Method for producing pyridine compounds

Abstract

To provide an industrial method for producing pyridine compounds.SOLUTION: The invention provides: a method for producing a compound represented by formula (3), e.g., by reacting a 2-chloropyridine compound represented by formula (1) with a Grignard reagent represented by formula (2); and a method for producing an isoindolinedione compound represented by formula (8). [In the formulas: R represents a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, or the like; and X represents a halogen atom.]SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a pyridine compound which is useful as a pharmaceutical or agricultural chemical or an intermediate for the production thereof. [Background technology]

[0002] It is known that certain pyridine compounds, such as 2-acetylpyridine compounds and pyridinyl-2-oxoethylisoindoline compounds, are useful as intermediates for biologically active compounds (see, for example, Patent Document 1 and Patent Document 2). Known methods for synthesizing 2-acetylpyridine compounds include a method using a 2-halopyridine compound and a vinyltin compound (see, for example, Patent Document 3 and Patent Document 4), or introducing an acetyl group into a pyridine ring (see, for example, Patent Document 5 and Non-Patent Document 1). On the other hand, a method for synthesizing pyridinyl-2-oxoethylisoindoline compounds is known in which a 2-haloacetylpyridine compound is reacted with an isoindoline compound (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2005 / 058828 [Patent Document 2] International Publication No. 2014 / 010737 [Patent Document 3] International Publication No. 2014 / 141153 [Patent Document 4] International Publication No. 2013 / 185103 [Patent Document 5] JP 2002-212167 A Summary of the Invention [Problem to be solved by the invention]

[0004] Many methods for synthesizing 2-acetylpyridine compounds are known, but the problem with conventional techniques is that many of these methods are not suitable for industrial mass production. For example, the vinyltin compounds used in Patent Document 3 and Patent Document 4 are not suitable for industrial use in terms of worker safety and environmental burden. Furthermore, palladium used in Patent Document 5 is one of the elements that is concerned about depletion, and it is necessary to develop an alternative synthesis method in order to continue mass production. On the other hand, as a method for synthesizing pyridinyl-2-oxoethylisoindoline compounds, for example, Patent Document 1 describes a method of reacting a 2-haloacetylpyridine compound with an isoindoline compound, but the yield is low and it is not suitable for mass production. [Means for solving the problem]

[0005] As a result of intensive investigations aimed at solving the above problems, a simple method for producing a pyridine compound was discovered, and the present invention was completed.

[0006] That is, the present invention relates to the following descriptions [1] to

[30] . [1] Formula (1):

[0007] [ka]

[0008] [In the formula, R is substituted by a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl. a 2-picolinonitrile compound represented by the formula (2):

[0009] [ka]

[0010] [wherein X represents a halogen atom],

[0011] [ka]

[0012]

[0013] A method for producing a pyridinyl ethanone compound represented by the formula:

[0014] wherein R has the same meaning as defined above. [2] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; The method for producing a pyridinyl ethanone compound according to [1], wherein X represents a chlorine atom, a bromine atom, or an iodine atom. [3] Formula (4):

[0013] [ka]

[0014] [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, C represents phenylsulfonyl which may be substituted with 1-C4 alkyl, phenylsulfonyloxy which may be substituted with C1-C4 alkyl, phenylsulfonyl which may be substituted with halogen, phenylsulfonyloxy which may be substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl, and Y represents a hydrogen atom or a halogen atom], with an oxidizing agent to obtain a compound represented by the formula (3):

[0015] [ka]

[0016] A method for producing a pyridinyl ethanone compound represented by the formula: [wherein R has the same meaning as defined above]. [4] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; The method for producing a pyridinyl ethanone compound according to [3], wherein Y represents a hydrogen atom, a chlorine atom, a bromine atom, or an iodine atom. [5] Formula (5):

[0017] [ka]

[0018] [In the formula, R is a fluorine-containing alkyl group which may be substituted by a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl.

[0043] By reacting a 2-ethylpyridine compound represented by the formula (6):

[0019] [ka]

[0020] [In the formula, R has the same meaning as defined above, and X represents a halogen atom], and the resulting 2-(1-halogeno)pyridine compound represented by formula (6) is reacted with an oxidizing agent to obtain a 2-(1-halogeno)pyridine compound represented by formula (3):

[0021] [ka]

[0022] A method for producing a pyridinyl ethanone compound represented by the formula: [wherein R has the same meaning as defined above]. [6] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; The method for producing a pyridinyl ethanone compound according to [5], wherein X represents a chlorine atom, a bromine atom, or an iodine atom. [7] Formula (7):

[0023] [ka]

[0024] [In the formula, R is a fluorine-containing alkyl group which may be substituted by a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl.

[0036] To obtain a 2-pyridylpropionic acid compound represented by the formula (3):

[0025] [ka]

[0026] A method for producing a pyridinyl ethanone compound represented by the formula: [wherein R has the same meaning as defined above]. [8] The method for producing a pyridinylethanone compound according to [7], wherein R represents a halogen atom, a C1 to C6 alkyl, a C2 to C8 alkenyl, or a C2 to C8 alkynyl. [9] Formula (7):

[0027] [ka]

[0028] [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, substituted with C1-C4 alkyl. phenylsulfonyl optionally substituted with C1-C4 alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl.

[10] The 2-pyridylpropionic acid compound according to [9], wherein R represents a halogen atom, a C1 to C6 alkyl, a C2 to C8 alkenyl, or a C2 to C8 alkynyl.

[11] Formula (8):

[0029] [ka]

[0030] [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, C1 phenylsulfonyl optionally substituted with C1-C4 alkyl, phenylsulfonyloxy optionally substituted with C1-C4 alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl; R 1 represents a hydrogen atom, a C1-C6 alkyl, or a C2-C8 alkynyl], to obtain a compound represented by the formula (3):

[0031] [ka]

[0032] A method for producing a pyridinyl ethanone compound represented by the formula: [wherein R has the same meaning as defined above].

[12] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; R 1 represents C1 to C6 alkyl.

[13] Formula (8):

[0033] [ka]

[0034] [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, C1 phenylsulfonyl optionally substituted with C1-C4 alkyl, phenylsulfonyloxy optionally substituted with C1-C4 alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl; R 1 represents a hydrogen atom, a C1-C6 alkyl, or a C2-C8 alkynyl.

[14] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; R 1 represents C1 to C6 alkyl.

[15] Formula (3):

[0035] [ka]

[0036] [In the formula, R is a fluorine-containing alkyl group which may be substituted by a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl.

[0043] A pyridinyl ethanone compound represented by the formula (9):

[0037] [ka]

[0038] [wherein R is as defined above, and X is a halogen atom] to synthesize a 2-halogeno-1-pyridinyl ethanone compound represented by formula (9), and reacting the resulting 2-halogeno-1-pyridinyl ethanone compound represented by formula (10):

[0039] [ka]

[0040] A method for producing an isoindolinedione compound represented by the formula: [wherein R has the same meaning as defined above].

[16] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; The method for producing a pyridinylethanone compound according to

[15] , wherein X represents a chlorine atom, a bromine atom, or an iodine atom.

[17] Equation (11):

[0041] [ka]

[0042] [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, phenylsulfonyl which may be substituted with a C1-C4 alkyl. , phenylsulfonyloxy which may be substituted with C1-C4 alkyl, phenylsulfonyl which may be substituted with halogen, phenylsulfonyloxy which may be substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl, and X represents a halogen atom, to obtain a 2,2-dihalo-1-pyridinylethanone compound represented by the formula (9):

[0043] [ka]

[0044] [wherein R and X are as defined above], and the resulting 2-halogeno-1-pyridinyl ethanone compound represented by formula (9) is reacted with phthalimide or potassium phthalimide in the presence of a phase transfer catalyst to obtain a compound represented by formula (10):

[0045] [ka]

[0046] A method for producing an isoindolinedione compound represented by the formula: [wherein R has the same meaning as defined above].

[18] R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl; The method for producing a pyridinylethanone compound according to

[17] , wherein X represents a chlorine atom, a bromine atom, or an iodine atom.

[19] Equation (11):

[0047] [ka]

[0048] [In the formula, R is a phenyl group which may be substituted by a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl. wherein X represents a halogen atom, phenylsulfonyl, phenylsulfonyloxy which may be substituted with C1-C4 alkyl, phenylsulfonyl which may be substituted with halogen, phenylsulfonyloxy which may be substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl, and X represents a halogen atom.

[20] The 2,2-dihalo-1-pyridinylethanone compound according to

[17] , wherein R represents a halogen atom, a C1 to C6 alkyl, a C2 to C8 alkenyl or a C2 to C8 alkynyl, and X represents a bromine atom. 〔twenty one〕 Formula (12):

[0049] [ka]

[0050] [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, phenylsulfur optionally substituted with C1-C4 alkyl. a pyridinylacetonitrile compound represented by the formula (13):

[0051] [ka]

[0052] A method for producing a pyridinylacrylonitrile compound represented by the formula: [wherein R has the same meaning as defined above]. 〔twenty two〕 The method for producing a pyridinylacrylonitrile compound according to

[21] , wherein R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl or a C2-C8 alkynyl. 〔twenty three〕 Equation (13):

[0053] [ka]

[0054] [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or phenyl which may be substituted with C1-C4 alkyl. a pyridinyl acrylonitrile compound represented by the formula (14):

[0055] [ka]

[0056] A method for producing a pyridinyloxirane compound represented by the formula (14), wherein R has the same meaning as defined above. 〔twenty four〕 The method for producing a pyridinyloxirane compound according to

[23] , wherein R represents a halogen atom, a C1-C6 alkyl, a C2-C8 alkenyl or a C2-C8 alkynyl. 〔twenty five〕 Equation (14):

[0057] [ka]

[0058] [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, phenylsulfonyl optionally substituted with C1-C4 alkyl. , phenylsulfonyloxy which may be substituted with C1-C4 alkyl, phenylsulfonyl which may be substituted with halogen, phenylsulfonyloxy which may be substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl, by reacting a pyridinyloxirane compound represented by the formula (10):

[0059] [ka]

[0060] A method for producing an isoindoline compound represented by the formula: [wherein R has the same meaning as defined above].

[26] The method for producing an isoindoline compound according to

[25] , wherein R represents a halogen atom, a C1 to C6 alkyl, a C2 to C8 alkenyl, or a C2 to C8 alkynyl.

[27] Equation (13):

[0061] [ka]

[0062] [In the formula, R is substituted by a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl. pyridinyl acrylonitrile compounds represented by the formula (1), which represents phenylsulfonyl optionally substituted with C1-C4 alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl.

[28] The pyridinylacrylonitrile compound according to

[27] , wherein R represents a halogen atom, a C1 to C6 alkyl, a C2 to C8 alkenyl, or a C2 to C8 alkynyl.

[29] Equation (14):

[0063] [ka]

[0064] [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, cyano, nitro, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, halo(C2-C6)alkoxy, C2-C8 alkenyl, halo(C2-C8)alkenyl, C2-C8 alkynyl, halo(C2-C8)alkynyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyloxy, halo(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyloxy, or C1-C4 alkyl. pyridinyloxirane compounds represented by the formula (I), which represents phenylsulfonyl optionally substituted with C1-C4 alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, halo(C1-C6)alkylcarbonyl, halo(C1-C6)alkylcarbonyloxy or C1-C6 alkoxycarbonyl.

[30] The pyridinyloxirane compound according to

[29] , wherein R represents a halogen atom, a C1 to C6 alkyl, a C2 to C8 alkenyl, or a C2 to C8 alkynyl. Effect of the Invention

[0065] The present invention can provide an industrial production method for pyridine compounds useful as pharmaceuticals, agrochemicals, or production intermediates thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] When the compound of the present invention and the compounds serving as starting materials in the production method have one or more asymmetric carbon atoms, the present invention includes all optically active forms, racemates or diastereomers.

[0067] Specific examples of the substituents shown in the present specification are shown below, where n- means normal, i- means iso, s- means secondary, t- means tertiary, and m- means meta.

[0068] In the present invention, the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present specification, the term "halo" also represents these halogen atoms.

[0069] In this specification, "C a ~C b The term "alkyl" refers to a straight-chain or branched-chain hydrocarbon group having a to b carbon atoms, and examples of such groups include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a neopentyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methyl Specific examples include a pentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,1,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group, each of which is selected within the specified range of carbon numbers.

