Method for producing 2-heteroaryl pyridine compound

Abstract

Provided is a method for producing a compound represented by formula (3), the method comprising: a first step for preparing a reaction solution containing a precursor of the compound represented by formula (3) by adding a compound represented by formula (2) to a reaction solution containing a compound represented by formula (1) and an organic base within the range of 40-80 DEG C; and a second step for obtaining the compound represented by formula (3) by adding ammonia or an ammonium salt to a reaction solution containing the precursor of the compound represented by formula (3) within the range of 20-60 DEG C. # imgabs0 #

Description

Technical Field

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

[0002] Nitrogen-containing heterocycles are the main structural components (building blocks) of compounds that are the active ingredients of pharmaceuticals and pesticides. In recent years, the development of harmful arthropod control agents having a pyridine ring has been in full swing. For example, Patent Documents 1 to 5 describe a pyridine compound having a 5-membered heteroaryl group and a sulfur-containing hydrocarbon group.

[0003] In addition, Non-Patent Document 1 discloses the following: 3-phenyl-5-chloro-2-pyridone (4g) and 3-hydroxycarbonyl-5-chloro-2-pyridone (4h) were prepared by reacting 2-chloro-N,N-dimethylaminotrimethylene hexafluorophosphate with methyl phenylacetate and 3-methoxy-3-oxopropionic acid.

[0004]

[0005] Patent Document 6 discloses a method for constructing a pyridine ring using the following scheme.

[0006]

[0007] 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 2 represents a C1-C6 alkyl group which may have one or more halogen atoms or the like, and R 3 , R 4 and R 5 represent a hydrogen atom or the like, and n represents 0 or the like.

[0008] Patent Document 7 discloses a method for constructing a pyridine ring using the following scheme.

[0009]

[0010] In the above scheme, X b represents a chlorine atom or a bromine atom, A 2 represents a nitrogen atom or CR 4a , A 3 represents a nitrogen atom or CR 4b , R 4a and R 4b each independently represent a C1-C6 chain hydrocarbon group, a hydrogen atom or the like, and R 2 represents a C1-C6 alkyl group which may be substituted with one or more halogen atoms, and R 51 represents a methyl group, an ethyl group or a benzyl group.

[0011] R52 and R 54 represent the same or different C1-C6 alkyl groups, and R 53 represents a C1-C6 chain hydrocarbon group, etc., and X d represents a fluorine atom, a chlorine atom, etc.

[0012] Prior art documents

[0013] Patent documents

[0014] Patent Document 1: WO 2017 / 016910A

[0015] Patent Document 2: WO 2017 / 050685A

[0016] Patent Document 3: WO 2020 / 050212A

[0017] Patent Document 4: WO 2020 / 071304A

[0018] Patent Document 5: WO 2020 / 090585A

[0019] Patent Document 6: WO 2018 / 194077A

[0020] Patent Document 7: Japanese Unexamined Patent Application Publication No. 2019-65018A

[0021] Non-patent documents

[0022] Non-patent Document 1: Jean-Francuois Marcoux et al. "AGeneral Preparation of Pyridines and Pyridones via the Annulation of Ketones and Esters" J. Org. Chem., Vol. 66, No. 12, 2001, 4194-4199 Summary of the invention

[0023] An object of the present invention is to provide a method for producing a 2-heteroaryl pyridine compound having a sulfur-containing functional group as one of the components.

[0024] In order to achieve the above object, intensive studies were conducted, and as a result, the present invention was completed. The present invention includes the following aspects.

[0025] 〔1〕A method for producing a compound represented by formula (3), comprising:

[0026] In the first step, in the range of 40°C to 80°C, the compound represented by formula (2) is added to a reaction solution containing the compound represented by formula (1) and an organic base to prepare a reaction solution containing a precursor of the compound represented by formula (3); and

[0027] In the second step, in the range of 20°C to 60°C, ammonia or an ammonium salt is added to the reaction solution containing the precursor of the compound represented by formula (3) to obtain the compound represented by formula (3).

[0028]

[0029] (In formula (1), Q represents a substituted or unsubstituted 5- to 6-membered heteroaryl group, and R 1 represents a C1-6 alkyl group.)

[0030]

[0031] (In formula (2), R 2 represents a substituted or unsubstituted C3-6 cycloalkyl group, R a represents a C1-6 alkyl group, and X － represents a halide ion.)

