Method for producing nitrogenated heterocyclic ring-containing compound

Abstract

The present invention provides a method for producing a nitrogenated heterocyclic ring-containing compound using a nickel-based catalyst, the method making it possible to efficiently synthesize the nitrogenated heterocyclic ring-containing compound in a short time. More specifically, provided is a method for producing a nitrogenated heterocyclic ring-containing compound represented by formula (1), the method including a reaction step in which a first starting compound represented by formula (10) is reacted with a second starting compound represented by formula (11) in the presence of an aprotic polar solvent having a boiling point of 90°C or higher and a nickel-based catalyst represented by formula (12) to synthesize the nitrogenated heterocyclic ring-containing compound represented by formula (1).

Description

Method for producing nitrogen-containing heterocycle-containing compound REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority based on Japanese Patent Application No. 2024-010538 filed on January 26, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a method for producing a nitrogen-containing heterocycle-containing compound.

[0003] The Suzuki-Miyaura coupling (Pd-SMC), which involves cross-coupling of aryl halides with arylboronic acids in the presence of a palladium catalyst and a base, is one of the most widely used cross-coupling reactions. This reaction is widely used industrially because it affords high yields of unsymmetrical biaryls that are useful in the fields of medicine, agrochemicals, electronics, and functional materials. However, palladium catalysts present problems, such as inactivity with some raw materials, their high cost, and difficulty in removing palladium residues from the product.

[0004] To address the above-mentioned problems, research into the use of inexpensive nickel catalysts as a substitute has been reported. Nickel catalysts have the following characteristics: they can use raw materials that are difficult to use with palladium catalysts, they are inexpensive, and catalytic metal residues are easy to remove. However, there is still much room for improvement in terms of activity and yield. In Non-Patent Document 1, NiCl ２ (tmeda) and PPh ３ It is described that a nickel-amine-phosphine ternary catalyst consisting of the above has been found to be effective for the synthesis of unsymmetrical biaryls.

[0005] On the other hand, although there is a demand in the pharmaceutical industry and the like for coupling reactions of Lewis basic aryls such as pyridine, the above-mentioned Non-Patent Document 1 does not disclose such reactions.

[0006] H. Yano, TOSOH Research & Technology Review, 2009, Vol.53, pp.33-39

[0007] The present inventors have found that although a nitrogen-containing heterocycle-containing compound represented by formula (1) described below can be synthesized by reacting a first raw material compound represented by formula (10) described below with a second raw material compound represented by formula (11) described below in the presence of a nickel-based catalyst represented by formula (12) described below and 2-methyltetrahydrofuran (2-MeTHF), the yield and conversion rate are low in a short period of time, resulting in poor efficiency.

[0008] As a result of extensive investigations aimed at solving the above problems, the present inventors have found that, in order to synthesize a nitrogen-containing heterocycle-containing compound represented by formula (1), a first raw material compound represented by formula (10) is reacted with a second raw material compound represented by formula (11) in the presence of a nickel-based catalyst represented by formula (12) and an aprotic polar solvent having a boiling point of 90°C or higher, thereby enabling the nitrogen-containing heterocycle-containing compound to be synthesized efficiently in a short time.

[0009] Therefore, one object of the present invention is to synthesize the nitrogen-containing heterocycle-containing compound represented by formula (1) efficiently in a short time when producing the nitrogen-containing heterocycle-containing compound using a nickel-based catalyst.

[0010] That is, according to the present invention, the following inventions are provided: [1] A nitrogen-containing heterocycle-containing compound represented by the following formula (1): (In formula (1), W １ are the following formulas (2) to (4): (In formula (2), R １ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an ethoxycarbonyl group, or a tert-butoxycarbonyl (Boc) group; Y １ represents CH or N, are each independently a single or double bond, and the wavy line represents W ２ ) (In formula (3), R ２ represents a hydrogen atom, a benzyl group, or a methoxyalkyl group having 1 to 6 carbon atoms in the alkyl group, and a wavy line represents W ２ ), and (In formula (4), the wavy line represents W２ In formula (1), W represents a bond to a heterocyclic compound (also referred to as a nitrogen-containing heterocyclic group) represented by a chemical formula selected from the group consisting of ２ are the following formulas (5) to (9): (In formula (5), Y ２ , Y ３ and Y ４ are each independently CH or N, R ３ represents a hydrogen atom, a methoxycarbonyl group, a propanoyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or an amino group; and the wavy line represents W. １ ) (In formula (6), Y ５ represents CH or N, R ４ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the wavy line represents W １ ) (In formula (7), Y ６ and Y ７ are each independently CH or N, R ５ represents a hydrogen atom, a phenylsulfonyl group, or a 2-(trimethylsilyl)ethoxymethyl group, and the wavy line represents W １ ) (In formula (8), Y ８ represents CH or N, R ６ represents hydrogen or a methoxycarbonyl group, and the wavy line represents W １ ), and (In formula (9), R ７ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the wavy line represents W １ A method for producing a compound represented by the following formula (10): (In formula (10), W １ The wavy line is an X. １ The formula (1) is the same as that of the formula (1) except that X represents a bond to １represents at least one selected from the group consisting of a pinacolborane (Bpin) group, a boronic acid diaminonaphthalene amide (B(dan)) group, a boronic acid N-methyliminodiacetic acid (MIDA) ester group, and a trifluoroborate base.) with a first raw material compound represented by the following formula (11): (In formula (11), X ２ represents a halogen atom, W ２ The wavy line is an X. ２ a second raw material compound represented by the formula (12): (in formula (12), Ph represents a phenyl group, and Me represents a methyl group), to synthesize the nitrogen-containing heterocycle-containing compound represented by formula (1). [2] The production method according to [1], wherein the aprotic polar solvent having a boiling point of 90°C or higher is selected from the group consisting of cyclopentyl methyl ether, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, and propylene carbonate. [3] The production method according to [1] or [2], wherein the reaction step further comprises an aqueous potassium phosphate solution obtained by dissolving potassium phosphate in water before the reaction. [4] The production method according to any one of [1] to [3], wherein the reaction temperature in the reaction step is 90°C or higher. [5] The production method according to any one of [1] to [4], comprising a purification step of separating and isolating the nitrogen-containing heterocycle-containing compound represented by formula (1) obtained in the reaction step by chromatography using a mixed solution of hexane and ethyl acetate containing 50% by volume or more of ethyl acetate as a developing solution. [6] In the nitrogen-containing heterocycle-containing compound represented by formula (1), W １ represents the chemical formula (2), and R １ represents a hydrogen atom, and Y １ indicates CH, Both represent a double bond, W ２ represents the chemical formula (5), and Y ２ , Y ３ and Y ４All of the symbols represent CH, and R ３ represents a methoxycarbonyl group, and in the first raw material compound represented by formula (10), X １ represents a pinacolborane group, and in the second raw material compound represented by formula (11), X ２ [7] The method according to any one of [1] to [5], wherein represents a bromine atom. [7] The method according to any one of [1] to [5], wherein nickel chloride hexahydrate and methyldiphenylphosphine are reacted in the presence of ethanol to produce a compound represented by the following formula (12): A method for producing a nickel catalyst, comprising a reaction step of synthesizing a nickel catalyst represented by the formula:

