Method for producing nitrogen-containing heteroarylcarboxamide acetic acid derivative

Abstract

To provide a novel process for preparing the compound I containing the compound [I(A)] (vadadustat) and the compound [I(B)] (roxadustat) which are useful as a medicine in an industrially advantageous manner.SOLUTION: The present invention provides a process for preparing the compound I which comprises reacting specific two compounds and carbon monoxide molecules in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, within a solvent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing nitrogen-containing heteroarylcarboxamidoacetic acid derivatives. [Background technology]

[0002] [5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxamido]acetic acid (hereinafter also referred to as compound [I(A)] or vadadustat), a type of nitrogen-containing heteroarylcarboxamidoacetic acid derivative, has HIF-1α prolyl hydroxylase inhibitory activity and has been reported to improve blood flow, oxygen delivery, and energy utilization in ischemic tissues, or to upregulate erythropoietin production to treat anemia (Patent Document 1). [ka] According to the description in Patent Document 1, compound [I(A)] can be produced by the following reaction scheme (1). Reaction Scheme (1): [ka]

[0003] Another method for producing the compound [I(A)] is disclosed in Patent Document 2. According to the description in the document, the compound [I(A)] can be produced by the following reaction scheme (2). Reaction Scheme (2): [ka]

[0004] However, in these reaction schemes, the production process from 2-cyano-3,5-dichloropyridine, which is used as the starting material, to compound [I(A)] is long, and the starting material is expensive, so that these production methods cannot be said to be optimal for implementation on an industrial scale.

[0005] Patent Document 3 discloses yet another method for producing the compound [I(A)]. According to the description in the document, the compound [I(A)] can be produced by the following reaction scheme (3). Reaction Scheme (3): [ka]

[0006] However, the starting material used in this reaction scheme, 3,5-dichloropyridine-2-carboxylic acid, is expensive, and therefore this is not an optimal production method for carrying out on an industrial scale.

[0007] Furthermore, Patent Document 4, which was published after the filing of Patent Application No. 2019-222845, which is the basis of the priority of this application, discloses a method for producing intermediate (3X) and intermediate (4X) of compound [I(A)] shown in the following scheme (4). According to the description in this document, intermediate (3X) can be produced by reacting compound (1X) and compound (2X) in the presence of carbon monoxide. Furthermore, intermediate (4X) can be produced by subjecting intermediate (3X) and 3-chlorophenylboronic acid to a Suzuki coupling reaction. Reaction Scheme (4): [ka] However, in the examples of producing intermediate (4X) in the present application, the reaction solution of the reaction is analyzed to confirm the reaction efficiency, and there is no disclosure of isolating and purifying intermediate (4X) and carrying out instrumental analysis, and there is no evidence that intermediate (4X) was produced by selectively reacting with the 5-position chlorine atom of the two chlorine atoms at the 3- and 5-positions of intermediate (3X).

[0008] In addition, 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid (hereinafter also referred to as compound [[I(B)] or Roxadustat)) has been reported as one type of nitrogen-containing heteroarylcarboxamidoacetic acid derivative. According to Patent Document 5, compound [[I(B)] can be produced by the following scheme (5). Reaction Scheme (5): [ka] However, in this reaction scheme, the production process from methyl 2-chloromethyl-4-phenoxybenzoate, which is used as the starting material, to compound [[I(B)] is long, and this production method cannot be said to be optimal for implementation on an industrial scale. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2008 / 002576 [Patent Document 2] WO2012 / 170377 [Patent Document 3] CN105837502A [Patent Document 4] WO2020 / 217733 [Patent Document 5] WO2014 / 014834 Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention provides a novel process for industrially advantageously producing compound (I), including the above-mentioned compound [I(A)] and compound [[I(B)], which are useful as pharmaceuticals. Here, the present inventors re-examined the method of converting compound (X) to compound (Y) described in Patent Document 3, but the Suzuki coupling reaction hardly proceeded, and the small amount of coupling product obtained was a positional isomer reacted at the 3-position of pyridine, and the target compound (Y) could not be produced. In addition, the reaction in Patent Document 4 was carried out with reference to Patent Document 3, and considering the results of the re-examination of Patent Document 3 by the present inventors described above, it was presumed that a positional isomer reacted at the 3-position of pyridine was similarly produced. [Means for solving the problem]

[0011] As a result of intensive research to solve the above problems, the present inventors have found that the production method consisting of the reaction schemes (I) {(II) to (I-VII)}, (II) {(II-I) to (I-III)}, and (III) shown in the following formulas can produce the target compound [[I(A)] from a cheaper starting material in a shorter process by performing an aminocarbonylation reaction of 2-halogenopyridine, as compared with the production methods in Patent Documents 1 and 2 that use 2-cyano-3,5-dichloropyridine as a starting material, and have completed the present invention. Furthermore, the present inventors have also found that the target compound (I) containing [(4-hydroxy-1-methyl-7-phenoxyisoquinoline)3-carboxamido]acetic acid (hereinafter also referred to as compound [[I(B)] or Roxadustat) can be produced, and have completed the present invention. [ka]

[0012] In addition, Patent Document 1 discloses the following compound (a3-1-A), but there is no description regarding the solid state, physicochemical properties, and crystal form of compound (a3-1-A), and there is no suggestion that a crystal form exists. [ka] The present inventors have found that residual impurities are a problem in the production of compound [I(A)]. As a result of examining various purification methods, they have found that impurities can be efficiently removed by crystallizing and purifying intermediate compound (a3-1-A), and high-quality compound [[I(A)] can be produced. That is, compound (a3-1-A) has two types of crystal forms, and impurities can be efficiently removed by purifying these two types of crystals. Among them, type II crystals are the most efficient for removing impurities. On the other hand, type I crystals are the most thermodynamically stable crystals, and are preferred from the viewpoint of robustness of the production method.

[0013] That is, the present invention is as follows, but is not limited thereto. [1] A compound of the following formula (a1): [ka] {where, R 2 represents a hydrogen atom or an optionally substituted methyl; R a3 represents a phenyl group which may be substituted with halogen; R a4 represents a hydrogen atom, or R a3 and R a4 are bonded to each other together with the adjacent pyridine to form an isoquinoline which may be substituted by phenyloxy; Z 1 represents a chlorine atom, a bromine atom, or an iodine atom, Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) Represents.} , a compound of the following formula (2): [ka] (In the formula, R 1represents an optionally substituted alkyl, a hydrogen atom, or a resin residue. Alternatively, a salt of compound (2) and a carbon monoxide molecule are reacted in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence of a base in a solvent to obtain a compound (a3) ​​of the following formula: [ka] (wherein the symbols have the same meanings as defined above) A method for manufacturing the same. [2] The method according to [1], wherein the pressure during the reaction of the carbon monoxide molecules is between 0.01 MPa and 1 MPa. [3] The method according to [1] or [2], wherein the molar ratio of compound (a1) to compound (2) used in the reaction is 2:1 to 1:2. [4] The method according to any one of [1] to [3], wherein the solvent is a nitrile and the reaction is carried out at a reaction temperature of 20°C to 150°C. [5] The compound (a1) is a compound (a1-5-a) of the following formula: [ka] (In the formula, Z 1 represents a chlorine atom, a bromine atom, or an iodine atom) and The compound (a3) ​​is a compound (a3-3-a) of the following formula: [ka] (In the formula, R 1 represents an optionally substituted alkyl, a hydrogen atom, or a resin residue. The compound according to any one of [1] to [4], wherein [6] A compound (a3-1) of the following formula, obtained by the method according to any one of [1] to [4]: [ka] {where, R 1-1 represents an optionally substituted alkyl or resin residue, R 2represents a hydrogen atom or an optionally substituted methyl; R a3 represents a phenyl group which may be substituted with halogen; R a4 represents a hydrogen atom, or R a3 and R a4 are bonded to each other together with the adjacent pyridine to form an isoquinoline which may be substituted by phenyloxy; Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) Represents.} and converting the compound (a3-1) to obtain a compound (aI) of the following formula: [ka] {wherein the symbols have the same meanings as defined above.} A method for manufacturing the same. [7] (i)R 2 is a hydrogen atom, R a3 is 3-chlorophenyl, and R a4 is a hydrogen atom, or (ii)R 2 is methyl, and R a3 and R a4 The method according to any one of [1] to [4] and [6], wherein each of the pyridines is bonded to the adjacent pyridine to form 7-phenyloxy-isoquinoline. [8] Compound (a3-1) is a compound (a3-2-a) of the following formula: [ka] (In the formula, R 1-1 represents an optionally substituted alkyl or resin residue. and Compound (aI) is a compound of the following formula [I(A)]: [ka] The method according to [6], [9] The compound (a1) has the following formula (a1-1-a): [ka] {where Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) Represents.} The compound (a1-1-a) is a compound (a4) represented by the following formula: [ka] (In the formula, Z a3 represents a bromine atom, an iodine atom, or trifluoromethanesulfoxy; Z a2 has the same meaning as above) , a compound of the following formula (a5): [ka] (In the formula, X a1 and X a2 each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. or an equivalent of compound (a5) in the presence or absence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in a solvent or without a solvent, to produce compound (a1-1-a).

[10] The compound (a1-1-a) is a compound (a1-4-a) of the following formula: [ka] and The compound (a4) is a compound (a4-2) of the following formula: [ka] (In the formula, Z a3 represents a bromine atom or an iodine atom) The method according to [9],

[11] A compound of the formula [I(A)]: [ka] A method for producing (i) A compound (a4) of the following formula: [ka] {where Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P a1 represents a hydroxy protecting group) represents Z a3 represents a bromine atom, an iodine atom, or trifluoromethanesulfoxy. and a compound (a5) of the formula: [ka] (In the formula, X a1 and X a2 each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. Alternatively, an equivalent of compound (a5) is reacted with a compound represented by the following formula (a1-1-a): [ka] (In the formula, Z a2 has the same meaning as above) A process for producing a compound represented by the formula: (ii) The compound (a1-1-a), a compound (2-1) of the following formula: [ka] (In the formula, R 1-1 represents an optionally substituted alkyl or resin residue. Alternatively, a salt of the compound (2-1) and a carbon monoxide molecule are reacted in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base, in a solvent or without a solvent to obtain a compound (a3-1-a) of the following formula: [ka] (In the formula, R 1-1 , and Z a2 has the same meaning as above) and (iii) converting the compound (a3-1-a) to obtain a compound [I(A)] of the following formula: [ka] A method for producing compound [I(A)], comprising the step of producing

[12] Compound (a4) is a compound (a4-2) of the following formula: [ka] (In the formula, Z a3 represents a bromine atom or an iodine atom) and The compound (a1-1-a) is a compound (a1-4-a) of the following formula: [ka] and The compound (a3-1-a) is a compound (a3-2-a) of the following formula: [ka] (In the formula, R 1-1represents an optionally substituted alkyl or resin residue. The method according to

[11] ,

[13] A compound of the formula [I(A)]: [ka] A method for producing (i) A compound of the following formula (a4-1): [ka] {where Z a2-1 is a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) represents Z a3 represents a bromine atom, an iodine atom, or trifluoromethanesulfoxy. and a compound (a5) of the formula: [ka] (In the formula, X a1 and X a2 each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. Alternatively, an equivalent of compound (a5) is reacted with a compound represented by the following formula (a1-3-a): [ka] (In the formula, Z a2-1 has the same meaning as above) A process for producing a compound represented by the formula: (ii) converting the compound (a1-3-a) to obtain a compound (a1-4-a) of the following formula: [ka] A process for producing (iii) The compound (a1-4-a), a compound (2-1) of the following formula: [ka] (In the formula, R 1-1 represents an optionally substituted alkyl or resin residue. Alternatively, a salt of the compound (2-1) and a carbon monoxide molecule are reacted in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base, in a solvent or without a solvent to obtain a compound (a3-2-a) of the following formula: [ka] (In the formula, R 1-1 has the same meaning as above) and (iv) converting the compound (a3-2-a) to obtain a compound [I(A)] of the following formula: [ka] A method for producing compound [I(A)], comprising the step of producing

[14] Compound (b3-1) of the following formula: [ka] (In the formula, R 1 represents an optionally substituted alkyl, a hydrogen atom, or a resin residue, R 2 represents a hydrogen atom or an optionally substituted methyl; R 3 represents phenyl optionally substituted with halogen, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R 4 represents a hydrogen atom, or R 3 and R 4 are bonded together with the adjacent pyridine to form an isoquinoline which may be substituted with phenyloxy. A method for producing (i) A compound of the following formula (b1): [ka] (In the formula, Z 1 represents a chlorine atom, a bromine atom, or an iodine atom, Z b2 represents a chlorine atom, a bromine atom, or an iodine atom, R 2 , R 3 , and R 4 has the same meaning as above) , a compound of the following formula (2): [ka] (In the formula, R 1 represents an optionally substituted alkyl, a hydrogen atom, or a resin residue. or a salt of compound (2) and carbon monoxide molecules in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to obtain a compound (b3) of the following formula: [ka] (wherein the symbols have the same meanings as defined above) and (ii) reacting said compound (b3) with a compound (b4) of the following formula: [ka] (In the formula, R b5 represents an optionally substituted aryl or an optionally substituted alkyl. is reacted in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence of a base in a solvent to obtain a compound (b3-1) of the following formula: [ka] (wherein the symbols have the same meanings as defined above) A method for producing compound (b3-1), comprising the step of producing

[15] The method according to

[14] , wherein the pressure during the reaction of the carbon monoxide molecules is between 0.01 MPa and 1 MPa.

[16] The method according to

[14] or

[15] , wherein the molar ratio of compound (b1) to compound (2) used in the reaction is 2:1 to 1:2.

[17] The method according to any one of

[14] to

[16] , wherein the solvent is a nitrile and the reaction is carried out at a reaction temperature of 20°C to 150°C.

[18] A compound of the following formula (b3-2-2): [ka] (In the formula, R 1 represents an optionally substituted alkyl, a hydrogen atom, or a resin residue, R b3 represents a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy. and synthesizing the compound (b3-2-2) and a compound (b6) of the following formula: [ka] (In the formula, X b1 and X b2 each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. Alternatively, an equivalent of compound (b6) is reacted with a compound represented by the following formula (b3-2-a): [ka] (wherein the symbols have the same meanings as defined above) A method for manufacturing the same.

[19] A compound of the following formula (b3-1-1): [ka] (In the formula, R 1-1represents an optionally substituted alkyl or resin residue, R 2 represents a hydrogen atom or an optionally substituted methyl; R 3 represents phenyl optionally substituted with halogen, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R 4 represents a hydrogen atom or R 3 and R 4 represent that they are bonded together with the adjacent pyridine to form an isoquinoline which may be substituted with phenyloxy. and converting the compound (b3-1-1) to obtain a compound (I) of the following formula: [ka] (wherein the symbols have the same meanings as defined above) A method for manufacturing the same.

[20] (i)R 2 is a hydrogen atom, R 3 is 3-chlorophenyl, and R 4 is a hydrogen atom, or (ii)R 2 is methyl, and R 3 and R 4 The method according to any one of

[14] to

[17] and

[19] , wherein each is bonded to an adjacent pyridine to form 7-phenyloxy-isoquinoline.

[21] Compound (bI-1) of the following formula: [ka] (In the formula, R 2 represents a hydrogen atom or an optionally substituted methyl; R b3-3 represents 3-chlorophenyl, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R b4-3 represents a hydrogen atom, or R b3-3 and R b4-3 represent bonds with adjacent pyridines to form 7-phenyloxy-isoquinoline. A method for producing (i) A compound (b1-2) of the following formula: [ka] (In the formula, Z 1 represents a chlorine atom, a bromine atom, or an iodine atom, Z b2 represents a chlorine atom, a bromine atom, or an iodine atom, R 2 is R b3-3 and R b4-3 has the same meaning as above.) , a compound of the following formula (2-1): [ka] (In the formula, R 1-1 represents an optionally substituted alkyl or resin residue. Alternatively, a salt of the compound (2-1) and a carbon monoxide molecule are reacted in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of a base, in a solvent or without a solvent to obtain a compound represented by the following formula (b3-4): [ka] (wherein the symbols have the same meanings as defined above) A process for producing a compound represented by the formula: (ii) The compound (b3-4) and a compound (b4) of the following formula: [ka] (In the formula, R b5 represents an optionally substituted aryl or an optionally substituted alkyl. is reacted in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to obtain a compound (b3-5) of the following formula: [ka] (wherein the symbols have the same meanings as defined above) and (iii) converting the compound (b3-5) to obtain a compound (bI-1) of the following formula: [ka] (wherein the symbols have the same meanings as defined above) A method for producing compound (bI-1), comprising the step of producing

[22] Compound (a1-a) of the following formula: [ka] {where Z 1 represents a chlorine atom, a bromine atom, or an iodine atom, Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) Represents.}

[23] Compound (a3-1-A) of the following formula: [ka] (wherein Et represents ethyl) Crystals.

