Method for producing ketone derivative

Abstract

The present invention relates to a method for producing a ketone derivative. The purpose of the present invention is to provide a method for producing a ketone derivative in which an acyl chloride derivative other than an aromatic acyl chloride derivative may be used as a substrate in addition to an aromatic acyl chloride derivative. The present invention provides a method for producing a ketone derivative, which comprises a step for producing a ketone derivative by bringing an acyl chloride derivative into contact with a Grignard reagent in the presence of a copper salt and a polydentate ligand that coordinates with Mg in the Grignard reagent, and a polydentate ligand containing two or more donor atoms selected from the group consisting of an oxygen atom and a nitrogen atom.

Description

Technical Field

[0001] The present invention relates to a method for producing a ketone derivative. Background Art

[0002] Ketone derivatives are useful compounds as agricultural and pharmaceutical agents, chemical raw materials, synthetic intermediates, and the like.

[0003] In Non-Patent Document 1, the following method is described:

[0004] In the following formula:

[0005] [Chemical Formula 1]

[0006]

[0007] in the presence of bis(2-dimethylaminoethyl) ether represented by the formula:

[0008] reacting an acyl chloride derivative represented by the following formula:

[0009] [Chemical Formula 2]

[0010]

[0011] with

[0012] a Grignard reagent represented by the following formula:

[0013] [Chemical Formula 3]

[0014] R 2 MgX

[0015] to produce a ketone derivative represented by the following formula.

[0016] [Chemical Formula 4]

[0017]

[0018] The combinations of the acyl chloride derivative, the Grignard reagent, and the ketone derivative described in Non-Patent Document 1 are as follows.

[0019] [Table 1]

[0020]

[0021] [Table 2]

[0022]

[0023] Prior Art Documents

[0024] Non-Patent Documents

[0025] Non-Patent Document 1: Organic Letters, Vol. 7, No. 25, 2005, pp. 5593-5595 Summary of the Invention

[0026] Problems to be Solved by the Invention

[0027] The acyl chloride derivatives used in Non-Patent Document 1 are limited to aromatic acyl chloride derivatives.

[0028] An object of the present invention is to provide a method for producing a ketone derivative, which can use, in addition to aromatic acyl chloride derivatives, acyl chloride derivatives other than aromatic acyl chloride derivatives as substrates.

[0029] Means for Solving the Problems

[0030] The present invention includes the following inventions.

[0031] [1] A method for producing a ketone derivative (I) represented by the following formula (I), the method comprising the following steps:

[0032] Step (S1), in the presence of a copper salt and a polydentate ligand, contacting an acyl chloride derivative (II) represented by the following formula (II) with a Grignard reagent (III) selected from a Grignard reagent (IIIa) represented by the following formula (IIIa) and a Grignard reagent (IIIb) represented by the following formula (IIIb) to form the aforementioned ketone derivative (I);

[0033] The aforementioned polydentate ligand is a polydentate ligand that coordinates with Mg in the aforementioned Grignard reagent (III), and is a polydentate ligand containing two or more donor atoms selected from oxygen atoms and nitrogen atoms.

[0034] [Chemical Formula 5]

[0035]

[0036] [In the formula, R 1 and R 2 each independently represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent.]

[0037] [Chemical Formula 6]

[0038]

[0039] [In the formula, the meaning of R 1 is the same as above.]

[0040] [Chemical Formula 7]

[0041] R 2 MgX (IIIa)

[0042] [wherein, R 2 has the same meaning as above, and X represents a halogen atom.]

[0043] [Chemical Formula 8]

[0044] R 2 MgX·LiCI (IIIb)

[0045] [wherein, R 2 and the meaning of X are the same as above.]

[0046] [2] The method as described in [1], wherein the aforementioned multidentate ligand is a multidentate ligand represented by the following formula (IV) or a multidentate ligand represented by the following formula (VI).

[0047] [Chemical Formula 9]

[0048] L 1 -L 2 -L 3 (IV)

[0049] [wherein,

[0050] L 1 and L 3 each independently represent an amino group which may have a substituent, an alkyloxy group which may have a substituent, or a group represented by the following formula (V),

[0051] [Chemical Formula 10]

[0052]

[0053] (wherein,

[0054] R 100 represents the formula: -[(Y 1 ) a -Z 1 ) b -(Y 1 ) c -shown divalent group,

[0055] Y 1 each independently represents a methylene group which may have a substituent or a phenylene group which may have a substituent,

[0056] Z 1 each independently represents an ether group or an imino group which may have a substituent,

[0057] a represents an integer of 1 or more,

[0058] b represents an integer of 0 or more,

[0059] c represents an integer of 1 or more.)

[0060] L 2 Expression: -[(Y 2 )d - Z 2 e - (Y 2 )f - the divalent group shown,

[0061] Y 2 each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent,

[0062] Z 2 each independently represents an ether group, or an imino group which may have a substituent,

[0063] d represents an integer of 1 or more,

[0064] e represents an integer of 1 or more,

[0065] f represents an integer of 1 or more.)

[0066] [Chemical Formula 11]

[0067]

[0068] [In the formula,

[0069] R 200 represents an alkyl group which may have a substituent,

[0070] R 300 represents the expression: -[(Y 3 ) g - Z 3 h -(Y 3 ) i - the divalent group shown,

[0071] Y 3 each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent,

[0072] Z 3 each independently represents an ether group, or an imino group which may have a substituent,

[0073] g represents an integer of 1 or more,

[0074] h represents an integer of 1 or more,

[0075] i represents an integer of 1 or more.)

[0076] ​[3] The method according to [2], wherein the multi-dentate ligand is selected from the multi-dentate ligands represented by the following formulas (A) to (F).

[0077] [Table 3]

[0078]

[0079] [4] The method according to [3], wherein the multi-dentate ligand is the multi-dentate ligand represented by the foregoing formula (A).

[0080] [5] The method according to any one of [1] to [4], wherein the copper salt is selected from copper(I) cyanide, copper(I) chloride, copper(I) bromide, copper(I) iodide, and copper(I) thiophene-2-carboxylate.

[0081] [6] The method according to any one of [1] to [5], wherein, relative to 1 mole of the acyl chloride derivative (II), the amount of the Grignard reagent (III) used is 0.5 to 3 moles.

[0082] [7] The method according to any one of [1] to [6], wherein, relative to 1 mole of the Grignard reagent (III), the amount of the copper salt used is 0.005 to 2 moles.

[0083] [8] The method according to any one of [1] to [7], wherein, relative to 1 mole of the Grignard reagent (III), the amount of the multi-dentate ligand used is 0.05 to 3 moles.

[0084] [9] The method according to any one of [1] to [8], wherein the step (S1) includes the following steps:

[0085] Step (T1) of mixing the acyl chloride derivative (II) and the copper salt to prepare a first mixture;

[0086] Step (T2) of mixing the Grignard reagent (III) and the multi-dentate ligand to prepare a second mixture; and

[0087] Step (T3) of mixing the first mixture and the second mixture to form the ketone derivative (I).

[0088]

[10] The method according to [9], wherein in step (T3), the second mixture is added dropwise to the first mixture.

[0089]

[11] The method according to any one of [1] to [8], wherein the step (S1) includes the following steps:

[0090] Step (U1) of mixing the aforementioned copper salt, the aforementioned Grignard reagent (III) and the aforementioned multidentate ligand to prepare a third mixture; and

[0091] Step (U2) of mixing the aforementioned third mixture with the aforementioned acyl chloride derivative (II) to form the aforementioned ketone derivative (I).

[0092]

[12] The method according to any one of [1] to

[11] , wherein the aforementioned method further comprises the following step:

[0093] Step (S0) of contacting a carboxylic acid derivative (II’) represented by the following formula (II’) with a chlorinating agent to produce the aforementioned acyl chloride derivative (II).

[0094] [Chemical formula 12]

[0095]

[0096] [In the formula, the meaning of R 1 is the same as above.]

[0097]

[13] The method according to

[12] , wherein in the aforementioned step (S0), the aforementioned carboxylic acid derivative (II’) is contacted with the aforementioned chlorinating agent in the presence of a catalytic amount of N,N-dimethylformamide.

[0098]

[14] The method according to

[12] or

[13] , wherein the aforementioned chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphoryl chloride and phosphorus pentachloride.

[0099] Advantages of the Invention

[0100] According to the present invention, a method for manufacturing a ketone derivative can be provided, and in addition to using an aromatic acyl chloride derivative, an acyl chloride derivative other than the aromatic acyl chloride derivative can also be used as a substrate.

[0101] According to the present invention, by contacting an acyl chloride derivative (II) with a Grignard reagent (III) in the presence of a copper salt and a multidentate ligand, a high yield of the ketone derivative (I) can be achieved and the amount of the copper salt used can be reduced. Detailed Embodiments

[0102] Hereinafter, the present invention will be described. Two or more embodiments described in this specification can be combined, and the combination of two or more embodiments is also included in the present invention.

[0103] 《Explanation of Terms》

[0104] Hereinafter, the terms used in this specification will be described. Unless otherwise specified, the following explanations apply throughout this specification. It should be noted that, unless otherwise specified, the expression "value A to value B" means greater than or equal to value A and less than or equal to value B.

[0105] organic solvent

[0106] Examples of the organic solvent include nitrile solvents such as acetonitrile and propionitrile; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, dibutyl ether, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, and diethylene glycol dimethyl ether; ketone solvents such as acetone, methyl ethyl ketone, and diethyl ketone; ester solvents such as methyl acetate, ethyl acetate, and butyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbon solvents such as toluene and xylene; and aliphatic hydrocarbon solvents such as hexane and heptane.

[0107] halogen atom

[0108] The halogen atom is selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0109] alkyl

[0110] The number of carbon atoms of the alkyl group is, for example, 1 to 50, preferably 1 to 20, more preferably 1 to 15, and even more preferably 1 to 12 (for example, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2). The alkyl group may be linear or branched. The number of carbon atoms of the linear alkyl group is 1 or more, and the number of carbon atoms of the branched alkyl group is 3 or more.

[0111] alkenyl

[0112] The number of carbon atoms of the alkenyl group is, for example, 2 to 50, preferably 2 to 20, more preferably 2 to 15, and even more preferably 2 to 12 (for example, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3). The alkenyl group may be linear or branched. The number of carbon atoms of the linear alkenyl group is 2 or more, and the number of carbon atoms of the branched alkenyl group is 3 or more.

[0113] cycloalkyl

[0114] The number of carbon atoms of the cycloalkyl group is, for example, 3 to 10, preferably 3 to 8, and more preferably 3 to 6.

[0115] heterocycloalkyl

[0116] A heterocycloalkyl group is a monocyclic saturated aliphatic heterocyclic group. In this saturated aliphatic heterocyclic group, as ring-constituting atoms, in addition to carbon atoms, it contains one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. The saturated aliphatic heterocyclic group is an aliphatic heterocyclic group in which the ring is composed only of saturated bonds. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2. The ring size of the heterocycloalkyl group is, for example, 3 to 8-membered, preferably 4 to 7-membered, more preferably 5 to 7-membered, and even more preferably 5 or 6-membered. Examples of the heterocycloalkyl group include a heterocycloalkyl group containing 1 to 2 oxygen atoms, a heterocycloalkyl group containing 1 to 2 sulfur atoms, a heterocycloalkyl group containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, a heterocycloalkyl group containing 1 to 4 nitrogen atoms, a heterocycloalkyl group containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, etc. The heterocycloalkyl group preferably contains an oxygen atom as a heteroatom. Examples of the heterocycloalkyl group include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl (the sulfur atom on the ring can be oxidized), azepanyl, diazepanyl, oxepanyl, azocanyl, diazocanyl, etc.

[0117] In one embodiment, the heterocycloalkyl group is selected from tetrahydrofuryl and tetrahydropyranyl.

[0118] In one embodiment, the heterocycloalkyl group is tetrahydrofuryl.

[0119] aryl

[0120] An aryl group is, for example, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic hydrocarbon ring group having 4 to 14 carbon atoms, preferably 6 to 14 carbon atoms, and more preferably 6 to 10 carbon atoms. The polycyclic form is preferably a fused ring form. Examples of the aryl group include a phenyl group, a naphthyl group, etc. The aryl group is preferably a phenyl group.

[0121] heteroaryl

[0122] A heteroaryl group is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic heterocyclic group in which, as ring-constituting atoms, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom are included. The polycyclic form is preferably a fused-ring form. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The ring size of the heteroaryl group is preferably 4 to 14-membered, more preferably 5 to 10-membered. Examples of the heteroaryl group include a heteroaryl group containing 1 to 2 oxygen atoms, a heteroaryl group containing 1 to 2 sulfur atoms, a heteroaryl group containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, a heteroaryl group containing 1 to 4 nitrogen atoms, a heteroaryl group containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, and the like. The heteroaryl group is preferably a monocyclic or bicyclic 4- to 10-membered (preferably 5- to 10-membered) aromatic heterocyclic group.