[0011] The present invention includes a reaction step of synthesizing a nitrogen-containing heterocycle-containing compound represented by formula (1) by reacting a first raw material compound represented by formula (10) with a second raw material compound represented by formula (11) in the presence of a nickel-based catalyst represented by formula (12) and an aprotic polar solvent having a boiling point of 90° C. or higher, thereby enabling efficient synthesis of the nitrogen-containing heterocycle-containing compound represented by formula (1). Here, "efficient synthesis of the nitrogen-containing heterocycle-containing compound represented by formula (1) in a short time" means that the nitrogen-containing heterocycle-containing compound represented by formula (1) can be synthesized in a high yield and / or high conversion rate in a short time. Furthermore, the present invention is advantageous in that it uses only an inexpensive nickel-based catalyst as the catalyst, without using an expensive palladium catalyst or the like, and therefore enables the nitrogen-containing heterocycle-containing compound represented by formula (1) to be produced at low cost.

[0012] 1 shows the XRD pattern of the nickel-based catalyst obtained in Test Example 1. 2 shows the XRD pattern of the reaction mixture obtained in Test Example 2-1 before the reaction. １ The H-NMR spectrum of methyl 4-(pyridin-3-yl)benzoate obtained in Test Example 2-2 is shown. １３ The C-NMR spectrum of the reaction mixture obtained in Test Example 5-1 before the reaction is shown in Fig. 1. １ The lower part shows the H-NMR spectrum of the reaction mixture obtained in Test Example 5-1 after 5 hours of reaction. １ (B) shows an enlarged view of (A). The upper part shows the H-NMR spectrum of the reaction mixture obtained in Test Example 5-1 before the reaction. １The lower part shows the H-NMR spectrum of the reaction mixture obtained in Test Example 5-1 after 5 hours of reaction. １ The H-NMR spectrum is shown.

[0013] [Method for Producing Nitrogen-Containing Heterocycle-Containing Compound] The method for producing a nitrogen-containing heterocycle-containing compound represented by formula (1) (which may also be referred to as a compound represented by formula (1)) of the present invention includes a reaction step (hereinafter also referred to as a coupling reaction step) of synthesizing the nitrogen-containing heterocycle-containing compound represented by formula (1) by reacting a first raw material compound represented by formula (10) with a second raw material compound represented by formula (11) in the presence of an aprotic polar solvent having a boiling point of 90° C. or higher and a nickel-based catalyst represented by formula (12). The reaction step will be described in detail below.

[0014] (Reaction Product) The reaction product synthesized in the above reaction step is represented by the following formula (1): It is a nitrogen-containing heterocycle-containing compound represented by the formula:

[0015] In formula (1), W １ are the following formulas (2) to (4): The wavy lines in formulas (2) to (4) represent W ２ This shows the bond between .

[0016] W in formula (1) １ is preferably formula (2) or formula (3), more preferably formula (2).

[0017] In formula (2), R １ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an ethoxycarbonyl group, or a tert-butoxycarbonyl (Boc) group. The alkyl group preferably has 1 to 4 carbon atoms, and more preferably 1 to 2 carbon atoms. The alkoxy group preferably has 1 to 4 carbon atoms, and more preferably 1 to 2 carbon atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom is preferred.

[0018] R in formula (2) １is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and more preferably a hydrogen atom.

[0019] In formula (2), Y １ represents CH or N. Y in formula (2) １ is preferably CH.

[0020] In formula (2), are each independently a single bond or a double bond. are preferably both double bonds.

[0021] W in Equation (2) ２ The bond to Y may be located at any of the ortho, meta or para positions relative to the N atom in formula (2), preferably at the meta or para position, more preferably at the meta position. １ isn't it.

[0022] R in formula (2) １ may be located at the ortho, meta or para position relative to the N atom in formula (2), or may be bonded to the N atom, and is preferably located at the ortho position. １ isn't it.

[0023] In formula (2), R １ , Y １ , According to a preferred embodiment relating to the combination of bond positions, R １ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and is located in the ortho or meta position relative to the N atom; Y １ is CH, are both double bonds, and the bonds are located in the meta or para positions relative to the N atom. １ , Y １ , According to a more preferred embodiment relating to the combination of bond positions, R １ is a hydrogen atom located in the ortho position relative to the N atom, and Y １ is CH, are both double bonds, and the bond is located in the meta position relative to the N atom.

[0024] A preferred embodiment of the above formula (2) is the chemical formula represented by the following formula (2-1): In the following formula, Me represents a methyl group, Boc represents a tert-butoxycarbonyl group, and Et represents an ethyl group.

[0025]

[0026] In formula (3), R ２ represents a hydrogen atom, a benzyl group, or a methoxyalkyl group having 1 to 6 carbon atoms in the alkyl group. The number of carbon atoms in the alkyl group in the methoxyalkyl group is preferably 1 to 4, and more preferably 1 to 3. R in formula (3) ２ is preferably a benzyl group or a 1-methoxypropyl group.

[0027] A preferred embodiment of the above formula (3) is the chemical formula represented by the following formula (3-1): In the following formula, Me represents a methyl group, and Bn represents a benzyl group.

[0028]

[0029] W in Equation (4) ２ The bond to the indole ring may be located at any of the 1- to 7-positions, preferably the 4- or 5-position.

[0030] A preferred embodiment of the above formula (4) is the chemical formula represented by the following formula (4-1).

[0031] In formula (1), W ２ are the following formulas (5) to (9): The wavy lines in formulas (5) to (9) represent W １ This shows the bond between .

[0032] W in formula (1) ２ is preferably formula (5) or formula (6), more preferably formula (5).

[0033] In formula (5), Y ２ , Y３ and Y ４ are each independently CH or N, R ３ is a hydrogen atom, a methoxycarbonyl group, a propanoyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or an amino group. The alkoxy group preferably has 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms. The alkyl group preferably has 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms.

[0034] In formula (5), Y ２ represents CH or N. Y in formula (5) ２ is preferably CH.

[0035] In formula (5), Y ３ represents CH or N. Y in formula (5) ３ is preferably CH.

[0036] In formula (5), Y ４ represents CH or N. Y in formula (5) ４ is preferably CH.

[0037] R in formula (5) ３ is preferably a hydrogen atom, a methoxycarbonyl group, or an alkyl group having 1 to 6 carbon atoms, and more preferably a methoxycarbonyl group.

[0038] R in formula (5) ３ Is W １ It may be located at any of the ortho, meta or para positions relative to the bonding position with the aryl group, and is preferably located at the para position.