[0070] As used herein, the term "halo(C a ~C b The notation "alkyl" means a C 1 -alkyl group as defined above in which the hydrogen atoms bonded to the carbon atom are optionally replaced by halogen atoms as defined above. a ~C bSpecific examples of the alkyl group include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a difluoromethyl group, a trifluoromethyl group, a dichloromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a chlorodifluoromethyl group, a bromodifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, a heptafluoroisopropyl group, a 4-chlorobutyl group, and a 4-fluorobutyl group.

[0071] In this specification, "C a ~C b The term "alkoxy" represents an alkyl-O- group having a to b carbon atoms as defined above, and specific examples thereof include a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i-butyloxy group, an s-butyloxy group, a tert-butyloxy group, a pentyloxy group, and a hexyloxy group.

[0072] In this specification, "C a ~C b The term "alkenyl" refers to a linear or branched unsaturated hydrocarbon group having a to b carbon atoms and having one or more double bonds in the molecule. Specific examples include vinyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and 3-methyl-3-butenyl.

[0073] As used herein, "halo(C a ~C bThe term "alkenyl" refers to a linear or branched unsaturated hydrocarbon group having a to b carbon atoms, in which hydrogen atoms bonded to carbon atoms are optionally substituted with halogen atoms, and having one or more double bonds in the molecule. In this case, when substituted with two or more halogen atoms, the halogen atoms may be the same or different from each other. Specific examples include a 2-fluorovinyl group, a 2-chlorovinyl group, a 1,2-dichlorovinyl group, a 2,2-dichlorovinyl group, a 2,2-dibromovinyl group, a 2-fluoro-2-propenyl group, a 2-chloro-2-propenyl group, a 3-chloro-2-propenyl group, a 3,3-difluoro-2-propenyl group, a 2,3-dichloro-2-propenyl group, a 3,3-dichloro-2-propenyl group, a 2,3,3-trifluoro-2-propenyl group, a 2,3,3-trichloro-2-propenyl group, a 1-(trifluoromethyl)ethenyl group, a 4,4-difluoro-3-butenyl group, a 3,4,4-trifluoro-3-butenyl group, a 2,4,4,4-tetrafluoro-2-butenyl group, and a 3-chloro-4,4,4-trifluoro-2-butenyl group.

[0074] In this specification, "C a ~C b The term "alkynyl" refers to a linear or branched unsaturated hydrocarbon group having a to b carbon atoms and having one or more triple bonds in the molecule. Specific examples include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a 1-pentynyl group, a 2-pentynyl group, a 1-hexynyl group, a 3-hexynyl group, a 3-methyl-1-pentynyl group, a 4-methyl-1-pentynyl group, and a 3,3-dimethyl-1-butynyl group.

[0075] As used herein, the term "halo(C a ~C bThe term "alkynyl" refers to a linear or branched unsaturated hydrocarbon group having a to b carbon atoms and having one or more triple bonds in the molecule, in which hydrogen atoms bonded to carbon atoms are optionally substituted with halogen atoms, and in this case, when substituted with two or more halogen atoms, those halogen atoms may be the same or different from each other. Specific examples include a 2-chloroethynyl group, a 2-bromoethynyl group, a 2-iodoethynyl group, a 3-fluoro-1-propynyl group, a 3-chloro-1-propynyl group, a 3-chloro-2-propynyl group, a 3-bromo-1-propynyl group, a 3-bromo-2-propynyl group, a 3-iodo-2-propynyl group, a 3,3-difluoro-1-propynyl group, a 3,3,3-trifluoro-1-propynyl group, a 3-bromo-1-butynyl group, a 3-fluoro-3-methyl-1-butynyl group, a 3-chloro-3-methyl-1-butynyl group, and a 3-bromo-3-methyl-1-butynyl group. The expression "C1-C6 alkylsulfonyl" in the present specification represents a sulfonyl group having an alkyl group having a to b carbon atoms as defined above and bonded thereto, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i-butylsulfonyl group, a t-butylsulfonyl group, an s-butylsulfonyl group, an n-pentylsulfonyl group, a 1-methylbutylsulfonyl group, a 2-methylbutylsulfonyl group, a 3-methylbutylsulfonyl group, a 1-ethylpropylsulfonyl group, a 1,1-dimethylpropylsulfonyl group, a 1,2-dimethylpropylsulfonyl group, and a neopentylsulfonyl group. Specific examples include an n-hexylsulfonyl group, a 1-methylpentylsulfonyl group, a 2-methylpentylsulfonyl group, a 3-methylpentylsulfonyl group, a 4-methylpentylsulfonyl group, a 1-ethylbutylsulfonyl group, a 2-ethylbutylsulfonyl group, a 1,1-dimethylbutylsulfonyl group, a 1,2-dimethylbutylsulfonyl group, a 1,3-dimethylbutylsulfonyl group, a 2,2-dimethylbutylsulfonyl group, a 2,3-dimethylbutylsulfonyl group, a 3,3-dimethylbutylsulfonyl group, a 1,1,2-trimethylpropylsulfonyl group, a 1-ethyl-1-methylpropylsulfonyl group, and a 1-ethyl-2-methylpropylsulfonyl group.

[0076] In this specification, "C a ~C bThe notation of "alkylsulfonyloxy" represents an alkylsulfonyl-O- group having the above-mentioned meaning and containing a to b carbon atoms, and examples thereof include a methylsulfonyloxy group, an ethylsulfonyloxy group, an n-propylsulfonyloxy group, an i-propylsulfonyloxy group, an n-butylsulfonyloxy group, an i-butylsulfonyloxy group, a t-butylsulfonyloxy group, an s-butylsulfonyloxy group, an n-pentylsulfonyloxy group, a 1-methylbutylsulfonyloxy group, a 2-methylbutylsulfonyloxy group, a 3-methylbutylsulfonyloxy group, a 1-ethylpropylsulfonyloxy group, a 1,1-dimethylpropylsulfonyloxy group, a 1,2-dimethylpropylsulfonyloxy group, a neopentylsulfonyloxy group, an n-hexyl ...butylsulfonyloxy group, an ethylsulfonyloxy group, an n-butylsulfonyloxy group, an i-butylsulfonyloxy group, an i-butylsulfonyloxy group, an i-butylsulf Specific examples include a sulfonyloxy group, a 1-methylpentylsulfonyloxy group, a 2-methylpentylsulfonyloxy group, a 3-methylpentylsulfonyloxy group, a 4-methylpentylsulfonyloxy group, a 1-ethylbutylsulfonyloxy group, a 2-ethylbutylsulfonyloxy group, a 1,1-dimethylbutylsulfonyloxy group, a 1,2-dimethylbutylsulfonyloxy group, a 1,3-dimethylbutylsulfonyloxy group, a 2,2-dimethylbutylsulfonyloxy group, a 2,3-dimethylbutylsulfonyloxy group, a 3,3-dimethylbutylsulfonyloxy group, a 1,1,2-trimethylpropylsulfonyloxy group, a 1-ethyl-1-methylpropylsulfonyloxy group, and a 1-ethyl-2-methylpropylsulfonyloxy group.

[0077] As used herein, the term "halo(C a ~C bThe notation of "alkylsulfonyl" represents an alkylsulfonyl group as defined above having a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom, and examples thereof include a fluoromethylsulfonyl group, a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group, a chlorodifluoromethylsulfonyl group, a chloromethylsulfonyl group, a trichloromethylsulfonyl group, a 2,2,2-trifluoroethylsulfonyl group, a 2-chloro-2,2-difluoroethylsulfonyl group, and a 3,3,3-trifluoropropylsulfonyl group.

[0078] As used herein, the term "halo(C a ~C b The notation of "alkylsulfonyloxy" represents a haloalkylsulfonyl-O- group having a to b carbon atoms as defined above, and examples thereof include a fluoromethylsulfonyloxy group, a difluoromethylsulfonyloxy group, a trifluoromethylsulfonyloxy group, a chlorodifluoromethylsulfonyloxy group, a chloromethylsulfonyloxy group, a trichloromethylsulfonyloxy group, a 2,2,2-trifluoroethylsulfonyloxy group, a 2-chloro-2,2-difluoroethylsulfonyloxy group, and a 3,3,3-trifluoropropylsulfonyloxy group.

[0079] In this specification, "C a ~C b The notation of "phenylsulfonyl which may be substituted with alkyl" represents a phenylsulfonyl group which may be substituted with an alkyl group having a to b carbon atoms as defined above, and examples thereof include an o-toluenesulfonyl group, an m-toluenesulfonyl group, a p-toluenesulfonyl group, and a 2,4,6-trimethylbenzenesulfonyl group.

[0080] In this specification, "C a ~C bThe notation of "phenylsulfonyloxy which may be substituted with alkyl" represents a phenylsulfonyl-O- group which may be substituted with an alkyl group having a to b carbon atoms as defined above, and examples thereof include an o-toluenesulfonyloxy group, an m-toluenesulfonyloxy group, a p-toluenesulfonyloxy group, and a 2,4,6-trimethylbenzenesulfonyloxy group.

[0081] The term "phenylsulfonyl which may be substituted by halogen" in this specification represents a phenylsulfonyl group which may be substituted by 1 to 5 halogen atoms as defined above, and examples thereof include an o-fluorobenzenesulfonyl group, a p-fluorobenzenesulfonyl group, an o-chlorobenzenesulfonyl group, a p-chlorobenzenesulfonyl group, an o-bromobenzenesulfonyl group, a p-bromobenzenesulfonyl group, a 2,4-difluorobenzenesulfonyl group, a 2,4-dichlorobenzenesulfonyl group, a 2,6-difluorobenzenesulfonyl group, and a 2,6-dichlorobenzenesulfonyl group.

[0082] The expression "phenylsulfonyloxy which may be substituted by halogen" in this specification represents a phenylsulfonyl-O- group which may be substituted by a halogen atom as defined above, and examples thereof include an o-fluorobenzenesulfonyloxy group, a p-fluorobenzenesulfonyloxy group, an o-chlorobenzenesulfonyloxy group, a p-chlorobenzenesulfonyloxy group, an o-bromobenzenesulfonyloxy group, a p-bromobenzenesulfonyloxy group, a 2,4-difluorobenzenesulfonyloxy group, a 2,4-dichlorobenzenesulfonyloxy group, a 2,6-difluorobenzenesulfonyloxy group, and a 2,6-dichlorobenzenesulfonyloxy group.

[0083] In this specification, "C a ~C bThe term "alkylcarbonyl" refers to a carbonyl group to which an alkyl group having a to b carbon atoms is bonded, and examples of such groups include an acetyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an i-propylcarbonyl group, an n-butylcarbonyl group, an i-butylcarbonyl group, a t-butylcarbonyl group, an s-butylcarbonyl group, an n-pentylcarbonyl group, a 1-methylbutylcarbonyl group, a 2-methylbutylcarbonyl group, a 3-methylbutylcarbonyl group, a 1-ethylpropylcarbonyl group, a 1,1-dimethylpropylcarbonyl group, a 1,2-dimethylpropylcarbonyl group, a neopentylcarbonyl group, an n-hexylcarbonyl group, Specific examples include a 1-methylpentylcarbonyl group, a 2-methylpentylcarbonyl group, a 3-methylpentylcarbonyl group, a 4-methylpentylcarbonyl group, a 1-ethylbutylcarbonyl group, a 2-ethylbutylcarbonyl group, a 1,1-dimethylbutylcarbonyl group, a 1,2-dimethylbutylcarbonyl group, a 1,3-dimethylbutylcarbonyl group, a 2,2-dimethylbutylcarbonyl group, a 2,3-dimethylbutylcarbonyl group, a 3,3-dimethylbutylcarbonyl group, a 1,1,2-trimethylpropylcarbonyl group, a 1-ethyl-1-methylpropylcarbonyl group, and a 1-ethyl-2-methylpropylcarbonyl group.

[0084] In this specification, "C a ~C bThe term "alkylcarbonyloxy" represents an alkylcarbonyl-O- group as defined above, such as an acetyloxy group, an ethylcarbonyloxy group, an n-propylcarbonyloxy group, an i-propylcarbonyloxy group, an n-butylcarbonyloxy group, an i-butylcarbonyloxy group, a t-butylcarbonyloxy group, an s-butylcarbonyloxy group, an n-pentylcarbonyloxy group, a 1-methylbutylcarbonyloxy group, a 2-methylbutylcarbonyloxy group, a 3-methylbutylcarbonyloxy group, a 1-ethylpropylcarbonyloxy group, a 1,1-dimethylpropylcarbonyloxy group, a 1,2-dimethylpropylcarbonyloxy group, a neopentylcarbonyloxy group, an n-hexylcarbonyloxy group, Specific examples include a 1-methylpentylcarbonyloxy group, a 2-methylpentylcarbonyloxy group, a 3-methylpentylcarbonyloxy group, a 4-methylpentylcarbonyloxy group, a 1-ethylbutylcarbonyloxy group, a 2-ethylbutylcarbonyloxy group, a 1,1-dimethylbutylcarbonyloxy group, a 1,2-dimethylbutylcarbonyloxy group, a 1,3-dimethylbutylcarbonyloxy group, a 2,2-dimethylbutylcarbonyloxy group, a 2,3-dimethylbutylcarbonyloxy group, a 3,3-dimethylbutylcarbonyloxy group, a 1,1,2-trimethylpropylcarbonyloxy group, a 1-ethyl-1-methylpropylcarbonyloxy group, and a 1-ethyl-2-methylpropylcarbonyloxy group.

