0045] Formylamino group; C1-6 alkylcarbonylamino groups such as acetylamino groups, propanoylamino groups, butyrylamino groups, and i-propylcarbonylamino groups; C1-6 alkoxycarbonylamino groups such as methoxycarbonylamino groups, ethoxycarbonylamino groups, n-propoxycarbonylamino groups, and i-propoxycarbonylamino groups; Unsubstituted or substituted aminocarbonyl groups such as aminocarbonyl groups, dimethylaminocarbonyl groups, phenylaminocarbonyl groups, and N-phenyl-N-methylaminocarbonyl groups;

[0046] C1-6 alkylthio groups such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, and t-butylthio group; C1-6 haloalkylthio groups such as trifluoromethylthio group and 2,2,2-trifluoroethylthio group; C1-6 alkylsulfonyl groups such as methylsulfonyl groups, ethylsulfonyl groups, and t-butylsulfonyl groups; C1-6 haloalkylsulfonyl groups such as trifluoromethylsulfonyl group and 2,2,2-trifluoroethylsulfonyl group;

[0047] Cyano group; nitro group;

[0048] Furthermore, in these "substituents," any hydrogen atom in the substituent may be substituted with a group of a different structure. Examples of substituents in this case include C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, halogeno groups, cyano groups, and nitro groups.

[0049] Furthermore, the above-mentioned "3-6 membered heterocyclyl group" refers to a group that contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as constituent atoms of the ring. The heterocyclyl group may be monocyclic or polycyclic. In a polycyclic heterocyclyl group, at least one ring may be heterocyclic, and the remaining rings may be saturated alicyclic, unsaturated alicyclic, or aromatic rings. Examples of "3-6 membered heterocyclyl groups" include 3-6 membered saturated heterocyclyl groups, 5-6 membered heteroaryl groups, and 5-6 membered partially unsaturated heterocyclyl groups. Examples of 3-6 member saturated heterocyclyl groups include azilidinyl group, epoxy group, pyrrolidinyl group, tetrahydrofuranyl group, thiazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, dioxolanyl group, and dioxanyl group. Examples of five-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl groups. Examples of six-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, and triazinyl groups. Examples of five-membered partially unsaturated heterocyclyl groups include pyrrolinyl, dihydrofuranyl, imidazolinyl, pyrazolinyl, oxazolinyl, and isoxazolinyl groups. Examples of six-membered partially unsaturated heterocyclyl groups include the dihydropyranyl group. <Method for producing compound (3)>

[0050] The method for producing compound (3) of the present invention includes a chemical reaction (hereinafter sometimes referred to as the first reaction) between compound (1) and compound (2) in the presence of a metal alkoxide or a base. (Compound (1))

[0051] Compound (1) is represented by formula (1).

[0052] [ka]

[0053] In formula (1), R 1 This represents a C1-6 alkyl group. R 1 The C1-6 alkyl group in R may be a straight chain or a branched chain. 1 Examples of C1-6 alkyl groups in this compound include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, i-propyl group, i-butyl group, s-butyl group, t-butyl group, i-pentyl group, neopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, and i-hexyl group.

[0054] In formula (1), Q represents a substituted or unsubstituted 5-6 member or 9-10 member heteroaryl group.

[0055] Examples of "5-membered heteroaryl groups" include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl groups. Examples of "six-membered heteroaryl groups" include pyridyl groups, pyrazinyl groups, pyrimidinyl groups, pyridadinyl groups, and triazinyl groups.

[0056] Examples of "9-membered heteroaryl groups" include indolyl groups, isoindolyl groups, benzofuranyl groups, benzothienyl groups, indazolyl groups, benzimidazolyl groups, benzoxazolyl groups, benzoisoxaozolyl groups, benzothiazolyl groups, and benzoisothiazolyl groups. Examples of "10-membered heteroaryl groups" include isoquinolinyl group, quinazolinyl group, 1,2,4-benzotriazinyl group, and 1,2,3,4-benzotetradinyl group.