[0039] In formula (5), Y ２ , Y ３ , Y ４ and R ３ According to a preferred embodiment of the combination of ２ is CH or N, and Y ３ is CH or N, and Y ４ is CH or N, and R ３ is a hydrogen atom, a methoxycarbonyl group, or an alkyl group having 1 to 6 carbon atoms, and W １ In formula (5), Y is located at the para position relative to the bonding position with２ , Y ３ , Y ４ and R ３ According to a more preferred embodiment of the combination of ２ is CH and Y ３ is CH and Y ４ is CH and R ３ is a methoxycarbonyl group, and W １ It is located in the para position relative to the bonding position with

[0040] Preferred embodiments of the above formula (5) include chemical formulae represented by the following formulae (5-1) and (5-2): In the following formulae, Me represents a methyl group, and Et represents an ethyl group.

[0041]

[0042] In formula (6), Y ５ represents CH or N, and R ４ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group preferably has 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms.

[0043] In formula (6), Y ５ represents CH or N. Y in formula (6) ５ is preferably CH.

[0044] R in formula (6) ４ is preferably a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and more preferably a hydrogen atom.

[0045] R in formula (6) ４ Is Y ５ When is CH, that is, when the heterocycle of formula (6) is a quinoline ring, it may be located at any one of the 1- to 8-positions of the quinoline ring, and is preferably located at the 2-position.

[0046] R in formula (6) ４ Is Y ５ When is N, that is, when the heterocycle of formula (6) is a quinoxaline ring, it may be located at any one of the 1- to 8-positions of the quinoxaline ring, and is preferably located at the 7-position.

[0047] W in Equation (6) １ The bond to may be located at any of the 1- to 8-positions of the quinoline or quinoxaline ring, and is preferably located at the 5- or 6-position.

[0048] Preferred embodiments of the above formula (6) include chemical formulae represented by the following formulae (6-1) and (6-2): In the following formulae, Me represents a methyl group.

[0049]

[0050] In formula (7), Y ６ and Y ７ are each independently CH or N, R ５ represents a hydrogen atom, a phenylsulfonyl group, or a 2-(trimethylsilyl)ethoxymethyl group.

[0051] In formula (7), Y ６ represents CH or N. Y in formula (7) ６ is preferably N.

[0052] In formula (7), Y ７ represents CH or N. Y in formula (7) ７ is preferably N.

[0053] R in formula (7) ５ is preferably a hydrogen atom.

[0054] W in Equation (7) １ The bond with Y ６ is CH and Y ７ is CH, that is, it may be located at any of the 1- to 7-positions of the 1H-indole ring, and is preferably located at the 4-position.

[0055] W in Equation (7) １ The bond with Y ６ is CH and Y ７ When is N, that is, when the heterocycle of formula (7) is a 7-azaindole ring, it may be located at any one of the 1- to 7-positions of the 7-azaindole ring, and is preferably located at the 5-position.

[0056] W in Equation (7) １ The bond with Y６ is N and Y ７ is N, that is, when the heterocycle of formula (7) is a 7H-pyrrolo[2,3-d ]pyrimidine ring, it may be located at any one of positions 1 to 7 of the 7H-pyrrolo[2,3-d ]pyrimidine ring, and is preferably located at position 4.

[0057] Preferred embodiments of the above formula (7) include chemical formulas represented by the following formula (7-1) or formula (7-2): In the following formulas, Ph represents a phenyl group, and TMS represents a trimethylsilyl group.

[0058]

[0059] In formula (8), Y ８ represents CH or N, and R ６ represents hydrogen or a methoxycarbonyl group.

[0060] Preferred embodiments of the above formula (8) include chemical formulas represented by the following formula (8-1) or formula (8-2): In the following formulas, Me represents a methyl group.

[0061]

[0062] In formula (9), R ７ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group preferably has 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms.

[0063] A preferred embodiment of the above formula (9) is a chemical formula represented by the following formula (9-1): In the following formula, Me represents a methyl group.

[0064] The nitrogen-containing heterocycle-containing compound represented by formula (1) of the present invention is represented by formulas (2) to (4). １ and W expressed by equations (5) to (9) ２ According to a preferred embodiment of the combination of １ and W expressed by equation (5), (6), (7), (8) or (9) ２ The combination of W represented by formula (3) １and W expressed by equation (5), (6), (7), (8) or (9) ２ and the combination of W represented by formula (4) １ and W expressed by equation (5), (6), (7), (8) or (9) ２ and preferably a combination of W represented by formula (2) １ and W expressed by equation (5), (6) or (7) ２ The combination of W represented by formula (3) １ and W expressed by equation (5) ２ and the combination of W represented by formula (4) １ and W expressed by equation (5) or (7) ２ and more preferably, W represented by formula (2) １ and W expressed by equation (5) ２ W, which is represented by a combination of １ W expressed as ２ It is a combination of:

[0065] The nitrogen-containing heterocycle-containing compound represented by formula (1) of the present invention is represented by formula (2-1) to formula (4-1). １ and W expressed by equations (5-1) to (9-1) ２ According to a preferred embodiment of the combination of W represented by formula (2-1) １ and W represented by equations (5-1), (5-2), (6-1), (6-2), (7-1), (7-2), (8-1), (8-2) or (9-1) ２ The combination of W represented by formula (3-1) １ and W represented by equations (5-1), (5-2), (6-1), (6-2), (7-1), (7-2), (8-1), (8-2) or (9-1) ２ The combination of W represented by formula (4-1) １ and W represented by equations (5-1), (5-2), (6-1), (6-2), (7-1), (7-2), (8-1), (8-2) or (9-1). ２ and preferably a combination of W represented by formula (2-1) １ and W represented by equation (5-1), (5-2), (6-1), (6-2), (7-1) or (7-2). ２ The combination of W represented by formula (3-1) １and W represented by equation (5-1), (6-2), (7-2), (8-1) or (9-1) ２ The combination of W represented by formula (4-1) １ and W expressed by equation (5-1) or (7-1) ２ and more preferably, W represented by formula (2-1) １ and W expressed by equation (5-1) ２ It is a combination of:

[0066] Other preferred embodiments of the nitrogen-containing heterocycle-containing compound represented by formula (1) include compounds represented by the following formulas (1-1) to (1-9): In the following formulas, Me represents a methyl group, Boc represents a tert-butoxycarbonyl group, Et represents an ethyl group, Bn represents a benzyl group, Ph represents a phenyl group, and TMS represents a trimethylsilyl group.

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] The nitrogen-containing heterocycle-containing compound represented by formula (1) of the present invention is represented by formula (2-1) to formula (4-1). １ and W expressed by equations (5-1) to (9-1) ２ According to a preferred embodiment of the combination of the nitrogen-containing heterocycle-containing compound represented by formula (1-1) to (1-9), W represented by formula (2-1) １ and W expressed by equation (5-1) ２ and a nitrogen-containing heterocycle-containing compound represented by formula (1-1).