[0123] Examples of the monocyclic aromatic heterocyclic group include 5- to 7-membered monocyclic aromatic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, etc.), triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, etc.), tetrazolyl, triazinyl, and the like.

[0124] Examples of the fused polycyclic aromatic heterocyclic group include 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furanopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, α-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

[0125] In one embodiment, the heteroaryl group is selected from thienyl, benzothienyl, furyl, pyrrolyl, imidazolyl, and pyridyl.

[0126] In one embodiment, the heteroaryl group is selected from thienyl and benzothienyl.

[0127] haloalkyl, haloaryl and haloheteroaryl

[0128] The haloalkyl group, haloaryl group and haloheteroaryl group are respectively an alkyl group, an aryl group and a heteroaryl group having one or more halogen atoms, and the descriptions of the alkyl group, aryl group and heteroaryl group are as described above. The number of halogen atoms in the haloalkyl group, haloaryl group or haloheteroaryl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0129] alkylene, arylene and heteroarylene

[0130] The alkylene group, arylene group and heteroarylene group are respectively divalent functional groups formed by removing one hydrogen atom from the alkyl group, aryl group and heteroaryl group, and the descriptions of the alkyl group, aryl group and heteroaryl group are as described above.

[0131] haloalkylene, haloarylene and haloheteroarylene

[0132] The haloalkylene group, haloarylene group and haloheteroarylene group are respectively divalent functional groups formed by removing one hydrogen atom from the haloalkyl group, haloaryl group and haloheteroaryl group, and the descriptions of the haloalkyl group, haloaryl group and haloheteroaryl group are as described above.

[0133] arylalkyl

[0134] The arylalkyl group is an alkyl group having one or more aryl groups, and the descriptions of the alkyl group and aryl group are as described above. The number of aryl groups in the arylalkyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0135] arylalkenyl

[0136] The arylalkenyl group is an alkenyl group having one or more aryl groups, and the descriptions of the alkenyl group and aryl group are as described above. The number of aryl groups in the arylalkenyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0137] alkylcarbonyl and arylcarbonyl

[0138] The alkylcarbonyl group and arylcarbonyl group are respectively groups represented by the formula: -CO-alkyl and the formula: -CO-aryl, and the descriptions of the alkyl group and aryl group are as described above.

[0139] alkyloxy, haloalkyloxy, heterocycloalkyloxy and arylalkyloxy

[0140] The alkyloxy group, haloalkyloxy group, heterocyclic alkyloxy group and arylalkyloxy group are respectively groups represented by the formula: -O-alkyl, the formula: -O-haloalkyl, the formula: -O-heterocyclic alkyl and the formula: -O-arylalkyl, and the descriptions of the alkyl group, haloalkyl group, heterocyclic alkyl group and arylalkyl group are as described above.

[0141] alkylthio, haloalkylthio, heterocycloalkylthio and arylalkylthio

[0142] Alkylthio, haloalkylthio, heterocycloalkylthio, and arylalkylthio are groups represented by the formulas: -S-alkyl, -S-haloalkyl, -S-heterocycloalkyl, and -S-arylalkyl, respectively. The descriptions of alkyl, haloalkyl, heterocycloalkyl, and arylalkyl are as described above.

[0143] alkyloxycarbonyl

[0144] Alkyloxycarbonyl is a group represented by the formula: -CO-O-alkyl. The description of alkyl is as described above. The number of carbon atoms of the alkyl included in alkyloxycarbonyl is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2.

[0145] amino

[0146] Amino is a group represented by the formula: -NH 2 as shown (primary amino group).

[0147] monoalkylamino

[0148] Monoalkylamino is a group represented by the formula: -NH(-Q 1 ) [wherein, Q 1 represents alkyl.]. The description of alkyl is as described above. The number of carbon atoms of the alkyl represented by Q 1 is preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2.

[0149] dialkylamino

[0150] Dialkylamino is a group represented by the formula: -N(-Q 2 )(-Q 3 ) [wherein, Q 2 and Q 3 each independently represent alkyl.]. The description of alkyl is as described above. The number of carbon atoms of the alkyl represented by Q 2 or Q 3 is preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2.

[0151] alicyclic amino

[0152] The alicyclic amino group is, for example, an alicyclic amino group having a 5- or 6-membered ring. Examples of the alicyclic amino group having a 5- or 6-membered ring include a morpholino group, a thiomorpholino group, a pyrrolidin-1-yl group, a pyrazolidin-1-yl group, an imidazolidin-1-yl group, a piperidin-1-yl group, etc. The alicyclic amino group may contain, in addition to the nitrogen atom having a linking bond with the alicyclic amino group, a heteroatom (e.g., 1 heteroatom) independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom.

[0153] In one embodiment, the alicyclic amino group is a morpholino group.

[0154] aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and alicyclic aminocarbonyl

[0155] The aminocarbonyl group, the monoalkylaminocarbonyl group, the dialkylaminocarbonyl group, and the alicyclic aminocarbonyl group are groups represented by the formulas: -CO-amino, -CO-monoalkylamino, -CO-dialkylamino, and -CO-alicyclic amino, respectively. The descriptions of the monoalkylamino group, the dialkylamino group, and the alicyclic amino group are as described above.

[0156] substituent

[0157] The term "may have a substituent" means that it may have one or more substituents. The "one or more substituents" preferably means 1 to 3 substituents, more preferably 1 or 2 substituents.

[0158] substituent group α

[0159] The substituent group α is composed of the following substituents.

[0160] (α-1) A halogen atom

[0161] (α-2) A cyano group

[0162] (α-3) A nitro group

[0163] (α-4) An amino group

[0164] (α-5) An alkyl group

[0165] (α-6) A haloalkyl group

[0166] (α-7) A monoalkylamino group

[0167] (α-8) A dialkylamino group

[0168] (α-9) An alicyclic amino group

[0169] (α-10) An alkyloxycarbonyl group

[0170] (α-11) An aminocarbonyl group

[0171] (α-12) A monoalkylaminocarbonyl group

[0172] (α-13) Dialkylaminocarbonyl

[0173] (α-14) Alicyclic aminocarbonyl

[0174] (α-15) Hydroxy group which can be protected by a protecting group

[0175] (α-16) Mercapto group which can be protected by a protecting group

[0176] substituent group β

[0177] Substituent group β is composed of the following substituents.

[0178] (β-1) Substituent represented by formula (i)

[0179] (β-2) Substituent represented by formula (ii)

[0180] Hereinafter, substituent groups α and β will be described.

[0181] (α-5) In this case, the number of carbon atoms of the alkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2.

[0182] (α-6) In this case, the number of carbon atoms of the haloalkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2. The number of halogen atoms of the haloalkyl group is preferably 1 to 3, more preferably 1 or 2, still more preferably 1.

[0183] (α-15) hydroxyl group which may be protected by a protecting group

[0184] The hydroxy protecting group is preferably a group that can protect the hydroxy group during the target reaction and can be detached from the hydroxy group after the target reaction is completed. As the hydroxy protecting group, for example, an alkylcarbonyl type protecting group, an arylcarbonyl type protecting group, an arylalkyl type protecting group, an alkyl type protecting group, an arylalkyloxyalkyl type protecting group, an alkoxyalkyl type protecting group, a silyl type protecting group, an oxycarbonyl type protecting group, an acetal type protecting group, an aryl type protecting group, etc. can be mentioned. These protecting groups may have one or more halogen atoms.

[0185] As an alkylcarbonyl-type protecting group, for example, an alkylcarbonyl having 2 to 10 carbon atoms which may have one or more substituents can be mentioned. Examples of the substituent may be selected from a halogen atom, a nitro group, a cyano group, a phenyl group, an alkyl group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms), an alkoxy group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms), an alkoxycarbonyl group having 2 to 11 carbon atoms (preferably 2 to 9 carbon atoms, more preferably 2 to 7 carbon atoms, still more preferably 2 to 5 carbon atoms), etc. As the alkylcarbonyl having 2 to 10 carbon atoms which may have one or more substituents, for example, acetyl, propionyl, butyryl, isopropylcarbonyl, pivaloyl, etc. can be mentioned. The alkylcarbonyl-type protecting group is preferably an alkylcarbonyl having 2 to 5 carbon atoms, more preferably acetyl or pivaloyl, still more preferably acetyl.

[0186] As an arylcarbonyl-type protecting group, for example, an arylcarbonyl having 7 to 11 carbon atoms which may have one or more substituents can be mentioned. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. As the arylcarbonyl having 7 to 11 carbon atoms which may have one or more substituents, for example, benzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, 4-methylbenzoyl, 4-tert-butylbenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-phenylbenzoyl, 4-methoxycarbonylbenzoyl, etc. can be mentioned.

[0187] As an arylalkyl-type protecting group, for example, an arylalkyl having 7 to 11 carbon atoms which may have one or more substituents can be mentioned. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. As the arylalkyl having 7 to 11 carbon atoms which may have one or more substituents, for example, benzyl, 1-phenylethyl, diphenylmethyl, 1,1-diphenylethyl, naphthylmethyl, trityl, etc. can be mentioned. The arylalkyl-type protecting group is preferably benzyl.

[0188] As an alkyl-type protecting group, for example, an alkyl having 1 to 10 carbon atoms which may have one or more substituents can be mentioned. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The alkyl-type protecting group is preferably an alkyl having 1 to 5 carbon atoms which may have one or more substituents, more preferably methyl, ethyl, tert-butyl, still more preferably methyl.

[0189] As an arylalkyloxyalkyl type protecting group, for example, there can be mentioned arylalkyloxyalkyl such as arylalkyloxymethyl having 8 to 12 carbon atoms which may have one or more substituents, arylalkyloxyethyl having 9 to 13 carbon atoms which may have one or more substituents, arylalkyloxypropyl having 10 to 14 carbon atoms which may have one or more substituents, etc. Specific examples of the substituents are the same as those of the alkylcarbonyl type protecting group. The arylalkyloxyalkyl type protecting group is, for example, benzyloxymethyl which may have one or more substituents, preferably benzyloxymethyl which may be substituted by a halogen atom, nitro group, cyano group, methyl group or methoxy group, and more preferably benzyloxymethyl.

[0190] As an alkyloxyalkyl type protecting group, for example, there can be mentioned alkyloxyalkyl such as alkyloxymethyl having 2 to 10 carbon atoms which may have one or more substituents, alkyloxyethyl having 3 to 10 carbon atoms which may have one or more substituents, alkyloxypropyl having 4 to 10 carbon atoms which may have one or more substituents, etc. Specific examples of the substituents are the same as those of the alkylcarbonyl type protecting group. The alkyloxyalkyl type protecting group is preferably alkyloxymethyl having 2 to 10 carbon atoms which may have one or more substituents, more preferably alkyloxymethyl having 2 to 6 carbon atoms which may have a halogen atom, nitro group, cyano group, methoxy group or ethoxy group, and even more preferably methoxymethyl.

[0191] As a silyl type protecting group, for example, there can be mentioned silyl having a functional group selected from alkyl having 1 to 10 carbon atoms which may have one or more substituents, arylalkyl having 7 to 11 carbon atoms which may have one or more substituents, and aryl having 6 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl type protecting group. The silyl type protecting group is preferably silyl having a functional group selected from alkyl having 1 to 10 carbon atoms and aryl having 6 to 10 carbon atoms, more preferably silyl having a functional group selected from alkyl having 1 to 5 carbon atoms and phenyl, and even more preferably trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0192] As an oxycarbonyl type protecting group, for example, there can be mentioned alkyloxycarbonyl having 2 to 10 carbon atoms which may have one or more substituents, vinyloxycarbonyl having 3 to 10 carbon atoms which may have one or more substituents, arylalkyloxycarbonyl having 8 to 12 carbon atoms which may have one or more substituents, etc. Specific examples of the substituents are the same as those of the alkylcarbonyl type protecting group. The oxycarbonyl type protecting group is preferably alkyloxycarbonyl having 2 to 6 carbon atoms, vinyloxycarbonyl having 3 to 6 carbon atoms or benzyloxycarbonyl, and more preferably methoxymethyl, allyloxycarbonyl or benzyloxycarbonyl.

[0193] As an acetal-type protecting group, for example, tetrahydrofuranyl, tetrahydropyranyl, etc. can be mentioned.

[0194] As an aryl-type protecting group, for example, aryls such as phenyl can be mentioned.

[0195] The hydroxyl group protected by the protecting group is preferably a group represented by the formula: -O-Q. Q represents alkyl, haloalkyl, aryl, haloaryl, heterocycloalkyl, alkylcarbonyl, arylcarbonyl or arylalkyl. The number of carbon atoms of the group represented by the formula: -O-Q is preferably 1 to 10, more preferably 1 to 8. Q is preferably alkyl, heterocycloalkyl, alkylcarbonyl or arylalkyl, more preferably ethyl, tetrahydrofuranyl, acetyl or benzyl.

[0196] (α-16) mercapto group which may be protected by a protecting group

[0197] The thiol-protecting group is preferably a group that can protect the thiol group during the target reaction and can be detached from the thiol group after the target reaction is completed. As the thiol-protecting group, for example, alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, aryl-type protecting groups, etc. can be mentioned. These protecting groups may have one or more halogen atoms. The description of these protecting groups is as described above.