[0085] As used herein, the term "halo(C a ~C bThe expression "alkylcarbonyl" represents an alkylcarbonyl group as defined above in which a hydrogen atom bonded to a carbon atom is optionally substituted by a halogen atom as defined above, and examples thereof include a fluoromethylcarbonyl group, a chloromethylcarbonyl group, a bromomethylcarbonyl group, an iodomethylcarbonyl group, a 2-fluoroethylcarbonyl group, a 2-chloroethylcarbonyl group, a 2-bromoethylcarbonyl group, a 3-fluoropropylcarbonyl group, a 3-chloropropylcarbonyl group, a difluoromethylcarbonyl group, a trifluoromethylcarbonyl group, a Specific examples include a methylcarbonyl group, a dichloromethylcarbonyl group, a trichloromethylcarbonyl group, a 2,2-difluoroethylcarbonyl group, a 2,2,2-trifluoroethylcarbonyl group, a 2,2,2-trichloroethylcarbonyl group, a chlorodifluoromethylcarbonyl group, a bromodifluoromethylcarbonyl group, a pentafluoroethylcarbonyl group, a heptafluoropropylcarbonyl group, a heptafluoroisopropylcarbonyl group, a 4-chlorobutylcarbonyl group, and a 4-fluorobutylcarbonyl group.

[0086] As used herein, the term "halo(C a ~C bThe expression "alkylcarbonyloxy" represents an alkylcarbonyl group as defined above in which a hydrogen atom bonded to a carbon atom is optionally substituted by a halogen atom as defined above, and examples thereof include a fluoromethylcarbonyloxy group, a chloromethylcarbonyloxy group, a bromomethylcarbonyloxy group, an iodomethylcarbonyloxy group, a 2-fluoroethylcarbonyloxy group, a 2-chloroethylcarbonyloxy group, a 2-bromoethylcarbonyloxy group, a 3-fluoropropylcarbonyloxy group, a 3-chloropropylcarbonyloxy group, a difluoromethylcarbonyloxy group, a trifluoromethylcarbonyloxy group, a Specific examples include a carbonyloxy group, a dichloromethylcarbonyloxy group, a trichloromethylcarbonyloxy group, a 2,2-difluoroethylcarbonyloxy group, a 2,2,2-trifluoroethylcarbonyloxy group, a 2,2,2-trichloroethylcarbonyloxy group, a chlorodifluoromethylcarbonyloxy group, a bromodifluoromethylcarbonyloxy group, a pentafluoroethylcarbonyloxy group, a heptafluoropropylcarbonyloxy group, a heptafluoroisopropylcarbonyloxy group, a 4-chlorobutylcarbonyloxy group, and a 4-fluorobutylcarbonyloxy group.

[0087] In this specification, "C a ~C bThe term "alkoxycarbonyl" refers to a carbonyl group having an alkoxy group having a to b carbon atoms bonded thereto, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a t-butoxycarbonyl group, an s-butoxycarbonyl group, an n-pentyloxycarbonyl group, a 1-methylbutyloxycarbonyl group, a 2-methylbutyloxycarbonyl group, a 3-methylbutyloxycarbonyl group, a 1-ethylpropyloxycarbonyl group, a 1,1-dimethylpropyloxycarbonyl group, a 1,2-dimethylpropyloxycarbonyl group, a neopentyloxycarbonyl group, an n-hexyloxycarbonyl group, a 1- Specific examples include a methylpentyloxycarbonyl group, a 2-methylpentyloxycarbonyl group, a 3-methylpentyloxycarbonyl group, a 4-methylpentyloxycarbonyl group, a 1-ethylbutyloxycarbonyl group, a 2-ethylbutyloxycarbonyl group, a 1,1-dimethylbutyloxycarbonyl group, a 1,2-dimethylbutyloxycarbonyl group, a 1,3-dimethylbutyloxycarbonyl group, a 2,2-dimethylbutyloxycarbonyl group, a 2,3-dimethylbutyloxycarbonyl group, a 3,3-dimethylbutyloxycarbonyl group, a 1,1,2-trimethylpropyloxycarbonyl group, a 1-ethyl-1-methylpropyloxycarbonyl group, and a 1-ethyl-2-methylpropyloxycarbonyl group.

[0088] Next, the process for producing the 2-acetylpyridine compound represented by formula (3) of the present invention will be described.

[0089] The 2-acetylpyridine compound represented by formula (3) can be produced by the methods shown in the following reaction schemes 1 to 5.

[0090] (Reaction Scheme 1)

[0091] [ka]

[0092] (In the formula, R and X have the same meanings as above.) A 2-cyanopyridine compound represented by formula (1) [hereinafter abbreviated as compound (1)] and a methylmagnesium halide compound represented by formula (2) [hereinafter abbreviated as compound (2)] can be reacted in a solvent or without a solvent to produce a 2-acetylpyridine compound represented by formula (3) [hereinafter abbreviated as compound (3)].

[0093] Examples of the compound (2) used in this reaction include methylmagnesium iodide, methylmagnesium bromide, and methylmagnesium chloride, and preferably methylmagnesium iodide and methylmagnesium bromide. The equivalent of the compound (2) is up to 20 equivalents, preferably 10 equivalents, and more preferably 5 equivalents, and up to 0.1 equivalents, preferably 0.8 equivalents, relative to the compound (1).

[0094] In this reaction, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent to be used is not particularly limited as long as it does not inhibit the progress of the reaction, and examples thereof include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, tertiary butyl methyl ether, and dioxane, ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, and water. Preferred are aliphatic hydrocarbon solvents and ether solvents, and more preferred are diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, tertiary butyl methyl ether, hexane, heptane, toluene, and xylene. Two or more of these solvents can also be mixed and used.

[0095] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0096] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 80°C.

[0097] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0098] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0099] Some of the compounds (1) used herein are known compounds, and some are commercially available. Other compounds can be synthesized according to known methods described in the literature, such as the method of converting a pyridine N-oxide compound to a 2-cyanopyridine compound described in WO 2009 / 12430, the method of chlorinating the 3-position of a 2-cyanopyridine compound described in Tetrahedron, 2006, Vol. 62, No. 25, p. 5862, and the method of substituting the 2-position of a 2-chloropyridine compound with a cyano group described in WO 2001 / 12627.

[0100] (Reaction Scheme 2)

[0101] [ka]

[0102] (In the formula, R and Y are as defined above.) Compound (3) can be produced by oxidizing a 2-pyridylpropionitrile compound represented by formula (4) [hereinafter abbreviated as compound (4)] in a solvent or without a solvent.

[0103] The oxidizing agent used in this reaction includes metal oxides such as manganese dioxide, chromium dioxide, chromium trioxide, and osmium tetroxide, metal oxide salts such as pyridinium chlorochromate, potassium chromate, potassium dichromate, and sodium tungstate, metal persalts such as potassium permanganate, perhalogen salts such as sodium perchlorate and sodium periodate, organic peroxides such as hydrogen peroxide, peracetic acid, and pyridine N-oxide, dimethyl sulfoxide, and oxygen. Preferred are hydrogen peroxide, peracetic acid, pyridine N-oxide, and oxygen. The equivalent of the oxidizing agent can be up to 20 equivalents, preferably 10 equivalents, and can be up to 0.1 equivalents, preferably 0.5 equivalents, relative to compound (4).

[0104] In this reaction, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent to be used is not particularly limited as long as it does not inhibit the progress of the reaction, and examples of the solvent include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2,2-dimethyl-1-propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, Examples of the solvent include alcohol solvents such as diethylene glycol, hydrogen halides such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and tertiary butyl methyl ether, ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, nitrile solvents such as acetonitrile and propionitrile, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, and water. Preferred are hydrocarbon solvents, alcohol solvents, ether solvents, nitrile solvents, and water, and more preferred are toluene, xylene, methanol, 2,2-dimethyl-1-propanol, acetonitrile, and water. Two or more of these solvents can also be used in combination.

[0105] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0106] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0107] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0108] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0109] Some of the compounds (4) used here are known compounds, and some are commercially available. Other compounds can be synthesized according to known methods described in the literature, such as the method of methylating 2-pyridinylacetonitrile compounds described in U.S. Patent Application Publication No. 2014 / 0088046, the method of substituting a halogen atom at the 2-position of pyridine with propionitrile described in Journal of Heterocyclic Chemistry, Vol. 24, No. 4, p. 1061, 1987, and the method of halogenating 2-pyridinylpropionitrile compounds described in Journal of Organic Chemistry, Vol. 56, No. 18, p. 5318, 1991.

[0110] (Reaction Scheme 3)

[0111] [ka]

[0112] (In the formula, R and X have the same meanings as above.) A 2-ethylpyridine compound represented by formula (5) (hereinafter referred to as compound (5)) is halogenated in a solvent or without a solvent to produce a 1-haloethylpyridine compound represented by formula (6) (hereinafter referred to as compound (6)) (hereinafter referred to as step 1). Compound (3) can be produced by oxidizing the resulting compound (6) (hereinafter referred to as step 2). (1st step) Compound (6) can be produced by halogenating compound (5) in a solvent or without a solvent.

[0113] Examples of the halogenating agent used in this reaction include hypohalites such as sodium hypochlorite and sodium hypobromite, carbon halides such as carbon tetrachloride and carbon tetrabromide, sulfuryl chloride, sulfuryl bromide, and other sulfonyl halides, N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, trichloroisocyanuric acid, dibromoisocyanuric acid, and 1,3-diiodo-5,5-dimethylhydantoin, and other halogenated imides, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, and tetramethyldichloroiodite, and other quaternary ammonium trihalogen salts, hydrogen chloride, hydrogen bromide, and hydrogen iodide, and other hydrogen halides, and halogen elements such as chlorine, bromine, and iodine. Preferred are sulfonyl halides, halogenated imides, and halogen elements, and more preferred are sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide, N-bromosuccinimide, chlorine, and bromine.

[0114] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0115] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0116] The compound (6) obtained in the first step can also be used in the second step without purification or isolation after completion of the reaction.

[0117] In this reaction, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and examples thereof include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2,2-dimethyl-1-propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, and diethylene glycol, hydrogen halide solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and tertiary butyl methyl ether, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, dimethyl sulfoxide, and water. Preferred examples of the solvent include alcohol solvents, halogenated carbon solvents, ether solvents, amide solvents, and water, and more preferred examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, tetrahydrofuran, cyclopentyl methyl ether, tertiary butyl methyl ether, dimethylformamide, dimethylacetamide, and water. Two or more of these solvents may be mixed and used.

[0118] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0119] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0120] Some of the compounds (5) used here are known compounds, and some are commercially available. Other compounds can be synthesized according to known methods described in the literature, such as the method of converting a halogen atom at the 2-position of pyridine to an alkyl group by Grignard reaction described in WO 2006 / 18725, the method of reacting a 2-halopyridine compound with a malonic acid ester compound and then decarbonating the compound described in WO 2006 / 67446, and the method of reducing a vinylpyridine compound described in WO 2014 / 74660. (2nd process) Compound (6) can be oxidized in a solvent or without a solvent to produce compound (3).

[0121] The oxidizing agent used in this reaction includes metal oxides such as manganese dioxide, chromium dioxide, chromium trioxide, and osmium tetroxide, metal oxide salts such as pyridinium chlorochromate, potassium chromate, potassium dichromate, and sodium tungstate, metal persalts such as potassium permanganate, perhalogen salts such as sodium perchlorate and sodium periodate, hypohalogen salts such as sodium hypochlorite and sodium hypobromite, organic peroxides such as hydrogen peroxide, peracetic acid, m-chlorobenzoic acid, and pyridine N-oxide, dimethyl sulfoxide, and oxygen. Preferred are hydrogen peroxide, dimethyl sulfoxide, and oxygen. The equivalent of the oxidizing agent can be used up to 20 equivalents, preferably 10 equivalents, and at least 0.1 equivalents, preferably 0.5 equivalents, relative to compound (6).