[0077] (First Raw Material Compound) The first raw material compound used in the present invention is represented by the following formula (10): (In formula (10), W １ The wavy line is an X. １ The formula (1) is the same as that of the formula (1) except that X represents a bond to １ represents at least one selected from the group consisting of a pinacolborane (Bpin) group, a boronic acid diaminonaphthalene amide (B(dan)) group, a boronic acid N-methyliminodiacetic acid (MIDA) ester group, and a trifluoroborate base.

[0078] In the above formula (10), X １ is preferably a pinacolborane (Bpin) group or a trifluoroborate base. Here, examples of the trifluoroborate base include potassium trifluoroborate base and sodium trifluoroborate base, and potassium trifluoroborate base is preferred.

[0079] W represented by formula (2) to formula (4) in the first raw material compound represented by formula (10) of the present invention １ and X １ According to a preferred embodiment in combination with １ is represented by formula (2), X １ is a pinacolborane (Bpin) group or a trifluoroborate base, more preferably a pinacolborane (Bpin) group; W １ is represented by formula (3), X １ is a pinacolborane (Bpin) group, and W １ When is represented by formula (4), X １ is a pinacolborane (Bpin) group.

[0080] W represented by formula (2-1) to formula (4-1) in the first raw material compound represented by formula (10) of the present invention １ and X １ According to a preferred embodiment in combination with １ is represented by formula (2-1), X １is a pinacolborane (Bpin) group or a trifluoroborate base (preferably a potassium trifluoroborate base), and W １ is represented by formula (3-1), X １ is a pinacolborane (Bpin) group, and W １ is represented by formula (4-1), X １ is a pinacolborane (Bpin) group.

[0081] Preferred embodiments of the first raw material compound represented by formula (10) include compounds represented by the following formulas (10-1) to (10-4): In the following formulas, Bpin represents a pinacolborane group, Me represents a methyl group, Boc represents a tert-butoxycarbonyl group, Et represents an ethyl group, and Bn represents a benzyl group.

[0082]

[0083]

[0084]

[0085]

[0086] The amount of the first starting compound used is not particularly limited as long as it does not impair the effects of the present invention, and can be, for example, 0.5 to 2.0 times, and preferably 1.0 to 1.6 times, the amount of the second starting compound used, or an equivalent ratio of, for example, 0.5 to 2.0, and preferably 1.0 to 1.6.

[0087] (Second Raw Material Compound) The second raw material compound used in the present invention is represented by the following formula (11): (In formula (11), X ２ represents a halogen atom, W ２ The wavy line is an X. ２ It has the same meaning as formula (1) except that it indicates a bond to

[0088] In the above formula (11), X ２ Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom or a bromine atom is preferred.

[0089] W represented by formula (5) to formula (9) in the second raw material compound represented by formula (11) of the present invention ２ and X ２ According to a preferred embodiment in combination with ２ When is represented by formula (5), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ When is expressed by formula (6), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ is expressed by formula (7), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ When is expressed by formula (8), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ When is expressed by formula (9), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom.

[0090] W represented by formula (5-1) to formula (9-1) in the second raw material compound represented by formula (11) of the present invention ２ and X ２ According to a preferred embodiment in combination with ２ is represented by formula (5-1), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ is represented by formula (5-2), X ２ is a chlorine atom or a bromine atom, more preferably a chlorine atom; W ２ is represented by formula (6-1), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ When is represented by formula (6-2), X ２ is a chlorine atom or a bromine atom, more preferably a chlorine atom; W ２ is represented by formula (7-1), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ is represented by formula (7-2), X ２is a chlorine atom or a bromine atom, more preferably a chlorine atom; W ２ is represented by formula (8-1), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom; W ２ is represented by formula (8-2), X ２ is a chlorine atom or a bromine atom, more preferably a chlorine atom; W ２ is represented by formula (9-1), X ２ is a chlorine atom or a bromine atom, more preferably a bromine atom.

[0091] Preferred embodiments of the second raw material compound represented by formula (11) include compounds represented by the following formulas (11-1) to (11-9): In the following formulas, Me represents a methyl group, Et represents an ethyl group, Ph represents a phenyl group, and TMS represents a trimethylsilyl group.

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] A preferred embodiment of the combination of the nitrogen-containing heterocycle-containing compound represented by the formula (1), the first raw material compound represented by the formula (10), and the second raw material compound represented by the formula (11) is a combination of the nitrogen-containing heterocycle-containing compound represented by the formula (1), and the nitrogen-containing heterocycle-containing compound represented by the formula (11) is a combination of the nitrogen-containing heterocycle-containing compound represented by the formula (1) and the second raw material compound represented by the formula (12). １ represents the chemical formula (2), and R １ represents a hydrogen atom, and Y １ indicates CH, Both represent double bonds, and W ２ The bond to R is located at the meta position relative to the N atom in formula (2), １ is located at the ortho position relative to the N atom in formula (2), and W ２ represents the chemical formula (5), and Y ２ , Y ３ and Y ４ All of the symbols represent CH, and R ３ is a compound showing a methoxycarbonyl group, and R ３ Is W １ As a first raw material compound represented by formula (10), １ represents a pinacolborane group, and the second raw material compound represented by formula (11) is a compound represented by formula (12) ２ represents a bromine atom.

[0102] (Nickel-based catalyst) The nickel-based catalyst used in the coupling reaction step is not particularly limited as long as it is a catalyst that can cause the Suzuki-Miyaura coupling reaction between the first raw material compound and the second raw material compound. Preferably, the nickel-based catalyst is a compound represented by the following formula (12) (hereinafter, referred to as (PPh ２ Me) ２ NiCl ２ (also called). (In formula (12), Ph represents a phenyl group, and Me represents a methyl group.)

[0103] The present invention is advantageous in that it allows the nitrogen-containing heterocycle-containing compound represented by formula (1) to be produced at low cost using an inexpensive nickel-based catalyst without using an expensive palladium-based catalyst.

[0104] The amount of nickel-based catalyst used is not particularly limited as long as it does not impair the effects of the present invention, but it is, for example, 0.005 to 0.1 times by mole, and preferably 0.01 to 0.08 times by mole, relative to the second raw material compound.

[0105] (Solvent) The solvent used in the coupling reaction step is not particularly limited, but is preferably an aprotic polar solvent having a boiling point of 90°C or higher, more preferably cyclopentyl methyl ether (CPME), N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, propylene carbonate, or a combination thereof, and is preferably cyclopentyl methyl ether.

[0106] The amount of the solvent used is not particularly limited, but may be, for example, 10 parts by mass or more and 100,000 parts by mass or less, preferably 30 parts by mass or more and 10,000 parts by mass or less, and more preferably 100 parts by mass or more and 1,000 parts by mass or less, relative to 100 parts by mass of the first raw material compound and the second raw material compound in total.