[0057] Substituents on the "5-6 member or 9-10 member heteroaryl group" in Q include: halogen groups such as fluoro, chloro, bromo, and iod groups; C1-6 alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl groups; C1-6 haloalkyl groups such as difluoromethyl, trifluoromethyl, perfluoroethyl, 1,2,2,3,3,3-hexafluoropropyl, perfluoropropyl, and 1,2,3,3,3-pentafluoro-2-(trifluoromethyl)propyl groups; and C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl groups. C2-6 haloalkynyl groups such as 3,3,4,4,4-pentafluorobuta-1-en-1-yl group, 2-chloro-3,3,3-trifluoropropa-1-en-1-yl group, 2,2-dichloroethynyl group, 2,3,3,4,4,4-hexafluorobuta-1-en-1-yl group, and 2-chloro-3,3,4,4,4-pentafluorobuta-1-en-1-yl group; C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, and t-butoxy group; C1-6 haloalkoxy groups such as difluoromethoxy group, trifluoromethoxy group, 2,2-difluoroethyl group, and 2,2,2-trifluoroethyl group; phenyl group; Examples include phenyl groups substituted with halogen groups, C1-6 alkyl groups, C1-6 haloalkyl groups, or C1-6 haloalkoxy groups, such as 4-chlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, and 4-trifluoromethoxyphenyl group; formyl group, dimethoxymethyl group, diethoxymethyl group, 1,3-dioxolan-2-yl group, or cyano group.

[0058] In the present invention, Q is preferably a group represented by formula (5).

[0059] [ka]

[0060] In equation (5), * indicates a bonding site, and R 3 R represents a C1-6 alkyl group, 4 This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.

[0061] Specifically, compound (1) is preferably the compound represented by formula (1a) (hereinafter sometimes referred to as compound (1a)).

[0062] [ka]

[0063] In formula (1a), R 1 R represents a C1-6 alkyl group, 3 R represents a C1-6 alkyl group, 4 This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group. Compound (1a) is particularly useful as a substrate in the production method of the present invention.

[0064] R 3 and R 4 The C1-6 alkyl groups in R 1 We can cite the same thing as in [the previous example].

[0065] R 4 Examples of C2-6 alkenyl groups in this compound include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, and 5-hexenyl group.

[0066] R 4 Substituents on the "C1-6 alkyl group" and "C2-6 alkenyl group" in the above include halogen groups such as fluoro, chloro, bromo, and iod groups; hydroxyl groups; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, and trifluoromethoxy; phenyl groups; phenyl groups substituted with halogen groups, C1-6 haloalkyl groups, or C1-6 haloalkoxy groups, such as 4-chlorophenyl, 4-trifluoromethylphenyl, and 4-trifluoromethoxyphenyl; or cyano groups. Of these, halogen groups are preferred.

[0067] R 4 The halogenosubstituted C1-6 alkyl groups in this include fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 1-chloro-2,2,3,3,3-pentafluoropropyl group, 1,2,2,3,3,3-hexafluoropropyl group, perfluoropropyl group, 2,2,2-trifluoro-1-trifluoromethylethyl group, perfluoroisopropyl group, 4 Examples include fluorobutyl group, 1,4,4,4-tetrafluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, 1,2,2,3,3,4,4,4-octafluorobutyl group, perfluorobutyl group, 3,3,3-trifluoro-2-trifluoromethylpropyl group, 1-chloro-2,3,3,3-tetrafluoro-2-trifluoromethylpropyl group, 1,2,3,3,3-pentafluoro-2-trifluoromethylpropyl group, perfluoropentyl group, perfluorohexyl group, and the like.

[0068] R 4Examples of halogen-substituted C2-6 alkenyl groups in this context include C2-6 haloalkenyl groups such as 2,3,3,3-tetrafluoro-1-propenyl group, 3,3,3-trifluoro-1-propenyl group, 2-chloro-3,3,3-trifluoro-1-propenyl group, 2-bromo-3,3,3-trifluoro-1-propenyl group, 3,3,3-trifluoro-2-trifluoromethyl-1-propenyl group, 3,3,4,4,4-pentafluoro-1-butenyl group, 2,3,3,4,4,4-hexafluoro-1-butenyl group, and 2-chloro-3,3,4,4,4-pentafluoro-1-butenyl group. R 4 Preferably, this is a 2-chloro-3,3,3-trifluoro-1-propenyl group. The stereoisomer of the 2-chloro-3,3,3-trifluoro-1-propenyl group may be a mixture of E and Z isomers, or it may be the Z isomer alone or the E isomer alone.

[0069] The compound (1) used in the present invention may be synthesized by the present inventor using known methods, or it may be synthesized by another party using some method and commercially available. Specifically, the following compounds can be cited.

[0070] [ka]

[0071] The following notations in chemical formulas represent undefined double stereo bonds.

[0072] [ka]

[0073] (Compound (2))

[0074] Compound (2) is represented by formula (2).

[0075] [ka]

[0076] In formula (2), R 2 This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group.

[0077] R 2 The C1-6 alkyl groups in R 1 We can cite the same thing as in [the previous example].