[0198] The thiol group protected by the protecting group is preferably a group represented by the formula: -S-Q. The description of Q is as described above.

[0199] (β-1) substituent shown in formula (i)

[0200] [Chemical formula 13]

[0201]

[0202] In formula (i), R 11 , R 12 and R 13 each independently represent alkyl, haloalkyl, aryl, haloaryl or a hydroxyl group that can be protected by a protecting group. The hydroxyl group that can be protected by a protecting group is preferably the group represented by the above formula: -O-Q. a is 0 or more and 3 or less.

[0203] (β-2) substituent shown in formula (ii)

[0204] [Chemical formula 14]

[0205] -(V 10 ) b -(W 10 ) c -(X 10 ) (ii)

[0206] In formula (ii), V 10 represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond or a carbonyl group. The number of carbon atoms of the alkylene group and the haloalkylene group is each preferably 1 to 10, more preferably 1 to 8. The number of carbon atoms of the arylene group and the haloarylene group is each preferably 4 to 14, more preferably 6 to 14. The number of carbon atoms of the heteroarylene group and the haloheteroarylene group is each preferably 4 to 14. V 10 is preferably an alkylene group, more preferably a methylene group or an ethylene group.

[0207] In formula (ii), b represents 0 or 1. b is preferably 1.

[0208] In formula (ii), W 10 represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond or a carbonyl group. W 10 is preferably a heteroarylene group, more preferably a heteroarylene group of a 5-membered ring containing a sulfur atom as a heteroatom, and still more preferably a thienylene group.

[0209] In formula (ii), c represents 0 or 1. c is preferably 1.

[0210] In formula (ii), X 10 represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent or a heteroaryl group which may have a substituent. The alkyl group, the aryl group and the heteroaryl group may each be unsubstituted or may have one or more substituents. One or more substituents may each independently be selected from the substituent group α. One or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group and a heterocycloalkylthio group, more preferably from a halogen atom, an alkoxy group having 1 to 3 carbon atoms and a heterocycloalkyloxy group, and still more preferably from a fluorine atom, an ethoxy group and a tetrahydrofuryloxy group. The heterocycloalkyloxy group preferably contains an oxygen atom as a heteroatom. The number of substituents which the alkyl group, the aryl group and the heteroaryl group may each have is preferably 1 to 3, more preferably 1 or 2.

[0211] X 10 is preferably an aryl group which may have a substituent or a heteroaryl group which may have a substituent, more preferably an aryl group having a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a heterocycloalkyloxy group, or an unsubstituted heteroaryl group, and still more preferably a phenyl group having a fluorine atom, an ethoxy group or a tetrahydrofuryloxy group, or an unsubstituted benzothienyl group. The heterocycloalkyloxy group preferably contains an oxygen atom as a heteroatom.

[0212] 《Keto Derivative (I)》

[0213] The keto derivative (I) is represented by the following formula (I).

[0214] [Chemical formula 15]

[0215]

[0216] In formula (I), R 1 and R 2 each independently represent:

[0217] (1) an alkyl group which may have a substituent,

[0218] (2) an alkenyl group which may have a substituent,

[0219] (3) a cycloalkyl group which may have a substituent,

[0220] (4) a heterocycloalkyl group which may have a substituent,

[0221] (5) an aryl group which may have a substituent,

[0222] (6) a heteroaryl group which may have a substituent,

[0223] (7) an arylalkyl group which may have a substituent, or,

[0224] (8) an arylalkenyl group which may have a substituent.

[0225] Hereinafter, the functional groups (1) to (8) will be described.

[0226] (1) alkyl which may have a substituent

[0227] As described above regarding the alkyl group. The alkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β. In one embodiment, one or more substituents are independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group. In one embodiment, one or more substituents are independently selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms. In one embodiment, one or more substituents are independently selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0228] (2) alkenyl which may have a substituent

[0229] The description of alkenyl is as above. The alkenyl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0230] (3) cycloalkyl which may have a substituent

[0231] The description of cycloalkyl is as above. The cycloalkyl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0232] (4) heterocycloalkyl which may have a substituent

[0233] The description of heterocycloalkyl is as above. The heterocycloalkyl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0234] (5) aryl which may have a substituent

[0235] The description of aryl is as above. The aryl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0236] (6) heteroaryl which may have a substituent

[0237] The description of heteroaryl is as above. The heteroaryl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0238] (7) arylalkyl which may have a substituent

[0239] The description of arylalkyl is as above. The arylalkyl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0240] (8) arylalkenyl which may have a substituent

[0241] The description of arylalkenyl is as above. The arylalkenyl may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of the functional group (1).

[0242] In the functional group (5) (i.e., an aryl that may have a substituent), the carbon atoms adjacent to the carbon atom having a linking bond in the aryl (i.e., the carbon atom bonded to -CO- in the formula (I)) preferably do not have substituents. The remaining carbon atoms may have substituents.

[0243] In the functional group (6) (i.e., a heteroaryl group which may have a substituent), the carbon atoms or heteroatoms at the left and right adjacent positions of the carbon atom having a linking bond in the heteroaryl group (i.e., the carbon atom bonded to the -CO- in formula (I)) preferably do not have a substituent. The remaining carbon atoms or heteroatoms may have a substituent.

[0244] In one embodiment, R 1 is the functional group (1), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (1), R 1 and R 2 may be the same or different.

[0245] In one embodiment, R 1 is the functional group (2), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (2), R 1 and R 2 may be the same or different.

[0246] In one embodiment, R 1 is the functional group (3), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (3), R 1 and R 2 may be the same or different.

[0247] In one embodiment, R 1 is the functional group (4), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (4), R 1 and R 2 may be the same or different.

[0248] In one embodiment, R 1 is the functional group (5), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (5), R 1 and R 2 may be the same or different.

[0249] In one embodiment, R 1is a functional group (6), R 2 is any one of the functional groups (1) to (8). In the case of R 1 and R 2 both being the functional group (6), R 1 and R 2 may be the same or different.

[0250] In one embodiment, R 1 is the functional group (7), R 2 is any one of the functional groups (1) to (8). In the case of R 1 and R 2 both being the functional group (7), R 1 and R 2 may be the same or different.

[0251] In one embodiment, R 1 is the functional group (8), R 2 is any one of the functional groups (1) to (8). In the case of R 1 and R 2 both being the functional group (8), R 1 and R 2 may be the same or different.

[0252] In one embodiment, one of R 1 and R 2 (for example, R 1 ) is any one of the functional groups (1) to (4), (7) and (8), preferably any one of the functional groups (1) to (4), more preferably any one of the functional groups (1) to (3), still more preferably the functional group (1) or (3), most preferably the functional group (1), and the other one (for example, R 2 ) is the functional group (5) or (6), preferably the functional group (5), more preferably a phenyl group which may have substituents.

[0253] In one embodiment, R 1 and R 2 are each independently any one of the functional groups (1) to (4), (7) and (8), preferably any one of the functional groups (1) to (4), more preferably any one of the functional groups (1) to (3), still more preferably the functional group (1) or (3), most preferably the functional group (1).

[0254] In one embodiment, R 1 and R 2 are each independently the functional group (5) or (6), preferably the functional group (5), more preferably a phenyl group which may have substituents.

[0255] As R1 and R 2 In the ketone derivative (I) wherein one of them is an alkyl group which may have a substituent and the other is an aryl group which may have a substituent, for example, the following compounds can be cited.

[0256] [Chemical formula 16]

[0257]

[0258] As R 1 and R 2 In the ketone derivative (I) wherein each independently is an aryl group which may have a substituent, for example, the following compounds can be cited.

[0259] [Chemical formula 17]

[0260]

[0261] As R 1 and R 2 In the ketone derivative (I) wherein one of them is a cycloalkyl group which may have a substituent and the other is an aryl group which may have a substituent, for example, the following compounds can be cited.

[0262] [Chemical formula 18]

[0263]

[0264] In one embodiment, one of R 1 and R 2 (for example, R 2 ) is a functional group represented by the following formula (iv).

[0265] [Chemical formula 19]

[0266] -*Y 10 )-(V 10 )b-(W 10 ) c -(X 10 ) (iv)

[0267] In formula (iv), Y 10Represents an alkylene group which may have substituents, an arylene group which may have substituents, or a heteroarylene group which may have substituents. The number of carbon atoms of the alkylene group is preferably 1 to 10, more preferably 1 to 8. The number of carbon atoms of the arylene group is preferably 4 to 14, more preferably 6 to 14. The number of carbon atoms of the heteroarylene group is preferably 4 to 14. Each of the alkylene group, the arylene group, and the heteroarylene group may be unsubstituted or may have one or more substituents. One or more substituents may each independently be selected from the substituent group α. One or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, and more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms. The number of substituents that each of the alkylene group, the arylene group, and the heteroarylene group may have is preferably 1 to 3, more preferably 1 or 2.

[0268] Y 10 Is preferably an arylene group having substituents, more preferably an arylene group having a halogen atom or an alkyl group having 1 to 3 carbon atoms, and even more preferably a phenylene group having a fluorine atom, a chlorine atom, or a methyl group.

[0269] Y 10 Is preferably an arylene group in which the carbon atoms adjacent to the left and right of the carbon atom bonded to -CO in formula (I) do not have substituents and the remaining carbon atoms may have substituents, or a heteroarylene group in which the carbon atoms or heteroatoms adjacent to the left and right of the carbon atom bonded to -CO in formula (I) do not have substituents and the remaining carbon atoms or heteroatoms may have substituents. Y 10 Is more preferably a phenylene group that does not have a substituent at the ortho position relative to the carbon atom bonded to -CO in formula (I) and may have substituents at the meta position and / or the para position.

[0270] In formula (iv), V 10 , W 10 , X 10 , b, and c are each synonymous with formula (ii).

[0271] In one embodiment, one of R 1 and R 2 (for example, R 2 ) is a functional group represented by the following formula (vi).

[0272] [Chemical formula 20]

[0273]

[0274] In formula (vi), R 41 and R 42Each independently represents a hydrogen atom or a protecting group for an amino group. As the protecting group for an amino group, any protecting group such as a carbamate-based, acyl-based, amide-based, sulfonamide-based, phthaloyl group, etc. can be used. As the protecting group for a carbamate-based, for example, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, etc. can be cited. As the protecting group for an acyl-based, for example, acetyl, pivaloyl, benzoyl, etc. can be cited. As the protecting group for an amide-based, for example, trifluoroacetyl, etc. can be cited. As the protecting group for a sulfonamide-based, for example, p-toluenesulfonyl, 2-nitrobenzenesulfonyl, etc. can be cited. The protecting group for an amino group is preferably an acyl-based or amide-based protecting group. The protecting group for an amino group is more preferably pivaloyl or trifluoroacetyl. R 41 and R 42 may be bonded to each other to form a protecting group for an amino group such as a phthaloyl group. If R 2 has the structure of formula (vi), the ketone derivative (I) can be suitably used as an intermediate for remdesivir.

[0275] In one embodiment, one of R 1 and R 2 (for example, R 1 ) is any one of functional groups (1) to (4), (7) and (8), preferably any one of functional groups (1) to (4), more preferably any one of functional groups (1) to (3), still more preferably functional group (1) or (3), and most preferably functional group (1), and the other one (for example, R 2 ) is the functional group represented by the above formula (iv) or the functional group represented by the above formula (vi).

[0276] As the ketone derivative (I) in which R 1 is an alkyl group which may have a substituent, for example, the ketone derivative (Ia) represented by the following formula (Ia) can be cited.

[0277] [Chemical formula 21]

[0278]

[0279] In formula (Ia), n represents 1 or 2.

[0280] In formula (Ia), each R independently represents an alkyl group which may have substituents or an aryl group which may have substituents. The descriptions of the alkyl group and the aryl group are as described above. The alkyl group may be linear or branched, but is preferably linear. The number of carbon atoms of the alkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, and still more preferably 1 to 3. The aryl group is preferably phenyl. Each of the alkyl group and the aryl group may be unsubstituted or may have one or more substituents. The number of substituents that each of the alkyl group and the aryl group may have is preferably 1 to 3, more preferably 1 or 2. One or more substituents may each independently be selected from substituent groups α and β. One or more substituents may also be selected from substituent group α and one or more substituents may be selected from substituent group β. One or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, and still more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0281] In formula (Ia), when n = 1, the four Rs may be different, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxy protecting group represented by the formula: -CO-R. In one embodiment, all four Rs are methyl groups. In one embodiment, all four Rs are phenyl groups.

[0282] In formula (Ia), when n = 2, the five Rs may be different, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxy protecting group represented by the formula: -CO-R. In one embodiment, all five Rs are methyl groups. In one embodiment, all five Rs are phenyl groups.

[0283] As the ketone derivative (Ia), for example, the following compounds can be cited. It should be noted that "Ac" represents an acetyl group.