[0107] (Reaction Conditions for Coupling Reaction Step) The atmosphere in which the first raw material compound and the second raw material compound are reacted in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90°C or higher is not particularly limited, but from the viewpoint of suppressing a decrease in activity of the catalyst due to moisture inclusion, the reaction is preferably carried out in an inert gas atmosphere, more preferably in a nitrogen or argon atmosphere.

[0108] The temperature at which the first raw material compound and the second raw material compound are reacted in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90°C or higher is not particularly limited, but from the viewpoint of shortening the reaction time, it is preferably 90°C or higher, more preferably 90 to 240°C, more preferably 90 to 200°C, even more preferably 93 to 150°C, and still more preferably 95 to 105°C.

[0109] The time period for reacting the first raw material compound and the second raw material compound in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90°C or higher is not particularly limited, but is, for example, 0.1 to 12 hours, and from the viewpoint of shortening the reaction time and facilitating removal of the heat of reaction, is preferably 1 to 10 hours, more preferably 2 to 8 hours, and even more preferably 3 to 6 hours.

[0110] According to one embodiment of the present invention, when the first raw material compound and the second raw material compound are reacted in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90° C. or higher, it is preferable to further add a base. Such a base is not particularly limited, but examples thereof include potassium phosphate and potassium carbonate, and potassium phosphate is preferred. The potassium phosphate is, for example, potassium dihydrogen phosphate (KH ２ P.O. ４ ), dipotassium hydrogen phosphate (K ２ HPO ４ ), tripotassium phosphate (K ３ P.O. ４ ), and preferably tripotassium phosphate.

[0111] According to a preferred embodiment of the present invention, before reacting the first raw material compound and the second raw material compound in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90°C or higher, the base (preferably potassium phosphate) is dissolved in water to prepare an aqueous solution of the base (preferably an aqueous potassium phosphate solution), and the aqueous solution can be present in the coupling reaction step.

[0112] The amount of the base used is not particularly limited as long as it does not impair the effects of the present invention, and can be, for example, 1.0 to 5.0 times, and preferably 2.0 to 3.0 times, the amount of the second starting compound used, or an equivalent ratio of, for example, 1.0 to 5.0, and preferably 2.0 to 3.0.

[0113] According to another embodiment of the present invention, when the first raw material compound and the second raw material compound are reacted in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90° C. or higher, it is preferable to further include a ligand. Examples of such a ligand include methyldiphenylphosphine (PPh ２ Me), tribenzylphosphine (PBn ３ ), 1,4-bis(dicyclohexylphosphino)butane (DCPB), and preferably PPh ２ This is Me.

[0114] The amount of the ligand used is not particularly limited as long as it does not impair the effects of the present invention, but may be, for example, 0.005 to 0.1 times by mole, and preferably 0.01 to 0.08 times by mole, relative to the second starting compound.

[0115] According to another embodiment of the present invention, it is preferable to further include a Grignard reagent when reacting a first raw material compound and a second raw material compound in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90° C. or higher. Examples of such a Grignard reagent include n-butylmagnesium chloride (n-BuMgCl) and tert-butylmagnesium chloride (tert-BuMgCl), with n-BuMgCl being preferred.

[0116] The amount of the Grignard reagent used is not particularly limited as long as it does not impair the effects of the present invention, but may be, for example, 0.01 to 0.2 times by mole, and preferably 0.04 to 0.1 times by mole, relative to the second starting compound.

[0117] According to another embodiment of the present invention, when a first raw material compound and a second raw material compound are reacted in the presence of a nickel-based catalyst and an aprotic polar solvent having a boiling point of 90°C or higher, the solvent, the base, the ligand, and the Grignard reagent may be used alone or in combination of two or more thereof, or all of them may be used in combination.

[0118] According to another embodiment of the present invention, a reaction step for synthesizing a nitrogen-containing heterocycle-containing compound represented by formula (1) by reacting a first raw material compound represented by formula (10) with a second raw material compound represented by formula (11) in the presence of a nickel-based catalyst represented by formula (12) and an aprotic polar solvent having a boiling point of 90° C. or higher includes a step of preparing solution A and a step of preparing solution B, and may further include a step of adding solution B to solution A to initiate the reaction. Here, solution A is a solution containing the first raw material compound represented by formula (10), the second raw material compound represented by formula (11), and the solvent, and optionally containing a base. Furthermore, solution B is a solution containing the nickel-based catalyst and the solvent, and optionally containing a ligand and a Grignard reagent (hereinafter also referred to as a catalyst solution).

[0119] According to a preferred embodiment of the present invention, the method for producing a nitrogen-containing heterocycle-containing compound represented by formula (1) of the present invention is characterized by the fact that it can efficiently synthesize a nitrogen-containing heterocycle-containing compound in a short time, i.e., it can synthesize a nitrogen-containing heterocycle-containing compound in a high yield (also referred to as isolated yield) and / or a high conversion rate in a short time. Here, a short time can be, for example, 0.1 to 12 hours, preferably 1 to 10 hours, more preferably 2 to 8 hours, and even more preferably 3 to 6 hours. The yield can be 60% or more, preferably 70% or more, and more preferably 80% or more. There is no particular upper limit, but 100% or less is preferred. The yield can be calculated by [moles of the nitrogen-containing heterocycle-containing compound represented by formula (1) / {moles of the starting compound (preferably the second starting compound)}] × 100 (%). The conversion can be 80% or more, preferably 85% or more, and more preferably 90% or more. There is no particular upper limit, but 100% or less is preferred. Here, the conversion rate is １ Specifically, the conversion rate can be calculated by taking the NMR integral ratio (equivalent ratio) of the target peak of the starting compound (preferably the second starting compound) before the reaction as the theoretical equivalent ratio corresponding to a 100% conversion rate of the nitrogen-containing heterocycle-containing compound represented by formula (1) as the denominator and the NMR integral ratio (equivalent ratio) of the target peak of the nitrogen-containing heterocycle-containing compound represented by formula (1) detected after the reaction as the numerator, and then calculating the conversion rate from the ratio of the numerical values ​​of the numerator and denominator.