[0078] R 2 Substituents on the "C1-6 alkyl group" in this can include halogen groups such as fluoro, chloro, bromo, and iod groups; hydroxyl groups; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, and trifluoromethoxy; phenyl groups; phenyl groups substituted with halogen groups, C1-6 haloalkyl groups, or C1-6 haloalkoxy groups, such as 4-chlorophenyl, 4-trifluoromethylphenyl, and 4-trifluoromethoxyphenyl; or cyano groups. Of these, halogen groups are preferred.

[0079] Examples of halogen-substituted C1-6 alkyl groups include fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 1-chloro-2,2,3,3,3-pentafluoropropyl group, 1,2,2,3,3,3-hexafluoropropyl group, perfluoropropyl group, 2,2,2-trifluoro-1-trifluoromethylethyl group, perfluoroisopropyl group, and 4-f Examples include chlorobutyl group, 1,4,4,4-tetrafluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, 1,2,2,3,3,4,4,4-octafluorobutyl group, perfluorobutyl group, 3,3,3-trifluoro-2-trifluoromethylpropyl group, 1-chloro-2,3,3,3-tetrafluoro-2-trifluoromethylpropyl group, 1,2,3,3,3-pentafluoro-2-trifluoromethylpropyl group, perfluoropentyl group, and perfluorohexyl group.

[0080] R 2 Examples of C3-6 cycloalkyl groups in this context include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0081] R 2 The 5-6 membered heteroaryl group in this context is a 5-membered or 6-membered ring containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. When there are two or more heteroatoms, they may be the same or different. Examples of 5-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl groups. Examples of six-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, and triazinyl groups.

[0082] R 2 Substituents on "C3-6 cycloalkyl groups", "phenyl groups", or "5-6 member heteroaryl groups" include: halogen groups such as fluoro groups, chloro groups, bromo groups, and iod groups; C1-6 alkyl groups such as methyl groups, ethyl groups, n-propyl groups, i-propyl groups, n-butyl groups, s-butyl groups, i-butyl groups, t-butyl groups, n-pentyl groups, and n-hexyl groups; C1-6 haloalkyl groups such as chloromethyl groups, chloroethyl groups, trifluoromethyl groups, 1,2-dichloro-n-propyl groups, and 1-fluoro-n-butyl groups; hydroxyl groups; and C1-6 alkoxy groups such as methoxy groups, ethoxy groups, n-propoxy groups, i-propoxy groups, n-butoxy groups, s-butoxy groups, i-butoxy groups, and t-butoxy groups. Examples include C1-6 haloalkoxy groups such as 2-chloro-n-propoxy groups, 2,3-dichlorobutoxy groups, and trifluoromethoxy groups; or cyano groups.

[0083] The compound (2) used in the present invention may be synthesized by the present inventors using known methods, or it may be synthesized by others and commercially available.

[0084] The amount of compound (2) used is not particularly limited, but is, for example, 1.0 to 5.0 moles, preferably 1.5 to 2.0 moles, per mole of compound (1).

[0085] Examples of bases to be present in the first reaction include inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases such as triethylamine, tetramethylethylenediamine, N,N-diisopropylamine, N,N-dimethylaniline, N,N-diethylaniline, 4-methylmorpholine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (abbreviation: DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]nona-5-ene, pyridine, 4-(dimethylamino)pyridine, and 2,6-dimethylpyridine. Examples of metal alkoxides to be present in the first reaction include sodium methoxide, sodium ethoxide, and potassium t-butoxide. The amount of metal alkoxide or base used is not particularly limited, but is, for example, 0.1 to 5.0 moles, preferably 0.2 to 1.0 mole, per mole of compound (1).

[0086] The presence of a metal alkoxide or inorganic base in combination with compound (1) may cause some or all of compound (1) to change into compound (1') (enolate formation), but this does not affect the first reaction.

[0087] [ka]

[0088] In formula (1'), M + These represent countercations, Q and R 1 These represent the same things as those in equation (1).

[0089] The first reaction can be carried out without a solvent or in a solvent. If compound (1) or compound (1') is liquid at the reaction temperature, a solvent may not be used. Considering ease of operation, the first reaction is preferably carried out in an organic solvent. The organic solvent is not particularly limited as long as it is inert to compound (1) or compound (1'). Examples of organic solvents include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: Diglyme), and tetrahydrofuran (abbreviation: THF); halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; aproton polar solvents such as N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropylene urea (abbreviation: DMPU), and hexamethyl phosphate triamide (abbreviation: HMPA); acetonitrile; and the like. The amount of organic solvent used is not particularly limited, but is preferably 5 to 500 parts by weight per 1 part by weight of compound (1) or compound (1').