[0122] In the second step, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and may be the same solvent as in the first step.

[0123] The second step can be carried out under an inert gas atmosphere such as nitrogen or argon, if necessary.

[0124] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0125] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0126] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0127] (Reaction Scheme 4)

[0128] [ka]

[0129] (In the formula, R and Y are as defined above.) Compound (3) can be produced by oxidizing a 2-pyridylpropionic acid compound represented by formula (7) [hereinafter, abbreviated as compound (7)] in a solvent or without a solvent.

[0130] The oxidizing agent used in this reaction includes metal oxides such as manganese dioxide, chromium dioxide, chromium trioxide, and osmium tetroxide, metal oxide salts such as pyridinium chlorochromate, potassium chromate, potassium dichromate, and sodium tungstate, metal persalts such as potassium permanganate, perhalogen salts such as sodium perchlorate and sodium periodate, hydrogen peroxide, peracetic acid, sodium peroxodisulfate, potassium peroxodisulfate, and organic peroxides such as pyridine N-oxide, dimethyl sulfoxide, and oxygen. Preferred are hydrogen peroxide, peracetic acid, potassium peroxodisulfate, pyridine N-oxide, and oxygen. The equivalent of the oxidizing agent can be up to 20 equivalents, preferably 10 equivalents, and can be up to 0.1 equivalents, preferably 0.5 equivalents, relative to compound (4).

[0131] In this reaction, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and examples of the solvent include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2,2-dimethyl-1-propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, diphenyl ether, dimethyl ... Examples of the solvent include alcohol solvents such as ethylene glycol, hydrogen halide solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and tertiary butyl methyl ether, ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, nitrile solvents such as acetonitrile and propionitrile, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, and water. Preferred are hydrocarbon solvents, alcohol solvents, ether solvents, nitrile solvents, and water, and more preferred are toluene, xylene, methanol, 2,2-dimethyl-1-propanol, acetonitrile, and water. Two or more of these solvents can also be used in combination.

[0132] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0133] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0134] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 48 hours.

[0135] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0136] Some of the compounds (7) used herein are known compounds, some of which are commercially available, and the rest can be synthesized according to known methods described in the literature, such as the method of hydrolyzing a 1-pyridylpropionitrile compound described in WO 2009 / 075874, or the method of hydrolyzing a malonic acid ester compound described in WO 2013 / 13817.

[0137] (Reaction Scheme 5)

[0138] [ka]

[0139] (Wherein, R and R 1 has the same meaning as above.) Compound (3) can be produced by decarboxylating a 3-oxo-3-pyridylpropionic acid compound represented by formula (8) [hereinafter abbreviated as compound (8)] under acidic conditions in a solvent or without a solvent.

[0140] The acid used in this reaction includes inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid, metal chlorides such as boron trifluoride, aluminum trichloride, tin tetrachloride, magnesium dichloride, iron trichloride, and titanium tetrachloride, metal alkoxides such as triisopropoxyaluminum, diethoxymagnesium, and tetraisopropoxytitanium, and metal triflates such as bis(trifluoromethanesulfonyl)tin, bis(trifluoromethanesulfonyl)copper, and tris(trifluoromethanesulfonyl)scandium. The acid equivalent can be up to 20 equivalents relative to compound (8), preferably 0.1 to 10 equivalents.

[0141] In this reaction, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and examples of the solvent include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2,2-dimethyl-1-propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, diphenyl ether, dimethyl ... Examples of the solvent include alcohol solvents such as ethylene glycol, hydrogen halide solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and tertiary butyl methyl ether, ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, nitrile solvents such as acetonitrile and propionitrile, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, and water. Preferred are hydrocarbon solvents, alcohol solvents, and water, and more preferably, methanol, ethanol, and water. Two or more of these solvents can be mixed and used.

[0142] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0143] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0144] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 24 hours, and more preferably 10 minutes to 48 hours.

[0145] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0146] Some of the compounds (8) used here are known compounds, and some are commercially available. Other compounds can be synthesized according to known methods described in the literature, such as the method of reacting a picolinic acid compound with a malonic acid compound described in Organic and Biomolecular Chemistry, Vol. 7, No. 23, p. 4960, 2009, or the method of reacting a picolinic acid compound with ethyl acetate described in Tetrahedron Letters, Vol. 52, No. 11, p. 1205, 2011.

[0147] Next, a method for producing the pyridinyl-2-oxoethylisoindoline compound represented by formula (10) of the present invention will be described.

[0148] The pyridinyl-2-oxoethylisoindoline compound represented by formula (10) can be produced by the methods shown in the following reaction schemes 6 and 7.

[0149] (Reaction Scheme 6)

[0150] [ka]

[0151] (In the formula, R and X have the same meanings as above.) A 2-(2-haloacetyl)pyridine compound represented by formula (9) [hereinafter, abbreviated as compound (9)] can be reacted with phthalimide in a solvent or without a solvent to produce a 2-acetylpyridine compound represented by formula (10) [hereinafter, abbreviated as compound (10)].

[0152] In this reaction, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and examples of the solvent include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2,2-dimethyl-1-propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, diphenyl ether, dimethyl ... Examples of the solvent include alcohol solvents such as ethylene glycol, hydrogen halide solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and tertiary butyl methyl ether, ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, nitrile solvents such as acetonitrile and propionitrile, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, and water. Preferred are hydrocarbon solvents, amide solvents, nitrile solvents, dimethyl sulfoxide, and water, and more preferred are toluene, xylene, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. Two or more of these solvents can also be mixed and used.

[0153] In this reaction, a base can be used as necessary. Examples of the base used in this reaction include organic bases and inorganic bases. Examples of the organic base include aromatic amines such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, and N,N-dimethylaniline, and aliphatic amines such as diethylamine, triethylamine, tri-n-butylamine, di(isopropyl)ethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, and 1,4-diazabicyclo[2.2.2]octane. Examples of inorganic bases include quaternary ammonium hydroxide salts such as tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, and tetrabutylammonium hydroxide, inorganic bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, and sodium hydride, and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide.Preferred examples include sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, tri-n-butylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene, and more preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide. The amount of the basic compound used may be up to 20 equivalents, preferably 10 equivalents, more preferably 5 equivalents, and may be up to 0.01 equivalents, preferably 0.1 equivalents, relative to compound (7).

[0154] In this reaction, potassium phthalimide can also be used instead of phthalimide.

[0155] In this reaction, a phase transfer catalyst can be used as necessary. Examples of the phase transfer catalyst used in this reaction include quaternary ammonium salts such as tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, tetraethylammonium iodide, and tributylammonium hydrogen sulfate, crown ethers such as 15-crown-5 and 18-crown-6, and quaternary phosphonium salts such as tributyloctylphosphonium bromide and tributyldodecylphosphonium bromide. Tetrabutylammonium bromide is preferred. The phase transfer catalyst is usually used in an amount of 0 to 10 equivalents, preferably 0 to 3 equivalents, relative to phthalimide.

[0156] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0157] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0158] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0159] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0160] Some of the compounds (9) used here are known compounds, and some are commercially available. Other compounds can be synthesized according to known methods described in the literature, such as the method of brominating a 2-acetylpyridine compound described in JP-A-2007-297541, the method of reducing a dihaloacetylpyridine compound described in Journal of Medicinal Chemistry, 2011, vol. 54, no. 12, p. 4042, or the method of brominating a vinylpyridine compound while oxidizing it described in Synlett, 2010, vol. 15, p. 2335.

[0161] (Reaction Scheme 7)

[0162] [ka]

[0163] (In the formula, R has the same meaning as above.) A pyridylacetonitrile compound represented by formula (12) [hereinafter referred to as compound (12)] is reacted with a formaldehyde derivative to produce a pyridinylacrylonitrile compound represented by formula (13) [hereinafter referred to as compound (13)] (hereinafter referred to as step 1). A pyridinyloxirane compound represented by formula (14) [hereinafter referred to as compound (14)] is produced by oxidizing the obtained compound (13) (hereinafter referred to as step 2). A compound (10) is produced by reacting the obtained compound (14) with phthalimide (hereinafter referred to as step 3). (1st step) Compound (13) can be produced by reacting compound (12) with a formaldehyde derivative.

[0164] Examples of the formamide derivative used in the first step include formaldehyde, dimethoxymethane, diethoxymethane, 1,3,5-trioxane, and the like, and preferred are formaldehyde and 1,3,5-trioxane.

[0165] In the first step, a base can be used as necessary. Examples of the base used in this reaction include organic bases and inorganic bases. Examples of the organic base include aromatic amines such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, and N,N-dimethylaniline, and aliphatic amines such as diethylamine, triethylamine, tri-n-butylamine, di(isopropyl)ethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, and 1,4-diazabicyclo[2.2.2]octane. Examples of inorganic bases include quaternary ammonium hydroxide salts such as tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, and tetrabutylammonium hydroxide, inorganic bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, and sodium hydride, and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide. Preferred examples include sodium hydroxide, sodium hydride, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, diethylamine, triethylamine, tri-n-butylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene. The equivalent of the basic compound can be used at most 20 equivalents, preferably 10 equivalents, more preferably 5 equivalents, and at most 0.01 equivalents, preferably 0.1 equivalents, relative to compound (12).

[0166] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0167] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0168] The compound (13) obtained in the first step can also be used in the second step without purification or isolation after completion of the reaction.

[0169] In the first step, a solvent may be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and examples thereof include aliphatic hydrocarbon solvents such as hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, and heptane, aromatic hydrocarbon solvents such as benzene, xylene, toluene, chlorobenzene, and nitrobenzene, alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2,2-dimethyl-1-propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ethylene glycol monomethyl ether, 1,3-propanediol monomethyl ether, and diethylene glycol, hydrogen halide solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and tertiary butyl methyl ether, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, dimethyl sulfoxide, and water. Preferred are aromatic hydrocarbon solvents and amide solvents, more preferred are toluene, xylene, dimethylformamide and dimethylacetamide. These solvents can also be used in combination of two or more.

[0170] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0171] In the first step, the reaction mixture after the reaction is completed can be subjected to a usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. When purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc.

[0172] Some of the compounds (12) used here are known compounds, and some are commercially available. Other compounds can be synthesized according to known methods described in the literature, such as the method of cyanating halomethylpyridine described in Journal of Heterocyclic Chemistry, Vol. 24, No. 4, p. 1061, 1987, or the method of substituting the halogen atom of a 2-halopyridine compound with acetonitrile, or the method of substituting the halogen atom of a 2-halopyridine compound with a cyanoacetate compound and then decarbonating, described in International Publication No. 2012 / 2297. (2nd process) Compound (14) can be produced by oxidizing compound (13) in a solvent or without a solvent.

[0173] Examples of the oxidizing agent used in the second step include metal oxides such as manganese dioxide, chromium dioxide, chromium trioxide, and osmium tetroxide, metal oxide salts such as pyridinium chlorochromate, potassium chromate, potassium dichromate, and sodium tungstate, metal persalts such as potassium permanganate, perhalogen salts such as sodium perchlorate and sodium periodate, hypohalogen salts such as sodium hypochlorite and sodium hypobromite, organic peroxides such as hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, and pyridine N-oxide, dimethyl sulfoxide, and oxygen. Preferred are hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and sodium hypochlorite. The equivalent of the oxidizing agent can be up to 20 equivalents, preferably 10 equivalents, and can be up to 0.1 equivalents, preferably 0.5 equivalents, relative to compound (13).

[0174] In the second step, a solvent can be used as necessary. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and may be the same solvent as in the first step.

[0175] The second step can be carried out under an inert gas atmosphere such as nitrogen or argon, if necessary.

[0176] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0177] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0178] In the second step, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc. (3rd step) Compound (10) can be produced by reacting compound (14) with phthalimide in a solvent or without a solvent.

[0179] A solvent can be used as necessary in Step 3. When a solvent is used in this reaction, the solvent is not particularly limited as long as it does not inhibit the progress of the reaction, and may be the same solvent as in Step 2.

[0180] In the third step, a base can be used as necessary. Examples of the base used in this reaction include organic bases and inorganic bases. Examples of the organic base include aromatic amines such as pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, and N,N-dimethylaniline, and aliphatic amines such as diethylamine, triethylamine, tri-n-butylamine, di(isopropyl)ethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, and 1,4-diazabicyclo[2.2.2]octane. Examples of inorganic bases include quaternary ammonium hydroxide salts such as tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, and tetrabutylammonium hydroxide, inorganic bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, and sodium hydride, and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide.Preferred examples include sodium hydroxide, sodium hydride, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, tri-n-butylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene, and more preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide. The amount of the basic compound used may be up to 20 equivalents, preferably 10 equivalents, more preferably 5 equivalents, and may be up to 0.01 equivalents, preferably 0.1 equivalents, relative to compound (14).