[24] The crystal according to

[23] , wherein the crystal of compound (a3-1-A) is a type I crystal of compound (a3-1-A).

[25] The crystal according to

[23] , wherein the crystal of compound (a3-1-A) is a type II crystal of compound (a3-1-A). Effect of the Invention

[0014] The production method of the present invention can produce the compound [IA)], which is a nitrogen-containing heteroarylcarboxamidoacetic acid useful as a medicine, in a short number of steps, and can be an industrially advantageous production method. [Brief description of the drawings]

[0015] [Figure 1] 1 is a drawing showing a powder X-ray diffraction pattern of the I-type crystal of the compound [I(A)] of the present invention. [Diagram 2] 1 is a drawing showing a powder X-ray diffraction pattern of the II-form crystal of the compound [I(A)] of the present invention. [Diagram 3] 3 is a diagram in which FIG. 2 is enlarged in the vertical direction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The definitions of each term used in this specification are as follows. The term "alkyl" refers to a straight or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, and various branched isomers thereof, and preferably refers to a straight or branched saturated hydrocarbon chain having from 1 to 4 carbon atoms.

[0017] The term "alkylene" refers to a divalent straight or branched saturated hydrocarbon chain having from 1 to 8 carbon atoms, for example, methylene, 1,2-ethylene, 1,3-propylene, 1,1,2,2-tetramethyl-1,2-ethylene, and the various branched chain isomers thereof.

[0018] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 11 ring carbon atoms, such as a monocyclic aromatic hydrocarbon group such as phenyl; or a bicyclic aromatic hydrocarbon group having 9 to 11 ring carbon atoms, such as naphthyl, tetrahydronaphthyl, indenyl, indanyl, or azulenyl.

[0019] The number of substituents in the term "optionally substituted aryl" and the term "optionally substituted phenyl" may be one or more (e.g., 1 to 3), and the substituents may be the same or different. Such substituents may include, for example, alkyl, cycloalkyl, alkoxy, cyano, halogen, hydroxy, and nitro, and preferably halogen (e.g., chlorine atom, bromine atom, and iodine atom).

[0020] The number of the substituents of the term "optionally substituted alkyl" may be one or more (e.g., 1 to 7), and the substituents may be the same or different. Examples of such substituents include cycloalkyl, alkoxy, halogen, oxo, and hydroxy.

[0021] The term "cycloalkyl" refers to a cyclic saturated hydrocarbon ring having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When referred to in this specification, cycloalkyl also includes fused rings and spiro rings.

[0022] The term "alkoxy" refers to an alkyl group as defined above linked to an oxygen atom and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.

[0023] The term "alkanoyl" refers to an alkyl group as defined above linked to a carbonyl group and includes, for example, acetyl, propanoyl, butyryl, pentanoyl, hexanoyl, and heptanoyl. The term "alkanoic acid" refers to a compound in which an alkyl group as described above is bonded to a carboxyl group, such as acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, and the like.

[0024] The term "isoquinoline optionally substituted with phenyloxy" refers to isoquinoline optionally substituted with one or more (e.g., 1 to 3) phenyloxy, such as 7-phenyloxy-isoquinoline. Here, phenyloxy includes phenyloxy which may be substituted, and the substituent may be one or more (e.g., 1 to 3), and the substituents may be the same or different. Examples of such substituents include alkyl, cycloalkyl, alkoxy, and the like.

[0025] The term "halogen" includes any one or more of fluorine, chlorine, bromine, and iodine atoms.

[0026] The term "ligand" includes, but is not limited to, phosphine ligands, as well as nitrogen-containing heterocyclic carbene ligands and the corresponding azolium salt ligand precursors.

[0027] The term "phosphine ligand" includes, but is not limited to, monodentate and bidentate phosphine ligands. The term "monodentate phosphine ligand" refers to a compound having one phosphine atom in the molecule, such as tricyclohexylphosphine, triphenylphosphine, 2-di-tert-butylphosphine-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (RockPhos), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (Me4tB uXPhos), 2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (tBuBrettPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (tBuXPhos), and 2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl (AdBrettPhos).

[0028] The term "bidentate phosphine ligand" refers to a compound having two phosphine atoms in the molecule, such as 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), 1,5-bis(diphenylphosphino)pentane (dpppe), 2,4-bis(diphenylphosphino)pentane (BDPP), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (rac-BINAP, (S)-BINAP, (R)-BINAP), 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (tolBINAP) (rac-tolBINAP, (S)-tolBINAP, (R)-tolBINAP), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos).

[0029] The term "nitrogen-containing heterocyclic carbene ligand" refers to a ligand having a nitrogen-containing monocyclic five-membered ring skeleton containing 2 to 4 nitrogen atoms in the ring, in which a carbon atom carbene constituting the five-membered ring is sandwiched between two nitrogen atoms in the ring, and examples of such ligands include 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, 1,3-bis(2,4,5-trimethylphenyl)imidazol-2-ylidene, and 1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2-imidazolylidene. The term "azolium salt ligand precursor" includes imidazolium salt ligand precursors, thiazolium salt ligand precursors, and triazolium salt ligand precursors, with imidazolium salt ligand precursors being preferred.

[0030] The term "resin residue" refers to resins used in solid phase peptide synthesis, including, for example, trityl resins (e.g., 2-chlorotrityl resin), Merrifield resins (e.g., 4-chloromethylpolystyrene resin), Wang resins (e.g., 4-benzyloxybenzyl alcohol resin), hydroxymethylpolystyrene resins (e.g., 4-hydroxymethylpolystyrene resin), aminomethylpolystyrene resins (e.g., 4-aminomethylpolystyrene resin), and thiol resins.

[0031] The process for producing compound (I) of the present invention will be specifically described below. Reaction Scheme (II) [ka] Reaction Scheme (III) [ka] Reaction Scheme (II-II) [ka]

[0032] Reaction Scheme (I-II) [ka] Reaction Scheme (I-II-I) [ka] Reaction Scheme (I-II-II) [ka]

[0033] Reaction Scheme (I-III) [ka]

[0034] Reaction Scheme (I-III-I) [ka]

[0035] Reaction Scheme (I-IV) [ka]

[0036] Reaction Scheme (IV) [ka] Reaction Scheme (IVI) [ka]

[0037] Reaction Scheme (I-VI) [ka]

[0038] Reaction Scheme (I-VII) [ka] (In the above reaction schemes (II) to (I-VII), R 1 represents an optionally substituted alkyl, a hydrogen atom or a resin residue, preferably an optionally substituted alkyl, more preferably an alkyl. R 1-1 represents an optionally substituted alkyl or a resin residue, preferably an optionally substituted alkyl, and more preferably an alkyl. R 2 represents a hydrogen atom or an optionally substituted methyl. R a3 represents phenyl optionally substituted with halogen; R a4 represents a hydrogen atom or R a3 and R a4are bonded to each other together with the adjacent pyridine to form an isoquinoline which may be substituted with phenyloxy. Z 1 represents a chlorine atom, a bromine atom or an iodine atom, and preferably represents a chlorine atom. Z a1 represents a chlorine atom, a bromine atom or an iodine atom, and preferably represents a chlorine atom or an iodine atom. Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) and preferably represents hydroxy. Z a2―1 is a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) Represents. Z a3 represents a bromine atom, an iodine atom or trifluoromethanesulfoxy, and preferably represents a bromine atom. Z a4 represents a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfoxy, and preferably represents a bromine atom. X a1 and X a2 each independently represents a hydrogen atom or an alkyl group, or both are bonded to each other to form an alkylene group, and preferably each represents a hydrogen atom. Here, R 2 The substituent in the optionally substituted methyl represented by the formula (I) is not particularly limited as long as it can be converted to an unsubstituted methyl. For example, the optionally substituted methyl may be methyl that is optionally substituted with dialkylamino or alkanoyloxy. R a3The phenyl which may be substituted with halogen, represented by the following formula (I), is preferably 3-chlorophenyl. R 2 , R a3 and R a4 As the compound, preferably, (i) R 2 is a hydrogen atom, and R a3 is 3-chlorophenyl, and R a4 is a hydrogen atom, or (ii)R 2 is methyl, and R a3 and R a4 are bonded together with the adjacent pyridine to form 7-phenyloxy-isoquinoline, More preferably, (i) R 2 is a hydrogen atom, R a3 is 3-chlorophenyl, and R a4 is a hydrogen atom.

[0039] P 1The protecting group for hydroxy represented by the formula (I) is not particularly limited, but preferably includes methyl optionally substituted with phenyl optionally substituted with 1 or 2 methoxy groups (e.g., methyl, benzyl, p-methoxybenzyl), alkoxymethyl optionally substituted with trialkylsilyl (e.g., methoxymethyl, triethylsilylethoxymethyl), alkanoyl (e.g., acetyl, pivaloyl), sulfonyl substituted with methyl optionally substituted or phenyl optionally substituted (e.g., methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl), alkyloxycarbonyl optionally substituted (e.g., t-butyloxycarbonyl, benzyloxycarbonyl), silyl substituted with three groups selected from alkyl and phenyl optionally substituted (e.g., triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl), and aminocarbonyl substituted with 1 or 2 substituents selected from alkyl optionally substituted and phenyl optionally substituted (e.g., dimethylaminocarbonyl, methylphenylaminocarbonyl). More preferred are methyl substituted with phenyl which may be substituted with 1 or 2 methoxy groups (e.g., benzyl, p-methoxybenzyl), alkanoyl (e.g., pivaloyl), and sulfonyl substituted with methyl which may be substituted or phenyl which may be substituted (e.g., methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl).

[0040] (Step a1, step a1-a, step a1-1-a, step a1-2-a, step a1-3-a and step a1-4-a) Compound (a1), compound (a1-a), compound (a1-1-a), compound (a1-2-a), compound (a1-4-a) or compound (a1-5-a) (hereinafter also referred to as compound (a1), etc.), compound (2) or compound (2-1) (hereinafter also referred to as compound (2)), or a salt thereof, and a carbon monoxide molecule are reacted in a solvent in the presence of a palladium catalyst (herein referred to as palladium catalyst (1)) and a base, in the presence or absence of a ligand, to produce compound (a3), compound (a3-a), compound (a3-1-a) or compound (a3-2-a) (hereinafter also referred to as compound (a3), etc.). R 1 When compound (2) or a salt thereof in which is a resin residue is used in the present reaction, the resin residue represents a resin used in solid-phase peptide synthesis, such as trityl resin (e.g., 2-chlorotrityl resin), Merrifield resin (e.g., 4-chloromethyl polystyrene resin), Wang resin (e.g., 4-benzyloxybenzyl alcohol resin), hydroxymethyl polystyrene resin (e.g., 4-hydroxymethyl polystyrene resin), aminomethyl polystyrene resin (e.g., 4-aminomethyl polystyrene resin), and thiol resin. The particle size and loading capacity (mol number of reaction sites per 1 g of resin: mmol / g) of the resin are not particularly limited as long as they do not adversely affect the reaction. In general, the particle size is preferably 35 to 500 μm, and the loading capacity is preferably 0.1 to 4 mmol / g.

[0041] In the compound (2) or its salt, the salt of the compound (2) or the like is not particularly limited, but examples thereof include hydrochloride, sulfate, p-toluenesulfonate, sodium salt, and calcium salt, and is preferably hydrochloride. As the compound (2) or its salt, the salt of the compound (2) or the like is preferred. The equivalent of the compound (2) or its salt used in this reaction varies depending on the reagent or reaction conditions used, but is usually about 1 molar equivalent relative to the compound (a1) or the like, for example, 0.5 to 2.0 molar equivalents, preferably 0.8 to 1.25 molar equivalents, and more preferably 1 to 1.1 molar equivalents.

[0042] An example of the carbon monoxide molecule is carbon monoxide molecular gas. The carbon monoxide molecular gas may be used alone or in a mixture with an inert gas, such as nitrogen gas or argon gas. When carbon monoxide molecular gas is used in this reaction, the pressure of the carbon monoxide molecular gas during the reaction varies depending on the reagents used or the reaction conditions, but is usually 0.01 to 1 MPa, preferably 0.02 to 0.8 MPa, and more preferably 0.05 to 0.6 MPa. Here, in the present specification, the pressure during the reaction of the carbon monoxide molecular gas means a partial pressure in a reaction system in which the carbon monoxide molecular gas is mixed with an inert gas and / or in a reaction system in which the reaction solvent is in a gaseous state under high temperature conditions.

[0043] The palladium catalyst (1) can be used in this reaction in the presence or absence of a ligand. The palladium catalyst (1) is not particularly limited as long as it is a general palladium catalyst, and examples thereof include tetrakis(triphenylphosphine)palladium(0), palladium acetate(II), bis(acetonitrile)dichloropalladium(II), dichlorobis(triphenylphosphine)palladium(II), dichloro[1,3-bis(diphenylphosphino)propane]palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloro(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)palladium(II), (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xantphos Pd G3), tris(dibenzylideneacetone)dipalladium(0), and palladium chloride(II). The ligand is not particularly limited as long as it is a common ligand, and examples thereof include bidentate phosphine ligands and monodentate phosphine ligands.

[0044] When the palladium catalyst (1) is used in the present reaction in the presence or absence of a ligand, it is preferable to use a palladium catalyst having one or more bidentate phosphine ligands selected from dichloro[1,3-bis(diphenylphosphino)propane]palladium(II) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the absence of a ligand, or a palladium catalyst having one or more bidentate phosphine ligands selected from palladium acetate(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride. A palladium catalyst having no phosphine ligand selected from palladium(II) acetate, bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride can be used in the presence of one or more bidentate phosphine ligands; more preferably, a palladium catalyst having no phosphine ligand selected from palladium(II) acetate, bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride can be used in the presence of one or more bidentate phosphine ligands; even more preferably, palladium(II) acetate can be used in the presence of one or more bidentate phosphine ligands.

[0045] Bidentate phosphine ligands include 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), 1,5-bis(diphenylphosphino)pentane (dpppe), 2,4-bis(diphenylphosphino)pentane (BDPP), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (rac-BINAP, (S)-BINAP, (R)-BINAP), 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (tolBINAP) (rac-tolBINAP, (S)- tolBINAP, (R)- tolBINAP), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), preferably dppp, dppb, dppf, more preferably dppp, and even more preferably dppb. The equivalent of the palladium catalyst (1) used in this reaction varies depending on the reagent or reaction conditions used, but is usually a catalytic amount of compound (a1) or the like, and is, for example, 0.001 to 0.1 molar equivalent relative to compound (a1) or the like, preferably 0.01 to 0.05 molar equivalent. When reacting in the presence of a ligand, the equivalent of the ligand varies depending on the reagent or reaction conditions used, but is usually 1 to 5 molar equivalent relative to the palladium catalyst (1), preferably 1.5 to 3 molar equivalent.

[0046] The base is not particularly limited as long as it is a common base, and examples thereof include trialkylamines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine), cyclic tertiary amines (e.g., 4-methylmorpholine, 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP)), dialkylamines (e.g., diisopropylamine, dibutylamine, tert-butylethylamine), alkali metal alkanoates (e.g., alkali metal acetates (sodium acetate, potassium acetate, cesium acetate, etc.), sodium propionate, sodium butyrate, sodium valerate), alkali metal phenylcarboxylates which may be substituted (e.g., sodium salicylate, disodium terephthalate), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate), and alkali metal phosphates (e.g., trisodium phosphate, tripotassium phosphate). Preferred are trialkylamines, alkali metal alkanoates and alkali metal phenylcarboxylates which may be substituted, more preferably trialkylamines. As trialkylamines, triethylamine, tripropylamine and tributylamine are preferred, and tripropylamine is more preferred. The equivalent of the base used in this reaction varies depending on the reagent or reaction conditions used, but is usually 1 to 10 molar equivalents relative to compound (a1) and the like, and preferably 2 to 5 molar equivalents.

[0047] The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include nitriles (e.g., acetonitrile, propionitrile, benzonitrile), esters (e.g., ethyl acetate, isopropyl acetate), aromatic hydrocarbons (e.g., toluene, xylene), aprotic polar solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), sulfoxides (e.g., dimethyl sulfoxide), and ethers (e.g., 1,2-dimethoxyethane, 1,2-diethoxyethane, 1,3-dimethoxypropane, diglyme, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diphenyl ether). Preferred are nitriles and ethers, and more preferred are nitriles. When nitriles are used, the production ratio of the target compound (a3) ​​and the like to the by-products increases. Acetonitrile is preferred as the nitrile. Tetrahydrofuran is preferred as the ether.