[0032]

[0033] (In formula (3), Q, R 1 and R 2 represent the same meanings as Q, R 1 and R 2 in formula (1) and formula (2).)

[0034] 〔2〕The production method according to 〔1〕, wherein Q in formula (1) and formula (3) is a group represented by formula (4).

[0035]

[0036] (In formula (4), * represents the bonding site, R 3 represents a C1-6 alkyl group, and R 4 represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or 1,3-dioxolan-2-yl.)

[0037] 〔3〕A compound represented by formula (1a).

[0038]

[0039] (In formula (1a), R 1 represents a C1-6 alkyl group, R 3 represents a C1-6 alkyl group, R 4represents 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.)

[0040] According to the production method of the present invention, the compound represented by formula (3) can be obtained in a high yield. Detailed implementation mode

[0041] In the present invention, the term "unsubstituted" means only the group that forms the parent nucleus. When it is described only by the name of the group that forms the parent nucleus without being described as "substituted", unless otherwise specified, it means "unsubstituted".

[0042] On the other hand, the term "substituted" means that any hydrogen atom in the group that forms the parent nucleus is substituted by a group (substituent) having the same or different structure from the parent nucleus. Therefore, a "substituent" is another group bonded to the group that forms the parent nucleus. The substituent can be one or two or more. Two or more substituents can be the same or different.

[0043] The term "C1-6", etc. means that the number of carbon atoms in the group that forms the parent nucleus is 1 to 6, etc. This number of carbon atoms does not include the number of carbon atoms present in the substituent. For example, butyl having an ethoxy group as a substituent is classified as C2 alkoxy C4 alkyl.

[0044] The "substituent" is not particularly limited as long as it is chemically acceptable and has the effects of the present invention.

[0045] Hereinafter, groups that can be used as the "substituent" are exemplified.

[0046] C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl;

[0047] C2-6 alkenyl groups such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl;

[0048] C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl;

[0049] C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0050] Phenyl;

[0051] 3- to 6-membered heterocyclic groups;

[0052] C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy;

[0053] C6-10 aryloxy groups such as phenoxy and naphthyloxy;

[0054] 5-6 membered heteroaryloxy groups such as thiazolyloxy and pyridyloxy;

[0055] C1-6 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl;

[0056] Halogen groups such as fluoro, chloro, bromo, iodo;

[0057] C1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1,2-dichloro-n-propyl, 1-fluoro-n-butyl, perfluoro-n-pentyl;

[0058] C1-6 haloalkoxy groups such as trifluoromethoxy, 2-chloro-n-propoxy, 2,3-dichlorobutoxy;

[0059] Formylamino;

[0060] C1-6 alkylcarbonylamino groups such as acetylamino, propionylamino, butyrylamino, isopropylcarbonylamino;

[0061] C1-6 alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino;

[0062] Unsubstituted or substituted aminocarbonyl groups such as aminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl, N-phenyl-N-methylaminocarbonyl;

[0063] C1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio;

[0064] C1-6 haloalkylthio groups such as trifluoromethylthio, 2,2,2-trifluoroethylthio;

[0065] C1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, tert-butylsulfonyl;

[0066] C1-6 haloalkylsulfonyl groups such as trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl;

[0067] Cyano; nitro;

[0068] In addition, for these "substituents", any hydrogen atom in the substituent can be replaced by a group with a different structure. As substituents in this case, C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, halogen groups, cyano groups, nitro groups, etc. can be cited.

[0069] In addition, the above-mentioned "3- to 6-membered heterocyclic group" refers to a group containing 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms as ring-constituting atoms. The heterocyclic group can be either a monocyclic or polycyclic group. As long as at least one ring of the polycyclic heterocyclic group is a heterocyclic ring, the remaining rings can be any one of a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring. Examples of the "3- to 6-membered heterocyclic group" include 3- to 6-membered saturated heterocyclic groups, 5- to 6-membered heteroaryl groups, 5- to 6-membered partially unsaturated heterocyclic groups, etc.

[0070] Examples of the 3- to 6-membered saturated heterocyclic group include aziridinyl, epoxy group, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxolanyl, di alkyl, etc.

[0071] Examples of the 5-membered heteroaryl group include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, iso oxazolyl, thiazolyl, isothiazolyl, triazolyl, dioxazolyl, thiadiazolyl, tetrazolyl, etc.