[0284] [Chemical formula 22]

[0285]

[0286] In one embodiment, R in formula (Ia) 2 is the functional group represented by the above formula (iv) or the functional group represented by the above formula (vi).

[0287] In one embodiment, R in formula (I) or (Ia) 2The same as the functional groups possessed by SGLT-2 inhibitors, or functional groups obtained by derivatizing the functional groups possessed by SGLT-2 inhibitors. Thus, the keto derivative (I) or (Ia) can be used as a raw material for the production of SGLT-2 inhibitors or their derivatives.

[0288] SGLT-2 inhibitors are useful as antidiabetic drugs. It should be noted that "SGLT-2" refers to sodium-glucose cotransporter-2. As SGLT-2 inhibitors, for example, canagliflozin (1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), empagliflozin ((1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol), ipragliflozin ((1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid), dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol), etc. are known.

[0289] SGLT-2 inhibitors represented by canagliflozin, empagliflozin, ipragliflozin, and dapagliflozin have the functional groups represented by the following formula (A).

[0290] In one embodiment, R in formula (I) or (Ia) 2 is the functional group represented by the following formula (A).

[0291] In one embodiment, R 1 is any one of the functional groups (1) to (4), (7), and (8), preferably any one of the functional groups (1) to (4), more preferably any one of the functional groups (1) to (3), still more preferably the functional group (1) or (3), and most preferably the functional group (1). R 2 is the functional group represented by the following formula (A).

[0292] [Chemical formula 23]

[0293]

[0294] In formula (A), d represents an integer from 0 to 4. d is preferably from 1 to 3, more preferably 1 or 2, and still more preferably 1. When d is 2 or more, the d R's a can be the same or different.

[0295] In formula (A), the d R's amay each independently be selected from the substituent group α. d Rs a are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, and more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0296] In formula (A), Ar' is a functional group represented by the following formula (v).

[0297] [Chemical formula 24]

[0298] -(W 10 ) c -(X 10 ) (v)

[0299] In formula (v), W 10 , X 10 and c are each synonymous with formula (ii).

[0300] In formula (A), Ar' is preferably a functional group represented by the following formula (Ar'-1), (Ar'-2), or (Ar'-3).

[0301] [Chemical formula 25]

[0302]

[0303] In formula (Ar'-1), (Ar'-2), and (Ar'-3), p is an integer of 0 to 5. p is preferably an integer of 0 to 3, more preferably an integer of 0 to 2, and even more preferably 0 or 1.

[0304] In formula (Ar'-1), (Ar'-2), and (Ar'-3), p Rs b may each independently be selected from the substituent group α, an aryl group which may have one or more substituents selected from the substituent group α, and a heteroaryl group which may have one or more substituents selected from the substituent group α. p Rs b are preferably each independently selected from the substituent group α and an aryl group which may have one or more substituents selected from the substituent group α. One or more substituents selected from the substituent group α are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a heterocycloalkyloxy group, and even more preferably selected from a fluorine atom, an ethoxy group, and a tetrahydrofuryloxy group. The number of substituents that the aryl group and the heteroaryl group may each have is preferably 1 to 3, more preferably 1 or 2.

[0305] When p is 2 or more, p Rsb They can be the same or different.

[0306] In formula (Ar’-1), p is preferably 1, and R b is preferably phenyl which may have substituents, more preferably phenyl having a halogen atom, and even more preferably phenyl having a fluorine atom. The position bonded with unsubstituted or substituted phenyl is preferably the 2-position of the thiophene ring. In the phenyl having a halogen atom, the position bonded with the halogen atom is preferably the 4-position of the benzene ring.

[0307] In formula (Ar’-2), p is preferably 0.

[0308] In formula (Ar’-3), p is preferably 1, and R b is preferably alkyloxy which may have substituents or heterocyclic alkyloxy which may have substituents. The alkyloxy which may have substituents is preferably alkyloxy having 1 to 3 carbon atoms, more preferably methoxy or ethoxy. The heterocyclic alkyloxy which may have substituents is preferably tetrahydrofuryloxy. The position bonded with alkyloxy which may have substituents or heterocyclic alkyloxy which may have substituents is preferably the 4-position of the benzene ring.

[0309] When d = 1, the functional group represented by formula (A) is preferably the functional group represented by the following formula (B).

[0310] [Chemical formula 26]

[0311]

[0312] In formula (B), R a and the meaning of Ar’ are the same as those in formula (A).

[0313] The functional group represented by formula (A) or (B) is preferably the functional group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4). It should be noted that "Et" represents ethyl.

[0314] [Chemical formula 27]

[0315]

[0316] In one embodiment, R in formula (I) or (Ia) 2 is the functional group represented by formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4).

[0317] In one embodiment, R 1For any one of functional groups (1) to (4), (7), and (8), preferably any one of functional groups (1) to (4), more preferably any one of functional groups (1) to (3), still more preferably functional group (1) or (3), and most preferably functional group (1), R 2 is a functional group represented by formula (Ar-1), (Ar-2), (Ar-3), or (Ar-4).

[0318] 《Acyl Chloride Derivative (II)》

[0319] The acyl chloride derivative (II) is represented by the following formula (II).

[0320] [Chemical Formula 28]

[0321]

[0322] In formula (II), R 1 has the same meaning as in formula (I). The above description of R 1 also applies to R in formula (II). 1 .

[0323] In one embodiment, R 1 is any one of functional groups (1) to (4), (7), and (8), preferably any one of functional groups (1) to (4), more preferably any one of functional groups (1) to (3), still more preferably functional group (1) or (3), and most preferably functional group (1).

[0324] In one embodiment, R 1 is functional group (5) or (6), preferably functional group (5), and more preferably a phenyl group which may have substituents.

[0325] When R in formula (II) 1 is an alkyl group which may have substituents, examples of the acyl chloride derivative (II) include the acyl chloride derivative (IIa) represented by the following formula (IIa).

[0326] [Chemical Formula 29]

[0327]

[0328] In formula (IIa), n represents 1 or 2.

[0329] In formula (IIa), the meaning of R is the same as in formula (Ia). The above description of R also applies to R in formula (IIa).

[0330] In formula (IIa), when n = 1, the four Rs can be different, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxyl-protecting group represented by the formula: -CO-R. In one embodiment, all four Rs are methyl. In one embodiment, all four Rs are phenyl.

[0331] In formula (IIa), when n = 2, the five Rs can be different, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxyl-protecting group represented by the formula: -CO-R. In one embodiment, all five Rs are methyl. In one embodiment, all five Rs are phenyl.

[0332] Examples of the acyl chloride derivative (IIa) include the following compounds. Note that "Ac" represents an acetyl group.

[0333] [Chemical formula 30]

[0334]

[0335] The acyl chloride derivative (II) can be produced by bringing the carboxylic acid derivative (II') represented by the following formula (II') into contact with a chlorinating agent.

[0336] [Chemical formula 31]

[0337]

[0338] In formula (II'), the meaning of R 1 is the same as that in formula (I). The above description of R 1 also applies to R in formula (II'). 1 .

[0339] Examples of the carboxylic acid derivative (II') in which R 1 is an alkyl group which may have a substituent include the carboxylic acid derivative (IIa') represented by the following formula (IIa').

[0340] [Chemical formula 32]

[0341]

[0342] In formula (IIa'), n represents 1 or 2.

[0343] In formula (IIa'), the meaning of R is the same as that in formula (Ia). The above description of R also applies to R in formula (IIa').

[0344] In formula (IIa’), when n = 1, the four Rs can be different, but from the viewpoint of efficient introduction and removal of the hydroxyl-protecting group represented by the formula: -CO-R, they are preferably the same. In one embodiment, all four Rs are methyl. In one embodiment, all four Rs are phenyl.

[0345] In formula (IIa’), when n = 2, the five Rs can be different, but from the viewpoint of efficient introduction and removal of the hydroxyl-protecting group represented by the formula: -CO-R, they are preferably the same. In one embodiment, all five Rs are methyl. In one embodiment, all five Rs are phenyl.

[0346] Examples of the carboxylic acid derivative (IIa’) include the following compounds. It should be noted that “Ac” represents an acetyl group.

[0347] [Chemical formula 33]

[0348]

[0349] The carboxylic acid derivative (II’) and the chlorinating agent can each be a commercially available product or can be produced according to a conventional method.

[0350] Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphoryl chloride, phosphorus pentachloride, etc. Among them, thionyl chloride and oxalyl chloride are preferred, and oxalyl chloride is more preferred.

[0351] The amount of the chlorinating agent used is preferably 0.2 to 10 moles, more preferably 0.5 to 5 moles, and still more preferably 1 to 3 moles relative to 1 mole of the carboxylic acid derivative (II’).

[0352] The temperature when the carboxylic acid derivative (II’) is brought into contact with the chlorinating agent is preferably -10 to 50 °C, more preferably 0 to 40 °C, and still more preferably 0 to 35 °C.

[0353] The contact time of the carboxylic acid derivative (II’) with the chlorinating agent is preferably 0.5 to 48 hours, more preferably 1 to 24 hours, and still more preferably 1 to 8 hours.

[0354] The contact between the carboxylic acid derivative (II’) and the chlorinating agent can be carried out in an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0355] The contact of the carboxylic acid derivative (II’) with the chlorinating agent is preferably carried out in a solvent. The carboxylic acid derivative (II’) and the chlorinating agent can be mixed in a solvent, whereby the carboxylic acid derivative (II’) is brought into contact with the chlorinating agent. As the solvent, an organic solvent is preferably used. One kind of organic solvent can be used alone, or a mixed solvent of two or more organic solvents can be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane and heptane, and more preferably dichloromethane.

[0356] With respect to 1 g of the carboxylic acid derivative (II’), the amount of the solvent used is preferably 1 to 100 mL, more preferably 3 to 20 mL, and even more preferably 5 to 15 mL.

[0357] The contact of the carboxylic acid derivative (II’) with the chlorinating agent is preferably carried out in the presence of a catalytic amount of N,N-dimethylformamide (DMF). The carboxylic acid derivative (II’), the chlorinating agent and DMF can be mixed in a solvent, whereby the carboxylic acid derivative (II’) is brought into contact with the chlorinating agent in the presence of DMF. By bringing the carboxylic acid derivative (II’) into contact with the chlorinating agent in the presence of a catalytic amount of DMF, the acyl chloride derivative (II) can be produced under milder conditions.

[0358] With respect to 1 mole of the carboxylic acid derivative (II’), the amount of DMF used is preferably 0.005 to 0.1 mole, more preferably 0.0075 to 0.1 mole, and even more preferably 0.01 to 0.1 mole.

[0359] The above conditions for the contact of the carboxylic acid derivative (II’) with the chlorinating agent can be suitably combined.

[0360] The obtained acyl chloride derivative (II) can be used in the next step after separation by a conventional method such as silica gel column chromatography, or can be used in the next step without separation. For example, the obtained acyl chloride derivative (II) can be used in the next step in the form of a concentrated residue in an unpurified state.

[0361] The structure of the acyl chloride derivative (II) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopy.

[0362] 《Grignard reagent (III)》

[0363] The Grignard reagent (III) is selected from the Grignard reagent (IIIa) represented by the following formula (IIIa) and the Grignard reagent (IIIb) represented by the following formula (IIIb). It should be noted that the Grignard reagent (IIIb) is called Turbo Grignard reagent.

[0364] [Chemical Formula 34]

[0365] R 2 MgX (IIIa)

[0366] [Chemical Formula 35]

[0367] R 2 MgX·LiCl (IIIb)

[0368] In Formulas (IIIa) and (IIIb), R 2 has the same meaning as in Formula (I). The above description of R 2 also applies to R in Formulas (IIIa) and (IIIb). 2 .

[0369] In one embodiment, R 2 is any one of functional groups (1) to (4), (7), and (8), preferably any one of functional groups (1) to (4), more preferably any one of functional groups (1) to (3), still more preferably functional group (1) or (3), and most preferably functional group (1).

[0370] In one embodiment, R 2 is functional group (5) or (6), preferably functional group (5), and more preferably a phenyl group which may have substituents.

[0371] In one embodiment, R 2 is a functional group having a β-carbon bonded to a hydrogen atom. The β-carbon is an adjacent carbon atom to the α-carbon (i.e., the carbon atom having a bonding bond of R 2 ). As the functional group having a β-carbon bonded to a hydrogen atom, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, cyclopentylidene, cyclohexylidene, etc. which may have one or more substituents can be cited. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents can be independently selected from substituent groups α and β. One or more substituents can be selected from substituent group α, and one or more substituents can be selected from substituent group β. One or more substituents can be independently selected from, for example, alkyloxy, phenoxy, phenylthio, nitro, ester group, halogen group, alkylthio, dialkylamino, etc.

[0372] In Formulas (IIIa) and (IIIb), X represents a halogen atom. The halogen atom is preferably selected from a chlorine atom, a bromine atom, and an iodine atom, more preferably selected from a chlorine atom and a bromine atom, and still more preferably a bromine atom.