[0181] In the third step, potassium phthalimide can be used instead of phthalimide.

[0182] Examples of the phase transfer catalyst used in this reaction include quaternary ammonium salts such as tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, tetraethylammonium iodide, and tributylammonium hydrogen sulfate, crown ethers such as 15-crown-5 and 18-crown-6, and quaternary phosphonium salts such as tributyloctylphosphonium bromide and tributyldodecylphosphonium bromide. Tetrabutylammonium bromide is preferred. The phase transfer catalyst is usually used in an amount of 0.0001 to 10 equivalents, preferably 0.001 to 3 equivalents, relative to the phthalimide.

[0183] If necessary, this reaction can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

[0184] The reaction temperature is usually from -100 to 200°C, preferably from -60 to 100°C, and more preferably from -20 to 100°C.

[0185] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but is usually 1 minute to 100 hours, preferably 10 minutes to 48 hours, and more preferably 10 minutes to 24 hours.

[0186] In this reaction, the reaction mixture after the completion of the reaction can be subjected to usual post-treatment such as direct concentration, dissolving in an organic solvent and washing with water followed by concentration of the organic layer obtained, or pouring into ice water and extracting with an organic solvent followed by concentration of the organic layer obtained, to obtain the target compound. In addition, when purification is required, the compound can be separated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, liquid chromatography fractionation, distillation, etc. EXAMPLES

[0187] The present invention will be described in more detail below by specifically describing synthesis examples of the present invention as examples, but the present invention is not limited to these.

[0188] The quantitative analysis described in the synthesis examples is a quantitative analysis by an internal standard method using high performance liquid chromatography (HPLC), and was performed under the following analysis conditions A or B. The peak area ratio described in the synthesis examples is the ratio of the area of ​​each peak to the total area of ​​the peaks detected in the chromatogram of HPLC (analysis conditions B or C) taken as 100%, calculated according to the following formula.

[0189] Each peak area ratio = each peak area / total peak area × 100 [HPLC analysis conditions] [Analysis conditions A] Column: Inertsil ODS-4, 4.6 x 150 mm, 3 μm (GL Science) Eluent: acetonitrile:water:trifluoroacetic acid =1200:1800:3 (volume ratio) Temperature; 40℃ Flow rate: 1.0ml / min. Wavelength: 254nm Measurement amount: 3μl Standard substance: 4-t-butylbiphenyl [Analysis conditions B] Column: Inertsil ODS-4, 4.6×250 mm, 5 μm (GL Science) Eluent: acetonitrile: 0.1% by volume trifluoroacetic acid aqueous solution =60:40 (15 min) → (25 min) → 95:5 (30 min) (volume ratio) Temperature; 40℃ Flow rate: 1.0ml / min. Wavelength: 225nm Measurement amount: 3μl Standard substance; 4-Methylbiphenyl [Analysis conditions C] Column: Inertsil ODS-SP, 4.6×150 mm, 3 μm (GL Science) Eluent: acetonitrile:water:trifluoroacetic acid =1050:1950:3 (volume ratio) Temperature; 40℃ Flow rate: 1.0ml / min. Wavelength: 225nm Measurement amount: 3μl In addition, the proton nuclear magnetic resonance spectrum described in the synthesis example (hereinafter, 1 The chemical shift values ​​of the NMR spectroscopy (hereinafter referred to as H-NMR) were measured in deuterated chloroform solvent using Me4Si (tetramethylsilane) as a standard substance with the following Model A or B.

[0190] [Model A] JNM-ECX300, 300MHz, JEOL [Model B] JNM-ECZ400S, 400MHz, JEOL 1 The symbols for H-NMR chemical shift values ​​are: d for doublet, t for triplet, q for quartet, dd for double doublet, and m for multiplet.

[0191] [Synthesis example] Synthesis Example 1: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone A solution of 40 g of 3,5-dichloropicolinonitrile in 200 g of toluene was cooled to 0°C, and 85 ml of a diethyl ether solution of methylmagnesium bromide (3 mol / L) was added dropwise over 23 minutes. After stirring this reaction solution at 0°C for 10 minutes, it was added dropwise to a 12% by mass aqueous hydrochloric acid solution cooled to 5°C. This reaction solution was stirred at 0°C for 1 hour. This reaction solution was separated, and the aqueous layer was extracted with 40 g of toluene. The organic layers were combined, washed with 200 g of water and 50 g of saturated saline solution, and then dehydrated with anhydrous sodium sulfate. The obtained organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [ethyl acetate:hexane = 1:9 (volume ratio, the same applies below)], and 24.51 g of the target product was obtained as a colorless oil (yield 55.8%). 1 H NMR (CDCl3, Me4Si, model A) δ8.50 (d, J=2.1Hz, 1H), 7.82 (d, J=2.1Hz, 1H), 2.68 (s, 3H) Synthesis Example 2: Synthesis of 1-(5-bromo-3-chloropyridin-2-yl)ethanone 3.84 g of 5-bromo-3-chloropicolinonitrile (80% purity) was suspended in 40 ml of diethyl ether and cooled to 0°C. 17 ml of a tetrahydrofuran solution (1 mol / l) of methylmagnesium bromide was added dropwise to this suspension. This reaction solution was stirred at 0°C for 2.5 hours. After the reaction was completed, the reaction solution was added dropwise to 30 ml of 12% by mass aqueous hydrochloric acid solution cooled to 5°C. After the addition was completed, the reaction solution was stirred at room temperature for 20 minutes. Then, the reaction solution was extracted with 50 ml of diethyl ether. The organic layer was washed with saturated saline, then dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in 5 ml of hexane and stirred for 5 minutes, after which the solid was filtered off, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 0:10 to 1:9 gradient) to obtain 1.45 g of the target product as a white solid (yield 44%). Melting point: 78~79℃ 1 H NMR (CDCl3, Me4Si, model A) δ8.51 (d, J=1.9Hz, 1H), 7.88 (d, J=1.9Hz, 1H), 4.67 (s, 2H) Synthesis Example 3: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone To a solution of 500 mg of 2-(3,5-dichloropyridin-2-yl)propionitrile in 1.0 g of acetonitrile, 500 mg of water and 312 mg of 48% by mass aqueous sodium hydroxide solution were added in sequence. After the addition was completed, the inside of the reactor was replaced with oxygen gas, and the mixture was stirred for 24 hours at 25°C under pressurized conditions (0.4 MPa). After the reaction was completed, a portion of the reaction solution was sampled and quantitatively analyzed by HPLC (analysis condition A), and it was confirmed that 340 mg of the target product was produced (yield 72.0%).

[0192] Synthesis Example 4: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone To a solution of 500 mg of 2-(3,5-dichloropyridin-2-yl)propionitrile in 750 mg of acetonitrile, 750 mg of water, 81 mg of tetrabutylammonium bromide, and 312 mg of 48% by mass aqueous sodium hydroxide solution were added in sequence. After the addition was completed, the inside of the reactor was replaced with oxygen gas, and the mixture was stirred for 24 hours at 25°C under pressurized conditions (0.4 MPa). After the reaction was completed, a portion of the reaction solution was sampled and quantitatively analyzed by HPLC (analysis condition A), and it was confirmed that 367 mg of the target product was produced (yield 77.6%).

[0193] Synthesis Example 5: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone A solution of 81 mg of tetrabutylammonium bromide and 830 mg of 48% by mass aqueous sodium hydroxide in 2.0 g of acetonitrile and 1.0 g of water was cooled to 10°C, and 424 mg of 30% by mass aqueous hydrogen peroxide was added. This reaction solution was stirred at room temperature for 1 hour. Next, 500 mg of 2-(3,5-dichloropyridin-2-yl)propionitrile was added to the reaction solution, and the mixture was stirred at room temperature for 41 hours. After the reaction was completed, a portion of the reaction solution was sampled and analyzed by HPLC (analysis condition C), and the area ratio of the target product was 69.3% (conversion rate 84.8%). Synthesis Example 6: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone Step 1: Synthesis of 2-bromo-2-(3,5-dichloropyridin-2-yl)propionitrile To a solution of 700 mg of 2-(3,5-dichloropyridin-2-yl)propionitrile in 5 ml of acetonitrile, 721 mg of potassium carbonate and then 744 mg of N-bromosuccinimide were added in sequence. The reaction solution was stirred at room temperature for 1 hour, and then stirred at 60°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and then 15 ml of water was added and extracted with 15 ml of ethyl acetate. The obtained organic layer was washed with 10 ml of water, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9) to obtain 455 mg of the target product as a white solid (yield 46.7%).

[0194] Step 2: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone To a solution of 210 mg of 2-bromo-2-(3,5-dichloropyridin-2-yl)propionitrile in 2 ml of 1,2-dichloroethane, 113.9 mg of triethylamine and then 0.23 ml of a decane solution (5 mol / L) of t-butyl hydroperoxide were added. The reaction solution was stirred at room temperature for 17 hours. After the reaction was completed, a portion of the reaction solution was sampled and analyzed by HPLC (analysis condition A), and it was confirmed that 58.9 mg of the target product was produced. Synthesis Example 7: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone A solution of 5 g of 2-(3,5-dichloropyridin-2-yl)propionitrile in 20 ml of 1,2-dichloroethane was added to a solution of 46.3 g of 8 mass% aqueous sodium hypochlorite solution and 5 ml of methanol. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, 30 ml of water was added to the reaction solution, and the solution was extracted with 30 ml of chloroform. The organic layer obtained was washed with 20 ml of water, dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 100 mg of the obtained yellow solid (5.44 g) was dissolved in 1 ml of dimethyl sulfoxide, and 64 mg of triethylamine was added. The reaction solution was stirred at room temperature for 19 hours. After the reaction was completed, a portion of the reaction solution was sampled and analyzed by HPLC (analysis condition C), and the peak area ratio of the target product was 37.5% (conversion rate 100%).

[0195] Synthesis Example 8: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone Step 1: Synthesis of 2-(1-bromoethyl)-3,5-dichloropyridine Azobisisobutyronitrile (700 mg) was added to a solution of 3,5-dichloro-2-ethylpyridine (15 g) in heptane (30 g). The reaction solution was heated to 70°C, and then a solution of N-bromosuccinimide (18.2 g) in acetonitrile (109 g) was added. The reaction solution was stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and 100 ml of water and 100 ml of heptane were added, followed by separation. The resulting organic layer was washed twice with 50 ml of water, dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 18.02 g of the target product as a yellow solid (yield 83.0%). 1 H NMR (CDCl3, Me4Si, model A)δ 8.45 (d, J=2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 5.57 (t, J=6.9 Hz, 4H), 2.08 (dd, J=6.9 Hz & 2.1 Hz, 4H) Step 2: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone 564 mg of sodium hydrogen carbonate was added to a solution of 1.14 g of 2-(1-bromoethyl)-3,5-dichloropyridine in 7 ml of dimethyl sulfoxide. The reaction solution was stirred at 60°C for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 10 ml of water was added, and the mixture was separated twice with 10 ml of toluene. The organic layers were combined and washed with 5 ml of saturated aqueous sodium hydrogen carbonate solution, 8.9 g of 1% by mass aqueous sodium hydroxide solution, and 10 ml of water, in that order. The obtained organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was analyzed by HPLC (analysis condition A), and it was confirmed that 598.0 mg of the target product was produced (yield 70.4%).

[0196] Synthesis Example 9: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone 300 mg of 2-(1-bromoethyl)-3,5-dichloropyridine was dissolved in a mixed solvent of 0.8 ml of toluene, 0.8 ml of acetonitrile, and 0.4 ml of water. 224 mg of pyridine oxide was added to the solution, followed by 100 mg of sodium hydrogen carbonate. The reaction solution was stirred at 80°C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and a portion of the reaction solution was sampled and quantitatively analyzed by HPLC (analysis condition A), confirming that 174.4 mg of the target product was produced (yield 78.0%).