[0048] The reaction temperature of this reaction varies depending on the reagents or reaction conditions used, but is usually under heating. The reaction temperature is preferably 20°C to 150°C, more preferably 40°C to 130°C, and further preferably 105°C to 115°C. The reaction time of this reaction varies depending on the reagents or reaction conditions used, but is usually until compound (a1) etc. or compound (2) etc. disappears from the reaction mixture. The reaction time is preferably 1 hour to 72 hours, more preferably 1 hour to 48 hours, and even more preferably 18 hours to 48 hours.

[0049] (Step a2, Step a2-a and Step a2-1-a) Compound (a3-1), compound (a3-1-a) or compound (a3-2-a) (hereinafter also referred to as compound (a3-1), etc.) can be subjected to a deprotection reaction in accordance with the method described in Patent Document 1 or 2 to produce compound (aI) or compound [I(A)] (hereinafter also referred to as compound (aI), etc.). R 1-1 The deprotection reaction of the compound R1-1 A deprotection reaction can be carried out using a conventional method according to the type of base. For example, compound (aI) can be produced by reacting compound (a3-1) in a solvent in the presence of a base. The base is not particularly limited, but examples include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal acetates (e.g., sodium acetate, potassium acetate, cesium acetate), and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate). The base is preferably an alkali metal hydroxide or an alkali metal carbonate, and more preferably an alkali metal hydroxide. The alkali metal hydroxide is preferably sodium hydroxide. The alkali metal carbonate is preferably potassium carbonate. R 1-1 When is tert-butyl, compound (aI) etc. can be produced by reacting compound (a3-1) etc. in a solvent in the presence of an acid. The acid is not particularly limited, but examples thereof include sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid), carboxylic acids (e.g., trifluoroacetic acid), and hydrogen chloride. P 1 The deprotection reaction of the compound P 1 Deprotection can be carried out by a conventional method depending on the type of compound. Examples of the deprotection method include acid treatment (e.g., hydrochloric acid treatment), base treatment (e.g., sodium hydroxide aqueous solution treatment), and hydrogenation (e.g., a method using a palladium carbon catalyst in a hydrogen molecule atmosphere).

[0050] (Step a3, Step a3-1 and Step a3-2) Compound (a1-1-a) or compound (a1-3-a) (hereinafter also referred to as compound (a1-1-a), etc.) can be produced by reacting compound (a4), compound (a4-1) or compound (a4-2) (hereinafter also referred to as compound (a4), etc.) with compound (a5) or an equivalent of compound (a5) in the presence of a palladium catalyst (herein referred to as palladium catalyst (2)), in the presence or absence of a ligand, and in the presence of a base, in a solvent. The amount of compound (a5) used in this reaction varies depending on the reagent or reaction conditions used. In general, the amount is preferably 1 molar equivalent to a slight excess amount relative to compound (a4) etc., for example, 1 to 1.5 molar equivalents, and preferably 1 to 1.1 molar equivalents.

[0051] An equivalent of the compound (a5) used in this reaction is, for example, a compound (a5-a) of the following formula: [ka] The amount of the compound (a5-a) used in this reaction varies depending on the reagent or reaction conditions used, but is usually, for example, 0.3 to 0.5 molar equivalents, and preferably 0.3 to 0.4 molar equivalents relative to the compound (a4).

[0052] Palladium catalyst (2) can be used in the reaction in the presence or absence of a ligand. The palladium catalyst (2) is not particularly limited as long as it is a general palladium catalyst, and examples thereof include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), palladium acetate(II), bis(acetonitrile)dichloropalladium(II), dichlorobis(triphenylphosphine)palladium(II), dichloro[1,3-bis(diphenylphosphino)propane]palladium(II), tris(dibenzylideneacetone)dipalladium(0), palladium chloride(II), nitrogen-containing heterocyclic carbene-palladium complex catalyst (NHC-Pd complex catalyst), and Buchwald catalyst precursor. Examples of the NHC-Pd complex catalyst include allylchloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II)(CX21), allylchloro[1,3-bis(2,4,5-trimethylphenyl)imidazol-2-ylidene]palladium(II)(CX22), chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II)(CX31), chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolylidene]palladium(II)(CX32), and chlorophenylallyl{1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2-imidazolylidene}palladium(II)(CX33), and more preferably CX33.As the Buchwald catalyst precursor, third generation Buchwald catalyst precursors (Buchwald 3rd Generation Palladacycles) are preferred, and examples thereof include (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate (XPhos Pd G3), (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate (SPhos Pd G3), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate (RuPhos Pd G3).

[0053] The ligand is not particularly limited as long as it is a common ligand, and examples thereof include phosphine ligands, and nitrogen-containing heterocyclic carbene ligands or corresponding azolium salt ligand precursors. Specific examples include 1,1'-bis(diphenylphosphino)ferrocene (dppf), triphenylphosphine, 1,3-bis(diphenylphosphino)propane (dppp), tri-tert-butylphosphine, 2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (RockPhos), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (Me4tBuXPhos), 2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (tBuBrettPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (tBuBrettPhos), and nyl (tBuXPhos), 2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl (AdBrettPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (SPhos), 2 -dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, 1,3-bis(2,4,5-trimethylphenyl)imidazol-2-ylidene, and 1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2-imidazolylidene.

[0054] When the palladium catalyst (2) is used in the present reaction in the presence or absence of a ligand, preferably, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) is used in the absence of a ligand, or a palladium catalyst selected from palladium acetate(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) and palladium chloride(II) is used in the presence of 1,1'-bis(diphenylphosphino)ferrocene (dppf), more preferably, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) is used in the absence of a ligand.

[0055] The equivalent of the palladium catalyst (2) used in this reaction varies depending on the reagents or reaction conditions used, but is usually a catalytic amount of compound (a4) etc., and is, for example, 0.001 to 0.1 molar equivalents, preferably 0.002 to 0.05 molar equivalents relative to compound (a4) etc. When the reaction is carried out in the presence of a ligand, the equivalent of the ligand varies depending on the reagents or reaction conditions used, but is usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, or 2 to 3 molar equivalents relative to the palladium catalyst (2).

[0056] The base is not particularly limited as long as it is a general base, and examples thereof include trialkylamines (e.g., triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine), alkali metal acetates (e.g., sodium acetate, potassium acetate, cesium acetate), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate), and alkali metal phosphates (e.g., trisodium phosphate, tripotassium phosphate). Preferred are alkali metal carbonates. Potassium carbonate is preferred as the alkali metal carbonate. The equivalent of the base used in this reaction varies depending on the reagent or reaction conditions used, but is usually 1 to 10 molar equivalents relative to compound (a4) and the like, and preferably 2 to 5 molar equivalents.

[0057] The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include aromatic hydrocarbons (e.g., toluene, xylene), esters (e.g., ethyl acetate, butyl acetate, isopropyl acetate), aprotic polar solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone), sulfoxides (e.g., dimethyl sulfoxide), alkyl alcohols (e.g., methanol, ethanol, isopropyl alcohol, t-butyl alcohol), ethers (e.g., 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane), ketones (e.g., methyl ethyl ketone), nitriles (e.g., acetonitrile, benzonitrile), and water, or a mixed solvent of two or more of these. Preferably, the mixed solvent is composed of water and other solvents (one or more solvents selected from esters, aprotic polar solvents, sulfoxides, alkyl alcohols, ethers, ketones, and nitriles), preferably, the mixed solvent is composed of water and ethers (preferably, tetrahydrofuran), or the mixed solvent is composed of water and aprotic polar solvent (preferably, N,N-dimethylformamide), more preferably, the mixed solvent is composed of water and ethers (preferably, tetrahydrofuran). When the reaction is carried out in a mixed solvent composed of water and other solvents, the mixing ratio of each solvent (ratio of water:other solvent) is usually 10:1 to 1:30. When the reaction is carried out in a mixed solvent of water and ethers, the ratio of water:ethers is preferably 2:1 to 1:10, more preferably 1:1 to 1:4. When this reaction is carried out in a mixed solvent of water and an aprotic polar solvent, the ratio of water: aprotic polar solvent is preferably 1:1 to 1:30, and more preferably 1:4 to 1:20.

[0058] The reaction temperature of this reaction varies depending on the reagents or reaction conditions used, but is usually under heating. The reaction temperature is preferably 20°C to 120°C, more preferably 50°C to 120°C, even more preferably 50°C to 90°C, and even more preferably 60°C to 90°C (e.g., 70°C). The reaction time of this reaction varies depending on the reagents or reaction conditions used, but is usually until compound (a4) etc. disappears from the reaction mixture. The reaction time is preferably 1 hour to 72 hours, more preferably 10 hours to 20 hours.

[0059] (Step a4) Compound (a7) can be produced by reacting compound (a6) and compound (a5) in the presence of a palladium catalyst (herein referred to as palladium catalyst (2)), in the presence or absence of a ligand, and in the presence of a base in a solvent. This reaction can be carried out under reaction conditions similar to those of the method in step a3.

[0060] (Step a5) Compound (a1-2-a) can be produced by reacting compound (a7) in the presence of a halogenating agent, in the presence of a base, and in the presence or absence of an alkali metal halide in a solvent.

[0061] The halogenating agent is Z in the compound (a1-2-a) to be produced. a1 A halogenating agent corresponding to Z can be used. a1 When producing a compound (a1-2-a) (compound (a1-1-a)) in which Z is a chlorine atom, examples of the halogenating agent include sodium hypochlorite, N-chlorosuccinimide, trichloroisocyanuric acid, and 1,3-dichloro-5,5-dimethylhydantoin. Sodium hypochlorite and N-chlorosuccinimide are preferred, and sodium hypochlorite is more preferred. Z a1 When producing the compound (a1-2-a) in which Z is a bromine atom, examples of the halogenating agent include N-bromosuccinimide. a1When compound (a1-2-a) in which is an iodine atom is produced, examples of the halogenating agent include iodine molecules and N-iodosuccinimide. Iodine molecules are preferred. When iodine molecules are used, iodination proceeds with high regioselectivity. The equivalent of the halogenating agent used in this reaction varies depending on the reagents or reaction conditions used, but is usually preferably 1 molar equivalent to a slight excess amount relative to compound (a7), for example, 1 to 1.5 molar equivalents, and preferably 1 to 1.2 molar equivalents. Compound (a1-2-a) produced by this reaction includes compounds in which Z a1 In the compound (a1-2-a), in which is an iodine atom, is preferred.

[0062] The base is not particularly limited as long as it is a general base, and examples thereof include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide) and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate). Preferred are alkali metal hydroxides. As the alkali metal hydroxide, sodium hydroxide is preferred. The equivalent of the base used in this reaction varies depending on the reagents or reaction conditions used, but is usually preferably 1 molar equivalent to an excess amount relative to compound (a7), for example, 1 to 5 molar equivalents, and preferably 1.5 to 3 molar equivalents.

[0063] The alkali metal halide is Z in the compound (a1-2-a) to be produced. a1 The corresponding alkali metal halides can be used. a1 In the case of producing a compound (a1-2-a) in which is an iodine atom, examples of the alkali metal halide include potassium iodide, sodium iodide, and cesium iodide, and potassium iodide is preferred. This reaction is preferably carried out in the presence of an alkali metal halide. The equivalent of the alkali metal halide used in this reaction varies depending on the reagent or reaction conditions used, but is usually preferably a catalytic amount to a slight excess amount relative to the compound (a7), for example, 0.01 to 2 molar equivalents, and preferably 0.05 to 0.3 molar equivalents.

[0064] The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include water, ethers (e.g., 1,2-dimethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran), and mixed solvents thereof. Water is preferred.

[0065] The reaction temperature for this reaction varies depending on the reagents or reaction conditions used, but is preferably 0°C to 50°C, more preferably 10°C to 40°C, and further preferably 20°C to 30°C. The reaction time of this reaction varies depending on the reagent or reaction conditions used, but is usually until compound (a7) disappears from the reaction mixture. The reaction time is preferably 1 hour to 48 hours, more preferably 5 hours to 18 hours.

[0066] (Step a6) Z of compound (a1-3-a) a2-1 Compound (a1-4-a) can be produced by deprotecting the compound (a1-4-a). This reaction is carried out by P 1 The deprotection can be carried out under reaction conditions similar to those of the deprotection method of 1.

[0067] In this reaction scheme (I) {reaction schemes (II) to (I-VII)}, the compound (a1) etc., the compound (2) etc., the compound (a3-1) etc., the compound (a4), the compound (a5), the compound (a6) and the compound (a7) used can be produced by known methods or combinations thereof, as appropriate. Compound (a1), etc., compound (2), etc., compound (a3-1), etc., compound (a4), compound (a5) and compound (a7) produced in this reaction scheme (I) can be converted to compound (aI) {compound (aI), compound [I(A)]} as appropriate by a known method or a combination thereof. R 2 The compound in which R is methyl which may be substituted with dialkylamino or alkanoyloxy can be prepared by the method described in Patent Document 5. 2can be converted to a compound in which

[0068] Reaction Scheme (II-I) [ka] (In reaction scheme (II-I), Z 1 and Z b2 each independently represents a chlorine atom, a bromine atom, or an iodine atom. R 1 represents an optionally substituted alkyl, a hydrogen atom or a resin residue, preferably an optionally substituted alkyl, more preferably an alkyl. R 1-1 represents an optionally substituted alkyl or a resin residue, preferably an optionally substituted alkyl, and more preferably an alkyl. R 2 represents a hydrogen atom or an optionally substituted methyl. R 3 represents phenyl optionally substituted with halogen, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R 4 represents a hydrogen atom or R 3 and R 4 are bonded to each other together with the adjacent pyridine to form an isoquinoline which may be substituted with phenyloxy. R b5 represents an optionally substituted aryl or an optionally substituted alkyl, preferably an optionally substituted aryl, more preferably an optionally substituted phenyl, and even more preferably phenyl. Here, R 2 The optionally substituted methyl represented by the formula (I) is not particularly limited as long as it is a substituent that can be converted to an unsubstituted methyl. For example, the optionally substituted methyl may be methyl that may be substituted with dialkylamino or alkanoyloxy. R 3 The phenyl which may be substituted with halogen, represented by the following formula: is preferably 3-chlorophenyl. R 3 When Z is a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfoxy, 1 , Z b2 , and R 3 each represents a chlorine atom or each represents a bromine atom, and more preferably, Z 1 , Z b2 , and R 3 Both represent chlorine atoms. R 2 , R 3 and R 4 As the compound, preferably, (i) R 2 is a hydrogen atom, R 3 is 3-chlorophenyl, and R 4 is a hydrogen atom, or (ii)R 2 is methyl, and R 3 and R 4 are bonded together with the adjacent pyridine to form 7-phenyloxy-isoquinoline.

[0069] Reaction Scheme (II-II) [ka]

[0070] (In the reaction scheme (II-II), Z 1 and Z b2 each independently represents a chlorine atom, a bromine atom, or an iodine atom; R b3 represents a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfoxy, and preferably Z 1 , Z b2 , and R b3 each represents a chlorine atom or each represents a bromine atom, and more preferably, Z 1 , Z b2 , and R b3 Both represent chlorine atoms. R 1represents an optionally substituted alkyl, a hydrogen atom or a resin residue, preferably an optionally substituted alkyl, more preferably an alkyl. R 1-1 represents an optionally substituted alkyl or a resin residue, preferably an optionally substituted alkyl, and more preferably an alkyl. R b5 represents an optionally substituted aryl or an optionally substituted alkyl, preferably an optionally substituted aryl, more preferably an optionally substituted phenyl, and even more preferably phenyl. X b1 and X b2 each independently represents a hydrogen atom or an alkyl group, or both are bonded to each other to form an alkylene group, and preferably each represents a hydrogen atom.

[0071] Reaction Scheme (II-III) [ka]

[0072] (In the reaction scheme (II-III), Z 1 and Z b2 each independently represents a chlorine atom, a bromine atom, or an iodine atom, and preferably, Z 1 and Z b2 each represents a chlorine atom or each represents a bromine atom, and more preferably, Z 1 and Z b2 Both represent chlorine atoms. R 1-1 represents an optionally substituted alkyl or a resin residue, preferably an optionally substituted alkyl, and more preferably an alkyl. R 2 represents a hydrogen atom or an optionally substituted methyl. R b3-3 represents 3-chlorophenyl, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; Rb4-3 represents a hydrogen atom, or R b3-3 and R b4-3 represents a bond between the pyridine and the adjacent pyridine to form 7-phenyloxy-isoquinoline. R b5 represents an optionally substituted aryl or an optionally substituted alkyl, preferably an optionally substituted aryl, more preferably an optionally substituted phenyl, and even more preferably phenyl. Here, R 2 The optionally substituted methyl represented by the formula (I) is not particularly limited as long as it is a substituent that can be converted to an unsubstituted methyl. For example, the optionally substituted methyl may be methyl that may be substituted with dialkylamino or alkanoyloxy. R 2 , R b3-3 and R b4-3 As the compound, preferably, (i) R 2 is a hydrogen atom, R b3-3 is 3-chlorophenyl, and R b4-3 is a hydrogen atom, or (ii)R 2 is methyl, and R b3-3 and R b4-3 are bonded together with the adjacent pyridine to form 7-phenyloxy-isoquinoline.