[0373] [Copper Salt]

[0374] As the copper salt, for example, cuprous chloride (CuCl), cupric chloride (CuCl2), cuprous bromide (CuBr), cupric bromide (CuBr2), cuprous iodide (CuI), cupric iodide (CuI2), cuprous cyanide (CuCN), copper(I) 3-methylsalicylate, copper(I) mesitylene (MesCu), copper(I) isopropoxide (iPrOCu), copper(I) tert-butoxide (CuO t Bu), copper(I) acetate (CuOAc), copper(II) acetate (Cu(OAc)2), copper(I) sulfate (Cu2SO4), copper(II) sulfate (CuSO4), cuprous oxide (Cu2O), cupric oxide (CuO), copper(I) pivalate (CuOPiv), copper(II) pivalate (Cu(OPiv)2), copper salts containing sulfur (S), etc.

[0375] As the copper salt containing sulfur (S), for example, copper(I) thiophene-2-carboxylate (CuTC), etc. S has a high affinity for Cu, and in the copper salt, S is easily coordinated to Cu. Through this coordination, Cu is activated, and a high yield of the ketone derivative (I) can be achieved.

[0376] The copper salt is preferably selected from CuCl, CuBr, CuI, CuCN, CuCl2, CuBr2, CuI2, Cu2O, CuO, CuOAc, CuTC, Cu(OAc)2, CuOPiv, Cu(OPiv)2, Cu2SO4 and CuSO4.

[0377] The valence of the copper atom contained in the copper salt is usually 1 or 2, but preferably 1. The catalytic action of the copper salt with a valence of 1 for the copper atom is excellent. Among the copper salts with a valence of 1 for the copper atom, the catalytic actions of CuCN, CuCl, CuBr, CuI and CuTC are particularly excellent. Therefore, the copper salt is preferably selected from CuCN, CuCl, CuBr, CuI and CuTC.

[0378] 《Polydentate Ligand》

[0379] The polydentate ligand used in the present invention is a polydentate ligand that coordinates with Mg in the Grignard reagent (III), and is a polydentate ligand containing two or more donor atoms selected from oxygen atoms and nitrogen atoms.

[0380] The donor atom is also called a coordinating atom. A polydentate ligand with 2 donor atoms is called a bidentate ligand, a polydentate ligand with 3 donor atoms is called a tridentate ligand, a polydentate ligand with 4 donor atoms is called a tetradentate ligand, and a polydentate ligand with n donor atoms is called an n-dentate ligand.

[0381] The number of donor atoms in the multidentate ligand is, for example, 2 or more and 10 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the number of donor atoms in the multidentate ligand is preferably 2 or more and 8 or less, more preferably 2 or more and 6 or less, still more preferably 2 or more and 4 or less, and most preferably 3.

[0382] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the multidentate ligand is preferably the multidentate ligand represented by the following formula (IV) or the multidentate ligand represented by the following formula (VI), and more preferably the multidentate ligand represented by formula (IV).

[0383] [Chemical formula 36]

[0384] L 1 -L 2 -L 3 (IV)[Chemical formula 37]

[0385]

[0386] Hereinafter, the multidentate ligand represented by formula (IV) will be described.

[0387] <The multidentate ligand represented by formula (IV)>

[0388] In formula (IV), L 1 and L 3 each independently represent an amino group which may have a substituent, an alkyloxy group which may have a substituent, or a group represented by the following formula (V).

[0389] [Chemical formula 38]

[0390]

[0391] Hereinafter, the amino group which may have a substituent, the alkyloxy group which may have a substituent, and the group represented by formula (V) will be described.

[0392] amino which may have a substituent

[0393] The amino group which may have a substituent is a primary amino group, a secondary amino group or a tertiary amino group.

[0394] The primary amino group is represented by the formula: -NH2. The secondary amino group is represented by the formula: -NHR 10 The tertiary amino group is represented by the formula: -NR 10 R 20 R

[0395] R 10 and R 20Each independently represents an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or an arylalkyl group which may have a substituent.

[0396] Hereinafter, the alkyl group which may have a substituent, the cycloalkyl group which may have a substituent, the aryl group which may have a substituent, and the arylalkyl group which may have a substituent will be described.

[0397] [Alkyl group which may have a substituent]

[0398] As described above, the description of the alkyl group is as follows. The number of carbon atoms of the alkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2. The alkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may be independently selected from the substituent group α. One or more substituents are preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, still more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0399] [Cycloalkyl group which may have a substituent]

[0400] As described above, the description of the cycloalkyl group is as follows. The cycloalkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may be independently selected from the substituent group α. One or more substituents are preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, still more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0401] [Aryl group which may have a substituent]

[0402] The description of the aryl group is as described above. The aryl group is preferably a phenyl group. The aryl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may be independently selected from the substituent group α. One or more substituents are preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, and even more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0403] [Arylalkyl which may have a substituent]

[0404] The description of the arylalkyl group is as described above. The number of carbon atoms of the alkyl group contained in the arylalkyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, even more preferably 1 or 2. The aryl group contained in the arylalkyl group is preferably a phenyl group. The arylalkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may be independently selected from the substituent group α. One or more substituents are preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, and even more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0405] The secondary amino group and the tertiary amino group may be an aliphatic amino group or an aromatic amino group, but is preferably an aliphatic amino group. As the aliphatic amino group, for example, there may be mentioned a secondary amino group in which R 10 is an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, R 10 and R 20 both of which are tertiary amino groups in which R is an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, etc. As the aromatic amino group, for example, there may be mentioned a secondary amino group in which R 10 is an aryl group which may have a substituent or an arylalkyl group which may have a substituent, a tertiary amino group in which at least one of R 10 and R 20 is an aryl group which may have a substituent or an arylalkyl group which may have a substituent, etc.

[0406] As the secondary amino group, for example, there can be mentioned aliphatic amino groups such as N-methylamino, N-ethylamino, N-propylamino, N-isopropylamino, etc., and aromatic amino groups such as N-phenylamino (anilino), etc. The secondary amino group is preferably a monoalkylamino group. The description of the monoalkylamino group is as described above.

[0407] As the tertiary amino group, for example, there can be mentioned aliphatic amino groups such as N,N-dimethylamino, N,N-diethylamino, N,N-methylethylamino, N,N-dipropylamino, N,N-diisopropylamino, etc., and aromatic amino groups such as N,N-diphenylamino, etc. The tertiary amino group is preferably a dialkylamino group. The description of the dialkylamino group is as described above.

[0408] The amino group which may have a substituent is preferably a tertiary amino group, more preferably a dialkylamino group, and still more preferably a dimethylamino group.

[0409] alkyloxy which may have a substituent

[0410] The description of the alkyloxy group is as described above. The number of carbon atoms of the alkyloxy group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2. The alkyloxy group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may be independently selected from the substituent group α. One or more substituents are preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a haloalkyloxy group having 1 to 3 carbon atoms, still more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0411] The alkyloxy group which may have a substituent is preferably an alkyloxy group having 1 to 6 carbon atoms, more preferably an alkyloxy group having 1 to 4 carbon atoms, still more preferably an alkyloxy group having 1 to 3 carbon atoms, and most preferably a methyloxy group.

[0412] group shown in formula (V)

[0413] In formula (V), R 100 represents the formula: -[(Y 1 ) a -Z 1 ) b -(Y 1 ) c -represents a divalent group.

[0414] Y 1Each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent.

[0415] Hereinafter, the methylene group which may have a substituent and the phenylene group which may have a substituent will be described.

[0416] [Methylene group which may have a substituent]

[0417] The methylene group (-CH2-) may be unsubstituted or may have one or more substituents. The number of substituents is 1 or 2. One or more substituents may each independently be selected from the substituent group α. One or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, and even more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0418] [Phenylene group which may have a substituent]

[0419] The phenylene group is a divalent group formed by removing one hydrogen atom from a phenyl group. The phenylene group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may each independently be selected from the substituent group α. One or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, and even more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0420] In the formula: -[(Y 1 ) a -Z 1 b -(Y 1 ) c - when multiple Y 1 appear (that is, when b is an integer of 1 or more and c is an integer of 1 or more, or when b is 0 and c is an integer of 2 or more), the multiple Y 1 may be the same group or different groups.

[0421] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Y 1 ​All are methylene groups. In Y 1 When all are methylene groups, R 100 is of the formula: -[(CH2) a -Z 1 b -(CH2) c - shown divalent group.

[0422] In formula (V), Z 1 each independently represents an ether group or an imino group which may have a substituent.

[0423] Hereinafter, the ether group and the imino group which may have a substituent will be described.

[0424] [Ether group]

[0425] The ether group is a divalent group represented by -O-.

[0426] [Imino group which may have a substituent]

[0427] The imino group is a divalent group represented by -NH-. The imino group may be unsubstituted or may have a substituent. The number of substituents is 1. The substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group and a haloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms and a haloalkoxy group having 1 to 3 carbon atoms, and still more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms and an alkoxy group having 1 to 3 carbon atoms.

[0428] In the formula: -[(Y 1 ) a -Z 1 b -(Y 1 ) c - when multiple Z 1 appear (that is, when b is 2 or more), the multiple Z 1 can be the same group or different groups.

[0429] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that Z 1 are all ether groups or are imino groups, and more preferably are ether groups.

[0430] In the embodiment where all of Z 1 are ether groups, it is preferred that all of Y 1 are methylene groups. When all of Y 1 are methylene groups, R 100 is of the formula: -[(CH2) a ​​-O] b -(CH2) c -divalent group represented by

[0431] In the embodiment where Z 1 is all imino groups, Y is preferably 1 all methylene groups. In the case where Y 1 is all methylene groups, R 100 is of the formula: -[(CH2) a -NH] b -(CH2) c -divalent group represented by

[0432] a represents an integer of 1 or more. For example, a is an integer of 1 or more and 6 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, a is preferably an integer of 2 or more and 5 or less, more preferably an integer of 2 or more and 4 or less, still more preferably 2 or 3, and most preferably 2.

[0433] b represents an integer of 0 or more. For example, b is an integer of 0 or more and 5 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, b is preferably an integer of 1 or more and 4 or less, more preferably an integer of 1 or more and 3 or less, still more preferably 1 or 2, and most preferably 1.

[0434] c represents an integer of 1 or more. For example, c is an integer of 1 or more and 6 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, c is preferably an integer of 2 or more and 5 or less, more preferably an integer of 2 or more and 4 or less, still more preferably 2 or 3, and most preferably 2.

[0435] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, a and c are preferably the same integer, and more preferably both are 2.

[0436] In the embodiment where both a and c are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Y is preferably 1 all methylene groups. In the case where Y 1 is all methylene groups, R 100 is of the formula: -[(CH2)2-Z 1 b -divalent group represented by -(CH2)2-.

[0437] In the embodiment where Y 1 is methylene and both a and c are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Z is preferably 1 ​All are ether groups or imino groups, more preferably ether groups. In Z 1 When all are ether groups, R 100 is a divalent group represented by the formula: -[(CH2)2-O] b -(CH2)2-. When Z 1 are all imino groups, R 100 is a divalent group represented by the formula: -[(CH2)2-NH] b -(CH2)2-.

[0438] In the embodiment where all of Y 1 are methylene groups, all of Z 1 are ether groups and both a and c are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, b is preferably 1 or 2, more preferably 1. When b is 1, R 100 is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-. When b is 2, R 100 is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-.

[0439] In the embodiment where all of Y 1 are methylene groups, all of Z 1 are imino groups and both a and c are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, b is preferably 1 or 2, more preferably 1. When b is 1, R 100 is a divalent group represented by the formula: -(CH2)2-NH-(CH2)2-. When b is 2, R 100 is a divalent group represented by the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-.

[0440] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, R 100 is preferably a divalent group represented by the formula: -[(CH2)2-O] b -(CH2)2- or the formula: -[(CH2)2-NH] b -(CH2)2-, more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-, the formula: -(CH2)2-NH-(CH2)2- or the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-, even more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-.

[0441] In R 100 In the case of a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, the group represented by formula (V) is a morpholino group.

[0442] In one embodiment, L 1 and L 3 are each independently an amino group which may have a substituent. The amino group which may have a substituent is preferably a tertiary amino group, more preferably a dialkylamino group, and still more preferably a dimethylamino group.

[0443] In one embodiment, L 1 and L 3 are each independently an alkyloxy group which may have a substituent. The alkyloxy group which may have a substituent is preferably an alkyloxy group having 1 to 6 carbon atoms, more preferably an alkyloxy group having 1 to 4 carbon atoms, still more preferably an alkyloxy group having 1 to 3 carbon atoms, and most preferably a methyloxy group.

[0444] In one embodiment, L 1 and L 3 are each independently a group represented by formula (V). The group represented by formula (V) is preferably a morpholino group.

[0445] In formula (IV), L 2 represents a divalent group represented by the formula: -[(Y 2 ) d -Z 2 ) e -(Y 2 ) f -.

[0446] Hereinafter, the divalent group represented by the formula: -[(Y 2 ) d -Z 2 ) e -(Y 2 ) f - will be described.

[0447] Y 2 each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent. The description of the methylene group which may have a substituent and the phenylene group which may have a substituent is the same as that of Y 1 . Unless otherwise specified, the description of Y 1 also applies to Y 2 .