[0072] Examples of the 6-membered heteroaryl group include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.

[0073] Examples of the 5-membered partially unsaturated heterocyclic group include pyrrolinyl, dihydrofuranyl, imidazolinyl, pyrazolinyl, oxazolinyl, iso oxazolinyl, etc.

[0074] Examples of the 6-membered partially unsaturated heterocyclic group include dihydropyranyl, etc.

[0075] <Manufacturing Method of Compound (3)>

[0076] The manufacturing method of the compound (3) of the present invention includes: a first step of adding the compound represented by formula (2) to a reaction solution containing the compound represented by formula (1) and an organic base in the range of 40°C to 80°C to prepare a reaction solution containing a precursor of the compound represented by formula (3); and a second step of adding ammonia or an ammonium salt to the reaction solution containing the precursor of the compound represented by formula (3) in the range of 20°C to 60°C to obtain the compound represented by formula (3).

[0077] (Compound (1))

[0078] Compound (1) is represented by formula (1).

[0079]

[0080] In formula (1), R 1 represents a C1-6 alkyl group.

[0081] R 1 The C1-6 alkyl group in can be straight-chain or branched-chain. As the C1-6 alkyl group in R 1 Examples of the C1-6 alkyl group include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylbutyl, 2,2-dimethylpropyl, isohexyl, etc.

[0082] In formula (1), Q represents a substituted or unsubstituted 5- to 6-membered heteroaryl group.

[0083] Examples of the "5-membered heteroaryl group" include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, is oxazolyl, thiazolyl, isothiazolyl, triazolyl, diazolyl, thiadiazolyl, tetrazolyl, etc.

[0084] Examples of the "6-membered heteroaryl group" include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.

[0085] Examples of the substituents on the "5- to 6-membered heteroaryl group" in Q include halogen groups such as fluoro, chloro, bromo, and iodo; C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl; 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; C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl; C2-6 haloalkynyl groups such as 3,3,4,4,4-pentafluorobut-1-en-1-yl, 2-chloro-3,3,3-trifluoroprop-1-en-1-yl, 2,2-dichloroethynyl, 2,3,3,4,4,4-hexafluorobut-1-en-1-yl, and 2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy; C1-6 haloalkoxy groups such as difluoromethoxy, trifluoromethoxy, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl; phenyl; phenyl substituted by a halogen group, a C1-6 alkyl group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group such as 4-chlorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, and 4-trifluoromethoxyphenyl; formyl, dimethoxymethyl, diethoxymethyl, 1,3-dioxolan-2-yl, or cyano.

[0086] In the present invention, Q preferably represents a group represented by formula (4).

[0087]

[0088] (In formula (4), * represents a bonding site, and R 3 represents a C1-6 alkyl group, and R 4 represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolane-2-yl group.)

[0089] Specifically, the compound (1) is preferably a compound represented by formula (1a) (hereinafter, sometimes referred to as compound (1a)).

[0090]

[0091] In formula (1a), R 1 represents a C1-6 alkyl group, R 3 represents a C1-6 alkyl group, R 4 represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a 1,3-dioxolane-2-yl group.)

[0092] Compound (1a) is a novel compound and is useful as a matrix in the production method of the present invention.

[0093] For the C1-6 alkyl groups in R 3 and R 4 , groups the same as those of the C1-6 alkyl group in R 1 can be cited.

[0094] As the C2-6 alkenyl group in R 4 , vinyl, 1-propenyl, 2-propenyl, 1-buteneyl, 2-buteneyl, 3-buteneyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc. can be cited.

[0095] As the substituents on the "C1-6 alkyl group" and "C2-6 alkenyl group" in R 4 , halogen groups such as fluorine group, chlorine group, bromine group, iodine group; hydroxyl group; C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, tert-butoxy group; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy group, 2,3-dichlorobutoxy group, trifluoromethoxy group; phenyl group; phenyl groups substituted by halogen groups, C1-6 haloalkyl groups, or C1-6 haloalkoxy groups such as 4-chlorophenyl group, 4-trifluoromethylphenyl group, 4-trifluoromethoxyphenyl group; or cyano group. Among them, halogen groups are preferred.