[0073] (Step b1, Step b1-a and Step b1-b) Compound (b1), compound (b1-1-1) or compound (b1-2) (hereinafter also referred to as compound (b1), etc.), compound (2) or a salt thereof, and carbon monoxide molecules are reacted in a solvent in the presence of a palladium catalyst (herein referred to as palladium catalyst (b1)), in the presence or absence of a ligand, and in the presence of a base, to produce compound (b3), compound (b3-2-1) or compound (b3-4) (hereinafter also referred to as compound (b3), etc.). This reaction can be carried out under the same reaction conditions as in the method of step a1.

[0074] (Step b2, Step b2-a and Step b2-b) Compound (b3) etc. and compound (b4) can be reacted in a solvent in the presence of a palladium catalyst (herein referred to as palladium catalyst (b2)), in the presence or absence of a ligand, and in the presence of a base, to produce compound (b3-1), compound (b3-2-2) or compound (b3-5) (hereinafter also referred to as compound (b3-1), etc.). The amount of compound (b4) used in this reaction varies depending on the reagent or reaction conditions used. In general, the amount is preferably 1 molar equivalent to an excess amount relative to compound (b3) etc., for example, 1 to 5 molar equivalents, and preferably 1 to 1.5 molar equivalents.

[0075] The palladium catalyst (b2) can be used in the reaction in the presence or absence of a ligand. The palladium catalyst (b2) is not particularly limited as long as it is a general palladium catalyst. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium(0), dichlorobis(tricyclohexylphosphine)palladium(II), palladium acetate(II), bis(acetonitrile)dichloropalladium(II), dichlorobis(triphenylphosphine)palladium(II), dichloro[1,3-bis(diphenylphosphino)propane]palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), palladium chloride(II), [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate (RockPhos Pd G3), (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (Me4tBuXPhos Pd G3), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)]palladium(II) methanesulfonate (tBuBrettPhos Pd G3), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (AdBrettPhos Pd G3). The ligand is not particularly limited as long as it is a common ligand, and examples thereof include monodentate phosphine ligands.

[0076] When the palladium catalyst (b2) is used in the present reaction in the presence or absence of a ligand, it is preferably tetrakis(triphenylphosphine)palladium(0), dichlorobis(tricyclohexylphosphine)palladium(II), [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate (RockPhos Pd G3), (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (Me4tBuXPhos Pd G3), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)]palladium(II) methanesulfonate (tBuBrettPhos Pd G3), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (AdBrettPhos Pd G3) in the absence of a ligand, or a palladium catalyst having no monodentate phosphine ligand selected from palladium(II) acetate, bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride in the presence of one or more monodentate phosphine ligands, more preferably palladium(II) acetate, bis(acetonitrile)dichloropalladium(II), [1,Palladium catalysts having no monodentate phosphine ligands selected from 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) and palladium(II) chloride can be used in the presence of one or more monodentate phosphine ligands, and more preferably, palladium(II) acetate can be used in the presence of one or more monodentate phosphine ligands.

[0077] Monodentate phosphine ligands include tricyclohexylphosphine, triphenylphosphine, 2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (RockPhos), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (Me4tBuXPhos), 2-di-tert-butylphosphino-3,6-di Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl (tBuBrettPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (tBuXPhos), 2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl (AdBrettPhos) are mentioned, and tricyclohexylphosphine and RockPhos are preferred. In terms of the cost of the ligand, tricyclohexylphosphine is inexpensive and is preferred.

[0078] The equivalent of the palladium catalyst (b2) used in this reaction varies depending on the reagents or reaction conditions used, but is usually a catalytic amount of the compound (b3) etc., and is, for example, 0.001 to 0.1 molar equivalents, preferably 0.01 to 0.05 molar equivalents relative to the compound (b3) etc. When the reaction is carried out in the presence of a ligand, the equivalent of the ligand varies depending on the reagents or reaction conditions used, but is usually 1 to 5 molar equivalents, preferably 2 to 3 molar equivalents relative to the palladium catalyst (b2).

[0079] The base is not particularly limited, but examples thereof include trialkylamines (e.g., triethylamine, N,N-diisopropylethylamine), sodium salts (e.g., sodium acetate, sodium carbonate, sodium bicarbonate, trisodium phosphate), potassium salts (potassium acetate, potassium carbonate, potassium bicarbonate, tripotassium phosphate), and cesium salts (cesium acetate, cesium carbonate, cesium bicarbonate). Potassium salts and cesium salts are preferred, with cesium salts being particularly preferred. As the potassium salt, tripotassium phosphate is preferred. As the cesium salt, cesium carbonate is preferred. The amount of the base used in this reaction varies depending on the reagent or reaction conditions used, but is usually 1 to 10 molar equivalents, and preferably 1.5 to 5 molar equivalents, relative to compound (b3) etc.

[0080] The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include nitriles (e.g., acetonitrile, benzonitrile), esters (e.g., ethyl acetate, isopropyl acetate), aromatic hydrocarbons (e.g., toluene, xylene), aprotic polar solvents (e.g., N,N-dimethylformamide, N-methylpyrrolidone), sulfoxides (e.g., dimethyl sulfoxide), and ethers (e.g., 1,2-dimethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran). Ethers are preferred. As the ether, 2-methyltetrahydrofuran is preferred.

[0081] The reaction temperature of this reaction varies depending on the reagents or reaction conditions used, but is usually under heating. The reaction temperature is preferably 60°C to 100°C, more preferably 70°C to 90°C. The reaction time of this reaction varies depending on the reagents or reaction conditions used, but is usually until compound (b3) etc. disappears from the reaction mixture. The reaction time is preferably 1 hour to 72 hours, more preferably 5 hours to 25 hours.

[0082] (Step b3, Step b3-a and Step b3-b) Compound (b3-1-1), compound (b3-3-a) or compound (b3-5) (hereinafter also referred to as compound (b3-1-1), etc.) can be subjected to a deprotection reaction in accordance with the method described in Patent Document 1 or 2 to produce compound (I), compound [I(A)] or compound (bI-1). This reaction can be carried out under the same reaction conditions as in the method of step a2.

[0083] (Step b4) Compound (b3-2-2) and compound (b6) or an equivalent of compound (b6) are reacted in a solvent in the presence of a trialkylamine, in the presence of a palladium catalyst (referred to here as palladium catalyst (b3)), in the presence or absence of a ligand, to produce compound (b3-2-a). The amount of compound (b6) used in this reaction varies depending on the reagent or reaction conditions used, but is usually preferably 1 molar equivalent to a slight excess amount relative to compound (b3-2-2), for example, 1 to 1.5 molar equivalents, and preferably 1 to 1.1 molar equivalents. An equivalent of the compound (b6) used in this reaction is, for example, a compound (b6-a) of the following formula: [ka] The amount of compound (b6-a) used in this reaction varies depending on the reagent or reaction conditions used, but is usually, for example, 0.3 to 0.5 molar equivalents, and preferably 0.3 to 0.4 molar equivalents relative to compound (b5-1-a).

[0084] The trialkylamine is not particularly limited, but examples thereof include triethylamine and N,N-diisopropylethylamine, and preferably N,N-diisopropylethylamine. The equivalent of the trialkylamine used in this reaction varies depending on the reagent or reaction conditions used, but is usually preferably 1 molar equivalent to an excess amount relative to compound (b3-2-2), for example, 1 to 10 molar equivalents, and preferably 2 to 5 molar equivalents.

[0085] Palladium catalyst (b3) can be used in the reaction in the presence or absence of a ligand. Palladium catalyst (b3) is not particularly limited as long as it is a general palladium catalyst, and examples thereof include nitrogen-containing heterocyclic carbene-palladium complex catalyst (NHC-Pd complex catalyst (b3-1)), palladium acetate (II), bis(acetonitrile)dichloropalladium (II), tris(dibenzylideneacetone)dipalladium (0) and palladium chloride (II). Ligands are not particularly limited as long as they are general ligands, and examples thereof include nitrogen-containing heterocyclic carbene ligands and corresponding azolium salt ligand precursors (e.g., imidazolium salt ligand precursors).

[0086] When the palladium catalyst (b3) is used in the present reaction in the presence or absence of a ligand, preferably, the NHC-Pd complex catalyst (b3-1) is used in the absence of a ligand, or a palladium catalyst having no nitrogen-containing heterocyclic carbene ligand selected from palladium acetate(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), and palladium chloride(II) can be used in the presence of one or more nitrogen-containing heterocyclic carbene ligands or corresponding azolium salt ligand precursors, and more preferably, the NHC-Pd complex catalyst (b3-1) can be used in the absence of a ligand.

[0087] Examples of the NHC-Pd complex catalyst (b3-1) include allylchloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II)(CX21), allylchloro[1,3-bis(2,4,5-trimethylphenyl)imidazol-2-ylidene]palladium(II)(CX22), chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II)(CX31), chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolylidene]palladium(II)(CX32), and chlorophenylallyl{1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2-imidazolylidene}palladium(II)(CX33), and more preferably CX33. Examples of the nitrogen-containing heterocyclic carbene ligand include 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, 1,3-bis(2,4,5-trimethylphenyl)imidazol-2-ylidene, and 1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2-imidazolylidene. The corresponding azolium salt ligand precursor is not particularly limited as long as it is an azolium salt ligand precursor that reacts with a base to generate the desired nitrogen-containing heterocyclic carbene ligand.

[0088] The equivalent of the palladium catalyst (b3) used in this reaction varies depending on the reagent or reaction conditions used, but is usually a catalytic amount of the compound (b3-2-2), for example, 0.001 to 0.1 molar equivalent relative to the compound (b3-2-2), preferably 0.01 to 0.05 molar equivalent. When the reaction is carried out in the presence of a ligand, the equivalent of the ligand varies depending on the reagent or reaction conditions used, but is usually 1 to 5 molar equivalent relative to the palladium catalyst (b3), preferably 2 to 3 molar equivalent.

[0089] The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include aromatic hydrocarbons (e.g., toluene, xylene), esters (e.g., ethyl acetate, butyl acetate, isopropyl acetate), aprotic polar solvents (e.g., N,N-dimethylformamide, N-methylpyrrolidone), sulfoxides (e.g., dimethyl sulfoxide), alkyl alcohols (e.g., methanol, ethanol, isopropyl alcohol, t-butyl alcohol), ethers (e.g., 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane), nitriles (e.g., acetonitrile, benzonitrile), and water, or a mixed solvent of two or more of these. Preferably, the mixed solvent is one or more solvents selected from water and other solvents (aromatic hydrocarbons, esters, aprotic polar solvents, sulfoxides, alkyl alcohols, ethers, and nitriles), preferably, a mixed solvent of water and aromatic hydrocarbons (preferably toluene) or a mixed solvent of water and alkyl alcohol (preferably methanol), more preferably, a mixed solvent of water and aromatic hydrocarbons (preferably toluene). When the reaction is carried out in a mixed solvent of water and other solvents, the mixing ratio of each solvent is usually 10:1 to 1:10, preferably 4:1 to 1:4.

[0090] The reaction temperature of this reaction varies depending on the reagents or reaction conditions used, but is usually under heating. The reaction temperature is preferably 50°C to 120°C, more preferably 70°C to 90°C. The reaction time of this reaction varies depending on the reagent or reaction conditions used, but is usually until compound (b3-2-2) disappears from the reaction mixture. The reaction time is preferably 1 hour to 72 hours, more preferably 10 hours to 20 hours.

[0091] In this reaction scheme (II) {reaction schemes (II-I) to (II-II)}, the compound (b1) etc., the compound (2) or a salt thereof, the compound (b3) etc., the compound (b3-1-1) etc., and the compound (b3-2-2) used can be produced appropriately by known methods or combinations thereof. Compound (b3), compound (b3-1), and compound (b3-2-a) produced in this reaction scheme (II) can be converted into compound (I), compound [I(A)], or compound (bI-1) by a known method or a combination thereof, as appropriate. R 2 The compound in which R is methyl which may be substituted with dialkylamino or alkanoyloxy can be prepared by the method described in Patent Document 5. 2 can be converted to a compound in which

[0092] Reaction Scheme (III) [ka]

[0093] (In the formula, Z c1 , Z c2 , and Z c3 each independently represents a chlorine atom or a bromine atom, and preferably Z c1 , Z c2 , and Z c3 each represents a chlorine atom or each represents a bromine atom, and more preferably, Z c1 , Z c2 , and Z c3 Both represent chlorine atoms. R c1 represents alkyl. R c2 represents an optionally substituted aryl or an optionally substituted alkyl, preferably an optionally substituted aryl, more preferably an optionally substituted phenyl, and even more preferably phenyl. X c1 and X c2each independently represents a hydrogen atom or an alkyl group, or both are bonded to each other to form an alkylene group, and preferably each represents a hydrogen atom.

[0094] (Step c1) Compound (c3) can be produced by reacting compound (c1), compound (c2) and a carbon monoxide molecule in the presence of a palladium catalyst (herein referred to as palladium catalyst (c1)), in the presence or absence of a ligand, and in the presence of a base, in a solvent. This reaction can be carried out under reaction conditions similar to those in the method of step a1 or step b1.

[0095] (Step c2) Compound (c5) can be produced by reacting compound (c3) and compound (c4) in the presence of a palladium catalyst (referred to here as palladium catalyst (c2)), in the presence or absence of a ligand, and in the presence of a base, in a solvent. This reaction can be carried out under reaction conditions similar to those of the method in step b2.

[0096] (Step c3) Compound (c7) can be produced by reacting compound (c5) and compound (c6) in the presence of a base, in the presence of a palladium catalyst (referred to here as palladium catalyst (c3)), in the presence or absence of a ligand, in a solvent. This reaction can be carried out under reaction conditions similar to those in the method of step a3 or step b4.

[0097] (Step c4) Compound (c8) can be produced by reacting compound (c3) and compound (c6) in the presence of a base, in the presence of a palladium catalyst (herein referred to as palladium catalyst (c3)), in the presence or absence of a ligand, in a solvent. This reaction can be carried out under reaction conditions similar to those of the method in step c3.

[0098] (Step c5) Compound (c7) can be produced by reacting compound (c8) and compound (c4) in the presence of a palladium catalyst (referred to here as palladium catalyst (c2)), in the presence or absence of a ligand, and in the presence of a base, in a solvent. This reaction can be carried out under reaction conditions similar to those of the method in step c2.

[0099] (Step c6) Compound (c9) can be produced by subjecting compound (c7) to hydrolysis in accordance with the method described in step b3.

[0100] (Step c7) Compound (c9) can be deprotected, for example, by a method similar to the method described in Patent Document 2 to produce compound [I(A)]. In this reaction scheme (III), the compound (c1), the compound (c3), the compound (c5), the compound (c7), the compound (c8) and the compound (c9) used can be produced by any known method or a combination thereof, as appropriate. Compound (c3), compound (c5), compound (c7), compound (c8) and compound (c9) produced in this reaction scheme (III) can be converted to compound [I(A)], as appropriate, by a known method or a combination thereof.

[0101] Compound (a1-a) of the following formula: [ka] {where Z 1 represents a chlorine atom, a bromine atom, or an iodine atom, Z a2 is a hydroxyl or a substituent of the formula [ka] (In the formula, P 1 represents a hydroxy protecting group) Represents.} The compound represented by the formula (I) is a novel compound, and the compound is also included in the present invention. Here, P 1 The protecting group for hydroxy represented by the formula (I) is not particularly limited, but preferably includes methyl optionally substituted with phenyl optionally substituted with 1 or 2 methoxy groups (e.g., methyl, benzyl, p-methoxybenzyl), alkoxymethyl optionally substituted with trialkylsilyl (e.g., methoxymethyl, triethylsilylethoxymethyl), alkanoyl (e.g., acetyl, pivaloyl), sulfonyl substituted with methyl optionally substituted or phenyl optionally substituted (e.g., methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl), alkyloxycarbonyl optionally substituted (e.g., t-butyloxycarbonyl, benzyloxycarbonyl), silyl substituted with three groups selected from alkyl and phenyl optionally substituted (e.g., triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl), and aminocarbonyl substituted with 1 or 2 substituents selected from alkyl optionally substituted and phenyl optionally substituted (e.g., dimethylaminocarbonyl, methylphenylaminocarbonyl). More preferred are methyl substituted with phenyl which may be substituted with 1 or 2 methoxy groups (e.g., benzyl, p-methoxybenzyl), alkanoyl (e.g., pivaloyl), and sulfonyl substituted with optionally substituted methyl or optionally substituted phenyl (e.g., methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl). Preferably, Z 1 is a chlorine atom, a bromine atom, or an iodine atom, and Z a2 is hydroxy. More preferably, Z 1 is a chlorine atom, and Z a2 is hydroxy.