[0090] The order in which compound (1), compound (2), the metal alkoxide or base, and the organic solvent used as needed are added to the reaction site in the first reaction is not particularly limited. (Compound (3))

[0091] Compound (3) is represented by formula (3). Compound (3) can be obtained, for example, by the first reaction.

[0092] [ka]

[0093] In formula (3), Q, R 1 , and R 2 These represent the same things as those in equation (1) and equation (2).

[0094] Compound (3) is preferably the compound represented by formula (3a) (compound (3a)).

[0095] [ka]

[0096] In formula (3a), R 1 R represents a C1-6 alkyl group, 2 R represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. 3 R represents a C1-6 alkyl group, 4 This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group. Compound (3), and in particular compound (3a), are useful intermediates in the production of 2-heteroarylpyridine compounds. <Method for producing compound (4)> (Compound (4)) Compound (4) is represented by formula (4).

[0097] [ka]

[0098] In formula (4), Q, R 1 , and R 2 These represent the same things as those in equation (3). Compound (4) is preferably the compound represented by formula (4a) (compound (4a)).

[0099] [ka]

[0100] In formula (4a), R 1 R represents a C1-6 alkyl group, 2R represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. 3 R represents a C1-6 alkyl group, 4 This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group. Compound (4), and in particular compound (4a), are the target products of this manufacturing method and are useful compounds as active ingredients for pesticides.

[0101] (Second reaction (A)) One method for producing compound (4) of the present invention includes a chemical reaction between compound (3) and hydroxylamine or a salt thereof (hereinafter sometimes referred to as the second reaction (A)), and a dehydration reaction of the product of the second reaction (A). The hydroxylamine used in the second reaction (A) is an inorganic compound represented by the structural formula NH2OH. The hydroxylamine salt used in the second reaction (A) is a compound produced by the neutralization reaction of hydroxylamine with an acid. Specific examples of hydroxylamine salts include hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine oxalate, and hydroxylamine phosphate.

[0102] The amount of hydroxylamine used is not particularly limited, but for example, it is 1.0 to 5.0 moles, preferably 1.1 to 2.0 moles, per mole of compound (3). The amount of hydroxylamine salt used is not particularly limited, but for example, per mole of compound (3), if it is a monovalent acid salt, it is for example 1.0 to 5.0 moles, preferably 1.1 to 2.0 moles, and if it is a divalent acid salt, it is for example 0.5 to 2.5 moles, preferably 0.55 to 1.0 mole.

[0103] In the second reaction (A), a solvent can be used. Suitable solvents include water, organic solvents, mixed solvents of water and organic solvents, and mixed solvents of organic solvents. Examples of the aforementioned organic solvents include alcohols such as methanol and ethanol; ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: Digrime), and tetrahydrofuran (abbreviation: THF); esters such as ethyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; aproton polar solvents such as N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropylene urea (abbreviation: DMPU), and hexamethylphosphate triamide (abbreviation: HMPA); and acetonitrile. The amount of solvent used is preferably 5 to 500 parts by weight per 1 part by weight of compound (3). The order in which compound (3), hydroxylamine or a salt of hydroxylamine, and any solvent used in the second reaction (A) are added to the reaction site is not particularly limited.

[0104] One embodiment involves mixing compound (1) and compound (2) in an organic solvent or without a solvent to obtain a mixture, adding a metal alkoxide or a base to this mixture and stirring to complete the first reaction, then adding hydroxylamine or a salt of hydroxylamine to the solution containing the product of the first reaction (compound (3)) and stirring to complete the second reaction (A), and then carrying out a dehydration reaction. Each substance may be added either all at once or gradually in small amounts. The first reaction, the second reaction (A), and the dehydration reaction may be carried out sequentially in a single reactor; or the first reaction may be carried out in the first reactor, the product of the first reaction may be transferred to the second reactor, the second reaction (A) may be carried out in the second reactor, the product of the second reaction (A) may be transferred to the third reactor, and the dehydration reaction may be carried out in the third reactor. After the completion of the first or second reaction (A), the resulting organic layer is extracted with an organic solvent and then dried and concentrated for post-treatment. Furthermore, if necessary, the product of the first reaction may be purified by operations such as recrystallization or chromatography.

[0105] The temperature during the first reaction is not particularly limited, for example, 0°C to 50°C. The pressure during the first reaction is not particularly limited, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time is not particularly limited, for example, 0.5 hours to 24 hours. The first reaction is preferably carried out under an inert gas atmosphere.