[0120] A nitrogen-containing heterocycle-containing compound (W １ -W ２ In the synthesis reaction of the compound represented by formula (10) (W １ -X １ ) and a second raw material compound (W ２ -X ２ When W reacts with CPME, the reaction mechanism is thought to proceed according to the following cycle: １-X １ X １ As B(Y) ２ Illustrates W ２ -X ２ X ２ Br is exemplified as K. ３ P.O. ４ where (Y) ２ is a protecting group for boronic acid, and examples thereof include pinacol ester (pin), diaminonaphthalene amide (dan), and MIDA ester. However, the method for producing a nitrogen-containing heterocycle-containing compound represented by formula (1) of the present invention is not limited to this reaction mechanism. 1. A second raw material compound represented by formula (11) is bonded to a zero-valent nickel-based catalyst (Ni(0)) to form W ２ -Ni(II)-X ２ Generate. 2. K ３ P.O. ４ and W ２ -Ni(II)-X ２ An exchange occurs between KBr and W ２ -Ni(II)-PO ４ Generate W. ２ -Ni(II)-PO ４ and boron ate complexes (W １ -B － (Y) ２ -PO ４ K ＋ ) and PO ４ -B － (Y) ２ -PO ４ K ＋ and W ２ -Ni(II)-W １ In addition, the boron ate complex (W １ -B － (Y) ２ -PO ４ K ＋ ) is W １ -B(Y) ２ - is K in the presence of CPME ３ P.O. ４ It is thought that CPME stabilizes the boron ate complex and promotes its formation. 4. W ２-Ni(II)-W １ Reductive elimination of Ni(II) occurs from W ２ -W １ (Go back to step 1 above).

[0121] (Purification step) According to one embodiment of the present invention, the method for producing the nitrogen-containing heterocycle-containing compound represented by formula (1) of the present invention may further include a step of purifying the nitrogen-containing heterocycle-containing compound synthesized above. The purification method is not particularly limited, and conventionally known purification methods can be applied. Examples of the purification method include chromatography, recrystallization, separation, reduced pressure filtration, solvent distillation, washing with a solvent, and ultrasonic washing.

[0122] As the purification step, from the viewpoint of improving the isolation yield, it is preferable to purify (preferably, fractionate) the nitrogen-containing heterocycle-containing compound by chromatography among the above methods. In particular, a chromatography method using a mixture of hexane and ethyl acetate as a developing solution, in which the ethyl acetate content is 50% by volume or more, can improve the isolation yield. The ethyl acetate content of the mixture of hexane and ethyl acetate as the developing solution is preferably 50% by volume or more, more preferably 50 to 99% by volume, and even more preferably 50 to 90% by volume. Examples of the chromatography method include preparative chromatography and silica gel packed filtration, with preparative chromatography being preferred. The column used in the chromatography method is not particularly limited, but normal phase is preferred. Examples of conditions for preparative chromatography include the following: Developing solvent: ethyl acetate / hexane = 50 / 50 mixed solvent Column: normal phase silica gel (preferably Universal Column (manufactured by Yamazen Co., Ltd.)) Instrument: Smart Flash AKROS (manufactured by Yamazen Co., Ltd.) Temperature: room temperature Detection wavelength: 254 nm

[0123] According to a preferred embodiment of the present invention, there is provided a method for producing a nitrogen-containing heterocycle-containing compound represented by formula (1), which comprises a reaction step of synthesizing a nitrogen-containing heterocycle-containing compound represented by formula (1) by reacting a first raw material compound represented by formula (10) with a second raw material compound represented by formula (11) in the presence of a nickel-based catalyst represented by formula (12) and an aprotic polar solvent having a boiling point of 90° C. or higher, and a step of further purifying the nitrogen-containing heterocycle-containing compound synthesized in the reaction step. Specifically, the purification step may include a step of adding water to a reaction mixture containing the nitrogen-containing heterocycle-containing compound synthesized in the reaction step, washing the mixture, and discharging the resulting mixture to obtain a crude product of the nitrogen-containing heterocycle-containing compound. The method may further include a step of concentrating the nitrogen-containing heterocycle-containing compound in the aprotic polar solvent (preferably CPME) in the crude product by distillation under reduced pressure using an evaporator apparatus, and removing the aprotic polar solvent (preferably CPME) to purify the nitrogen-containing heterocycle-containing compound. Among the aprotic polar solvents, for example, CPME is highly hydrophobic, eliminating the need for extraction by ethyl acetate substitution, as with 2-MeTHF. The one-pot method significantly simplifies the process, since only one reaction vessel is required for the purification step. Furthermore, the purification process requires a large amount of solvent, generates a large amount of waste, and is time-consuming and labor-intensive, so this method is advantageous from the perspective of speeding up the process and reducing costs.

[0124] (Method for Producing Nickel-Based Catalyst) According to another aspect of the present invention, there is provided a method for producing the nickel catalyst represented by the above formula (12). The method includes the steps of: ２ ・6H ２ O) and methyldiphenylphosphine (PPh ２ Preferably, the method includes a step of reacting (preferably contacting) the compound (Me) with the compound (Me). The reaction step is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethanol and methanol, and preferably ethanol.

[0125] The amount of methyldiphenylphosphine used is not particularly limited as long as it does not impair the effects of the present invention, but may be, for example, 0.5 to 5.0 times by mole, and preferably 1.5 to 3.0 times by mole, relative to nickel chloride hexahydrate.

[0126] The atmosphere in which nickel chloride hexahydrate and methyldiphenylphosphine are reacted is not particularly limited, but from the viewpoint of suppressing a decrease in activity due to moisture entrapment in the catalyst, an inert gas atmosphere is preferred, and a nitrogen or argon atmosphere is more preferred.

[0127] The temperature at which nickel chloride hexahydrate is reacted with methyldiphenylphosphine is not particularly limited, but is preferably 60 to 90°C, more preferably 70 to 80°C.

[0128] The time for reacting nickel chloride hexahydrate with methyldiphenylphosphine is not particularly limited, but is preferably 0.1 to 2.0 hours, more preferably 0.3 to 1.0 hour.

[0129] (Applications) The nitrogen-containing heterocycle-containing compound represented by formula (1) obtained by the production method of the present invention can be suitably used, for example, as a structural backbone of pharmaceuticals and nucleic acids, a large part of biomass (cellulose and related compounds), and many natural and synthetic dyes.

[0130] The present invention will be specifically explained below with reference to test examples, but the present invention is not limited to these test examples.

[0131] [Test Example 1] <Nickel-based catalyst (PMePh ２ ) ２ NiCl ２ Manufacturing > N ２ In a glove box, a 20 ml reaction vial was charged with NiCl. ２ ・6H ２ The solution in the vial was placed in a glove box under N 2 O (1.74 mmol, 414 mg), ethanol (6 mL), and a magnetic stirrer. ２ After sparging, PPh ２Me (3.83 mmol, 767 mg, 724 μL) was added in small portions over 5 minutes to obtain a mixture. The mixture was heated at 78°C for 30 minutes and then cooled to room temperature (Reaction Scheme I). The resulting solid was then collected by filtration under reduced pressure and washed twice with ethanol (2 mL). The washed solid was then air-dried in a glove box to obtain the nickel-based catalyst (PMePh ２ ) ２ NiCl ２ (846 mg, 92% yield) was obtained as a dark maroon crystalline solid.

[0132] <X-ray Diffraction Analysis of Nickel-Based Catalyst> The X-ray diffraction (XRD) analysis pattern of the nickel-based catalyst obtained in Example 1 was measured using a diffractometer (Rigaku SmartLab (Rigaku Corporation)) under the following conditions.