[0102] Compound (a3-1-A) of the following formula: [ka] The crystal of the compound represented by the formula (I) is a novel crystal, and the crystal is also included in the present invention. The two types of crystals of compound (a3-1-A) (I-type crystal and II-type crystal) are preferred crystals that can efficiently remove impurities. Of these, II-type crystal is preferred from the viewpoint of removing impurities. In addition, I-type crystal is more thermodynamically stable and is preferred from the viewpoint of robustness of the industrial production method. EXAMPLES

[0103] Next, the production method of the present invention will be specifically described below by giving examples, but the present invention is not limited to these examples. In the present embodiment, the symbols have the following meanings. Ac: Acetyl Bn: Benzyl Boc: tert-butyloxycarbonyl Cbz: benzyloxycarbonyl Me: Methyl Et: Ethyl nPr: Propyl iPr / 2-Pr: Isopropyl t-Bu: tert-butyl MOM: Methoxymethyl Ms: Methanesulfonyl Piv: Pivaloil PMB: p-Methoxybenzyl SEM: 2-(trimethylsilyl)ethoxymethyl Ts: p-Toluenesulfonyl Pd(OAc) 2 : Palladium(II) acetate Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl 2 : [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh 3 )4 : Tetrakis(triphenylphosphine)palladium(0) P(tBu) 3 PdG2: Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) PdCl 2 (amphos) 2 : Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) CX21: Allylchloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) CX22: Allylchloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]palladium(II) CX31: Chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II) CX32: Chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolylidene]palladium(II) CX33: Chlorophenylallyl{1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2-imidazolylidene}palladium(II) BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl tolBINAP: 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl dppp: 1,3-bis(diphenylphosphino)propane dppf: 1,1'-bis(diphenylphosphino)ferrocene RockPhos: 2-Di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl PCy 3 : Tricyclohexylphosphine Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Et 3N: Triethylamine iPr 2 NEt: N,N-diisopropylethylamine DBU: Diazabicycloundecene DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide MeCN: Acetonitrile THF: Tetrahydrofuran 2-MeTHF: 2-methyltetrahydrofuran MEK: Methyl ethyl ketone aq.: aqueous solution MsOH: methanesulfonic acid

[0104] The pressure values ​​used in this embodiment are absolute pressure values. For example, "0.6 MPa" in this embodiment means "0.6 MPa abs."

[0105] Example 1 Preparation of 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine [ka] 5-Bromo-2-chloro-3-hydroxypyridine (6.50 g, 31.184 mmol), Pd(dppf)Cl 2(22.9 mg, 0.031 mmol), (3-chlorophenyl)boronic acid (5.37 g, 34.302 mmol), potassium carbonate (21.55 g, 155.920 mmol), tetrahydrofuran (44.0 mL), and water (22.0 mL) were added to the reaction vessel, and the mixture was stirred under reflux conditions for 21.5 hours. After the internal temperature was increased to 40°C, water (44.0 mL) was added to the reaction mixture and stirred. Toluene (33.0 mL) was then added and stirred. After standing, the lower layer, which separated into two layers, was collected and water (19.5 mL) was added thereto. 2 mol / L hydrochloric acid (15.6 mL) was added dropwise to this to carry out neutralization crystallization. The obtained solid was filtered off and then dried under reduced pressure to obtain 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine (5.10 g). (Yield 68%) 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.21 (d, 1H, J = 2.3 Hz), 7.74 (t, 1H, J = 1.6 Hz), 7.62 (dt, 1H, J = 7.3, 1.6 Hz), 7.48-7.55 (m, 3H)

[0106] Example 2 Preparation of 5-(3-chlorophenyl)-3-hydroxypyridine [ka] 5-Bromo-3-hydroxypyridine (8.00 g, 45.977 mmol), Pd(dppf)Cl 2(841.0 mg, 1.149 mmol), (3-chlorophenyl)boronic acid (8.63 g, 55.172 mmol), potassium carbonate (7.28 g, 52.673 mmol), N,N-dimethylformamide (43.60 mL), and water (5.20 mL) were added to the reaction vessel, and the mixture was stirred at 80°C for 16 hours. Water (100 mL) and 2-methyltetrahydrofuran (50 mL) were added to the reaction mixture, and the mixture was stirred at room temperature. The mixture was separated, and the aqueous layer was extracted twice with 2-methyltetrahydrofuran (50 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (150 mL). Sodium sulfate was added to the separated organic layer to dehydrate it, and then it was filtered, and the filtrate was concentrated under reduced pressure. Acetone (50 mL) was added to the concentrated residue and stirred, and the insoluble matter was collected by filtration under reduced pressure and washed with acetone (20 mL). After drying under reduced pressure, a light brown solid of 5-(3-chlorophenyl)-3-hydroxypyridine (7.59 mg) was obtained (yield 80%). 1 H NMR (500 MHz, DMSO-d 6 ) δ10.12 (s, 1H), 8.37 (d, 1H, J = 1.8 Hz), 8.17 (d, 1H, J = 2.6 Hz), 7.74 (t, 1H, J = 1.8 Hz), 7.64 (dt, 1H, J = 7.6, 1.5 Hz), 7.45-7.54 (m, 2H), 7.41 (t, 1H, J = 2.4 Hz)

[0107] Example 3 Preparation of 5-(3-chlorophenyl)-3-hydroxy-2-iodopyridine [ka] 5-(3-Chlorophenyl)-3-hydroxypyridine (100.00 mg, 0.486 mmol), 8 mol / L sodium hydroxide aqueous solution (0.122 mL, 0.973 mmol), iodine (130.40 mg, 0.511 mmol), potassium iodide (43.10 mg, 0.258 mmol), and water (6.4 mL) were added to the reaction vessel, and the mixture was stirred at room temperature for 16 hours. Acetic acid (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was collected by suction filtration, and the obtained solid was dried under reduced pressure by heating to obtain the desired 5-(3-chlorophenyl)-3-hydroxy-2-iodopyridine (140.20 mg). (Yield 86%) 1 H NMR (500 MHz, DMSO-d 6 ) δ11.07 (br, 1H), 8.19 (d, 1H, J = 2.1 Hz), 7.72 (t, 1H, J = 1.6 Hz), 7.61 (dt, 1H, J = 7.2, 1.6 Hz), 7.48-7.56 (m, 2H), 7.32 (d, 1H, J = 2.3Hz)

[0108] Example 4 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-Chloro-5-(3-chlorophenyl)-3-hydroxypyridine (700.0 mg, 2.916 mmol), glycine ethyl ester hydrochloride (427.3 mg, 3.061 mmol), palladium acetate (20.5 mg, 0.087 mmol), 1,3-bis(diphenylphosphino)propane (72.7 mg, 0.175 mmol), triethylamine (1.22 mL, 8,747 mmol), and acetonitrile (35.0 mL) were added to a reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 72 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was concentrated under reduced pressure, and then acetonitrile (7.0 mL) and water (10.5 mL) were added and stirred, and the precipitated crystals were collected by filtration. This was further dissolved in acetonitrile (3.5 mL) by heating, and ethanol (7 mL) was added thereto to carry out crystallization. The resulting crystals were collected by filtration and dried under reduced pressure with heating to obtain ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (229.9 mg). (Yield 23%) The mother liquor was concentrated under reduced pressure, suspended and washed with a mixture of acetonitrile (0.7 mL) and ethanol (6.3 mL), filtered, and dried under reduced pressure to obtain ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (333.5 mg) (yield 34%). 1 H NMR (500 MHz, DMSO-d 6 ) δ12.30 (s, 1H), 9.51 (t, 1H, J = 6.1 Hz), 8.56 (d, 1H, J = 2.0 Hz), 7.92-7.95 (m, 1H), 7.77-7.83 (m, 2H), 7.52-7.58 (m, 2H), 4.15 (q, 2H, J = 7.1 Hz), 4.09 (d, 2H, J = 6.3 Hz), 1.22 (t, 3H, J = 7.1 Hz)

[0109] Example 5 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 5-(3-Chlorophenyl)-3-hydroxy-2-iodopyridine (966.5 mg, 2.916 mmol), glycine ethyl ester hydrochloride (430.4 mg, 3.062 mmol), palladium acetate (19.7 mg, 0.087 mmol), 1,3-bis(diphenylphosphino)propane (71.5 mg, 0.175 mmol), triethylamine (1.22 mL, 8,748 mmol), and acetonitrile (35.0 mL) were added to a reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 24 hours while maintaining the pressure of the reaction system at 0.5 MPa. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (15.0 mL) and water (10.0 mL) were added and the mixture was stirred and extracted, and the organic layer and the aqueous layer were separated. The organic layer obtained here was washed with water (7.00 mL), and the aqueous layer was washed with ethyl acetate (5.00 mL), and the organic layers were combined. The organic layer was concentrated under reduced pressure, and the concentrated residue was purified by column chromatography to obtain ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (also referred to as "compound (a3-1-A)" in this specification) (600.3 mg). (Yield 61%) 1 H NMR (500 MHz, DMSO-d 6 ) δ12.30 (s, 1H), 9.50 (t, 1H, J = 6.1 Hz), 8.55 (d, 1H, J = 2.0 Hz), 7.92-7.95 (m, 1H), 7.77-7.83 (m, 2H), 7.52-7.58 (m, 2H), 4.15 (q, 2H, J = 7.1 Hz), 4.09 (d, 2H, J = 6.3 Hz), 1.22 (t, 3H, J = 7.1 Hz)

[0110] Example 6 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]ethyl acetate (200.0 mg, 0.597 mmol), 1 mol / L aqueous sodium hydroxide solution (1.0 mL, 1.000 mmol), and tetrahydrofuran (1.0 mL) were added to the reaction vessel, and the mixture was stirred at 55°C for 4.5 hours. An additional 8 mol / L aqueous sodium hydroxide solution (0.25 mL, 2.000 mmol) was added to complete the reaction. 2 mol / L hydrochloric acid (1.5 mL, 2.987 mmol) was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The residue was back-extracted with 2 mol / L aqueous sodium hydroxide solution and ethyl acetate, and then the separated aqueous layer was extracted with 2 mol / L hydrochloric acid and ethyl acetate. The obtained organic layer was dehydrated with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was dried under reduced pressure to give 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid (151.3 mg) (yield 82%). 1 H NMR (500 MHz, DMSO-d 6 ) δ12.81 (br, 1H), 12.38 (s, 1H), 9.37 (t, 1H, J = 12.2 Hz), 8.55 (s, 1H), 7.93 (s, 1H), 7.75-7.84 (m, 2H), 7.50-7.59 (m, 2H), 4.02 (d, 2H, J = 12.2 Hz)

[0111] Example 7 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]tert-butyl acetate (102.1 mg, 0.281 mmol), water (1.0 mL), and methanesulfonic acid (1.0 mL, 15 mmol) were added to the reaction vessel, and the atmosphere was replaced with nitrogen, and the mixture was stirred at 50° C. for 15 hours. The progress of the reaction was evaluated by HPLC, and the raw material / target product ratio was 0.4 / 95.0 (area percentage).

[0112] Example 8 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]tert-butyl acetate (101.3 mg, 0.279 mmol), tetrahydrofuran (1.0 mL), and 1 mol / L sodium hydroxide (1.0 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen, and the mixture was stirred at 50°C for 15 hours. After cooling the reaction mixture to room temperature, 2 mol / L hydrochloric acid was added to adjust the mixture to pH 2, and the solvent was removed by concentration under reduced pressure. The resulting residue was washed with water and hexane, and then dried by heating under reduced pressure (50°C) to give 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid (73.2 mg). (Yield 85%) 1 H NMR (500 MHz, DMSO-d 6 ) δ12.82 (br, 1H), 12.38 (s, 1H), 9.37 (t, 1H, J = 12.2 Hz), 8.55 (s, 1H), 7.93 (s, 1H), 7.75-7.84 (m, 2H), 7.50-7.59 (m, 2H), 4.02 (d, 2H, J = 12.2 Hz)

[0113] Example 9 Preparation of methyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate [ka] 2,3,5-Trichloropyridine (2.09 g, 11.5 mmol), glycine methyl ester hydrochloride (1.73 g, 13.8 mmol), dppp (284.6 mg, 0.690 mmol), Pd(OAc) 2 (77.7 mg, 0.346 mmol), triethylamine (3.49 g, 34.5 mmol), and acetonitrile (21 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and carbon monoxide in sequence. The pressure was then increased to 0.6 MPa with carbon monoxide, and the mixture was stirred at 110°C for 12 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was filtered under reduced pressure and washed with acetonitrile (10 mL). The cake was suspended in acetonitrile (20 mL), filtered again, and washed with acetonitrile (20 mL). These filtrates and washes were combined and concentrated under reduced pressure. Acetonitrile (3 mL) was added to the concentrated residue and heated to 75°C to dissolve the precipitate. The mixture was stirred at room temperature, and water (11.5 mL) was added and further stirred at room temperature. The precipitate was filtered under reduced pressure and washed twice with a mixture of acetonitrile:water = 1:1 (3.0 mL). After drying under reduced pressure, methyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (1.90 g) was obtained as a white powder (yield 63%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.45 (d, 1H, J = 2.0 Hz), 8.18 (s, 1H), 7.86 (d, 1H, J = 2.1 Hz), 4.24 (d, 2H, J = 5.5 Hz), 3.80 (s, 3H)

[0114] Example 10 Preparation of tert-butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate [ka] 2,3,5-Trichloropyridine (2.62 g, 14.4 mmol), glycine tert-butyl ester hydrochloride (2.52 g, 15.1 mmol), dppp (355.3 mg, 0.861 mmol), Pd(OAc) 2 (96.9 mg, 0.432 mmol), triethylamine (4.36 g, 43.1 mmol), and acetonitrile (26 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide, and the mixture was stirred at 110°C for 12 hours. The reaction mixture was filtered under reduced pressure, and the cake was washed with acetonitrile (26 mL). The filtrate and the washings were combined and concentrated under reduced pressure to 10.4 g. Water (13 mL) was added, and the mixture was stirred at room temperature. The precipitate was filtered under reduced pressure, and washed twice with a mixture of acetonitrile:water = 1:1 (6.5 mL). The mixture was dried under reduced pressure to obtain tert-butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (3.22 g) as a white powder. (Yield 74%) 1 H NMR (500 MHz, CDCl 3 ) δ 8.44 (d, 1H, J = 2.1 Hz), 8.15 (s, 1H), 7.86 (d, 1H, J = 2.1 Hz), 4.12 (d, 2H, J = 5.3 Hz), 1.50 (s, 9H)

[0115] Example 11 Preparation of methyl 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]acetate [ka] Methyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (3.00 g, 11.4 mmol), Pd 2 (dba) 3(313.2 mg, 0.3420 mmol), RockPhos (320.8 mg, 0.6844 mmol), cesium carbonate (8.18 g, 25.1 mmol), (E)-benzaldehyde oxime (1.80 g, 14.9 mmol), and 2-MeTHF (35 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen, and the mixture was stirred at 85°C for 20 hours. The reaction mixture was concentrated under reduced pressure, and water (75 mL) and chloroform (70 mL) were added to the concentrated residue, and the mixture was stirred at room temperature. The mixture was separated, and the aqueous layer was extracted twice with chloroform (70 mL). The organic layers were combined, dehydrated by adding sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. Methanol (25 mL) was added to the concentrated residue, and the mixture was stirred, and the precipitate was filtered under reduced pressure and washed with methanol (15 mL). After drying under reduced pressure, a pale green solid of methyl 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]acetate (807.8 mg) was obtained (yield 29%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.44 (br, 1H), 9.53 (brt, 1H, J = 5.7 Hz), 8.25 (d, 1H, J = 2.0 Hz), 7.70 (d, 1H, J = 2.1 Hz), 4.08 (d, 2H, J = 6.1 Hz), 3.67 (s, 3H)