[0106] The temperature for the second reaction (A) can be selected as appropriate, but is, for example, 50°C to 120°C. Heating under reflux may be used to raise the temperature. Low-boiling point substances generated in the first reaction may be removed by distillation under reflux. The pressure for the second reaction (A) is not particularly limited, but is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time for the second reaction (A) is, for example, 1 to 24 hours. The second reaction is preferably carried out under an inert gas atmosphere.

[0107] Although the details are unclear, it is presumed that the product of the second reaction (A) is represented by equations (6) and (7), etc.

[0108] [ka]

[0109] [ka]

[0110] In equations (6) and (7), Q, R 1 , and R 2 These represent the same things as those in equation (3).

[0111] Compound (4) can be obtained by dehydrating the product of the second reaction (A).

[0112] While dehydration reactions can sometimes proceed simply by applying heat, i.e., heating, it is preferable to apply a dehydrating agent to accelerate the dehydration reaction. The dehydrating agent is not particularly limited as long as it has the effect of removing hydrogen and oxygen atoms from the product of the second reaction (A) as water molecules. Examples of dehydrating agents include concentrated sulfuric acid, diphosphorus pentoxide, anhydrous zinc chloride, acetyl chloride, acetic anhydride, oxalic acid, polyphosphate, magnesium sulfate, zinc chloride, alumina, and molecular sieves (e.g., molecular sieves).

[0113] The amount of dehydrating agent used is not particularly limited, but for example, it is 1.0 to 5.0 moles, preferably 1.1 to 2.0 moles, per mole of compound (3). The temperature during the dehydration reaction is not particularly limited, for example, from 60°C to the boiling point of the solvent used. The pressure during the dehydration reaction is not particularly limited, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time is not particularly limited, for example, 1 to 24 hours. The dehydration reaction can be carried out under an inert gas atmosphere.

[0114] After the dehydration reaction is complete, the resulting organic layer is extracted with an organic solvent, and then dried and concentrated for further post-treatment. If necessary, it can be purified by procedures such as recrystallization and chromatography. (Second reaction (B))

[0115] Another method for producing compound (4) of the present invention includes a chemical reaction (hereinafter sometimes referred to as the second reaction (B)) in the presence of ammonia or an ammonium salt and an alcohol, and oxidation of the product of the chemical reaction in the presence of an organic oxidizing agent. In the second reaction (B), ammonia can be used not only as ammonia gas, but also as a methanol solution of ammonia, an ethanol solution of ammonia, an isopropanol solution of ammonia, a 1,4-dioxane solution of ammonia, or a tetrahydrofuran solution of ammonia. Examples of ammonia salts used in the second reaction (B) include ammonium chloride, ammonium acetate, ammonium carbamate, ammonium formate, ammonium bicarbonate, and ammonium carbonate.

[0116] The amount of ammonia used is not particularly limited, but is, for example, 1.0 to 5.0 moles, preferably 1.1 to 4.0 moles, per mole of compound (3).

[0117] In the second reaction (B), an alcohol is used. Specific examples include methanol, ethanol, n-propanol, and isopropanol. The amount of alcohol used is not particularly limited, but is preferably 5 to 100 parts by weight per 1 part by weight of compound (3). In addition to alcohol, other organic solvents may be used. The other organic solvents are not particularly limited as long as they are inert to compound (3).

[0118] To accelerate the reaction, an acid may be added. Examples of acids include carboxylic acids such as acetic acid, formic acid, oxalic acid, benzoic acid, and 4-chlorobenzoic acid; phosphoric acid; sulfonic acids such as methanesulfonic acid, 4-toluenesulfonic acid monohydrate, and trifluoromethanesulfonic acid; hydrogen halides such as hydrogen chloride, hydrogen bromide, hydrogen iodide, and hydrogen fluoride; sulfuric acid, nitric acid, and tetrafluoroboric acid, with carboxylic acids being preferred, and acetic acid being even more preferred. The amount of acid used is not particularly limited, but is usually 0.1 to 10 moles per mole of compound (3).

[0119] The order in which compound (3), alcohol, ammonia or ammonium salt, and organic solvent used as needed are added to the reaction site in the second reaction (B) is not particularly limited.