[0448] In the formula: -[(Y 2 ) d -Z 2 ) e -(Y 2 ) fMultiple Ys appearing in 2 may be the same group or different groups.

[0449] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, Y is preferably 2 all methylene groups. When Y 2 are all methylene groups, L 2 is of the formula: -[(CH2) d -Z 2 e -(CH2) f -represents a divalent group.

[0450] Z 2 each independently represents an ether group or an imino group which may have a substituent. The description of the ether group and the imino group which may have a substituent is the same as that of Z 1 Except as otherwise specified, the description of Z 1 also applies to Z 2 .

[0451] In the formula: -[(Y 2 ) d -Z 2 e -(Y 2 ) f -when multiple Zs 2 appear (i.e., when e is 2 or more), the multiple Zs 2 may be the same group or different groups.

[0452] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, Z is preferably 2 all ether groups or imino groups, and more preferably ether groups.

[0453] In the embodiment where Z 2 are all ether groups, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, Y is preferably 2 all methylene groups. When Y 2 are all methylene groups, L 2 is of the formula: -[(CH2) d -O] e -(CH2) f -represents a divalent group.

[0454] In the embodiment where Z 2 are all imino groups, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, Y is preferably 2 ​​All are methylene groups. In Y 2 When all are methylene groups, L 2 is of the formula: -[(CH2) d -NH] e -(CH2) f - represents a divalent group shown by

[0455] d represents an integer of 1 or more. d is, for example, an integer of 1 or more and 6 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, d is preferably an integer of 2 or more and 5 or less, more preferably an integer of 2 or more and 4 or less, still more preferably 2 or 3, and most preferably 2.

[0456] e represents an integer of 1 or more. e is, for example, an integer of 1 or more and 5 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, e is preferably an integer of 1 or more and 4 or less, more preferably an integer of 1 or more and 3 or less, still more preferably 1 or 2, and most preferably 1.

[0457] f represents an integer of 1 or more. f is, for example, an integer of 1 or more and 6 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, f is preferably an integer of 2 or more and 5 or less, more preferably an integer of 2 or more and 4 or less, still more preferably 2 or 3, and most preferably 2.

[0458] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, d and f are preferably the same integer, and more preferably both are 2.

[0459] In an embodiment where both d and f are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that Y 2 All are methylene groups. In Y 2 When all are methylene groups, L 2 is of the formula: -[(CH2)2-Z 2 e -(CH2)2- represents a divalent group shown by

[0460] In Y 2 When all are methylene groups and both d and f are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that Z 2 All are ether groups or is an imino group, and more preferably is an ether group. In Z 2 When all are ether groups, L 2 is of the formula: -[(CH2)2-O] e -(CH2)2- represents a divalent group shown by 2 ​When all are imino groups, L 2 is of the formula: -[(CH2)2-NH] e a divalent group represented by -(CH2)2-.

[0461] In the embodiment where Y 2 are all methylene groups, Z 2 are all ether groups and both d and f are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, e is preferably 1 or 2, more preferably 1. When e is 1, L 2 is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-. When e is 2, L 2 is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-.

[0462] In the embodiment where Y 2 are all methylene groups, Z 2 are all imino groups and both d and f are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, e is preferably 1 or 2, more preferably 1. When e is 1, L 2 is a divalent group represented by the formula: -(CH2)2-NH-(CH2)2-. When e is 2, L 2 is a divalent group represented by the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-.

[0463] In the embodiment where L 1 and L 3 are each independently an amino group which may have a substituent (preferably a tertiary amino group, more preferably a dialkylamino group, still more preferably a dimethylamino group), from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, L 2 is preferably a divalent group represented by the formula: -[(CH2)2-O] e -(CH2)2-, or a divalent group represented by the formula: -[(CH2)2-NH] e -(CH2)2-, more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-, the formula: -(CH2)2-NH-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-, still more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2-.

[0464] In the case of L1 and L 3 In the embodiment where each independently represents an alkoxy group which may have a substituent (preferably an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 4 carbon atoms, still more preferably an alkoxy group having 1 to 3 carbon atoms, and most preferably a methoxy group), from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, L 2 is preferably a group represented by the formula: -[(CH2)2-O] e -(CH2)2-, or a divalent group represented by the formula: -[(CH2)2-NH] e -(CH2)2-, and more preferably a divalent group represented by the formula: -[(CH2)2-O] e -(CH2)2-, and more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2- or the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-.

[0465] In the case of L 1 and L 3 each independently represents a group represented by the formula (V) (preferably a morpholino group), from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, L 2 is preferably a group represented by the formula: -[(CH2)2-O] e -(CH2)2-, or a divalent group represented by the formula: -[(CH2)2-NH] e -(CH2)2-, and more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-, the formula: -(CH2)2-NH-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-, and still more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2- or the formula: -(CH2)2-NH-(CH2)2-.

[0466] Hereinafter, the polydentate ligand represented by the formula (VI) will be described.

[0467] <The polydentate ligand represented by the formula (VI)>

[0468] In the formula (VI), R 200 represents an alkyl group which may have a substituent.

[0469] The description of the alkyl group is as described above. The number of carbon atoms of the alkyl group is preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2. The alkyl group may be unsubstituted or may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. One or more substituents may each independently be selected from the substituent group α. One or more substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group, more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a haloalkoxy group having 1 to 3 carbon atoms, still more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms.

[0470] In formula (VI), R 300 represents the formula: -[(Y 3 ) g -Z 3 h -(Y 3 ) i -represents a divalent group shown.

[0471] Y 3 each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent. The description of the methylene group which may have a substituent and the phenylene group which may have a substituent is the same as that of Y 1 . Unless otherwise specified, the description of Y 1 also applies to Y 3 .

[0472] In the formula: -[(Y 3 ) g -Z 3 h -(Y 3 ) i -the plurality of Y 3 appearing may be the same group or different groups.

[0473] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that all of Y 3 are methylene groups. When all of Y 3 are methylene groups, R 300 is the formula: -[(CH2) g -Z 3 h -(CH2) i -represents a divalent group shown. ​​​

[0474] Z 3 each independently represents an ether group or an imino group which may have a substituent. The descriptions of the ether group and the imino group which may have a substituent are the same as those of Z 1 Likewise. Unless otherwise specified, the description of Z 1 also applies to Z 3 .

[0475] In the formula: -[(Y 3 ) g -Z 3 h -(Y 3 ) i - when there are multiple Z 3 's (that is, when h is 2 or more), the multiple Z 3 's can be the same group or different groups.

[0476] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that all of the Z 3 's are ether groups or imino groups, and more preferably ether groups.

[0477] In the embodiment where all of the Z 3 's are ether groups, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that all of the Y 3 's are methylene groups. When all of the Y 3 's are methylene groups, R 300 is a divalent group represented by the formula: -[(CH2) g -O] h -(CH2) i -.

[0478] In the embodiment where all of the Z 3 's are imino groups, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, it is preferred that all of the Y 3 's are methylene groups. When all of the Y 3 's are methylene groups, R 300 is a divalent group represented by the formula: -[(CH2) g -NH] h -(CH2) i -.

[0479] g represents an integer of 1 or more. g is, for example, an integer of 1 or more and 6 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, g is preferably an integer of 2 or more and 5 or less, more preferably an integer of 2 or more and 4 or less, still more preferably 2 or 3, and most preferably 2. ​

[0480] h represents an integer of 1 or more. For example, h is an integer of 1 or more and 5 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, h is preferably an integer of 1 or more and 4 or less, more preferably an integer of 1 or more and 3 or less, still more preferably 1 or 2, and most preferably 1.

[0481] i represents an integer of 1 or more. For example, i is an integer of 1 or more and 6 or less. From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, i is preferably an integer of 2 or more and 5 or less, more preferably an integer of 2 or more and 4 or less, still more preferably 2 or 3, and most preferably 2.

[0482] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, g and i are preferably the same integer, and more preferably both are 2.

[0483] In the embodiment where both g and i are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Y 3 is preferably all methylene groups. When Y 3 is all methylene groups, R 300 is a divalent group represented by the formula: -[(CH2)2-Z 3 h -(CH2)2-.

[0484] In the embodiment where Y 3 is all methylene groups and both g and i are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Z 3 is preferably all ether groups or an imino group, and more preferably an ether group. When Z 3 is all ether groups, R 300 is a divalent group represented by the formula: -[(CH2)2-O] h -(CH2)2-. When Z 3 is all imino groups, R 300 is a divalent group represented by the formula: -[(CH2)2-NH] h -(CH2)2-.

[0485] In the embodiment where Y 3 is all methylene groups, Z 3 is all ether groups and both g and i are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, h is preferably 1 or 2, and more preferably 1. When h is 1, R 300 ​A divalent group represented by the formula: -(CH2)2-O-(CH2)2-. When h is 2, R 300 is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-.

[0486] When Y 3 are all methylene groups, Z 3 are all imino groups and in the embodiment where both g and i are 2, from the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, h is preferably 1 or 2, more preferably 1. When h is 1, R 300 is a divalent group represented by the formula: -(CH2)2-NH-(CH2)2-. When h is 2, R 300 is a divalent group represented by the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-.

[0487] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, R 200 is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, still more preferably an alkyl group having 1 to 3 carbon atoms, and still more preferably a methyl group, R 300 is preferably represented by the formula: -[(CH2)2-O] h -(CH2)2-, or the formula: -[(CH2)2-NH] h -(CH2)2- as a divalent group, more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-, the formula: -(CH2)2-NH-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2-NH-(CH2)2-, and still more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-.

[0488] Preferred specific examples of the multidentate ligand are as described below.

[0489] [Table 4]

[0490]

[0491] The multidentate ligands (A) to (E) are specific examples of the multidentate ligand represented by the formula (IV), and the multidentate ligand (F) is a specific example of the multidentate ligand represented by the formula (VI).

[0492] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, among the multidentate ligands (A) to (E), the multidentate ligands (A) to (D) are preferred, the multidentate ligands (A) and (C) are more preferred, and the multidentate ligand (A) is even more preferred.

[0493] "Method for Producing Ketone Derivative (I)"

[0494] The method for producing the ketone derivative (I) according to the present invention includes the following steps:

[0495] Step (S1), in the presence of a copper salt and a multidentate ligand, bringing the acyl chloride derivative (II) into contact with the Grignard reagent (III) to form the ketone derivative (I).

[0496] The multidentate ligand used in the present invention is a multidentate ligand that coordinates with Mg in the Grignard reagent (III), and is a multidentate ligand containing two or more donor atoms selected from oxygen atoms and nitrogen atoms.

[0497] By bringing the acyl chloride derivative (II) into contact with the Grignard reagent (III) in the presence of a copper salt and a multidentate ligand, a high yield of the ketone derivative (I) can be achieved and the amount of the copper salt used can be reduced. It is considered that since the multidentate ligand inhibits the reactivity of the Grignard reagent (III), the formation of an alcohol (for example, R 1 -C(-OH)(-R 2 )(-R 2 )) as a by-product can be inhibited, and a high yield of the ketone derivative (I) can be achieved and the amount of the copper salt used can be reduced. It should be noted that it is considered that the organocopper reagent formed by the contact of the Grignard reagent (III) with the copper salt also participates in achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used.

[0498] Each of the acyl chloride derivative (II), the Grignard reagent (III), the copper salt, and the multidentate ligand can be a commercially available product or can be produced according to a conventional method.

[0499] The acyl chloride derivative (II) can be produced, for example, by bringing the carboxylic acid derivative (II’) into contact with a chlorinating agent.

[0500] The method for producing the ketone derivative (I) according to the present invention may further include the following steps:

[0501] Step (S0), bringing the carboxylic acid derivative (II’) into contact with a chlorinating agent to produce the acyl chloride derivative (II).

[0502] Step (S0) is carried out before step (S1), and the acyl chloride derivative (II) produced in step (S0) is used in step (S1).

[0503] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the amount of the Grignard reagent (III) used is preferably 0.5 to 3 moles, more preferably 0.8 to 2 moles, still more preferably 0.9 to 1.5 moles, and still more preferably 1 to 1.3 moles, per 1 mole of the acyl chloride derivative (II). As the Grignard reagent (III), either one of the Grignard reagents (IIa) or (IIb) can be used, or both of the Grignard reagents (IIa) and (IIb) can be used. When both of the Grignard reagents (IIa) and (IIb) are used, the amount of the Grignard reagent (IIb) used is, for example, 10% by mass or more and 90% by mass or less based on the total mass of the Grignard reagents (IIa) and (IIb). Regarding the "amount of the Grignard reagent (III) used", in the case of using one kind of Grignard reagent, it means the amount of that one kind of Grignard reagent, and in the case of using two or more kinds of Grignard reagents, it means the total amount of those two or more kinds of Grignard reagents used.