[0133] The XRD pattern of the nickel-based catalyst obtained in Test Example 1 is shown in Figure 1. The obtained XRD pattern was consistent with CIF number 2109558 registered in the crystal structure database of the Cambridge Crystal Data Centre (CCDC), and it was confirmed that the nickel-based catalyst was the nickel-based catalyst of formula (12) above.

[0134] Test Example 2-1 Synthesis and Sampling of Nitrogen-Containing Heterocycle-Containing Compound Represented by Formula (1) (Methyl 4-(pyridin-3-yl)benzoate) ２ In a glove box, methyl 4-bromobenzoate (430 mg, 2.00 mmol, 1.00 equivalents) (second raw material compound), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (574 mg, 2.80 mmol, 1.40 equivalents) (first raw material compound), K ３ P.O. ４ (1.062 g, 5.00 mmol, 2.5 eq) and 2.5 mL of 2-MeTHF. In a separate vial 2, 2.5 mL of 2-MeTHF, (PPh ２ Me) ２ NiCl ２ (31.8 mg, 0.06 mmol, 3 mol%) and PPh ２A nickel-based catalyst solution was prepared by dropwise addition of n-butylmagnesium chloride (n-BuMgCl) (66 μL of a 2 M solution in THF, 0.132 mmol, 6.6 mol%) to a stirred slurry of Me (24.0 mg, 0.12 mmol, 6 mol%). Upon addition of n-BuMgCl (corresponding to a Grignard reagent), the maroon slurry turned into a yellow-orange solution. Next, the nickel-based catalyst solution was added to reaction vial 1, followed by 1.0 mL of ion-exchanged water. The internal temperature of vial 1 was adjusted to 70°C, and the target reaction shown in Reaction Scheme II was monitored by periodically sampling the resulting reaction mixture.

[0135] <Consideration of tracking methods> The samples obtained above will be １ The product was analyzed by H-NMR. １ The conditions for adopting H-NMR analysis are that the target substance and the target substance have individual peak separation, and that the reaction invariant (solvent in this case) can be used as the internal standard. Here, the target substance specifically refers to methyl 4-bromobenzoate, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and the solvent. The target substance refers to methyl 4-(pyridin-3-yl)benzoate. NMR analysis was performed using the reaction solution before the reaction (also referred to as 0 hours), and the study was carried out under the following conditions. ( １ H-NMR conditions) NMR measurement device: manufactured by BRUKER JAPAN １ H-NMR measurement conditions: frequency 600.03 MHz; measurement time: approximately 10 minutes. The results are shown in Table 2. FIG. 2 shows the reaction mixture before reaction. １ 2 shows the H-NMR spectrum. In FIG. 2, a is derived from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, b is derived from methyl 4-bromobenzoate, and c is derived from the solvent used, 2-MeTHF, which serves as an internal standard. １The H-NMR assigned peaks are shown, of which a, b, and c indicate the detected peaks used in the quantitative analysis. From FIG. 2 and Table 2, it was found that the target substance and the target substance could be separated into individual peaks, and from Table 2, it was found that the charged equivalent ratio and the NMR integral ratio matched. It was also found that the target substance could be separated into peaks separately from other target substances. Therefore, １ The conversion rate of the target substance, methyl 4-(pyridin-3-yl)benzoate (hereinafter simply referred to as conversion rate) can be calculated by H-NMR using the detected peak derived from the solvent 2-MeTHF used as an internal standard. That is, the method for calculating the conversion rate is as follows: the NMR integral ratio (equivalent ratio) of the target peak of methyl 4-bromobenzoate, the raw material input before the reaction, is the theoretical equivalent ratio corresponding to a conversion rate of 100% of the target substance; this is used as the denominator; and the NMR integral ratio (equivalent ratio) of the target peak of the target substance detected after the reaction is used as the numerator; the conversion rate can be calculated as the ratio of the numerical values ​​of the numerator and denominator.

[0136] １ The measurement time for H-NMR analysis is shorter than the measurement time (usually about 60 minutes) for HPLC, which is a common analytical method, and analysis can be performed quickly, thereby achieving time reduction. １ Since H-NMR allows for faster analysis than HPLC, it also simplifies reaction tracking.

[0137] ​[Test Example 2-2] <Determination of Isolation and Purification Method for Target Substance> Next, the developer was investigated. The reaction mixture obtained in Test Example 2-1 after 7 hours of reaction was purified. Specifically, the resulting reaction mixture was first cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with ion-exchanged water and 20% by weight of NaCl water. The resulting ethyl acetate layer was concentrated under reduced pressure, and the resulting crude product was purified by preparative chromatography (column: normal-phase silica gel (Universal Column L size (Yamazen Co., Ltd.)), equipment: Smart Flash AKROS (Yamazen Co., Ltd.), temperature: room temperature). A mixture of ethyl acetate / hexane was used as the developer for preparative chromatography, and the ethyl acetate concentration was gradually changed to 10%, 30%, and 50% by volume. Detection was performed by UV absorption detection (254 nm), and the separation procedure was performed. As a result, the target substance was detected (isolation yield: 47%) when the ethyl acetate concentration of the chromatographic developer (ethyl acetate / hexane) was 50% by volume.

[0138] <Methyl 4-(pyridin-3-yl)benzoate １３ C-NMR measurement for the above target substance under the following conditions １３ C-NMR measurement was carried out. １３ C-NMR measurement conditions) NMR measurement device: manufactured by BRUKER JAPAN １３ C-NMR measurement conditions: frequency 150.89 MHz, CDCl ３ solvent

[0139] The obtained methyl 4-(pyridin-3-yl)benzoate １３ The C-NMR spectrum is shown in Figure 3. １３ C-NMR spectrum data was obtained, and the spectrum analysis confirmed that the product was methyl 4-(pyridin-3-yl)benzoate.

[0140] 13 C NMR (150.89MHz, CDCl3): δ 166.74, 149.30, 148.39, 142.25, 135.56, 134.50, 130.37, 129.77, 127.11, 123.66, 52.26 ppm

[0141] [Test Example 3] ３ P.O. ４ Calculation of Conversion Rate in Synthesis of Methyl 4-(pyridin-3-yl)benzoate When Benzyl Alcohol and Water Were Added Separately> Methyl 4-(pyridin-3-yl)benzoate was synthesized in the same manner as in Test Example 2-1. The conversion rates of the reaction mixture (sample) after reaction for 5 hours and 8 hours at an internal temperature of 70°C in reaction vial 1 were calculated. The results are shown in Table 3.