[0116] Example 12 Preparation of tert-butyl 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]acetate [ka] tert-Butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (2.99 g, 9.83 mmol), Pd 2 (dba) 3(270.4 mg, 0.295 mmol), RockPhos (276.1 mg, 0.590 mmol), cesium carbonate (7.1 g, 21.6 mmol), (E)-benzaldehyde oxime (1.55 g, 12.8 mmol), and 2-MeTHF (20 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen, followed by stirring at 80°C for 21 hours. The reaction mixture was cooled to room temperature, and the solid component was filtered. The solid component was dissolved by adding 2 mol / L hydrochloric acid (12 mL) and 2-MeTHF (20 mL), and the aqueous layer was separated, and the organic layer was concentrated under reduced pressure. The concentrated solid residue was washed with n-heptane, dried under reduced pressure, and further purified by column chromatography to obtain tert-butyl 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]acetate (1.40 g) as a white solid. (Yield 50%) 1 H NMR (500 MHz, CDCl 3 ) δ 12.02 (s, 1H), 8.34-8.20 (brs, 1H), 8.03 (d, 1H, J = 2.0 Hz), 7.33 (d, 1H, J = 2.0 Hz), 4.12 (d, 2H, J = 5.5 Hz), 1.51 (s, 9H)

[0117] Example 13 Preparation of tert-butyl 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]acetate [ka] tert-Butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (6.00 g, 19.7 mmol), Pd(OAc) 2 (132.6 mg, 0.590 mmol), PCy 3(331.1 mg, 1.180 mmol), cesium carbonate (14.1 g, 43.3 mmol), (E)-benzaldehyde oxime (3.10 g, 25.6 mmol), and 2-MeTHF (40 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen, and the mixture was stirred at 80°C for 21 hours. The reaction mixture was cooled to room temperature, filtered under reduced pressure, and the solid component was collected by filtration. The solid component was dissolved by adding 2 mol / L hydrochloric acid (21.6 mL, 43.3 mmol) and ethyl acetate (40 mL), and the aqueous layer was separated, and the organic layer was concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain a white solid, tert-butyl 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]acetate (4.45 g). (Yield 79%) 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.51 (s, 1H), 9.41 (brt, 1H, J = 6.0 Hz), 8.24 (d, 1H, J = 2.1 Hz), 7.70 (d, 1H, J = 2.1 Hz), 3.95 (d, 2H, J = 6.3 Hz), 1.42 (s, 9H)

[0118] Example 14 Preparation of tert-butyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]tert-butyl acetate (1.00 g, 3.50 mmol), CX21 (100.6 mg, 0.176 mmol), (3-chlorophenyl)boronic acid (572.4 mg, 3.66 mmol), toluene (5.0 mL), water (15 mL), and N,N-diisopropylethylamine (1.26 g, 9.77 mmol) were added to a reaction vessel, and the atmosphere was replaced with nitrogen, and the mixture was stirred at 85°C for 15 hours. After cooling to room temperature, the mixture was separated, and the aqueous layer was extracted with toluene (10 mL). The organic layers were combined, dehydrated by adding sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography. The concentrated residue was dissolved in ethyl acetate (500 μL), and n-heptane (20 mL) was added, and the precipitate was collected by filtration. After drying under reduced pressure, tert-butyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (462.3 mg) was obtained (yield 36%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.34 (s, 1H), 9.40, (t, 1H, J = 6.2 Hz), 8.55 (d, 1H, J = 1.9 Hz), 7.93 (s, 1H), 7.84-7.80 (m, 1H), 7.79 (d, 1H, J = 2.0 Hz), 7.57-7.53 (m, 2H), 3.98 (d, 2H, J = 6.2 Hz), 1.44 (s, 9H)

[0119] Example 15 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]tert-butyl acetate (101.3 mg, 0.2792 mmol), 1 mol / L aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol), and THF (1.0 mL) were added to the reaction vessel, and the mixture was stirred at 50°C for 15 hours to react. After cooling to room temperature, 2 mol / L hydrochloric acid (300 μL) was added to adjust the pH to 2.0. This mixture was concentrated under reduced pressure at an external bath of 35°C to remove THF. The concentrated residue was stirred at room temperature for 30 minutes, and the precipitated solid was filtered. The filtered solid was washed with water (2.0 mL)·n-hexane (2.0 mL) and dried under reduced pressure to obtain 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid (73.2 mg). (Yield 86%) 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.82 (brs, 1H), 12.38 (s, 1H), 9.37, (t, 1H, J = 6.2 Hz), 8.55 (d, 1H, J = 1.9 Hz), 7.95-7.92 (m, 1H), 7.83-7.80 (m, 1H), 7.79 (d, 1H, J = 1.8 Hz), 7.56-7.53 (m, 2H), 4.02 (d, 2H, J = 6.2 Hz)

[0120] Example 16 Preparation of methyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate [ka] 2,3,5-Trichloropyridine (700 mg, 3.84 mmol), glycine methyl ester hydrochloride (1.2 equiv.), ligand (6.0 mol%), Pd(OAc) 2(3.0 mol%), triethylamine (3.0 equivalents), and solvent (35 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 5 hours while maintaining the pressure of the reaction system at 0.6 MPa. The progress of the reaction was evaluated using HPLC, and the results are shown in Table 1 below.

[0121] Table 1 [Table 1]

[0122] Example 17 Preparation of 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetic acid [ka] 2,3,5-Trichloropyridine (2.62 g, 14.4 mmol), glycine (1.29 g, 17.2 mmol), dppp (355.2 mg, 0.861 mmol), Pd(OAc) 2 (97.0 mg, 0.432 mmol), triethylamine (4.36 g, 43.1 mmol), and acetonitrile (26 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 24 hours while maintaining the pressure of the reaction system at 0.6 MPa. The progress of the reaction was evaluated by HPLC, and the ratio of raw material / target product was 42.3 / 44.9 (area percentage).

[0123] Example 18 Preparation of ethyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate [ka] 2,3,5-Trichloropyridine (2.62 g, 14.4 mmol), glycine ethyl ester hydrochloride (2.40 g, 17.2 mmol), dppp (355.3 mg, 0.861 mmol), Pd(OAc) 2 (96.9 mg, 0.432 mmol), triethylamine (4.36 g, 43.1 mmol), and acetonitrile (26 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 12 hours while maintaining the pressure of the reaction system at 0.6 MPa. The progress of the reaction was evaluated by HPLC, and the ratio of raw material / target product was 0.7 / 82.6 (area percentage).

[0124] Example 19 Preparation of tert-butyl 2-[(3-chloro-5-hydroxypyridine-2-carbonyl)amino]acetate [ka]

[0125] Method A tert-Butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (100 mg, 0.328 mmol), Pd catalyst (5 mol%, 0.016 mmol), ligand (10 mol%, 0.033 mmol), cesium carbonate (235 mg, 0.721 mmol), (E)-benzaldehyde oxime (49 μL, 0.426 mmol), and solvent (1.0 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen, after which the mixture was stirred at 85° C. for 22 hours. The progress of the reaction was evaluated by HPLC, as shown in Table 2 below.

[0126] Method B tert-Butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (50.4 mg, 0.165 mmol), Pd(OAc)- 2 (1.1 mg, 0.0049 mmol), PCy 3(3.3 mg, 0.012 mmol), potassium carbonate (49.9 mg, 0.361 mmol), (E)-benzaldehyde oxime (25 μL, 0.213 mmol), and 2-MeTHF (0.33 mL) were added to the reaction vessel, the atmosphere was replaced with nitrogen, and the mixture was stirred at 80° C. for 15 hours. The progress of the reaction was evaluated by HPLC, as shown in Table 2 below.

[0127] Method C tert-Butyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (50.0 mg, 0.164 mmol), Pd(OAc)- 2 (1.1 mg, 0.0049 mmol), PCy 3 (3.1 mg, 0.011 mmol), tripotassium phosphate (76.5 mg, 0.360 mmol), (E)-benzaldehyde oxime (25 μL, 0.213 mmol), and 2-MeTHF (0.33 mL) were added to the reaction vessel, the atmosphere was replaced with nitrogen, and the mixture was stirred at 80° C. for 15 hours. The progress of the reaction was evaluated by HPLC, as shown in Table 2 below.

[0128] Table 2 [Table 2]

[0129] Example 20 Preparation of tert-butyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]tert-butyl acetate (50 mg, 0.174 mmol), Pd catalyst (5 mol%), (3-chlorophenyl)boronic acid (38.2 mg, 0.244 mmol), solvent (1.0 mL), and base (3.0 eq., 0.523 mmol) were added to the reaction vessel, the atmosphere was replaced with nitrogen, and the mixture was stirred at 85° C. for 15 hours. The progress of the reaction was evaluated by HPLC, as shown in Table 3 below.

[0130] Table 3 [Table 3]

[0131] Example 21 Preparation of tert-butyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-[(5-chloro-3-hydroxypyridine-2-carbonyl)amino]tert-butyl acetate (100 mg, 0.349 mmol), CX22 (8.5 mg, 0.017 mmol), (3-chlorophenyl)boronic acid (76.4 mg, 0.488 mmol), solvent (2.0 mL), and diisopropylethylamine (0.30 mL, 1.744 mmol) were added to the reaction vessel, the atmosphere was replaced with nitrogen, and the mixture was stirred at 85° C. for 15 hours. The progress of the reaction was evaluated by HPLC, as shown in Table 4 below.

[0132] Table 4 [Table 4]

[0133] Example 22 Preparation of tert-butyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-[(5-chloro-3-hydroxy-pyridine-2-carbonyl)amino]tert-butyl acetate (100 mg, 0.349 mmol), NHC-Pd cat. (5.0 mol%, 0.017 mmol), (3-chlorophenyl)boronic acid (76.4 mg, 0.488 mmol), solvent (2.0 mL), and diisopropylethylamine (0.17 mL, 0.977 mmol) were added to the reaction vessel, the atmosphere was replaced with nitrogen, and the mixture was stirred at 85° C. for 15 hours. The progress of the reaction was evaluated by HPLC and is shown in Table 5 below. Table 5 [Table 5]

[0134] Example 23 Preparation of 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine [ka] 5-Bromo-2-chloro-3-hydroxypyridine (7.00 g, 33.583 mmol), Pd(dppf)Cl 2(36.8 mg, 0.050 mmol), (3-chlorophenyl)boronic acid (6.30 g, 40.286 mmol mmol), potassium carbonate (6.96 g, 50.358 mmol), tetrahydrofuran (28.0 mL), and water (23.2 mL) were added to a reaction vessel, and the mixture was stirred under reflux conditions for 20 hours under a nitrogen atmosphere. The reaction mixture was adjusted to 40°C, and water (42.0 mL) and sodium chloride (14.0 g) were added and stirred, then separated, and the lower layer was removed. Toluene (35.0 mL), water (21.0 mL), and tripotassium phosphate (7.00 g) were added to the mixture, and the mixture was stirred at room temperature, then separated, and the lower layer was collected. Water (14.0 mL) and tripotassium phosphate (1.40 g) were added to the upper layer, and the mixture was stirred at room temperature, then separated, and the upper layer was removed. The lower layers were combined, sodium chloride (7.00 g) was added, and the mixture was stirred at room temperature, after which the liquids were separated and the lower layer was removed. The mixture was adjusted to 40°C, water (56.0 mL) was added, concentrated hydrochloric acid (3.85 g) was added dropwise, and the mixture was cooled to 20°C. The precipitated solid was filtered under reduced pressure and washed with a mixture of tetrahydrofuran (3.5 mL) and water (28.0 mL). Drying under reduced pressure gave 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine (7.34 g). (Yield 91%) 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.21 (d, 1H, J = 2.3 Hz), 7.74 (t, 1H, J = 1.6 Hz), 7.62 (dt, 1H, J = 7.4, 1.7 Hz), 7.48-7.55 (m, 3H)

[0135] Example 24 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-Chloro-5-(3-chlorophenyl)-3-hydroxypyridine (2.50 g, 10.413 mmol), glycine ethyl ester hydrochloride (1.53 g, 10.961 mmol), palladium acetate (5.8 mg, 0.026 mmol), 1,4-bis(diphenylphosphino)butane (22.3 mg, 0.052 mmol), tripropylamine (4.48 g, 31.270 mmol), and acetonitrile (30.0 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 46 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was filtered to remove solids and washed with acetonitrile (20 mL). The filtrate was concentrated under reduced pressure to 10 mL, and then isopropanol (15 mL) was added and heated to obtain a homogeneous solution. Water (10 mL) was added dropwise, and the mixture was cooled to 20°C. The precipitated solid was filtered under reduced pressure and washed with a mixture of isopropanol (7.5 mL) and water (5 mL). The mixture was dried under reduced pressure to obtain crude crystals of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (2.80 g). (Yield 80%)

[0136] Example 25 Purification of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] Crude crystals of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (5.00 g, 14.936 mmol), N-acetyl-L-cysteine ​​(24.4 mg, 0.150 mmol), a mixture of isopropanol (35.0 mL) and water (15.0 mL) were added to a reaction vessel, and the suspension was stirred at 56°C for 2 hours and then cooled to 20°C. The solid component was filtered under reduced pressure and washed with a mixture of isopropanol (14 mL) and water (6 mL). The solid was dried under reduced pressure to obtain ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (4.77 g). (Yield 95%) 1 H NMR (500 MHz, DMSO-d 6 ) δ12.30 (s, 1H), 9.50 (t, 1H, J = 6.4 Hz), 8.56 (d, 1H, J = 2.0 Hz), 7.92-7.95 (m, 1H), 7.77-7.83 (m, 2H), 7.52-7.58 (m, 2H), 4.15 (q, 2H, J = 7.1 Hz), 4.09 (d, 2H, J = 6.1 Hz), 1.22 (t, 3H, J = 7.1 Hz)

[0137] Example 26 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] Ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (1.50 g, 4.481 mmol), methyl ethyl ketone (7.5 mL), and activated carbon (75.7 mg) were added to a reaction vessel, and the mixture was stirred at 50°C for 2 hours under a nitrogen atmosphere. The solid matter was filtered off, washed with methyl ethyl ketone (6.0 mL), and the filtrate was collected. Potassium hydroxide (638.9 mg, 11.201 mmol) and water (6.0 mL) were added to the reaction vessel to dissolve the solid matter, and the filtrate was transferred using methyl ethyl ketone (1.5 mL) and reacted at 50°C for 2 hours by stirring. The reaction mixture was separated to remove the upper layer, and tert-butanol (3.75 ml) was added at 40°C. A solution of 86% phosphoric acid (1.54 g, 13.441 mmol), sodium chloride (601.1 mg), and water (1.8 mL) was added dropwise to the mixture, followed by a solution of sodium chloride (600.2 mg) and water (1.8 mL), and the mixture was stirred at 40°C for 30 minutes. The mixture was separated and the lower layer was removed, and water (10.5 mL) was added to precipitate crystals. The mixture was stirred at 40°C for 1 hour and then cooled to 5°C. The precipitate was filtered under reduced pressure and washed with a mixture of tert-butanol (0.75 ml) and water (6.75 mL). The precipitate was dried under reduced pressure to give 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid (1.28 g). (Yield 93%) 1 H NMR (500 MHz, DMSO-d 6 ) δ12.82 (br, 1H), 12.38 (s, 1H), 9.38 (t, 1H, J = 6.1 Hz), 8.55 (d, 1H, J = 1.83 Hz), 7.92-7.95 (m, 1H), 7.77-7.83 (m, 2H), 7.52-7.58 (m, 2H), 4.02 (d, 2H, J = 6.3 Hz)

[0138] Example 27 Preparation of protected 5-bromo-2-chloro-3-hydroxypyridine [ka]

[0139] 5-Bromo-2-chloro-3-hydroxypyridine and the reagents and solvents shown in Table 6 below were added to a reaction vessel, and the reaction was carried out under the reaction conditions shown in Table 6 below while adding reagents as needed. After post-treatment, the protected 5-bromo-2-chloro-3-hydroxypyridine was isolated by purification using silica gel column chromatography. The yield, yield and MS measurement results of the obtained protected 5-bromo-2-chloro-3-hydroxypyridine were as shown in Table 7 below.

[0140] Table 6 [Table 6]

[0141] Table 6 (continued) [Table 7]

[0142] Table 7 [Table 8]

[0143] Example 28 Preparation of protected 5-(3-chlorophenyl)-2-chloro-3-hydroxypyridine [ka] The amounts of protected 5-bromo-2-chloro-3-hydroxypyridine, (3-chlorophenyl)boronic acid, solvent, Pd(dppf)Cl shown in Table 8 below were 2(0.03 equivalents relative to the protected 5-bromo-2-chloro-3-hydroxypyridine) and potassium carbonate (1.2 equivalents relative to the protected 5-bromo-2-chloro-3-hydroxypyridine) were added to the reaction vessel, and the mixture was stirred under reflux conditions under a nitrogen atmosphere as appropriate, and reacted for the time shown in Table 8 below while adding (3-chlorophenyl)boronic acid. After post-treatment, the protected 5-(3-chlorophenyl)-2-chloro-3-hydroxypyridine was isolated by purification using silica gel column chromatography. The yield, yield and MS measurement results of the obtained protected 5-(3-chlorophenyl)-2-chloro-3-hydroxypyridine were as shown in Table 9 below.