[0504] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the amount of the copper salt used is preferably 0.005 to 2 moles, more preferably 0.01 to 1 mole, still more preferably 0.02 to 0.5 mole, and still more preferably 0.03 to 0.3 mole, per 1 mole of the Grignard reagent (III). As the copper salt, one kind of copper salt can be used alone, or two or more kinds of copper salts can be used in combination. Regarding the "amount of the copper salt used", in the case of using one kind of copper salt, it means the amount of that one kind of copper salt, and in the case of using two or more kinds of copper salts, it means the total amount of those two or more kinds of copper salts used.

[0505] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the copper salt is preferably selected from CuCl, CuBr, CuI, CuCN, CuCl2, CuBr2, CuI2, Cu2O, CuO, CuOAc, CuTC, Cu(OAc)2, CuOPiv, Cu(OPiv)2, Cu2SO4, and CuSO4, and more preferably selected from CuCN, CuCl, CuBr, CuI, and CuTC.

[0506] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the amount of the polydentate ligand used is preferably 0.05 to 3 moles, more preferably 0.5 to 2 moles, still more preferably 0.8 to 1.5 moles, and even more preferably 0.9 to 1.2 moles, relative to 1 mole of the Grignard reagent (III). As the polydentate ligand, one kind of polydentate ligand can be used alone, or two or more kinds of polydentate ligands can be used in combination. Regarding the "amount of the polydentate ligand used", in the case of using one kind of polydentate ligand, it refers to the amount of that one kind of polydentate ligand, and in the case of using two or more kinds of polydentate ligands, it refers to the total amount of those two or more kinds of polydentate ligands.

[0507] From the viewpoint of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, the polydentate ligand is preferably selected from the polydentate ligands (A) to (E), more preferably selected from the polydentate ligands (A) to (D), still more preferably selected from the polydentate ligands (A) and (C), and most preferably the polydentate ligand (A).

[0508] When the acyl chloride derivative (II) is brought into contact with the Grignard reagent (III) in the presence of the copper salt and the polydentate ligand, the temperature is preferably -50 to 50°C, more preferably -30 to 30°C, and still more preferably -20 to 20°C. If the temperature is within the above range, there is a tendency for the yield of the ketone derivative (I) to be further increased.

[0509] The time for bringing the acyl chloride derivative (II) into contact with the Grignard reagent (III) in the presence of the copper salt and the polydentate ligand is preferably 0.5 to 24 hours, more preferably 1 to 17 hours, and still more preferably 1 to 8 hours.

[0510] The contact of the acyl chloride derivative (II) with the Grignard reagent (III) in the presence of the copper salt and the polydentate ligand can be carried out, for example, in an inert atmosphere (for example, an argon atmosphere or a nitrogen atmosphere).

[0511] The contact of the acyl chloride derivative (II) with the Grignard reagent (III) in the presence of the copper salt and the polydentate ligand is preferably carried out in a solvent. The acyl chloride derivative (II), the Grignard reagent (III), the copper salt, and the polydentate ligand can be mixed in a solvent, whereby the acyl chloride derivative (II) is brought into contact with the Grignard reagent (III) in the presence of the copper salt and the polydentate ligand. As the solvent, an organic solvent is preferably used. One kind of organic solvent can be used alone, or a mixed solvent of two or more kinds of organic solvents can be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and toluene.

[0512] The amount of the solvent used is preferably 1 to 100 mL, more preferably 3 to 20 mL, and even more preferably 4 to 20 mL, relative to 1 g of the acyl chloride derivative (II).

[0513] The contact of the acyl chloride derivative (II) with the Grignard reagent (III) may be carried out in the presence of a copper salt and a polydentate ligand, and the addition order of the acyl chloride derivative (II), the Grignard reagent (III), the copper salt, and the polydentate ligand is not particularly limited.

[0514] In the first embodiment, the step (S1) includes the following steps:

[0515] Step (T1) of mixing the acyl chloride derivative (II) with the copper salt to prepare a first mixture;

[0516] Step (T2) of mixing the Grignard reagent (III) with the polydentate ligand to prepare a second mixture; and

[0517] Step (T3) of mixing the first mixture with the second mixture to form the ketone derivative (I).

[0518] According to the first embodiment, a high yield of the ketone derivative (I) and a reduction in the amount of the copper salt used can be achieved more effectively. According to the first embodiment, a reduction in the amount of the copper salt used can be achieved more effectively than in the second embodiment described later.

[0519] <Step (T1)>

[0520] When mixing the acyl chloride derivative (II) with the copper salt, the copper salt may be added to the acyl chloride derivative (II) and mixed, or the acyl chloride derivative (II) may be added to the copper salt and mixed.

[0521] The temperature when mixing the acyl chloride derivative (II) with the copper salt is preferably -30 to 0 °C, more preferably -25 to -5 °C, and even more preferably -20 to -10 °C.

[0522] The mixing time of the acyl chloride derivative (II) with the copper salt is preferably 0.5 to 3 hours, more preferably 0.5 to 2 hours, and even more preferably 0.5 to 1 hour.

[0523] The mixing of the acyl chloride derivative (II) with the copper salt can be carried out, for example, in an inert atmosphere (for example, an argon atmosphere or a nitrogen atmosphere).

[0524] The mixing of the acyl chloride derivative (II) and the copper salt is preferably carried out in a solvent. As the solvent, an organic solvent is preferably used. One kind of organic solvent can be used alone, or a mixed solvent of two or more kinds of organic solvents can be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and toluene.

[0525] With respect to 1 g of the acyl chloride derivative (II), the amount of the solvent used is preferably 2 to 50 mL, more preferably 3 to 30 mL, and even more preferably 5 to 30 mL.

[0526] The above conditions for the mixing of the acyl chloride derivative (II) and the copper salt can be suitably combined.

[0527] <Process (T2)>

[0528] When mixing the Grignard reagent (III) and the polydentate ligand, the polydentate ligand can be added to the Grignard reagent (III) for mixing, or the Grignard reagent (III) can be added to the polydentate ligand for mixing.

[0529] The temperature for mixing the Grignard reagent (III) and the polydentate ligand is preferably -30 to 0 °C, more preferably -20 to -5 °C, and even more preferably -15 to -10 °C.

[0530] The mixing time of the Grignard reagent (III) and the polydentate ligand is preferably 0.05 to 3 hours, more preferably 0.05 to 1 hour, and even more preferably 0.05 to 0.5 hours.

[0531] The mixing of the Grignard reagent (III) and the polydentate ligand can be carried out, for example, in an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0532] The mixing of the Grignard reagent (III) and the polydentate ligand is preferably carried out in a solvent. As the solvent, an organic solvent is preferably used. One kind of organic solvent can be used alone, or a mixed solvent of two or more kinds of organic solvents can be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and toluene.

[0533] The amount of the solvent used is preferably 1 to 50 mL, more preferably 2 to 30 mL, and still more preferably 5 to 20 mL, relative to 1 g of the Grignard reagent (III).

[0534] The above conditions regarding the mixing of the Grignard reagent (III) and the polydentate ligand can be suitably combined.

[0535] <Process (T3)>

[0536] When mixing the first mixture and the second mixture, the second mixture can be added to the first mixture and mixed, or the first mixture can be added to the second mixture and mixed.

[0537] When adding one of the first mixture and the second mixture to the other, the addition can be carried out by dropwise addition. From the viewpoint of effectively (preferably completely) carrying out the conversion from the Grignard reagent (III) to the organocopper reagent, it is preferred to dropwise add the second mixture to the first mixture.

[0538] The temperature when mixing the first mixture and the second mixture is preferably -50 to 50 °C, more preferably -30 to 30 °C, and still more preferably -20 to 20 °C.

[0539] The time for mixing the first mixture and the second mixture is preferably 0.5 to 24 hours, more preferably 1 to 17 hours, and still more preferably 1 to 8 hours.

[0540] The mixing of the first mixture and the second mixture can be carried out, for example, under an inert atmosphere (e.g., under an argon atmosphere or a nitrogen atmosphere).

[0541] When mixing the first mixture and the second mixture, a solvent other than the solvent contained in the first mixture and the solvent contained in the second mixture (hereinafter referred to as "additional solvent") can also be added. As the additional solvent, an organic solvent is preferably used. One kind of organic solvent can be used alone, or a mixed solvent of two or more organic solvents can be used. Specific examples of the organic solvent are the same as above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and toluene.

[0542] The above conditions regarding the mixing of the first mixture and the second mixture can be suitably combined.

[0543] In the second embodiment, process (S1) includes the following processes:

[0544] Step (U1) of mixing a copper salt, a Grignard reagent (III) and a polydentate ligand to prepare a third mixture; and

[0545] Step (U2) of mixing the third mixture with an acyl chloride derivative (II) to produce a ketone derivative (I).

[0546] According to the second embodiment, a high yield of the ketone derivative (I) and a reduction in the amount of the copper salt used can be achieved more effectively.

[0547] <Step (U1)>

[0548] When mixing the copper salt, the Grignard reagent (III) and the polydentate ligand, the polydentate ligand can be added and mixed after adding the Grignard reagent (III) to the copper salt, or the Grignard reagent (III) can be added and mixed after adding the polydentate ligand to the copper salt.

[0549] The addition of the Grignard reagent (III) and the polydentate ligand can be carried out by dropwise addition. From the viewpoint of effectively (preferably completely) carrying out the conversion from the Grignard reagent (III) to the organocopper reagent, it is preferred to add the polydentate ligand after dropwise adding the Grignard reagent (III) to the copper salt.

[0550] The temperature when mixing the copper salt, the Grignard reagent (III) and the polydentate ligand is preferably -30 to -15 °C, more preferably -25 to -15 °C, and even more preferably -20 to -15 °C.

[0551] The mixing time of the copper salt, the Grignard reagent (III) and the polydentate ligand is preferably 1 to 3 hours, more preferably 1.5 to 2.5 hours, and even more preferably 1.5 to 2 hours.

[0552] The mixing of the copper salt, the Grignard reagent (III) and the polydentate ligand can be carried out, for example, in an inert atmosphere (e.g., under an argon atmosphere or a nitrogen atmosphere).

[0553] The mixing of the copper salt, the Grignard reagent (III) and the polydentate ligand is preferably carried out in a solvent. As the solvent, an organic solvent is preferably used. One kind of organic solvent can be used alone, or a mixed solvent of two or more kinds of organic solvents can be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane and heptane, and more preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.

[0554] The amount of the solvent used is preferably 1 to 50 mL, more preferably 2 to 30 mL, and even more preferably 3 to 20 mL relative to 1 g of the polydentate ligand.

[0555] When a copper salt, a Grignard reagent (III) and a polydentate ligand are mixed in an organic solvent, the polydentate ligand can be added and mixed after adding the Grignard reagent (III) to the organic solvent containing the copper salt, or the Grignard reagent (III) can be added and mixed after adding the polydentate ligand to the organic solvent containing the copper salt.

[0556] The above conditions for the mixing of the copper salt, the Grignard reagent (III) and the polydentate ligand can be suitably combined.

[0557] <Process (U2)>

[0558] When mixing the third mixture with the acyl chloride derivative (II), the acyl chloride derivative (II) can be added to the third mixture and mixed, or the third mixture can be added to the acyl chloride derivative (II) and mixed.

[0559] When adding one of the third mixture and the acyl chloride derivative (II) to the other, the addition can be carried out by dropwise addition.

[0560] The temperature for mixing the third mixture with the acyl chloride derivative (II) is preferably -50 to 50 °C, more preferably -30 to 30 °C, and even more preferably -20 to 0 °C.

[0561] The time for mixing the third mixture with the acyl chloride derivative (II) is preferably 0.5 to 24 hours, more preferably 1 to 17 hours, and even more preferably 1 to 5 hours.

[0562] The mixing of the third mixture with the acyl chloride derivative (II) can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0563] When mixing the third mixture with the acyl chloride derivative (II), a solvent other than the solvent contained in the third mixture (hereinafter referred to as "additional solvent") can also be added. As the additional solvent, an organic solvent is preferably used. One organic solvent can be used alone, or a mixed solvent of two or more organic solvents can be used. Specific examples of the organic solvent are the same as above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, toluene, xylene, hexane and heptane, and more preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.

[0564] The above conditions for the mixing of the third mixture with the acyl chloride derivative (II) can be suitably combined.

[0565] The above conditions regarding the contact of the acyl chloride derivative (II) with the Grignard reagent (III) in the presence of a copper salt and a multidentate ligand can be suitably combined.

[0566] The obtained ketone derivative (I) can be separated by the following method. First, a quenching solution (e.g., water, aqueous HCl solution, etc.) is added to the reaction solution to stop the reaction. The reaction solution to which the quenching solution is added is stirred to separate it into an aqueous layer and an organic layer. After extraction of the organic layer, an organic solvent is added to the aqueous layer to separate it again into an organic layer and an aqueous layer. The organic layer is taken out and combined with the previously extracted organic layer to obtain a total organic layer. After washing the total organic layer with a washing solution (e.g., water, aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, etc.), it is dried using sodium sulfate, etc. to obtain a residue containing the ketone derivative (I).