[0142] [Test Example 4] ３ P.O. ４ Calculation of conversion rate in synthesis of methyl 4-(pyridin-3-yl)benzoate when pre-dissolved in water and added> K ３ P.O. ４ (1.062 g) and ion-exchanged water (1.0 mL) were mixed, and K ３ P.O. ４ Dissolve K ３ P.O. ４ An aqueous solution was obtained. ３ P.O. ４ Together with the aqueous solution, methyl 4-bromobenzoate (430 mg) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (574 mg) were charged into reaction vial 1. Methyl 4-(pyridin-3-yl)benzoate was synthesized in the same manner as in Test Example 2-1, except that the above charges were not added and ion-exchanged water was not added after the nickel-based catalyst solution was added to reaction vial 1. The conversion rates were calculated for samples after reaction for 3 hours, 5 hours, and 7 hours at an internal temperature of 70°C in reaction vial 1. The results are shown in Table 3.

[0143] [Test Example 5-1] <K ３ P.O. ４Calculation of Conversion Rate in the Synthesis of Methyl 4-(pyridin-3-yl)benzoate When Preliminarily Dissolved in Water and Added, and CPME Used as the Solvent> Methyl 4-(pyridin-3-yl)benzoate was synthesized in the same manner as in Test Example 4, except that the solvent used was changed from 2-MeTHF to CPME, and the internal temperature of reaction vial 1 was set to 100°C. The conversion rates were calculated for samples after reaction for 1 hour, 3 hours, and 5 hours at an internal temperature of 100°C in reaction vial 1. The results are shown in Table 3. The calculation of the conversion rate was performed in the same manner as in <Study on Additional Means> in Test Example 2-1, except that the internal standard substance was changed from 2-MeTHF to CPME.

[0144] <The reaction mixture obtained in Test Example 5-1 １ H-NMR Measurement> The reaction mixture before the reaction and the reaction mixture after 5 hours of reaction obtained in Test Example 5-1 were １ The reaction mixture was analyzed by H-NMR. The results are shown in Figure 4. In Figure 4(B), d indicates the peak derived from the methoxycarbonyl group of methyl 4-(pyridin-3-yl)benzoate, b indicates the peak derived from the methoxycarbonyl group of methyl 4-bromobenzoate, and e indicates the peak derived from the methoxy group of CPME. No peak derived from methyl 4-(pyridin-3-yl)benzoate was observed before the reaction (0 hours), but a peak derived from methyl 4-(pyridin-3-yl)benzoate was observed 5 hours after the reaction.

[0145] Test Example 5-2: Isolation and Purification of Methyl 4-(pyridin-3-yl)benzoate The reaction mixture obtained in Test Example 5-1 after 5 hours of reaction at 100°C was purified. Specifically, the resulting reaction mixture was cooled to ambient temperature. The reaction mixture was washed with ion-exchanged water to obtain a crude product. The obtained crude product was purified by preparative chromatography in the same manner as in Test Example 2-2 to obtain methyl 4-(pyridin-3-yl)benzoate (358 mg, 1.68 mmol, isolated yield 84%).

Claims

1. A nitrogen-containing heterocycle-containing compound represented by the following formula (1): (In formula (1), W １ are the following formulas (2) to (4): (In formula (2), R １ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an ethoxycarbonyl group, or a tert-butoxycarbonyl (Boc) group; Y １ represents CH or N, are each independently a single or double bond, and the wavy line represents W ２ ) (In formula (3), R ２ represents a hydrogen atom, a benzyl group, or a methoxyalkyl group having 1 to 6 carbon atoms in the alkyl group, and a wavy line represents W ２ ), and (In formula (4), the wavy line represents W ２ and wherein W represents a bond to the heterocyclic compound. ２ are the following formulas (5) to (9): (In formula (5), Y ２ , Y ３ and Y ４ are each independently CH or N, R ３ represents a hydrogen atom, a methoxycarbonyl group, a propanoyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or an amino group; and the wavy line represents W. １ ) (In formula (6), Y ５ represents CH or N, R ４ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the wavy line represents W １ ) (In formula (7), Y ６ and Y ７ are each independently CH or N, R ５ represents a hydrogen atom, a phenylsulfonyl group or a 2-(trimethylsilyl)ethoxymethyl group, and the wavy line indicates a bond with W １ represents a bond with W). (In formula (8), Y ８ represents CH or N, R ６ represents hydrogen or a methoxycarbonyl group, and the wavy line indicates a bond with W １ represents a bond with W). And (In formula (9), R ７ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the wavy line indicates a bond with W １ represents a bond with W).) It is a group represented by a chemical formula selected from the group consisting of).) A method for producing a nitrogen-containing heterocyclic compound represented by the following formula (10): (In formula (10), W １ is synonymous with formula (1) except that the wavy line indicates a bond with X １ , X １ represents at least one selected from the group consisting of a pinacolborane (Bpin) group, a boronic acid diaminonaphthalene amide (B(dan)) group, a boronic acid N-methyliminodiacetic acid (MIDA) ester group, and a trifluoroborate base.).) A first starting compound represented by the following formula (11): (In formula (11), X ２ represents a halogen atom, and W ２ is synonymous with formula (1) except that the wavy line indicates a bond with X ２ .) A second starting compound represented by the formula (1) is reacted with an aprotic polar solvent having a boiling point of 90 °C or higher and a nickel-based catalyst represented by the following formula (12): (In formula (12), Ph represents a phenyl group and Me represents a methyl group.) By reacting in the presence of), a method for producing a nitrogen-containing heterocyclic compound, which includes a reaction step of synthesizing a nitrogen-containing heterocyclic compound represented by the above formula (1).

2. The method for production according to claim 1, wherein the aprotic polar solvent having a boiling point of 90°C or higher is selected from the group consisting of cyclopentyl methyl ether, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, and propylene carbonate.

3. The method for production according to claim 1 or 2, wherein in the reaction step, there further exists an aqueous potassium phosphate solution obtained by dissolving potassium phosphate in water before the reaction.

4. The method for production according to claim 1 or 2, wherein the reaction temperature in the reaction step is 90°C or higher.

5. The method for production according to claim 1 or 2, including a purification step of separating the nitrogen-containing heterocyclic compound represented by the formula (1) obtained in the reaction step by a chromatographic method using a mixed solution of hexane and ethyl acetate containing 50% by volume or more of ethyl acetate as a developing solution.

6. In the nitrogen-containing heterocyclic compound represented by the formula (1), W １ represents the chemical formula of the formula (2), and R １ represents a hydrogen atom, Y １ represents CH, both represent a double bond, and W ２ represents the chemical formula of the formula (5), and Y ２ , Y ３ and Y ４ all represent CH, and R ３ represents a methoxycarbonyl group. In the first raw material compound represented by the formula (10), X １ represents a pinacol borane group. In the second raw material compound represented by the formula (11), X ２ represents a bromine atom. The production method according to claim 1.

7. By reacting nickel(II) chloride hexahydrate with methyldiphenylphosphine in the presence of ethanol, a reaction step for synthesizing a nickel catalyst represented by the following formula (12): A method for producing a nickel catalyst, comprising a reaction step for synthesizing a nickel catalyst represented by the formula.

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