[0096] As R 4 In the halogen-substituted C1-C6 alkyl group in R, examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 1-chloro-2,2,3,3,3-pentafluoropropyl, 1,2,2,3,3,3-hexafluoropropyl, perfluoropropyl, 2,2,2-trifluoro-1-trifluoromethylethyl, perfluoroisopropyl, 4-fluorobutyl, 1,4,4,4-tetrafluorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, 1,2,2,3,3,4,4,4-octafluorobutyl, perfluorobutyl, 3,3,3-trifluoro-2-trifluoromethylpropyl, 1-chloro-2,3,3,3-tetrafluoro-2-trifluoromethylpropyl, 1,2,3,3,3-pentafluoro-2-trifluoromethylpropyl, perfluoropentyl, perfluorohexyl, etc.

[0097] As R 4 In the halogen-substituted C2-C6 alkenyl group in R, examples include 2,3,3,3-tetrafluoro-1-propenyl, 3,3,3-trifluoro-1-propenyl, 2-chloro-3,3,3-trifluoro-1-propenyl, 2-bromo-3,3,3-trifluoro-1-propenyl, 3,3,3-trifluoro-2-trifluoromethyl-1-propenyl, 3,3,4,4,4-pentafluoro-1-butenyl, 2,3,3,4,4,4-hexafluoro-1-butenyl, 2-chloro-3,3,4,4,4-pentafluoro-1-butenyl and other C2-C6 haloalkenyl groups.

[0098] R 4 Preferably, it is 2-chloro-3,3,3-trifluoro-1-propenyl. The stereoisomers of 2-chloro-3,3,3-trifluoro-1-propenyl can be a mixture of E-type / Z-type, or a single Z-type or a single E-type.

[0099] The compound (1) used in the present invention can be a compound synthesized by a known method by itself or a commercially available compound. Specifically, the following compounds, etc., can be cited.

[0100]

[0101] The following representation in the chemical formula is a double bond with undetermined stereoconfiguration (undefined double stereobond).

[0102]

[0103] (Compound (2))

[0104] Compound (2) is represented by formula (2).

[0105]

[0106] In formula (2), R 2 represents a substituted or unsubstituted C3-6 cycloalkyl group.

[0107] As the C3-6 cycloalkyl group in R 2 , examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0108] As the substituent on the "C3-6 cycloalkyl group" in R 2 , examples include halogen groups such as fluoro, chloro, bromo, and iodo groups; C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl; C1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1,2-dichloro-n-propyl, and 1-fluoro-n-butyl; hydroxy group; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, and trifluoromethoxy; or cyano group.

[0109] In formula (2), R a represents a C1-6 alkyl group. As the C1-6 alkyl group in R a , examples include the same groups as those in R 1 .

[0110] In formula (2), X － represents a halide ion. As the halide ion in X － , examples include fluoride ion, chloride ion, bromide ion, and iodide ion.

[0111] The compound (2) used in the present invention can be a compound synthesized by a known method, such as the method described in WO 2020 / 009132A, or a commercially available compound.

[0112] For example, it can be synthesized according to the following scheme.

[0113]

[0114] That is, a method of reacting compound (a) with dimethylformamide and a chlorinating agent.

[0115] As the chlorinating agent, as long as it reacts with dimethylformamide to form a Vilsmeier reagent, examples include chlorine, phosgene, oxalyl chloride, thionyl chloride, phosphoryl chloride, etc. R in compound (a) 2 , R a represent the same meaning as R in formula (2) 2 , R a .

[0116] Alternatively, compound (b) can be used in the same way instead of compound (a).

[0117] R in compound (b) 2 , R a represents the same meaning as R 2 , R a in formula (2).

[0118]

[0119] The amount of compound (2) used is not particularly limited, and is, for example, 1.0 to 5.0 moles, preferably 1.0 to 2.0 moles, relative to 1 mole of compound (1).

[0120] Examples of the organic base present in the first step include 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]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, etc.

[0121] The amount of the organic base used is not particularly limited, and is, for example, 1.0 to 10.0 moles relative to 1 mole of compound (1).

[0122] The first step and the second step can be carried out without a solvent or in a solvent.