[0120] One embodiment involves mixing compound (1) and compound (2) in an organic solvent or solvent-free solution to obtain a mixture, adding a metal alkoxide or a base to this mixture and stirring to complete the first reaction, then adding an alcohol and ammonia or an ammonia salt to the solution containing the product of the first reaction (compound (3)) and stirring to complete the second reaction (B), and then oxidizing the mixture. Each substance may be added either all at once or gradually in small amounts. The first reaction, the second reaction (B), and oxidation may be carried out sequentially in a single reactor; or the first reaction may be carried out in the first reactor, the product of the first reaction may be transferred to the second reactor, the second reaction (B) may be carried out in the second reactor, the product of the second reaction (B) may be transferred to the third reactor, and oxidation may be carried out in the third reactor. After the completion of the first or second reaction (B), the resulting organic layer is extracted with an organic solvent and then dried and concentrated for post-treatment. Furthermore, if necessary, the product of the first reaction may be purified by operations such as recrystallization or chromatography.

[0121] The temperature during the first reaction is not particularly limited, for example, 0°C to 50°C. The pressure during the first reaction is not particularly limited, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time is not particularly limited, for example, 0.5 hours to 24 hours. The first reaction is preferably carried out under an inert gas atmosphere.

[0122] The temperature for the second reaction (B) can be selected as appropriate, but is, for example, 50°C to 120°C. This depends on the boiling point of the alcohol used. Heating under reflux may be used to raise the temperature. During heating under reflux, low-boiling point substances generated in the first reaction may be distilled off. The pressure for the second reaction (B) is not particularly limited, but is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time for the second reaction (B) is, for example, 1 hour to 24 hours. The second reaction (B) is preferably carried out under an inert gas atmosphere.

[0123] Although the details are unclear, it is presumed that the product of the second reaction (B) is represented by equations (8) and (9), etc.

[0124] [ka]

[0125] [ka]

[0126] In equations (8) and (9), Q, R 1 , and R 2 These represent the same elements as those in formula (3). In the formula, R is the alkyl group derived from the alcohol used. For methanol, it is a methyl group; for ethanol, it is an ethyl group.

[0127] Compound (4) can be obtained by oxidizing the product of the second reaction (B) in the presence of an organic oxidizing agent.

[0128] Examples of organic oxidizing agents include p-quinone-based oxidizing agents such as p-benzoquinone, chloranil, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); o-quinone-based oxidizing agents such as o-benzoquinone; N-halosuccinimide-based oxidizing agents such as N-chlorosuccinimide and N-bromosuccinimide; hypervalent iodine-based oxidizing agents such as (diacetoxyiodo)benzene and 2-iodoxybenzoic acid; and N-oxide compounds such as pyridine N-oxide, 4-chloropyridine N-oxide, and 2,6-lutidine N-oxide. Preferably, p-quinone-based oxidizing agents are used.

[0129] The amount of organic oxidizing agent used is not particularly limited, but is, for example, 1.0 to 10.0 moles, preferably 1.0 to 5.0 moles, per mole of compound (3). The oxidation reaction is usually carried out in an organic solvent. The organic solvent is not particularly limited as long as it is inert to the product of the second reaction (B). Examples include alcohols such as methanol, ethanol, and isopropanol; ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: Diglyme), and tetrahydrofuran (abbreviation: THF); halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; aprotonate solvents such as N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropylene urea (abbreviation: DMPU), and hexamethylphosphate triamide (abbreviation: HMPA); and acetonitrile. The amount of organic solvent used is not particularly limited, but is preferably 10 to 500 parts by weight per 1 part by weight of compound (3).

[0130] To accelerate the reaction, an acid may be added. Examples of acids include carboxylic acids such as acetic acid, formic acid, oxalic acid, benzoic acid, and 4-chlorobenzoic acid; phosphoric acid; sulfonic acids such as methanesulfonic acid, 4-toluenesulfonic acid monohydrate, and trifluoromethanesulfonic acid; hydrogen halides such as hydrogen chloride, hydrogen bromide, hydrogen iodide, and hydrogen fluoride; sulfuric acid, nitric acid, and tetrafluoroboric acid, with carboxylic acids being preferred, and acetic acid being even more preferred. The amount of acid used is not particularly limited, but is usually 0.01 to 100 moles per mole of compound (3).

[0131] The temperature at which the oxidation reaction is carried out is not particularly limited, for example, -20°C to 120°C, or between -20°C and the boiling point of the solvent used. The pressure at which the oxidation reaction is carried out is not particularly limited, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time is not particularly limited, for example, 0.5 hours to 24 hours. The oxidation reaction can be carried out under an inert gas atmosphere.

[0132] After the oxidation reaction is complete, the resulting organic layer is extracted with an organic solvent, and then dried and concentrated for post-treatment. Further purification can be performed as needed by procedures such as recrystallization and chromatography.

[0133] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples.