[0197] Synthesis Example 10: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone To a solution of 186 mg pyridine in 2 ml acetonitrile, 407 mg m-chlorobenzoic acid was added, followed by 491 mg sodium bicarbonate. The reaction solution was stirred at 30°C for 1 hour. Then, 1 ml acetonitrile, 1 ml water, and 170 mg m-chlorobenzoic acid were added to the reaction solution in that order. The reaction solution was heated to 80°C, and then a solution of 300 mg 2-(1-bromoethyl)-3,5-dichloropyridine in 1 ml toluene was added. The reaction solution was stirred at 80°C for 4 hours. After the reaction was completed, a portion of the reaction solution was sampled and quantitatively analyzed by HPLC (analysis condition A), confirming that 138.9 mg of the target product was produced (yield 62.1%).

[0198] Synthesis Example 11: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone Step 1: Synthesis of ethyl 3-(3,5-dichloropyridin-2-yl)-3-oxopropionate A suspension of 0.50 g of potassium t-butoxide in 3 g of toluene was cooled to 0°C, and while maintaining the temperature at 5°C or less, a solution of 0.66 g of 3,5-dichloro-2-ethyl picolinate and 0.53 g of ethyl acetate in 2 g of toluene was added over 17 minutes. The reaction solution was stirred at 0 to 5°C for 90 minutes, and then 10 ml of a 3% by mass aqueous hydrochloric acid solution was added dropwise while maintaining the temperature at 7°C or less. After separation, the aqueous layer was extracted twice with 10 ml of toluene. The organic layers were combined and extracted four times with 10 ml of water, and then dried with sodium sulfate. The solvent was distilled off to obtain 0.60 g of the target product (purity 88.6%) as a yellow liquid (yield 66.8%). 1 H NMR (CDCl3, Me4Si, model A)δ 8.49 (d, J=2.1 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 1.24 (t, J=7.2Hz, 3H) Step 2: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone 5.61 g of 11% by mass aqueous sulfuric acid solution was added to a solution of 1.01 g of ethyl 3-(3,5-dichloropyridin-2-yl)-3-oxopropionate in 5.0 g of ethanol. The reaction solution was stirred at 80° C. for 16.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then 40 ml of water was added and the mixture was separated twice with 40 ml of toluene. The organic layers were combined and analyzed by HPLC (analysis condition A), and it was confirmed that 0.65 g of the target product was produced (yield 85.5%).

[0199] Synthesis Example 12: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone Step 1: Synthesis of 2-(3,5-dichloropyridin-2-yl)propionic acid A solution of 5.8 g of diethyl 2-(3,5-dichloropyridin-2-yl)-2-methylmalonate in 17.4 g of ethanol was heated to 70° C., and 35.57 g of 10% by mass potassium hydroxide aqueous solution was added over 9 minutes. After stirring the reaction solution at 70° C. for 1 hour, the reaction solution was cooled to room temperature, and the solvent was distilled off. 10 ml of 3% by mass hydrochloric acid aqueous solution was added dropwise while maintaining the temperature at 7° C. or less. After separation, the aqueous layer was extracted twice with 10 ml of toluene. The organic layers were combined, extracted four times with 10 ml of water, and then dried over sodium sulfate. 25 g of the solvent was distilled off, and extraction was performed with 20 ml of ethyl acetate. 58 ml of 3% by mass hydrochloric acid aqueous solution was added to the aqueous layer, and extraction was performed with 30 ml of ethyl acetate. The organic layer was concentrated, and 3.73 g of the target product was obtained as a white solid (yield 93.5%). 1 H NMR (CDCl3, Me4Si, model A)δ 8.48-8.44 (m, 1H), 7.80-7.77 (m, 1H), 4.38 (q, J=7.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 4H) Step 2: Synthesis of 1-(3,5-dichloropyridin-2-yl)ethanone 0.14g of potassium hydrogen carbonate and 0.15g of 2-(3,5-dichloropyridin-2-yl)propionic acid were added to 1.86g of 20% by mass potassium peroxodisulfate aqueous solution, and 0.08g of potassium hydrogen carbonate was further added. The suspension was stirred at 60°C for 17.5 hours, 0.37g of potassium peroxodisulfate and 0.20g of potassium hydrogen carbonate were added, and the mixture was further stirred at 60°C for 6.5 hours. After cooling the reaction solution to room temperature, the reaction solution was analyzed by HPLC (analysis condition A), and it was confirmed that 32.2mg of the target product was produced (yield 25.0%).

[0200] Synthesis Example 13: Synthesis of 2-(2-(3,5-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione Step 1: Synthesis of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone To a solution of 10 g of 1-(3,5-dichloropyridin-2-yl)ethanone in 35 ml of acetic acid, 15.5 ml of 30% by mass hydrogen bromide in acetic acid, 5 ml of a solution of 9.25 g of bromine in acetic acid, and 20 ml of acetic acid were added in sequence at room temperature. The reaction solution was stirred at room temperature for 20 hours. Then, 3.1 ml of 30% by mass hydrogen bromide in acetic acid was added to the reaction solution, followed by 2.52 g of bromine. After the addition was completed, the reaction solution was stirred at room temperature for 22 hours. After the reaction was completed, 100 ml of diethyl ether was added to the reaction solution, and the precipitated solid was filtered off. The obtained solid was dissolved in 150 ml of chloroform, washed with 150 ml of water and 100 ml of saturated saline in that order, and the solvent was distilled off under reduced pressure to obtain 12.72 g of the target product as a white solid (yield 89.9%). 1 H NMR (CDCl3, Me4Si, model A) δ8.51 (d, J=1.9Hz, 1H), 7.88 (d, J=1.9Hz, 1H), 4.67 (s, 2H) Step 2: Synthesis of 2-(2-(3,5-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione A solution of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone 30g in dimethylformamide 50g was dropped into a solution of potassium phthalimide 21.28g in dimethylformamide 60. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, 100ml of water and 100ml of ethyl acetate were added to the reaction solution. The reaction solution was then stirred for 10 minutes, and the precipitated solid was filtered off. The obtained solid was washed with a mixed solvent of 50ml of water and 50ml of ethyl acetate, and 29.66g of the target product was obtained as a white solid (yield 79.3%). 1 H NMR (CDCl3, Me4Si, model A) δ8.58 (d, J=2.0Hz, 1H), 7.65-7.8 (m, 5H), 5.30 (s, 2H) Synthesis Example 14: Synthesis of 2-(2-(5-bromo-3-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione Step 1: Synthesis of 2-bromo-1-(5-bromo-3-chloropyridin-2-yl)ethanone To a 4ml toluene solution of 870mg of 1-(5-bromo-3-chloropyridin-2-yl)ethanone, 7ml of 30% by mass hydrogen bromide acetic acid solution was added, followed by 710mg of bromine. The reaction solution was stirred at room temperature for 13 hours. After the stirring was completed, 60mg of bromine was added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. Then, 60mg of bromine was added to the reaction solution, and after stirring for 3 hours, 50ml of water was added. Then, the reaction solution was extracted with 50ml of toluene and washed twice with 30ml of water. 50ml of ethyl acetate was added to the solution, and the solution was washed with 50ml of 2% by mass aqueous sodium hydrogen sulfite solution and saturated saline solution in that order, then dried and dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane = 0:10 to 1:9 gradient), and the target product 1.03 was obtained as a light yellow solid (yield 89%). 1 H NMR (CDCl3, Me4Si, model A) δ8.58 (d, J=1.8Hz, 1H), 7.97 (d, J=1.8Hz, 1H),2.67 (s, 3H) Step 2: Synthesis of 2-(2-(5-bromo-3-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione 62.06 g of potassium phthalimide was suspended in 150 ml of dimethylformamide, and a solution of 100 g of 2-bromo-1-(5-bromo-3-chloropyridin-2-yl)ethanone in 200 ml of dimethylformamide was added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, 300 ml of ethyl acetate and 400 ml of water were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered to obtain 105 g of the target product as a pale yellow solid (82.8%). 1 H NMR (CDCl3, Me4Si, model A) δ8.67 (d, J=1.8Hz, 1H), 8.03 (d, J=1.8Hz, 1H), 7.7-7.95 (m, 4H), 5.28 (s, 2H) Synthesis Example 15: Synthesis of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone Step 1: Synthesis of 2,2-dibromo-1-(3,5-dichloropyridin-2-yl)ethanone 7.2 g of bromine was added to 17 ml of 98% by mass aqueous sulfuric acid solution containing 3.9 g of 1-(3,5-dichloropyridin-2-yl)ethanone at 0°C, and the mixture was stirred at room temperature for 20 hours. The reaction liquid was added to 50 ml of water cooled to 0°C, and then 30 g of 10% by mass aqueous sodium hydrogen sulfite solution was added, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with 100 ml of diethyl ether, and the organic layer was washed with 30 ml of saturated saline. The organic layer was dehydrated and dried with sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.1 g of the target product as a yellow solid (yield 15.4%). 1 H NMR (CDCl3, Me4Si, model A) δ8.51 (d, J=1.8Hz, 1H), 7.91 (d, J=1.8Hz, 1H), 7.41 (s, 1H) Step 2: Synthesis of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone A solution of 6.6 mg of diethyl phosphite and 5.3 mg of triethylamine in 1 ml of tetrahydrofuran was added to a solution of 16.6 mg of 2,2-dibromo-1-(3,5-dichloropyridin-2-yl)ethanone in 1 ml of tetrahydrofuran at room temperature. After stirring at room temperature for 6 hours, the reaction solution was analyzed by HPLC (analysis condition A), and the raw material disappeared, and the area % of the target product was 61%.

[0201] Synthesis Example 16: Synthesis of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone To a solution of 15.3 g of 1-(3,5-dichloropyridin-2-yl)ethanone in 35 ml of toluene and 58 ml of methanol, 1.36 g of 47% by mass aqueous hydrogen bromide solution was added at room temperature at 0°C, and the mixture was heated to 55°C. 1.26 g of bromine was added to the mixture so that the temperature did not exceed 60°C, and the operation of stirring at 55°C for 1 hour was repeated six times. Furthermore, 1.26 g of bromine was added to the reaction solution so that the temperature did not exceed 60°C, and the operation of stirring at 55°C for 30 minutes was repeated ten times. After washing the reaction solution with 61.2 g of water, 76.5 g of toluene and 61.2 g of a 5% by mass aqueous sodium hydrogen sulfite solution were added to the organic layer, and the layers were separated. After washing the organic layer with 46 g of water, it was cooled to 5°C, and 3.3 g of methanol, 2.84 g of diethyl phosphite, and 1.04 g of triethylamine were added, and the mixture was stirred at 5°C for 2 hours. 30.6 g of 2% by mass aqueous hydrogen bromide solution was added to the reaction solution, and the solution was separated. The organic layer was washed with 30.6 g of water, and 78 g of the solvent was distilled off under reduced pressure. The solution was analyzed by HPLC (analysis condition A), and it was confirmed that 17.5 g of the target product was produced (yield 80.8%).

[0202] Synthesis Example 17: Synthesis of 2-(2-(3,5-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione Step 1: Synthesis of 2-(3,5-dichloropyridin-2-yl)oxirane-2-carbonitrile 0.39 g of diethylamine was added dropwise to a mixed solution of 1.74 g of 37% by mass aqueous formalin solution and 0.96 g of acetic acid. The reaction solution was stirred at 25°C for 1 hour. Then, a solution of 2.0 g of 2-(3,5-dichloropyridin-2-yl)acetonitrile in 6.0 g of toluene was added dropwise to the reaction solution. The reaction solution was stirred at 25°C for 20 hours. After the reaction was completed, 7.1 g of 5.5% by mass aqueous hydrochloric acid solution and 8.0 g of toluene were added to the reaction solution and the liquids were separated. The obtained organic layer was washed with 7.4 g of 18% by mass aqueous sodium hydrogen carbonate solution and 6.0 g of water in that order. The obtained organic layer was cooled to 10°C, and then 4.0 g of acetonitrile and 10.0 g of 5% by mass aqueous sodium hypochlorite solution were added. The reaction solution was stirred at the same temperature for 20 hours. After the reaction was completed, 10.0 g of water was added to the reaction solution and the liquids were separated at room temperature. The obtained organic layer was dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9 to 1:4) to obtain 1.6 g of the target product as a brown oil (yield 69.6%). 1 H NMR (CDCl3, Me4Si, model B): δ 8.46 (s, 1H), 7.83 (s, 1H), 3.63 (d, J=5.8Hz, 1H), 3.49 (d, J=5.8Hz, 1H) Step 2: Synthesis of 2-(2-(3,5-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione To a mixture of 0.16 g of phthalimide and 0.15 g of potassium carbonate suspended in 5 ml of dimethylformamide, 0.20 g of 2-(3,5-dichloropyridin-2-yl)oxirane-2-carbonitrile obtained in step 1 was added. The reaction solution was stirred at 25° C. for 4 hours. After the reaction was completed, a portion of the reaction solution was sampled and quantitatively analyzed by HPLC (analysis condition B), confirming that 0.10 g of the target product was produced (yield 40.2%).