[0123] If compound (1) is liquid at the reaction temperature, a solvent may not be used. Considering operability, it is preferred that the reaction is carried out in an organic solvent. The organic solvent only needs to be non-reactive with respect to compound (1) and is not particularly limited. Examples of the organic solvent include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF); halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, octane; aromatic hydrocarbons such as toluene, xylene; aprotic polar solvents such as N,N-dimethylformamide (abbreviation: DMF), N,N'-dimethylpropyleneurea (abbreviation: DMPU), hexamethylphosphoric triamide (abbreviation: HMPA); acetonitrile, etc. The amount of the organic solvent used is not particularly limited, and is preferably 10 to 500 parts by weight relative to 1 part by weight of compound (1).

[0124] Details are not yet clear, but it is presumed that the compounds represented by formula (5), formula (6), formula (7), etc. (equivalent to the precursors of compound (3)) are generated in the first step.

[0125]

[0126] In formula (5), formula (6) and formula (7), Q, R 1 and R 2 represent the same meanings as Q, R 1 and R 2 in formula (1) and formula (2).

[0127] As ammonia, ammonia gas or aqueous ammonia can be used. As ammonium salts, ammonium chloride, ammonium acetate, ammonium carbonate, ammonium sulfate, ammonium nitrate, etc. can be cited.

[0128] The amount of ammonia or ammonium salt used is not particularly limited, and is, for example, 1.0 to 5.0 moles, preferably 1.5 to 3.0 moles, relative to 1 mole of compound (1).

[0129] One embodiment includes the following steps: mixing compound (1) with an organic base in an organic solvent or without a solvent to obtain a mixed solution, adding compound (2) to the mixed solution and stirring in the range of 40°C to 80°C to complete the first step, and then, in the range of 20°C to 60°C, adding ammonia or ammonium salt to the reaction solution containing the product of the first step, i.e., the precursor of compound (3), and stirring to complete the second step.

[0130] Here, "adding compound (2) to the mixed solution in the range of 40°C to 80°C" in the first step means that in the first step, compound (2) is added while maintaining the temperature of the reaction system generated by adding compound (2) to the mixed solution in the range of 40°C to 80°C.

[0131] "Adding ammonia or ammonium salt to the reaction solution in the range of 20°C to 60°C" in the second step means that in the second step, ammonia or ammonium salt is added while maintaining the temperature of the reaction system generated by adding ammonia or ammonium salt to the reaction solution in the range of 20°C to 60°C.

[0132] The first step and the second step can be carried out sequentially in a single reactor, or the first step can be carried out in a first reactor, and the product of the first step is transferred to a second reactor, and the second step is carried out in the second reactor.

[0133] The pressure during the reaction of the first step is not particularly limited, and is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction time is not particularly limited, and is, for example, 0.5 hours to 24 hours. The reaction of the first step is preferably carried out in an inert gas atmosphere.

[0134] When carrying out the reaction of the second step, the pressure is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. An organic solvent can be used in the second step. Depending on the reaction temperature, the organic solvent used can be replaced from a low-boiling solvent to a high-boiling solvent. The reaction time is not particularly limited, for example, it is 1 hour to 24 hours. The reaction of the second step is preferably carried out in an inert gas atmosphere.

[0135] (Compound (3))

[0136] The compound (3) obtained by the production method of the present invention is represented by formula (3).

[0137]

[0138] In formula (3), Q, R 1 and R 2 represent the same meanings as Q, R 1 and R 2 in formula (1) and formula (2).

[0139] After the reaction is completed, it can be extracted in an organic solvent, and post-treatments such as drying and concentration are carried out on the obtained organic layer. Furthermore, purification can be carried out by operations such as recrystallization and chromatography according to needs.

[0140] Examples

[0141] Hereinafter, examples are shown to illustrate the present invention more specifically. It should be noted that the present invention is not limited to the following examples.

[0142] [Reference Example 1]

[0143]

[0144] Synthesis of 2-cyclopropyl-3-ethoxy-N,N-dimethylprop-2-en-1-iminium chloride (formula (2a))

[0145]

[0146] Under ice-cooling, oxalyl chloride (5.08 g) was added dropwise to a mixture of N,N-dimethylformamide (2.94 g) and chloroform (20 mL). After the addition was completed, the mixture was stirred at room temperature for 30 minutes. The liquid was heated to 65°C, (2,2-diethoxyethyl)cyclopropane (3.18 g) was added, and the mixture was stirred at the same temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain a concentrated dry residue containing the target compound (equivalent to 3.77 g), and this dry residue was dissolved in chloroform (7.0 mL) (hereinafter referred to as solution (2a)).