[0134] [Example 1] The following procedure yielded 2-(5-(2-chloro-3,3,3-trifluoropropan-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-5-cyclopropyl-3-(ethylsulfonyl)pyridine.

[0135] (Process 1) Manufacturing of 5-(5-(2-chloro-3,3,3-trifluoropropane-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-2-cyclopropyl-4-(ethylsulfonyl)-5-oxopentanal

[0136] [ka]

[0137] 1-(5-(2-chloro-3,3,3-trifluoropropan-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-2-(ethylsulfonyl)ethan-1-one (0.697 g, purity 93.0%, 1.88 mmol) and 2-cyclopropylacrylaldehyde (0.884 g, purity 40.3%, 3.71 mmol) were dissolved in a mixture of toluene (3.8 mL) and methanol (3.8 mL). This mixture was cooled in an ice bath. Subsequently, sodium methoxide (74.8 μL, 28% methanol solution, 0.38 mmol) was added, and the mixture was stirred for 3.4 hours under ice water cooling. Then, the temperature was raised to room temperature and the mixture was stirred for 3.0 hours. To this, a semi-saturated aqueous solution of ammonium chloride (10 mL) was added, and the organic phase was separated. The aqueous phase was extracted with toluene (10 mL), and the organic phase was separated. The separated organic phases were collected and washed with saturated saline solution (10 mL). The aqueous phase was separated. The remaining organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: hexane / ethyl acetate). The resulting fraction was concentrated to obtain 0.641 g of the target compound (purity 89.3%, 1.30 mmol, yield 69%).

[0138] (Process 2) Manufacturing of 2-(5-(2-chloro-3,3,3-trifluoropropan-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-5-cyclopropyl-3-(ethylsulfonyl)pyridine

[0139] [ka]

[0140] 5-(5-(2-chloro-3,3,3-trifluoropropan-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-2-cyclopropyl-4-(ethylsulfonyl)-5-oxopentanal (0.641 g, purity 89.3%, 1.30 mmol) was dissolved in a mixture of acetonitrile (5.2 mL) and water (1.3 mL). Hydroxylamine sulfate (0.116 g, 0.71 mmol) was added to this mixture, and the mixture was heated in an oil bath at 100 °C and refluxed for 4.0 hours. Next, sulfuric acid (36.6 μL, 0.69 mmol) was added and refluxed for 3.0 hours, and then another 36.6 μL, 0.69 mmol of sulfuric acid was added and refluxed for 2.5 hours. The obtained solution was cooled to room temperature. Then, water (10 mL) and 28% sodium hydroxide aqueous solution (600 μL) were added to separate the organic phase. The aqueous phase was extracted twice with chloroform (10 mL) to separate the organic phase. The separated organic phases were collected and washed with water (10 mL) and saturated saline solution (10 mL). The organic phase was then concentrated and purified by silica gel column chromatography (eluent: chloroform / ethyl acetate). The resulting fraction was concentrated to obtain 0.121 g of the target compound (100% purity, 0.29 mmol, yield 22%).

[0141] [Example 2] The following procedure yielded 2-(5-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-2-yl)-5-cyclopropyl-3-(ethylsulfonyl)pyridine.

[0142] (Process 1) 5-(5-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-2-yl)-2-cyclopropyl-4-(ethylsulfonyl)-5-oxopentanal (English name: 5-[5-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-2-yl]-2-cyclopropyl-4-(ethylsulfonyl)-5-oxopentanal preparation)

[0143] [ka]

[0144] 1-(5-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-2-yl)-2-(ethylsulfonyl)ethan-1-one (1.445 g, 100% purity, 5.01 mmol) and 2-cyclopropylacrylaldehyde (2.485 g, 38.5% purity, 9.95 mmol) were dissolved in a mixture of toluene (10 mL) and methanol (10 mL). Sodium methoxide (200 μL, 28% methanol solution, 1.00 mmol) was added to this mixture, and the mixture was stirred at room temperature for 3.9 hours.

[0145] To this, a semi-saturated aqueous solution of ammonium chloride (25 mL) was added, and the organic phase was separated. The aqueous phase was extracted twice with chloroform (25 mL), and the organic phase was separated. The separated organic phases were collected and washed with saturated saline solution (25 mL), and the aqueous phase was separated. The remaining organic phase was dried with sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: chloroform / acetonitrile). The resulting fraction was concentrated to obtain 1.783 g of the target compound (100% purity, 4.63 mmol, yield 93%).