[0144] Table 8 [Table 9]

[0145] Table 9 [Table 10]

[0146] Example 29 Preparation of ethyl [[3-benzyloxy-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate [ka] 3-(benzyloxy)-2-chloro-5-(3-chlorophenyl)pyridine (200 mg, 0.61 mmol), acetonitrile (3 mL), glycine ethyl ester hydrochloride (95 mg, 0.68 mmol), triethylamine (255 μL, 1.83 mmol), 1,3-bis(diphenylphosphino)propane (14.7 mg, 0.03 mmol), and palladium acetate (5.0 mg, 0.02 mmol) were added to a reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110° C. for 23 hours while maintaining the pressure of the reaction system at 0.6 MPa. Ethyl acetate was added, and the precipitated solid was filtered off and washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography to obtain ethyl 2-[[3-benzyloxy-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate (209 mg) (yield 75%). 1 H NMR (CDCl 3 ) δ:1.31 (3H, t, J = 7.2 Hz), 4.22-4.28 (4H, m), 5.34 (2H, s), 7.32-7.35 (1H, m), 7.39-7.43 (5H, m), 7.48-7.50 (2H, m), 7.53-7.55 (2H, m), 8.31 (1H, t, J = 4.8 Hz), 8.43 (1H, d, J = 1.6 Hz).

[0147] Example 30 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-[(4-methoxyphenyl) methoxy]pyridine-2-carbonyl]amino]acetate [ka] 2-Chloro-5-(3-chlorophenyl)-3-[(4-methoxyphenyl)methoxy]pyridine (201 mg, 0.56 mmol), acetonitrile (3.0 mL), glycine ethyl ester hydrochloride (88 mg, 0.64 mmol), triethylamine (234 μL, 1.68 mmol), 1,3-bis(diphenylphosphino)propane (15.0 mg, 0.04 mmol), and palladium acetate (4.2 mg, 0.02 mmol) were added to a reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110°C for 15 hours while maintaining the pressure of the reaction system at 0.6 MPa. Ethyl acetate was added, and the precipitated solid was filtered off and washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography to give ethyl 2-[[5-(3-chlorophenyl)-3-[(4-methoxyphenyl) methoxy]pyridine-2-carbonyl]amino]acetate (191 mg) (yield 73%). 1 H NMR (CDCl 3 ) δ:1.30 (3H, t, J = 7.2 Hz), 3.81 (3H, s), 4.18-4.27 (4H, m), 5.27 (2H, s), 6.93 (2H, d, J = 8.8 Hz), 7.41-7.51 (7H, m), 8.30 (1H, t, J = 5.2 Hz), 8.43 (1H, d, J = 2.0 Hz).

[0148] Example 31 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] Ethyl 2-[[3-benzyloxy-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate (170 mg, 0.40 mmol), dichloromethane (5 mL), and hydrogen bromide (30% acetic acid solution) (1 mL) were added to a reaction vessel, and the mixture was stirred at 40°C for 24 hours. The reaction mixture was cooled on ice, water was added, and the mixture was extracted three times with dichloromethane. The organic layers were combined and dried over sodium sulfate, and the solid matter was filtered off. The filtrate was concentrated under reduced pressure, and toluene was added and the mixture was concentrated under reduced pressure again. The concentrated residue was purified by silica gel column chromatography to give 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid (37 mg). (Yield 30%) 1 H NMR (DMSO-d 6 ) δ:3.93 (2H, d, J = 5.6 Hz), 7.52-7.57 (2H, m), 7.78 (1H, d, J = 2.0 Hz), 7.79-7.81 (1H, m), 7.92-7.93 (1H, m), 8.54 (1H, d, J = 2.0 Hz), 9.27 (1H, t, J = 5.6 Hz), 12.41-12.49 (1H, br).

[0149] Example 32 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate [ka] 2-[[5-(3-chlorophenyl)-3-[(4-methoxyphenyl)methoxy]pyridine-2-carbonyl]amino]ethyl acetate (163 mg, 0.36 mmol), dichloromethane (10 mL), and hydrogen bromide (30% acetic acid solution) (1 mL) were added to the reaction vessel, and the mixture was stirred at 40°C for 2 hours. The reaction mixture was cooled on ice, and saturated sodium bicarbonate water was added, followed by extraction with dichloromethane twice. The organic layers were combined and dried over sodium sulfate, after which the solid matter was filtered off, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography, and then further purified by amino silica gel column chromatography to obtain a crude product. This was purified using a reversed-phase silica gel column to obtain 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]ethyl acetate (84 mg). (Yield 68%) 1 H NMR (CDCl 3 ) δ:1.33 (3H, t, J = 7.2 Hz), 4.24-4.31 (4H, m), 7.41-7.49 (4H, m), 7.57-7.58 (1H, m), 8.30 (1H, d, J = 2.0 Hz), 8.42 (1H, br), 11.8 (1H, s).

[0150] Example 33 Preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid [ka] 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]ethyl acetate (76 mg, 0.22 mmol), tetrahydrofuran (0.71 mL), and 1 mol / L aqueous sodium hydroxide solution (0.7 mL, 0.7 mmol) were added to the reaction vessel and stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1 mol / L hydrochloric acid (0.8 mL, 0.8 mmol), and the pH was adjusted to about 2 using 1 mol / L aqueous sodium hydroxide solution. The mixture was concentrated under reduced pressure to remove the solvent, and the precipitated solid was filtered under reduced pressure and washed with water. It was dried under reduced pressure to obtain 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid (64 mg). (Yield 95%) 1 H NMR (DMSO-d 6 ) δ:3.94 (2H, d, J = 6.0 Hz), 7.52-7.57 (2H, m), 7.78 (1H, d, J = 1.6 Hz), 7.79-7.81 (1H, m), 7.92-7.93 (1H, m), 8.55 (1H, d, J = 1.6 Hz), 9.28 (1H, t, J = 6.0 Hz), 12.4-12.5 (1H, br).

[0151] Example 34 Preparation of 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid [ka] According to the method described in Patent Document 2, 3,5-dichloropyridine-2-carbonitrile (13.50 g, 86.33 mmol), (3-chlorophenyl)boronic acid (15.68 g, 90.64 mmol), potassium carbonate (14.32 g, 103.62 mmol), dimethylformamide (85 mL), water (10 mL), Pd(dppf)Cl 2(316 mg, 0.43 mmol) and dimethylformamide (4.3 mL) were added to the reaction vessel in that order, and the reaction was carried out for 19 hours at 50°C (bath temperature) under a nitrogen atmosphere. After post-treatment, 3-chloro-5-(3-chlorophenyl)pyridine-2-carbonitrile (21.51 g) was obtained. (Yield quant.)

[0152] 3-Chloro-5-(3-chlorophenyl)pyridine-2-carbonitrile (30.70 g, 123.25 mmol), ethanol (153 mL), and 1 mol / L aqueous sodium hydroxide solution (271 mL, 271 mmol) were added to a reaction vessel and reacted at 80°C (bath temperature) for 26 hours. After post-treatment, 3-chloro-5-(3-chlorophenyl)pyridine-2-carboxylic acid (33.83 g) was obtained. (Yield quant.)

[0153] 3-Chloro-5-(3-chlorophenyl)pyridine-2-carboxylic acid (33.83 g), dimethylformamide (352 mL), glycine methyl ester hydrochloride (20.12 g, 160.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (35.44 g, 184.87 mmol), 1-hydroxybenzotriazole monohydrate (HOBt·H 2 O) (25.00 g, 185.00 mmol) and diisopropylethylamine (85 mL, 493.23 mmol) were added to the reaction vessel and reacted at room temperature for 15 hours. After post-treatment, methyl 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate (32.63 g) was obtained (yield 78.1%).

[0154] Methyl 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate (32.67 g, 99.27 mmol), 2 mol / L aqueous sodium hydroxide solution (168 mL, 336 mmol), and water (96 mL) were added to a reaction vessel and reacted at 50°C (bath temperature) for 3 hours. After cooling to room temperature, hydrochloric acid was added to adjust the pH to 4. The precipitate was filtered and dried to obtain 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid (32.19 g). Yield (99.7%) 1 H NMR (DMSO-d 6 ) δ:3.95 (2H, d, J = 6.0 Hz), 7.54-7.59 (2H, m), 7.82-7.87 (1H, m), 7.98-7.99 (1H, m), 8.43 (1H, d, J = 2.0 Hz), 8.93-8.96 (2H, m), 12.71 (1H, br).

[0155] In two-dimensional NMR, NOESY correlation was observed between the protons at the 4- and 6-positions of the pyridine ring and the protons of the chlorophenyl group, confirming that this isomer is the same as the pyridine isomer.

[0156] Example 35 Preparation of methyl 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate [ka] Methyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (1.00g, 3.80 mmol), (3-chlorophenyl)boronic acid (595.9 mg, 3.81 mmol), and dimethylformamide (8.0 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen. A solution of potassium carbonate (1.05 g, 7.60 mmol) and water (1.0 mL), Pd(dppf)Cl 2(278.4 mg, 0.38 mmol) and dimethylformamide (2.0 mL) were added to the mixture, and the atmosphere was replaced with nitrogen again, after which the reaction was carried out at 47°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate and water were added for extraction, and the organic layer was concentrated under reduced pressure. Methanol was added to the concentrated residue, and the solid components were separated off, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography to give methyl 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate (45 mg). (Yield 3.5%) MS: m / z=339 / 341

[0157] Example 36 Preparation of methyl 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate and 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid [ka] Methyl 2-[(3,5-dichloropyridine-2-carbonyl)amino]acetate (1.01g, 3.84 mmol), (3-chlorophenyl)boronic acid (1.18 g, 7.55 mmol), potassium carbonate (0.51 g, 3.69 mmol), CX32 (127.6 mg, 0.20 mmol), and methanol (3.0 mL) were added to a reaction vessel, and the atmosphere was replaced with nitrogen, and the reaction was carried out at 60°C for 21 hours. The reaction mixture was extracted with 2 mol / L hydrochloric acid (10 mL) and ethyl acetate (20 mL), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to give methyl 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetate (559 mg) and 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid (110 mg).

[0158] 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid methyl ester Yield: 43%

[0159] 2-[[5-chloro-3-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid Yield: 9% 1 H NMR (CDCl 3 ): δ 8.55 (d, J=2.3 Hz, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.37 (dt, J=8.1, 1.7 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.29 (t, J=1.6 Hz, 1H), 7.19 (dt, J=7.4, 1.5 Hz, 1H), 4.18 (d, J=5.7 Hz, 2H).

[0160] In 2D NMR, NOESY correlation was observed between the proton at position 4 of the pyridine ring and the proton of the chlorophenyl group, but no NOESY correlation was observed for the proton at position 6 of the pyridine ring. Based on this, it was determined that this isomer is the same as the chlorophenyl group.

[0161] Example 37 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (I-type crystals) [ka] 2-Chloro-5-(3-chlorophenyl)-3-hydroxypyridine (4.00 g, 16.661 mmol), glycine ethyl ester hydrochloride (2.44 g, 17.481 mmol), palladium acetate (9.4 mg, 0.042 mmol), 1,4-bis(diphenylphosphino)butane (35.8 mg, 0.084 mmol), tripropylamine (7.16 g, 49.976 mmol), sodium propionate (160.2 mg, 1.666 mmol), and acetonitrile (48 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110° C. for 18 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was filtered to remove solids and washed with acetonitrile (32 mL).

[0162] Separately, 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine (4.00 g, 16.661 mmol), glycine ethyl ester hydrochloride (2.44 g, 17.481 mmol), palladium acetate (9.4 mg, 0.042 mmol), 1,4-bis(diphenylphosphino)butane (35.6 mg, 0.083 mmol), tripropylamine (7.15 g, 49.906 mmol), and acetonitrile (48 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110° C. for 46 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was filtered to remove solids and washed with acetonitrile (32 mL). The filtrate was concentrated under reduced pressure to 16 mL. Separately, 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine (4.00 g, 16.661 mmol), glycine ethyl ester hydrochloride (2.44 g, 17.481 mmol), palladium acetate (9.4 mg, 0.042 mmol), 1,4-bis(diphenylphosphino)butane (71.1 mg, 0.167 mmol), tripropylamine (7.16 g, 49.976 mmol), and acetonitrile (48 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110° C. for 46 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was filtered to remove solids and washed with acetonitrile (32 mL). The mixture of the three reactions was concentrated under reduced pressure until half of the combined solution was 24 mL. Isopropanol (36 mL) was added and heated to 65°C to dissolve, then water (12 mL) was added and stirred at 50°C. Water (24 mL) was added dropwise, and the mixture was heated again to 65°C with stirring, then cooled to 30°C. The precipitated solid was filtered under reduced pressure and washed with a mixture of isopropanol (18 mL) and water (12 mL). It was dried under reduced pressure to obtain type I crystals of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (5.99 g). (Yield 72%)

[0163] X-ray crystallography was carried out on the obtained type I crystal under the following conditions. Powder X-ray diffraction measurement conditions Equipment: MiniFlex600 (Rigaku) Operating conditions: X-ray output: Cu-Kα, tube voltage: 40 kV, tube current: 15 mA, sampling width: 0.02° Scanning range: 3°~40° Measurement temperature: room temperature The XRD diffraction pattern of the I-type crystal is shown in Figure 1. The diffraction angle (2θ) value of the I-type crystal is shown in Table 10. Table 10 [Table 11]

[0164] The type I crystal of the compound (a3-1-A) of the present invention is characterized by one or more of the following characteristic peaks in a powder X-ray diffraction pattern. (1) It is preferable that the powder X-ray diffraction pattern is substantially the same as that shown in FIG. (2) The characteristic peaks in the powder X-ray diffraction pattern of the I-type crystals are, in terms of diffraction angles 2θ, 7.96°±0.2°, 11.82°±0.2°, 14.14°±0.2°, and / or 15.94°±0.2°. Other characteristic peaks are 14.54°±0.2°, 15.08°±0.2°, 24.10°±0.2°, 24.68°±0.2°, and / or 26.82°±0.2°. Further characteristic peaks may include 5.72°±0.2°, 11.04°±0.2°, 17.74°±0.2°, 18.20°±0.2°, 20.40°±0.2°, 20.78°±0.2°, 25.10°±0.2° and / or 39.22°±0.2°.

[0165] Example 38 Preparation of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (crystal type II) [ka] 2-Chloro-5-(3-chlorophenyl)-3-hydroxypyridine (4.00 g, 16.661 mmol), glycine ethyl ester hydrochloride (2.44 g, 17.481 mmol), palladium acetate (9.3 mg, 0.041 mmol), 1,4-bis(diphenylphosphino)butane (35.6 mg, 0.083 mmol), tripropylamine (11.94 g, 83.339 mmol), and acetonitrile (48 mL) were added to the reaction vessel, and the atmosphere was replaced with nitrogen and then carbon monoxide, and the pressure was increased to 0.6 MPa with carbon monoxide. The mixture was stirred at 110° C. for 46 hours while maintaining the pressure of the reaction system at 0.6 MPa. The reaction mixture was filtered to remove solids and washed with acetonitrile (32 mL). The filtrate was concentrated under reduced pressure to 12 mL and transferred using acetonitrile (4 mL). Isopropanol (24 mL) was added dropwise and stirred at 35°C, water (16 mL) was added dropwise and further stirred at 30°C. Water (8 mL) was added dropwise and stirred at 30°C, the precipitated solid was filtered under reduced pressure and washed with a mixture of isopropanol (12 mL) and water (8 mL). It was dried under reduced pressure to obtain type II crystals of ethyl 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetate (3.61 g). (Yield 65%)

[0166] X-ray crystallography was carried out on the obtained type II crystal under the following conditions. Powder X-ray diffraction measurement conditions Equipment: MiniFlex600 (Rigaku) Operating conditions: X-ray output: Cu-Kα, tube voltage: 40 kV, tube current: 15 mA, sampling width: 0.02° Scanning range: 3°~40° Measurement temperature: room temperature

[0167] The XRD diffraction patterns of the II-type crystals are shown in Figures 2 and 3. The diffraction angle (2θ) values ​​of the II-type crystals are shown in Table 11. Table 11 [Table 12]

[0168] The type II crystal of the compound (a3-1-A) of the present invention is characterized by one or more of the following characteristic peaks in a powder X-ray diffraction pattern. (1) It is preferable that the powder X-ray diffraction pattern is substantially identical to the pattern shown in FIG. 2 and / or FIG. (2) The characteristic peaks in the powder X-ray diffraction pattern of the II-type crystals can be 8.52°±0.2°, 16.98°±0.2°, 20.16°±0.2°, and / or 26.12°±0.2°, as diffraction angles represented by 2θ. Other characteristic peaks can be 10.78°±0.2°, 23.56°±0.2°, 29.90°±0.2°, and / or 34.34°±0.2°. Still other characteristic peaks can be 5.64°±0.2°, 17.66°±0.2°, 18.08°±0.2°, 18.66°±0.2°, 20.60°±0.2°, 21.34°±0.2°, 22.64°±0.2°, and / or 25.08°±0.2°.