[0147] [Reference Example 2]

[0148]

[0149] Synthesis of N-(3-butoxy-2-cyclopropylallylidene)-N-methylmethanaminium chloride (Formula (2b))

[0150]

[0151] Under ice-cooling, phosgene (14.8 g) was bubbled into a mixture of N,N-dimethylformamide (8.01 g) and chloroform (150 mL). After the bubbling was completed, the mixture was stirred under ice-cooling for 30 minutes. 50 mL of chloroform was distilled off from the reaction mixture under reduced pressure, and the phosgene gas was expelled. The resulting residue after distillation under reduced pressure was heated to 65°C.

[0152] (2-Butoxyvinyl)cyclopropane (13.82 g) was added dropwise to this liquid over 30 minutes, and then the mixture was stirred at 65°C for 2 hours.

[0153] The resulting reaction mixture was concentrated under reduced pressure to obtain a residue of 23.34 g containing the target compound (the compound of Formula (2b)).

[0154] [Example 1]

[0155]

[0156] 2-(5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-5-cyclopropyl-3-(ethylsulfonyl)pyridine (hereinafter referred to as the compound of formula (3a)) is produced according to the following steps.

[0157]

[0158] Dissolve 1-[5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methylimidazol-2-yl]-2-(ethylsulfonyl)ethan-1-one (4.98 g) in chloroform (7 mL). Add triethylamine (4.78 g) at room temperature and warm to 50 °C. Dropwise add solution (2a) to this solution over 1 hour and stir at the same temperature for 2 hours. Analyze the reaction solution by HPLC to confirm the disappearance of 1-[5-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-methylimidazol-2-yl]-2-(ethylsulfonyl)ethan-1-one.

[0159] Add 28% aqueous ammonia (1.93 mL) to the resulting liquid at 50 °C and stir for 1 hour. After completion of the reaction, cool to 0 °C and then wash the organic layer with water. Extract the washed aqueous layer again with chloroform and mix with the organic layer. Perform quantitative analysis on the organic layer, and the yield of the target substance is 89%.

[0160] It is considered that the intermediate (Inter.) is a compound represented by the following chemical formula, etc.

[0161]

[0162]

[0163] [Example 2]

[0164] Use the compound of formula (2b) obtained in Reference Example 2 instead of the compound of formula (2a), and otherwise obtain the compound of formula (3a) in the same manner as in Example 1.

[0165] Specifically, dissolve the residue containing the compound of formula (2b) obtained in Reference Example 2 in chloroform and add it.

[0166] In this case, it is considered that the intermediate (Inter.) is the compounds represented by the above formula (6a) and formula (7a), and the following compound represented by formula (5b).

[0167]

[0168] Industrial Applicability

[0169] The production method of the present invention can efficiently obtain a 2-heteroaryl pyridine compound having a sulfur-containing functional group, which is a main partial structure of a compound serving as a raw drug for pharmaceuticals and agricultural chemicals.

Claims

1. A method for manufacturing the compound represented by formula (3), comprising: In the first step, in the range of 40°C to 80°C, the compound represented by formula (2) is added to the reaction solution containing the compound represented by formula (1) and an organic base to prepare a reaction solution containing a precursor of the compound represented by formula (3); and in the second step, in the range of 20°C to 60°C, ammonia or an ammonium salt is added to the reaction solution containing the precursor of the compound represented by formula (3) to obtain the compound represented by formula (3); In formula (1), Q represents a substituted or unsubstituted 5- to 6-membered heteroaryl group, and R 1 represents a C1-6 alkyl group. In formula (2), R 2 represents a substituted or unsubstituted C3-6 cycloalkyl group, R a represents a C1-6 alkyl group, and X － represents a halide ion. In formula (3), Q and R 1 and R 2 represent the same meanings as Q, R 1 and R 2 in formula (1) and formula (2).

2. The manufacturing method according to claim 1, wherein, Q in formula (1) and formula (3) is a group represented by formula (4), In formula (4), * represents a bonding site, and R 3 represents a C1-6 alkyl group, and R 4 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. A compound represented by formula (1a), In formula (1a), R 1 represents a C1-C6 alkyl group, R 3 represents a C1-C6 alkyl group, R 4 represents a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group or 1,3-dioxolan-2-yl.

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