[0146] (Process 2) Manufacturing of 2-(5-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-2-yl)-5-cyclopropyl-3-(ethylsulfonyl)pyridine

[0147] [ka]

[0148] To an acetonitrile solution (6.267 g, purity 9.2%, 1.50 mmol) of 5-(5-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-2-yl)-2-cyclopropyl-4-(ethylsulfonyl)-5-oxopentanal, an aqueous solution of hydroxylamine (88.4 μL, purity 50%, 1.50 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Sulfuric acid (42.2 μL, 0.75 mmol) was added to this mixture, and it was refluxed for 4.3 hours. Then, water (300 μL) and sulfuric acid (42.2 μL, 0.75 mmol) were added, and the mixture was refluxed for another 3.2 hours. The resulting solution was cooled to room temperature. Then, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was collected, dried over sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: chloroform / acetonitrile). The resulting fraction was concentrated to obtain 0.078 g of the target compound (100% purity, 0.24 mmol, yield 16%).

[0149] [Example 3] The following procedure yielded 2-(5-(2-chloro-3,3,3-trifluoropropan-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-5-cyclopropyl-3-(ethylsulfonyl)pyridine.

[0150] [ka]

[0151] 2.393 g (36.85% purity, 2.00 mmol) of a methanol solution of 5-(5-(2-chloro-3,3,3-trifluoropropan-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-2-cyclopropyl-4-(ethylsulfonyl)-5-oxopentanal was mixed with methanol (2 mL (36.85% purity, 2.00 mmol)) and acetic acid (0.12 g, 4.00 mmol), and the mixture was refluxed. Then, 0.37 g (50% purity, 2.40 mmol) of an aqueous solution of ammonium acetate was added dropwise, and the mixture was refluxed for 1 hour. Subsequently, benzoquinone (0.22 g, 2.00 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, acetonitrile (10 mL) was added to dissolve the compound, and 11.91 g of a solution containing the target compound was obtained (purity 4.99%, 1.42 mmol, yield 70.8%). [Industrial applicability]

[0152] The manufacturing method of the present invention can efficiently produce 2-heteroarylpyridine compounds having sulfur-containing functional groups, which are major substructures constituting compounds that serve as active ingredients for pharmaceuticals and agrochemicals, and intermediates for their production.

Claims

1. A method for producing a compound represented by formula (3), comprising chemically reacting a compound represented by formula (1) with a compound represented by formula (2) in the presence of a metal alkoxide or a base. 【Chemistry 1】 (In formula (1), Q represents a substituted or unsubstituted 5-6 membered or 9-10 membered heteroaryl group, R 1 (This represents a C1-6 alkyl group.) 【Chemistry 2】 (In formula (2), R ２ (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group.) 【Transformation 3】 (In formula (3), Q, R 1 , and R 2 (These represent the same things as those in equation (1) and equation (2).)

2. The manufacturing method according to claim 1, wherein Q in formulas (1) and (3) is a group represented by formula (5). 【Chemistry 4】 (In equation (5), * indicates the bonding site, R ３ R represents a C1-6 alkyl group, ４ (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.)

3. Chemically reacting a compound represented by formula (3) with hydroxylamine or its salt, and Dehydrating the product of the aforementioned chemical reaction, A method for producing a compound represented by formula (4), including the following. 【Transformation 5】 (In formula (3), Q represents a substituted or unsubstituted 5-6 membered or 9-10 membered heteroaryl group, R 1 R represents a C1-6 alkyl group, ２ (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group.) 【Transformation 6】 (In formula (4), Q, R 1 , and R 2 represent the same ones as those in formula (3).)

4. The chemical reaction of the compound represented by formula (3) with ammonia or an ammonium salt in the presence of an alcohol, and The product of the aforementioned chemical reaction is oxidized in the presence of an organic oxidizing agent. A method for producing a compound represented by formula (4), including the following. 【Transformation 7】 (In formula (3), Q represents a substituted or unsubstituted 5-6 membered or 9-10 membered heteroaryl group, R 1 R represents a C1-6 alkyl group, ２ (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group.) 【Transformation 8】 (In formula (4), Q, R 1 , and R 2 (This represents the same things as those in equation (3).)

5. The manufacturing method according to claim 3 or claim 4, wherein Q in formulas (3) and (4) is a group represented by formula (5). 【Chemistry 9】 (In equation (5), * indicates the bonding site, R ３ R represents a C1-6 alkyl group, ４ (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.)

6. The compound represented by formula (3a). 【Chemistry 10】 (In formula (3a), R １ R represents a C1-6 alkyl group, ２ R represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. ３ R represents a C1-6 alkyl group, ４ (This represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolan-2-yl group.)

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