[0203] Synthesis Example 18: Synthesis of 2-(3,5-dichloropyridin-2-yl)acrylonitrile 0.39 g of diethylamine was added dropwise to a mixed solution of 1.74 g of 37% by mass aqueous formalin solution and 0.96 g of acetic acid. The reaction solution was stirred at 25°C for 1 hour. Then, a solution of 2.0 g of 2-(3,5-dichloropyridin-2-yl)acetonitrile in 6.0 g of toluene was added dropwise to the reaction solution. The reaction solution was stirred at 25°C for 28 hours. After the reaction was completed, 11.1 g of 3.5% by mass aqueous hydrochloric acid solution and 6.0 g of toluene were added to the reaction solution and separated. The obtained organic layer was washed with 12.6 g of 21% by mass aqueous sodium hydrogen carbonate solution and 10.0 g of water in that order, then dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:4) to obtain 1.8 g of the target product as a brown oil (yield 84.6%). 1 H NMR (CDCl3, Me4Si, model B): δ 8.49 (s, 1H), 7.78 (s, 1H), 6.73 (s, 1H), 6.53 (s, 1H) Synthesis Example 19: Synthesis of 2-(3,5-dichloropyridin-2-yl)acrylonitrile (part 2) 0.5 g of 2-(3,5-dichloropyridin-2-yl)acetonitrile and 0.2 g of paraformaldehyde were suspended in 2.5 g of toluene, and 0.4 g of triethylamine was added. The reaction solution was stirred at room temperature for 40 hours. After the reaction was completed, the reaction solution was analyzed by HPLC (analysis condition B), and the peak area ratio of the target product was 26.8% (conversion rate 100%).

[0204] Synthesis Example 20: Synthesis of 2-(3,5-dichloropyridin-2-yl)oxirane-2-carbonitrile 0.2 g of 2-(3,5-dichloropyridin-2-yl)acrylonitrile and 0.43 g of metachloroperbenzoic acid (Kanto Chemical Co., Ltd.: purity 65% ​​or higher) were dissolved in 5 ml of toluene and stirred for 3 hours at 60° C. After the reaction was completed, a portion of the reaction solution was sampled and analyzed by HPLC (analysis condition B). As a result, the peak area ratio of the target product was 33.5% (conversion rate 53.1%).

[0205] Synthesis Example 21: Synthesis of 2-(3,5-dichloropyridin-2-yl)oxirane-2-carbonitrile 0.2 g of 2-(3,5-dichloropyridin-2-yl)acrylonitrile was dissolved in 5 ml of toluene, and then 0.5 g of water, 0.2 g of acetonitrile, and 0.25 g of sodium hypochlorite pentahydrate were added. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, a part of the organic layer of the reaction solution was sampled and analyzed by HPLC (analysis condition B). As a result, the peak area ratio of the target product was 84.2% (conversion rate 98.5%).

[0206] Synthesis Example 22: Synthesis of 2-(2-(3,5-dichloropyridin-2-yl)-2-oxoethyl)isoindoline-1,3-dione 0.16 g of phthalimide, 0.43 g of acetone, and 0.15 g of potassium carbonate were suspended in 5 ml of dimethylformamide, and 0.20 g of 2-(3,5-dichloropyridin-2-yl)oxirane-2-carbonitrile was added. The reaction solution was stirred at 25°C for 19 hours. Then, 0.18 g of diethyl sulfate was added to the reaction solution, and the reaction solution was stirred for 1 hour. After the reaction was completed, the total amount of the reaction solution was quantitatively analyzed by HPLC (analysis condition B), and it was confirmed that 0.20 g of the target product was produced (yield 79.0%).

[0207] Synthesis Example 23: Synthesis of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone 0.55g of 98% by mass aqueous sulfuric acid solution was added to a solution of 10g of 1-(3,5-dichloropyridin-2-yl)ethanone in 23ml of toluene and 25ml of methanol at room temperature, and the mixture was heated to 40°C. 4.3g of bromine was added to the mixture so that the temperature did not exceed 45°C, and the mixture was stirred at 40°C for 2 hours. Furthermore, 2.6g of bromine was added to the reaction solution so that the temperature did not exceed 45°C, and the reaction solution was stirred at 40°C for 1 hour. This operation was repeated twice. Furthermore, 2.1g of bromine was added to the reaction solution so that the temperature did not exceed 45°C, and the reaction solution was stirred at 40°C for 1 hour. Furthermore, 1.4g of bromine was added to the reaction solution so that the temperature did not exceed 45°C, and the reaction solution was stirred at 40°C for 1 hour. 30.6g of water and 12ml of toluene were added to the reaction solution, and the mixture was separated. 12.5g of water and 18.5g of 47% by mass aqueous hydrogen bromide solution were added to the organic layer, and the mixture was stirred at 40°C for 7 hours. After the reaction solution was separated, 40.8 g of water and 35 ml of toluene were added to the organic layer, and the organic layer was separated. After washing with 20.4 g of water, the organic layer was analyzed by HPLC (analysis condition B), and it was confirmed that 11.9 g of the target product was produced (yield 82.4%).

[0208] Reference Example 1: Synthesis of methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)acetate To a solution of 50 g of 2,3,5-trichloropyridine in 300 ml of dimethyl sulfoxide, 60 g of methyl cyanoacetate and 196.5 g of cesium carbonate were added in sequence. The reaction solution was stirred at 70°C for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then 300 ml of water and then a 35% by mass aqueous hydrochloric acid solution were added to adjust the pH of the reaction solution to about 3. Then, the solid precipitated in the reaction solution was filtered. The obtained solid was washed twice with 100 ml of water and once with 100 ml of hexane, then dissolved in 200 ml of chloroform and washed with 100 ml of water. The obtained organic layer was washed with 100 ml of water, dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with 100 ml of a mixed solution of isopropyl ether and hexane (1:1), and 50 g of the target product was obtained as a yellow solid. Melting point: 112-114℃ 1H NMR (CDCl3, Me4Si, model A) δ 8.50 (d, J=2.05 Hz, 1H), 7.82 (d, J=2.05 Hz, 1H), 5.34 (s, 1H), 3.87 (s, 3H) Reference Example 2: Synthesis of methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)propionate To a solution of 23.4 g of methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)acetate in 100 ml of dimethylformamide, 14.5 g of dimethyl sulfate and then 12.2 g of sodium carbonate were added. The reaction solution was stirred at 50°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with 150 ml of ethyl acetate. The obtained organic layer was washed twice with 50 ml of water, dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 5:95 to 10:90 gradient) to obtain 6.46 g of the target product as a colorless oil. 1 H NMR (CDCl3, Me4Si, model A) δ8.49 (d, J=2.05 Hz, 1H), 7.80 (d, J=2.05 Hz, 1H), 4.21 (q, J=7.15 Hz, 2H), 2.10 (s, 3H), 1.29 (t, J=7.15, 3H) Reference Example 3: Synthesis of 2-(3,5-dichloropyridin-2-yl)propionitrile 17.9g of sodium chloride was added to a solution of 50g of methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)propionate in 150g of dimethyl sulfoxide. The reaction solution was stirred at 100°C for 1 hour, then at 120°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then 150ml of water and 150ml of ethyl acetate were added, followed by separation. The resulting organic layer was washed three times with 50ml of water, dehydrated and dried with 30ml of saturated aqueous sodium chloride solution and then with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane = 2:1) to obtain 13.3g of the target product as a colorless oil. 1H NMR (CDCl3, Me4Si, model A)δ 8.51 (d, J=2.05 Hz, 1H), 7.75 (d, J=2.05 Hz, 1H), 4.46 (q, J=7.16 Hz, 1H), 1.69 (d, J=7.16 Hz, 3H) Reference Example 4: Synthesis of methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)propionate To a solution of 15.0 g of 2,3,5-trichloropyridine in 45 g of dimethyl sulfoxide, 17.9 g of methyl cyanoacetate and then 25.0 g of potassium carbonate were added. The reaction solution was stirred at 110°C for 3 hours. After that, the reaction solution was cooled to room temperature, and 23.3 g of iodomethane was added. The reaction solution was stirred at room temperature for 20 hours. After the reaction was completed, 15 g of water was added to the reaction solution and stirred for 5 hours. After the stirring was completed, the reaction solution was cooled to room temperature, and then 135 g of water was added and extracted twice with 75 g of toluene. The obtained organic layer was washed twice with 75 g of water, and then washed with 75 g of saturated saline, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 5:95 to 10:90 gradient) to obtain 7.90 g of the target product as a colorless oil.

[0209] Reference Example 5: Synthesis of 2-(3,5-dichloropyridin-2-yl)propionitrile To a solution of 500 mg of 2,3,5-trichloropyridine in 5 ml of dimethyl sulfoxide, 767 mg of 2-cyanopropionate and then 833 mg of potassium carbonate were added. The reaction solution was stirred at 100°C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 10 ml of water was added, and the mixture was separated with 20 ml of ethyl acetate. The organic layer obtained was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:2) to obtain 270 mg of the target product as a colorless oil (yield 49.0%).

[0210] Reference Example 6: Synthesis of 2-(3,5-dichloropyridin-2-yl)propionitrile To a solution of 1.0 g of 2,3,5-trichloropyridine in 10 ml of xylene, 21.92 ml of a tetrahydrofuran solution of potassium t-butoxide (1 mol / L) and then 694 mg of propionitrile were added at room temperature. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, 20 ml of water was added to the reaction solution, and the solution was extracted with 10 ml of toluene. The resulting organic layer was washed with 10 ml of water and 10 ml of saturated saline solution in that order, and then dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.07 g of residue. 1 As a result of H NMR analysis, it was confirmed that the residue was a mixture of the target substance, 1-(3,5-dichloropyridin-2-yl)ethanone and 2-(t-butoxy)-3,5-dichloropyridine, and that the residue contained 609 mg of the target substance based on the ratio of the peak integral values.

[0211] Reference Example 7: Synthesis of diethyl 2-(3,5-dichloropyridin-2-yl)malonate To a solution of 50.0 g of 2,3,5-trichloropyridine in 300 ml of dimethyl sulfoxide, 96.6 g of diethyl malonate and then 196 g of cesium carbonate were added. The reaction solution was stirred at 110°C for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added dropwise to 1.2 kg of water at 5°C. After the addition was completed, the reaction solution was extracted twice with 600 ml of hexane, and the organic layer was washed successively with 500 ml of water and 300 ml of saturated saline, then dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane) to obtain 66.9 g of the target product as a yellow oil (yield 79.8%). 1 H NMR (CDCl3, Me4Si, model A) δ 8.45 (d, J=2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 5.16 (s, 1H), 4.28 (q, J=7.2 Hz, 4H), 1.28 (t, J=7.2 Hz, 6H) Reference Example 8: Synthesis of diethyl 2-(3,5-dichloropyridin-2-yl)-2-methylmalonate To a solution of 12.57 g of diethyl 2-(3,5-dichloropyridin-2-yl)malonate in 41 ml of dimethylsulfoxide, 6.8 g of potassium carbonate and then 7.0 g of iodomethane were added. The reaction solution was stirred at room temperature for 2.5 hours. After the reaction was completed, 50 ml of water was added to the reaction solution, and it was extracted with 150 ml of hexane. The obtained organic layer was washed with 100 ml of water and 100 ml of saturated saline solution in that order, then dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 0:10 to 2:8 gradient) to obtain 10.22 g of the target product as a colorless oil (yield 77.7%). 1 H NMR (CDCl3, Me4Si, model A)δ 8.37 (d, J=2.1 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 4.16-4.33 (m, 4H), 1.92 (s, 3H), 1.30-1.24 (m, H) Reference Example 9: Synthesis of 3,5-dichloro-2-ethylpyridine 495 mg and 2.97 g of water were added to a solution of 990 mg of 2-(3,5-dichloropyridin-2-yl)-2-methylmalonate diethyl in toluene. The reaction solution was heated to 70°C, and then 2.2 ml of 28% by mass potassium hydroxide aqueous solution was added at the same temperature. The reaction solution was stirred at the same temperature for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and then 1.0 g of toluene and 1.0 g of water were added to the obtained residue and separated. The obtained aqueous layer was heated to 100°C, and 2.0 g of 35% by mass hydrochloric acid aqueous solution was added. After the addition was completed, the aqueous solution was stirred at the same temperature for 2.5 hours. After the stirring was completed, the aqueous solution was cooled to room temperature and extracted with 2.0 g of heptane. The obtained organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:99) to obtain 300 mg of the desired product as a colorless oil (yield 55.2%). 1H NMR (CDCl3, Me4Si, model A)δ 8.39 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 2.93 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H) Reference Example 10: Synthesis of 3,5-dichloro-2-ethylpyridine To a solution of 50 g of 2,3,5-trichloropyridine in 300 ml of dimethyl sulfoxide, 87.8 g of diethyl malonate and 179 g of cesium carbonate were added. The reaction solution was stirred at 100°C for 20 hours. After that, the reaction solution was cooled to room temperature, and 58.3 g of iodomethane was added. The reaction solution was stirred at the same temperature for 3 hours. After the reaction was completed, 300 ml of water was added to the reaction solution, and it was extracted with 300 ml of hexane. The obtained organic layer was washed with 300 ml of water, dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 150 ml of ethanol, 150 ml of water, and 79.9 g of 48 mass% aqueous sodium hydroxide solution were added to the obtained residue in that order, and the mixture was stirred at 60°C for 3 hours. Then, the reaction solution was cooled to room temperature, and 200 ml of the solvent was distilled off under reduced pressure. 150 ml of heptane was added to the obtained aqueous solution, and 35 mass% aqueous hydrochloric acid solution was added to the aqueous layer until the pH became 1. After the addition was completed, the solid precipitated in the aqueous layer was filtered off. The obtained solid was suspended in 200 ml of water and stirred at 100°C for 5 hours. After stirring was completed, the aqueous solution was cooled to room temperature and extracted with 200 ml of hexane. The obtained organic layer was washed with 100 ml of water, dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 28.67 g of the target product as a yellow oil (yield 59.4%).