[0169] Example 39 Preparation of 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine [ka] [2-Chloro-5-(3-chlorophenyl)-3-pyridyl] 2,2-dimethylpropionate (99.9 mg, 0.308 mmol), methanol (1.03 mL), and 8 mol / L aqueous sodium hydroxide solution (0.116 mL) were added to the reaction vessel, and the mixture was stirred at room temperature for 1.5 hours, then heated to 40°C and stirred for another 3 hours. 8 mol / L aqueous sodium hydroxide solution (0.116 mL) was added and the mixture was stirred at 40°C for 1.5 hours, and the disappearance of the raw materials was confirmed. 6 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to about 3, and then water was added and extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated to dryness to obtain a crude product. This was purified by silica gel column chromatography to obtain 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine (68.7 mg). (Yield 92%) 1 H NMR (CDCl 3 ) δ:5.70 (1H, brs), 7.38-7.45 (3H, m), 7.50 (1H, d, J = 2.3 Hz), 7.53-7.54 (1H, m), 8.19 (1H, d, J = 2.1 Hz).

[0170] Example 40 Preparation of 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine [ka] [2-chloro-5-(3-chlorophenyl)-3-pyridyl] methanesulfonate (504.1 mg, 1.584 mmol), methanol (5.20 mL), and 8 mol / L aqueous sodium hydroxide solution (0.99 mL) were added to the reaction vessel, and the mixture was stirred at 40°C for 13 hours. After confirming the disappearance of [2-chloro-5-(3-chlorophenyl)-3-pyridyl] methanesulfonate, 6 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to about 3, and then water was added and the mixture was extracted three times with chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated to dryness to obtain a crude product. This was purified by silica gel column chromatography to obtain 2-chloro-5-(3-chlorophenyl)-3-hydroxypyridine (380.3 mg). (Yield 92%) 1 H NMR (CDCl 3 ) δ:5.69 (1H, brs), 7.38-7.45 (3H, m), 7.50 (1H, d, J = 2.1 Hz), 7.53-7.54 (1H, m), 8.19 (1H, d, J = 2.3 Hz). [Industrial Applicability]

[0171] According to the present invention, there is provided a process for producing compound (I) in good yield, which is suitable for industrial-scale production as a pharmaceutical.

Claims

1. Compound (a1) of the following formula: 【Chemistry 1】 {In the formula, R ２ represents a hydrogen atom or an optionally substituted methyl; R ａ３ represents a phenyl group which may be substituted with halogen; R ａ４ represents a hydrogen atom, or R ａ３ and R ａ４ are bonded to each other together with the adjacent pyridine to form an isoquinoline which may be substituted by phenyloxy; Z １ represents a chlorine atom, a bromine atom, or an iodine atom, Z ａ２ is a hydroxyl or a substituent of the formula 【Chemistry 2】 (In the formula, P １ represents a hydroxy protecting group) represents. , a compound of the following formula (2): 【Chemistry 3】 (In the formula, R １ represents an optionally substituted alkyl, a hydrogen atom, or a resin residue. Alternatively, a salt of compound (2) and a carbon monoxide molecule are reacted in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence of a base in a solvent to obtain a compound (a3) ​​of the following formula: 【Chemistry 4】 (wherein the symbols have the same meanings as defined above) A method for manufacturing the same.

2. 2. The method of claim 1, wherein the pressure during the reaction of the carbon monoxide molecules is between 0.01 MPa and 1 MPa.

3. The method according to claim 1 or 2, wherein the molar ratio of the compound (a1) to the compound (2) used in the reaction is from 2:1 to 1:

2.

4. The method according to any one of claims 1 to 3, wherein the solvent is a nitrile and the reaction is carried out at a reaction temperature of 20°C to 150°C.

5. The compound (a1) is a compound (a1-5-a) of the following formula: 【Chemistry 5】 (In the formula, Z １ represents a chlorine atom, a bromine atom, or an iodine atom) and The compound (a3) ​​is a compound (a3-3-a) of the following formula: 【Chemistry 6】 (In the formula, R １ represents an optionally substituted alkyl, a hydrogen atom, or a resin residue. The compound according to any one of claims 1 to 4,

6. The compound (a3-1) of the following formula is obtained by the method according to any one of claims 1 to 4: 【Chemistry 7】 {In the formula, R １－１ represents an optionally substituted alkyl or resin residue, R ２ represents a hydrogen atom or an optionally substituted methyl; R ａ３ represents a phenyl group which may be substituted with halogen; R ａ４ represents a hydrogen atom, or R ａ３ and R ａ４ are bonded to each other together with the adjacent pyridine to form an isoquinoline which may be substituted by phenyloxy; Z ａ２ is a hydroxyl or a substituent of the formula 【Chemistry 8】 (In the formula, P １ represents a hydroxy protecting group) represents. and converting the compound (a3-1) to obtain a compound (aI) of the following formula: 【Chemistry 9】 {wherein the symbols have the same meanings as defined above.} A method for manufacturing the same.

7. (i) R ２ is a hydrogen atom, R ａ３ is 3-chlorophenyl, and R ａ４ is a hydrogen atom, or (ii) R ２ is methyl, and R ａ３ and R ａ４ The method according to any one of claims 1 to 4 and 6, wherein are linked together with adjacent pyridines to form 7-phenyloxy-isoquinoline.

8. The compound (a3-1) is a compound (a3-2-a) of the following formula: 【Chemistry 10】 (In the formula, R １－１ represents an optionally substituted alkyl or resin residue) and Compound (aI) is a compound of the following formula [I(A)]: 【Chemistry 11】 The method of claim 6, wherein

9. The compound (a1) is represented by the following formula (a1-1-a): 【Chemistry 12】 {In the formula, Z ａ２ is a hydroxyl or a substituent of the formula 【Chemistry 13】 (In the formula, P １ represents a hydroxy protecting group) represents. The compound (a1-1-a) is a compound (a4) represented by the following formula: 【Chemistry 14】 (In the formula, Z ａ３ represents a bromine atom, an iodine atom or trifluoromethanesulfoxy; Z ａ２ has the same meaning as above) , a compound (a5) of the following formula: 【Chemistry 15】 (In the formula, X ａ１ and X ａ２ each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. or an equivalent of compound (a5) in the presence or absence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, in a solvent or without a solvent, to produce compound (a1-1-a).

10. The compound (a1-1-a) is a compound (a1-4-a) of the following formula: 【Chemistry 16】 and The compound (a4) is a compound (a4-2) of the following formula: 【Chemistry 17】 (In the formula, Z ａ３ represents a bromine atom or an iodine atom) The method of claim 9, wherein

11. The compound of the formula I(A): 【Chemistry 18】 A method for producing (i) A compound (a4) of the following formula: 【Chemistry 19】 {In the formula, Z ａ２ is a hydroxyl or a substituent of the formula 【Chemistry 20】 (In the formula, P ａ１ represents a hydroxy protecting group) represents Z ａ３ represents a bromine atom, an iodine atom, or trifluoromethanesulfoxy. and a compound (a5) of the following formula: 【Chemistry 21】 (In the formula, X ａ１ and X ａ２ each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. Alternatively, an equivalent of compound (a5) is reacted with a compound represented by the following formula (a1-1-a): 【Chemical 22】 (In the formula, Z ａ２ has the same meaning as above) A step of producing a compound represented by the formula: (ii) The compound (a1-1-a), a compound (2-1) of the following formula: 【Chemistry 23】 (In the formula, R １－１ represents an optionally substituted alkyl or resin residue) Alternatively, a salt of the compound (2-1) and a carbon monoxide molecule are reacted in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, and in the presence or absence of a base, in a solvent or without a solvent, to obtain a compound (a3-1-a) of the following formula: 【Chemistry 24】 (In the formula, R １－１ , and Z ａ２ has the same meaning as above) and (iii) converting the compound (a3-1-a) to obtain a compound of the following formula [I(A)]: 【Chemistry 25】 A method for producing compound [I(A)], comprising the step of producing

12. The compound (a4) is a compound (a4-2) of the following formula: 【Chemistry 26】 (In the formula, Z ａ３ represents a bromine atom or an iodine atom) and The compound (a1-1-a) is a compound (a1-4-a) of the following formula: 【Chemical 27】 and The compound (a3-1-a) is a compound (a3-2-a) of the following formula: 【Chemistry 28】 (In the formula, R １－１ represents an optionally substituted alkyl or resin residue) The method of claim 11, wherein

13. The compound of the formula I(A): 【Chemical 29】 A method for producing (i) A compound (a4-1) of the following formula: 【Chemistry 30】 {In the formula, Z a2-1 is a substituent of the formula 【Chemistry 31】 (In the formula, P １ represents a hydroxy protecting group) represents Z ａ３ represents a bromine atom, an iodine atom, or trifluoromethanesulfoxy. and a compound (a5) of the following formula: 【Chemistry 32】 (In the formula, X ａ１ and X ａ２ each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. Alternatively, an equivalent of compound (a5) is reacted with a compound represented by the following formula (a1-3-a): 【Chemical 33】 (In the formula, Z a2-1 has the same meaning as above) A step of producing a compound represented by the formula: (ii) converting the compound (a1-3-a) to obtain a compound (a1-4-a) of the following formula: 【Chemical 34】 manufacturing a (iii) The compound (a1-4-a), a compound (2-1) having the following formula: 【Chemistry 35】 (In the formula, R １－１ represents an optionally substituted alkyl or resin residue) Alternatively, a salt of the compound (2-1) and a carbon monoxide molecule are reacted in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, and in the presence or absence of a base, in a solvent or without a solvent, to obtain a compound (a3-2-a) of the following formula: 【Chemical 36】 (In the formula, R １－１ has the same meaning as above) and (iv) converting the compound (a3-2-a) to obtain a compound of the following formula [I(A)]: 【Chemical 37】 A method for producing compound [I(A)], comprising the step of producing

14. Compound (b3-1) of the following formula: 【Chemical 38】 (In the formula, R １ represents an optionally substituted alkyl, a hydrogen atom, or a resin residue, R ２ represents a hydrogen atom or an optionally substituted methyl; R ３ represents phenyl optionally substituted with halogen, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R ４ represents a hydrogen atom, or R ３ and R ４ are bonded together with the adjacent pyridine to form an isoquinoline which may be substituted with phenyloxy. A method for producing (i) A compound (b1) of the following formula: 【Chemical Formula 39】 (In the formula, Z １ represents a chlorine atom, a bromine atom, or an iodine atom, Z ｂ２ represents a chlorine atom, a bromine atom, or an iodine atom, R ２ , R ３ , and R ４ has the same meaning as above) , a compound of the following formula (2): 【Chemistry 40】 (In the formula, R １ represents an optionally substituted alkyl, a hydrogen atom, or a resin residue. or a salt of compound (2) and a carbon monoxide molecule in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence of a base in a solvent to obtain a compound (b3) of the following formula: 【Chemistry 41】 (wherein the symbols have the same meanings as defined above) and (ii) Reacting the compound (b3) with a compound (b4) of the following formula: 【Chemistry 42】 (In the formula, R ｂ５ represents an optionally substituted aryl or an optionally substituted alkyl. in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence of a base, in a solvent to obtain a compound (b3-1) of the following formula: 【Chemistry 43】 (wherein the symbols have the same meanings as defined above) A method for producing compound (b3-1), comprising the step of producing

15. 15. The method of claim 14, wherein the pressure during the reaction of the carbon monoxide molecules is between 0.01 MPa and 1 MPa.

16. The method according to claim 14 or 15, wherein the molar ratio of the compound (b1) to the compound (2) used in the reaction is 2:1 to 1:

2.

17. The method according to any one of claims 14 to 16, wherein the solvent is a nitrile and the reaction is carried out at a reaction temperature of 20°C to 150°C.

18. The method according to any one of claims 14 to 17, wherein a compound of the following formula (b3-2-2): 【Chemistry 44】 (In the formula, R １ represents an optionally substituted alkyl, a hydrogen atom, or a resin residue, R ｂ３ represents a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy. and synthesizing the compound (b3-2-2) and a compound (b6) of the following formula: 【Chemistry 45】 (In the formula, X ｂ１ and X ｂ２ each independently represents a hydrogen atom or an alkyl, or both are bonded to each other to form an alkylene. Alternatively, an equivalent of compound (b6) is reacted with a compound represented by the following formula (b3-2-a): 【Chemistry 46】 (wherein the symbols have the same meanings as defined above) A method for manufacturing the same.

19. The method according to any one of claims 14 to 18, wherein a compound of the following formula (b3-1-1): 【Chemistry 47】 (In the formula, R １－１ represents an optionally substituted alkyl or resin residue, R ２ represents a hydrogen atom or an optionally substituted methyl; R ３ represents phenyl optionally substituted with halogen, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R ４ represents a hydrogen atom, or R ３ and R ４ represent that they are bonded together with the adjacent pyridine to form an isoquinoline which may be substituted with phenyloxy. and converting the compound (b3-1-1) to obtain a compound (I) of the following formula: 【Chemistry 48】 (wherein the symbols have the same meanings as defined above) A method for manufacturing the same.

20. (i) R ２ is a hydrogen atom, R ３ is 3-chlorophenyl, and R ４ is a hydrogen atom, or (ii) R ２ is methyl, and R ３ and R ４ The method of any one of claims 14 to 17 and 19, wherein are linked together with adjacent pyridines to form 7-phenyloxy-isoquinoline.

21. Compound (bI-1) of the following formula: 【Chemistry 49】 (In the formula, R ２ represents a hydrogen atom or an optionally substituted methyl; R ｂ３－３ represents 3-chlorophenyl, a chlorine atom, a bromine atom, an iodine atom, or trifluoromethanesulfoxy; R ｂ４－３ represents a hydrogen atom, or R ｂ３－３ and R ｂ４－３ represent bonds with each other and adjacent pyridines to form 7-phenyloxy-isoquinoline. A method for producing (i) A compound (b1-2) of the following formula: 【Chemistry 50】 (In the formula, Z １ represents a chlorine atom, a bromine atom, or an iodine atom, Z ｂ２ represents a chlorine atom, a bromine atom, or an iodine atom, R ２ is R ｂ３－３ and R ｂ４－３ has the same meaning as above.) , a compound of the following formula (2-1): 【Chemistry 51】 (In the formula, R １－１ represents an optionally substituted alkyl or resin residue) Alternatively, a salt of the compound (2-1) and a carbon monoxide molecule are reacted in the presence or absence of a palladium catalyst, in the presence or absence of a ligand, and in the presence or absence of a base, in a solvent or without a solvent, to obtain a compound represented by the following formula (b3-4): 【Chemistry 52】 (wherein the symbols have the same meanings as defined above) A process for producing a compound represented by the formula: (ii) The compound (b3-4) and a compound (b4) of the following formula: 【Chemistry 53】 (In the formula, R ｂ５ represents an optionally substituted aryl or an optionally substituted alkyl. in the presence of a palladium catalyst, in the presence or absence of a ligand, and in the presence of a base, in a solvent to obtain a compound (b3-5) of the following formula: 【Chemical 54】 (wherein the symbols have the same meanings as defined above) and (iii) converting the compound (b3-5) to obtain a compound (bI-1) of the following formula: 【Chemistry 55】 (wherein the symbols have the same meanings as defined above) A method for producing compound (bI-1), comprising the step of producing

22. A compound of the following formula (a1-a). 【Chemistry 56】 {In the formula, Z １ represents a chlorine atom, a bromine atom, or an iodine atom, Z ａ２ is a hydroxyl or a substituent of the formula 【Chemistry 57】 (In the formula, P １ represents a hydroxy protecting group) represents.

23. Compound (a3-1-A) of the following formula: 【Chemistry 58】 (wherein Et represents ethyl) Crystals.

24. The crystal of compound (a3-1-A) according to claim 23, wherein the crystal is type I crystal of compound (a3-1-A).

25. The crystal of compound (a3-1-A) according to claim 23, wherein the crystal is a type II crystal of compound (a3-1-A).

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