[0212] Reference Example 11: Synthesis of methyl 2-cyano-2-(3,5-dichloropyridin-2-yl)acetate 40.0 g of 2,3,5-trichloropyridine was dissolved in 240 g of dimethyl sulfoxide. 65.2 g of methyl cyanoacetate and 75.8 g of potassium carbonate were added to this reaction solution in order. The reaction solution was stirred at 120°C for 7.5 hours. After the reaction was completed, the reaction solution was cooled to 40°C, and then 200 g of water and 114 g of 35% by mass aqueous hydrochloric acid solution were added to the reaction solution. The reaction solution was stirred at room temperature for 1 hour. The solid precipitated in the reaction solution was filtered off. The obtained solid was washed with 50 g of water, 50 g of normal hexane, and 100 g of diisopropyl ether in that order, and then dried under reduced pressure to obtain 41.8 g of the target product as a yellow solid (yield 77.7%). 1 H NMR (CDCl3, Me4Si, model B): δ 8.51 (s, 1H), 7.82 (s, 1H), 5.34 (s, 1H), 3.88 (s, 3H). Reference Example 12: Synthesis of 2-(3,5-dichloropyridin-2-yl)acetonitrile 2-Cyano-2-(3,5-dichloropyridin-2-yl)acetic acid methyl ester 38.4 g of the product was dissolved in 115 g of dimethyl sulfoxide. 19.2 g of water was added to the reaction solution. The reaction solution was stirred at 120°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then 192 ml of water and 221 ml of toluene were added and separated. The obtained organic layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:4) to obtain 28.2 g of the target product as a yellow oil (yield 96.4%). 1 H NMR (CDCl3, Me4Si, model B): δ 8.50 (s, 1H), 7.78 (s, 1H), 4.03 (s, 2H). Reference Example 13: Synthesis of 2-(2-bromo-1,1-dimethoxyethyl)-3,5-dichloropyridine 0.11 g of 95% by mass aqueous sulfuric acid solution was added to a solution of 2.0 g of 1-(3,5-dichloropyridin-2-yl)ethanone in 5 ml of toluene and 5 ml of methanol at room temperature, and the mixture was heated to 40°C. 0.84 g of bromine was added to the mixture so that the temperature did not exceed 45°C, and the mixture was stirred at 40°C for 2 hours. Furthermore, 0.50 g of bromine was added to the reaction solution so that the temperature did not exceed 45°C, and the mixture was stirred at 40°C for 1 hour. This operation was repeated twice. Furthermore, 0.34 g of bromine was added to the reaction solution so that the temperature did not exceed 45°C, and the mixture was stirred at 40°C for 1 hour. Furthermore, 0.17 g of bromine was added to the reaction solution so that the temperature did not exceed 45°C, and the mixture was stirred at 40°C for 1 hour. The reaction solution was washed with 6.0 g of water, and then separated. The organic layer was dehydrated and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9) to obtain 0.4 g of the target product as a yellow oil.

[0213] 1 H NMR (CDCl3, Me4Si, model B) δ8.61 (d, J=1.8Hz, 1H), 7.78 (d, J=1.8Hz, 1H), 3.96 (s, 2H), 3.32 (s, 6H) [Industrial Applicability]

[0214] INDUSTRIAL APPLICABILITY The present invention is extremely useful as a method for industrially producing a 2-acetylpyridine compound and a pyridinyl-2-oxoethylisoindoline compound.

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ and a 2-picolinonitrile compound represented by the formula (2): 【Chemistry 2】 [wherein X represents a halogen atom], 【Chemistry 3】 [0023] In the formula, R has the same meaning as defined above.

2. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, The method for producing a pyridinyl ethanone compound according to claim 1, wherein X represents a chlorine atom, a bromine atom, or an iodine atom.

3. Formula (4): 【Chemistry 4】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ represents an alkoxycarbonyl; and Y represents a hydrogen atom or a halogen atom], with an oxidizing agent to obtain a 2-pyridylpropionitrile compound represented by the formula (3): 【Chemistry 5】 A method for producing a pyridinyl ethanone compound represented by the formula: wherein R has the same meaning as defined above.

4. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, The method for producing a pyridinyl ethanone compound according to claim 3, wherein Y represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom.

5. Formula (5): 【Chemistry 6】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ [representing an alkoxycarbonyl] is reacted with a halogen to obtain a 2-ethylpyridine compound represented by the formula (6): 【Chemistry 7】 [In the formula, R has the same meaning as defined above, and X represents a halogen atom], and the resulting 2-(1-halogeno)pyridine compound represented by formula (6) is reacted with an oxidizing agent to obtain a 2-(1-halogeno)pyridine compound represented by formula (3): 【Chemistry 8】 A method for producing a pyridinyl ethanone compound represented by the formula: wherein R has the same meaning as defined above.

6. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, The method for producing a pyridinyl ethanone compound according to claim 5, wherein X represents a chlorine atom, a bromine atom or an iodine atom.

7. Formula (7): 【Chemistry 9】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ [0036] A 2-pyridylpropionic acid compound represented by the formula (3): 【Chemistry 10】 A method for producing a pyridinyl ethanone compound represented by the formula: wherein R has the same meaning as defined above.

8. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ A method for producing the pyridinyl ethanone compound according to claim 7, wherein the alkynyl is selected from the group consisting of alkynyl and alkynyl.

9. Formula (7): 【Chemistry 11】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ The 2-pyridylpropionic acid compound represented by the formula:

10. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ 2-Pyridylpropionic acid compound according to claim 9, wherein the alkynyl is 2-pyridylpropionic acid compound.

11. Formula (8): 【Chemistry 12】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ represents an alkoxycarbonyl; R １ is a hydrogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ alkynyl] to obtain a 3-oxo-3-pyridylpropionic acid compound represented by the formula (3): 【Chemistry 13】 A method for producing a pyridinyl ethanone compound represented by the formula: wherein R has the same meaning as defined above.

12. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, R １ is C １ ~C ６ The method for producing the pyridinyl ethanone compound according to claim 11, wherein the alkyl is selected from the group consisting of aryl, aryl, aryl, and aryl.

13. Formula (8): 【Chemistry 14】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ represents an alkoxycarbonyl; R １ is a hydrogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ The compound represented by the formula (1) is a 3-oxo-3-pyridylpropionic acid compound represented by the formula (1).

14. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, R １ is C １ ~C ６ The 3-oxo-3-pyridylpropionic acid compound according to claim 13, wherein the 3-oxo-3-pyridylpropionic acid compound is alkyl.

15. Formula (3): 【Chemistry 15】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ [0043] A pyridinyl ethanone compound represented by the formula (9): 【Chemistry 16】 [wherein R is as defined above, and X is a halogen atom], and the resulting 2-halogeno-1-pyridinylethanone compound represented by formula (9) is reacted with phthalimide or potassium phthalimide in the presence of a phase transfer catalyst to obtain a compound represented by formula (10): 【Chemistry 17】 A method for producing an isoindolinedione compound represented by the formula: wherein R has the same meaning as defined above.

16. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, The method for producing a pyridinyl ethanone compound according to claim 15, wherein X represents a chlorine atom, a bromine atom, or an iodine atom.

17. Formula (11): 【Chemistry 18】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ and X represents a halogen atom], thereby obtaining a 2,2-dihalo-1-pyridinyl ethanone compound represented by the formula (9): 【Chemistry 19】 [wherein R and X are as defined above], and the resulting 2-halogeno-1-pyridinylethanone compound represented by formula (9) is reacted with phthalimide or potassium phthalimide in the presence of a phase transfer catalyst to obtain a compound represented by formula (10): 【Chemistry 20】 A method for producing an isoindolinedione compound represented by the formula: wherein R has the same meaning as defined above.

18. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ represents alkynyl, The method for producing a pyridinyl ethanone compound according to claim 17, wherein X represents a chlorine atom, a bromine atom, or an iodine atom.

19. Formula (11): 【Chemistry 21】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a nitro group, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ represents an alkoxycarbonyl group, and X represents a halogen atom.

20. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ The 2,2-dihalo-1-pyridinyl ethanone compound according to claim 17, wherein X represents an alkynyl group and X represents a bromine atom.

21. Formula (12): 【Chemical 22】 [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, a nitro, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ [0036] A pyridinylacetonitrile compound represented by the formula (13): 【Chemistry 23】 A method for producing a pyridinyl acrylonitrile compound represented by the formula: wherein R has the same meaning as defined above.

22. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ The method for producing a pyridinyl acrylonitrile compound according to claim 21, wherein alkynyl is represented by the formula (1).

23. Formula (13): 【Chemistry 24】 [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, a nitro, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ [0043] By reacting a pyridinyl acrylonitrile compound represented by the formula (14): 【Chemistry 25】 A method for producing a pyridinyloxirane compound represented by the formula (14): wherein R has the same meaning as defined above.

24. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ A method for producing a pyridinyloxirane compound according to claim 23, wherein the alkynyl is an alkynyl group.

25. Formula (14): 【Chemistry 26】 [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, a nitro, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ [0036] A pyridinyloxirane compound represented by the formula (10): 【Chemistry 27】 A method for producing an isoindoline compound represented by the formula: wherein R has the same meaning as defined above.

26. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ The method for producing the isoindoline compound according to claim 25, wherein the alkynyl is selected from the group consisting of alkynyl and alkynyl.

27. Formula (13): 【Chemistry 28】 [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, a nitro, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ The pyridinyl acrylonitrile compound represented by the formula (1) is an alkoxycarbonyl.

28. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ The pyridinyl acrylonitrile compound of claim 27, wherein the pyridinyl acrylonitrile compound is an alkynyl group.

29. Formula (14): 【Chemical 29】 [In the formula, R is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, a nitro, １ ~C ６ Alkyl, halo (C １ ~C ６ ) alkyl, C １ ~C ６ Alkoxy, halo(C ２ ~C ６ ) Alkoxy, C ２ ~C ８ Alkenyl, halo(C ２ ~C ８ ) alkenyl, C ２ ~C ８ Alkynyl, halo(C ２ ~C ８ ) alkynyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl sulfonyloxy, halo(C １ ~C ６ ) alkylsulfonyl, halo(C １ ~C ６ ) alkylsulfonyloxy, C １ ~C ４ Phenylsulfonyl optionally substituted with alkyl, １ ~C ４ Phenylsulfonyloxy optionally substituted with alkyl, phenylsulfonyl optionally substituted with halogen, phenylsulfonyloxy optionally substituted with halogen, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkylcarbonyloxy, halo(C １ ~C ６ ) alkylcarbonyl, halo(C １ ~C ６ ) alkylcarbonyloxy or C １ ~C ６ The pyridinyloxirane compound represented by the formula:

30. R is a halogen atom, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ 30. The pyridinyl oxirane compound of claim 29, which represents alkynyl.

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