[0567] Specific examples of the organic solvent added to the aqueous layer are as described above. One organic solvent can be used, or two or more organic solvents can be used in combination. The organic solvent is preferably selected from ethyl acetate, toluene, tert-butyl methyl ether, dichloromethane, and chloroform.

[0568] The ketone derivative (I) can be purified by a conventional method such as silica gel column chromatography. The structure of the ketone derivative (I) can be confirmed by, for example, nuclear magnetic resonance (NMR) spectroscopy analysis.

[0569] Examples

[0570] <Example 1>

[0571] Compound 3a was prepared from compound 1a and compound 2a according to the following reaction formula. Compound 1a is 3,3-dimethylbutanoyl chloride, and compound 2a is PhMgBr (wherein Ph represents a phenyl group).

[0572] [Chemical formula 39]

[0573]

[0574] Under vacuum, a Schlenk tube dried in an oven was heated 3 times for 5 minutes at intervals of 3 minutes using a hot air blower, and argon was backfilled 3 times each time. After returning to room temperature, CuCl (5 mol% (=0.05 equivalent), 0.025 mmol, 0.0024 g) was added under argon. After adding 1 mL of tetrahydrofuran (THF), the temperature of the reaction system was set to -15 °C, and compound 1a (1 equivalent, 0.5 mmol, 0.067 g) was slowly added.

[0575] To another Schlenk tube containing 0.5 mL of THF at 0 °C, compound 2a (1 M THF solution, 1 equiv., 0.5 mmol, 0.0906 g, 0.5 mL) was added, and then bis(2-dimethylaminoethyl) ether (1 equiv., 0.5 mmol, 0.0801 g) was added dropwise. The reaction mixture was stirred for 10 minutes. The resulting reaction mixture was slowly added dropwise to the suspension of CuCl and compound 1a prepared above at -15 °C, and the reaction was carried out for 2 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was carried out with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20) to obtain the purified compound 3a in the form of a colorless liquid (0.0633 g, yield 72%).

[0576] The analysis results of the obtained compound 3a are shown below.

[0577] 1 H NMR (500 MHz, CDCl3) δ (ppm): 7.80 - 7.76 (m, 2H), 7.39 - 7.34 (m, 1H), 7.30 - 7.25 (m, 2H), 2.70 (s, 2H), 0.91 (s, 9H).

[0578] 13 C NMR (126 MHz, CDCl3) δ (ppm): 200.3, 138.4, 132.6, 128.3, 128.1, 49.9, 31.2, 29.9.

[0579] <Comparative Example 1>

[0580] Compound 3a was prepared from compound 1a and compound 2a according to the following reaction formula. It should be noted that Comparative Example 1 is different from Example 1 in that no copper salt was used.

[0581] [Chemical Formula 40]

[0582]

[0583] Under vacuum, using a hot air blower, the oven-dried Schlenk tube was heated three times for 5 minutes at 3-minute intervals, and argon was backfilled three times each time. After returning to room temperature, 1 mL of tetrahydrofuran (THF) was added, and the temperature of the reaction system was set to -15 °C. Compound 1a (1 equiv., 0.5 mmol, 0.067 g) was slowly added.

[0584] To another oven-dried Schlenk tube containing 0.5 mL of THF, compound 2a (1 M solution in THF, 1 equiv., 0.5 mmol, 0.0906 g, 0.5 mL) was added at 0 °C. Then, bis(2-dimethylaminoethyl) ether (1 equiv., 0.5 mmol, 0.0801 g) was added dropwise, and the reaction mixture was stirred for 10 minutes. The resulting reaction mixture was slowly added dropwise to the THF solution of compound 1a prepared above at -15 °C, and the reaction was carried out for 4 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was carried out with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20) to obtain the purified compound 3a in the form of a colorless liquid (0.0228 g, yield 26%).

[0585] The analysis results of the obtained compound 3a are shown below.

[0586] 1 H NMR (500 MHz, CDCl3) δ (ppm) 7.80 - 7.76 (m, 2H), 7.39 - 7.34 (m, 1H), 7.30 - 7.25 (m, 2H), 2.70 (s, 2H), 0.91 (s, 9H).

[0587] 13 C NMR (126 MHz, CDCl3) δ (ppm) 200.3, 138.4, 132.6, 128.3, 128.1, 49.9, 31.2, 29.9.

[0588] <Example 2>

[0589] Compound 3b was prepared from compound 1b and compound 2b according to the following reaction formula. Compound 1b is benzoyl chloride, and compound 2b is EtMgBr (where Et represents ethyl).

[0590] [Chemical formula 41]

[0591]

[0592] Under vacuum, the oven-dried Schlenk tube was heated three times for 5 minutes at 3-minute intervals using a hot air blower, and argon was backfilled three times each time. After returning to room temperature, CuCl (20 mol% (= 0.2 equiv.), 0.1 mmol, 0.009 g) was added under argon. After adding 1 mL of tetrahydrofuran (THF), the temperature of the reaction system was set to -15 °C, and compound 1b (1 equiv., 0.5 mmol, 0.070 g) was slowly added.

[0593] To another Schlenk tube containing 0.5 mL of THF at 0 °C, compound 2b (1 M THF solution, 1 equivalent, 0.5 mmol, 0.066 g, 0.5 mL) was added, and then bis(2-dimethylaminoethyl) ether (1 equivalent, 0.5 mmol, 0.0801 g) was added dropwise. The reaction mixture was stirred for 10 minutes. The resulting reaction mixture was slowly added dropwise to the suspension of CuCl and compound 1b prepared above at -15 °C, and the reaction was continued for 2 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was performed with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 25) to obtain the purified compound 3b in the form of a colorless liquid (0.0569 g, yield 85%).

[0594] The analysis results of the obtained compound 3b are shown below.

[0595] 1 H NMR (301 MHz, CDCl3) δ (ppm): 8.05 - 7.88 (m, 2H), 7.58 - 7.50 (m, 1H), 7.49 - 7.36 (m, 2H), 3.00 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 1.22 (t, J = 7.2, 7.2 Hz, 3H).

[0596] 13 C NMR (76 MHz, CDCl3) δ (ppm): 200.7, 136.8, 132.8, 128.4, 127.8, 31.6, 8.1.

[0597] <Comparative Example 2>

[0598] Compound 3b was prepared from compound 1b and compound 2b according to the following reaction formula. It should be noted that Comparative Example 2 is different from Example 2 in that bis(2-dimethylaminoethyl) ether was not used.

[0599] [Chemical formula 42]

[0600]

[0601] Under vacuum, using a hot air blower, the Schlenk tube dried in an oven was heated three times for 5 minutes at intervals of 3 minutes, and argon was backfilled three times each time. After returning to room temperature, CuCl (1 equivalent, 0.5 mmol, 0.049 g) was added under argon. After adding 1 mL of tetrahydrofuran (THF), the temperature of the reaction system was set to -15 °C, and compound 2b (1 M THF solution, 1 equivalent, 0.5 mmol, 0.066 g, 0.5 mL) was added dropwise, and the reaction mixture was stirred for 10 minutes. Compound 1b (1 equivalent, 0.5 mmol, 0.070 g) was slowly added to the resulting reaction mixture, and the reaction was continued for 2 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was carried out using ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20) to obtain the purified compound 3b in the form of a colorless liquid (0.0164 g, yield 23%).

[0602] The analysis results of the obtained compound 3b are shown below.

[0603] 1 H NMR (300 MHz, CDCl3) δ (ppm): 7.98 - 7.88 (m, 2H), 7.56 - 7.49 (m, 1H), 7.47 - 7.38 (m, 2H), 2.98 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 1.21 (t, J = 7.3, 7.3 Hz, 3H).

[0604] 13 C NMR (76 MHz, CDCl3) δ (ppm): 200.78, 136.88, 132.81, 128.49, 127.91, 31.71, 8.17.

[0605] <Example 3>

[0606] Compound 3b was prepared from compound 1b and compound 2b according to the following reaction formula. It should be noted that Example 3 is different from Example 2 in that the amount of copper salt used was increased to 1 equivalent.

[0607] [Chemical formula 43]

[0608]

[0609] Under vacuum, using a hot air blower, the Schlenk tube dried in an oven was heated 3 times for 5 minutes at intervals of 3 minutes, and argon was backfilled 3 times each time. After returning to room temperature, CuCl (1 equivalent, 0.5 mmol, 0.049 g) was added under argon. After adding 1 mL of tetrahydrofuran (THF), the temperature of the reaction system was set to -15 °C. After dropping compound 2b (1 M THF solution, 1 equivalent, 0.5 mmol, 0.066 g, 0.5 mL), bis(2-dimethylaminoethyl) ether (1 equivalent, 0.5 mmol, 0.0801 g) was dropped, and the reaction mixture was stirred for 10 minutes. Compound 1b (1 equivalent, 0.5 mmol, 0.070 g) was slowly added to the resulting reaction mixture, and the reaction was continued for 4 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was carried out with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20) to obtain the purified compound 3b in the form of a colorless liquid (0.0498 g, yield 74%).

[0610] The following shows the analysis results of the obtained compound 3.

[0611] 1 H NMR (300 MHz, CDCl3) δ (ppm): 7.98 - 7.88 (m, 2H), 7.56 - 7.49 (m, 1H), 7.47 - 7.38 (m, 2H), 2.98 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 1.21 (t, J = 7.3, 7.3 Hz, 3H).

[0612] 13 C NMR (76 MHz, CDCl3) δ (ppm): 200.78, 136.88, 132.81, 128.49, 127.91, 31.71, 8.17.

[0613] <Reference Example 1>

[0614] According to the following reaction formula, compound 3c was prepared from compound 1b and compound 2a.

[0615] [Chemical formula 44]

[0616]

[0617] Under vacuum, using a hot air blower, the Schlenk tube dried in an oven was heated 3 times for 5 minutes at 3-minute intervals, and argon was backfilled 3 times each time. After returning to room temperature, CuCl (1 equivalent, 0.5 mmol, 0.049 g) was added under argon. After adding 1 mL of tetrahydrofuran (THF), the temperature of the reaction system was set to 0 °C, and compound 2a (1 M THF solution, 1 equivalent, 0.5 mmol, 0.0906 g, 0.5 mL) was added dropwise, and the reaction mixture was stirred for 10 minutes. Compound 1b (1 equivalent, 0.5 mmol, 0.070 g) was slowly added to the resulting reaction mixture, and further stirred for 1.5 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was performed with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20) to obtain the purified compound 3c in the form of a white solid (0.0795 g, yield 87%).

[0618] The following shows the analysis results of the obtained compound 3c.

[0619] 1 H NMR (500 MHz, CDCl3) δ (ppm): 7.81 (dd, J = 8.0, 2.4 Hz, 4H), 7.57 (dt, J = 7.6, 3.9, 3.9 Hz, 2H), 7.47 (t, J = 6.9, 6.9 Hz, 4H).

[0620] 13 C NMR (126 MHz, CDCl3) δ (ppm): 196.62, 137.44, 132.31, 129.92, 128.15.

[0621] <Reference Example 2>

[0622] According to the following reaction formula, compound 3d was prepared from compound 1c and compound 2a. Compound 1c is 2-cyclopentylacetyl chloride.

[0623] [Chemical formula 45]

[0624]

[0625] Under vacuum, using a hot air blower, the Schlenk tube dried in an oven was heated three times for 5 minutes at intervals of 3 minutes, and argon was backfilled three times each time. After returning to room temperature, CuCl (1 equivalent, 0.5 mmol, 0.049 g) was added under argon. After adding 1 mL of tetrahydrofuran (THF), the temperature of the reaction system was set to 0 °C, and compound 2a (1 M THF solution, 1 equivalent, 0.5 mmol, 0.0906 g, 0.5 mL) was added dropwise, and the reaction mixture was stirred for 10 minutes. Compound 1c (1 equivalent, 0.5 mmol, 0.0733 g) was slowly added to the resulting reaction mixture, and stirring was continued for 2 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), extraction was carried out with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 30) to obtain the purified compound 3d in the form of a colorless liquid (0.0789 g, yield 84%).

[0626] The analysis results of the obtained compound 3d are shown below.

[0627] 1 H NMR (500 MHz, CDCl3) δ (ppm): 8.00 - 7.90 (m, 2H), 7.58 - 7.51 (m, 1H), 7.49 - 7.41 (m, 2H), 2.98 (dd, J = 7.2, 1.5 Hz, 2H), 2.38 (dq, J = 14.6, 7.7, 7.7, 7.4 Hz, 1H), 1.88 (dq, J = 11.9, 6.9, 6.7, 6.7 Hz, 2H), 1.67 - 1.53 (m, 4H), 1.23 - 1.13 (m, 2H).

[0628] 13 C NMR (126 MHz, CDCl3) δ (ppm): 200.39, 137.30, 132.80, 128.52, 128.09, 44.81, 36.07, 32.72, 24.98.

Claims

1. A method for producing a ketone derivative (I) represented by the following formula (I), the method comprising the following steps: Step (S1) of contacting an acyl chloride derivative (II) represented by the following formula (II) with a Grignard reagent (III) selected from a Grignard reagent (IIIa) represented by the following formula (IIIa) and a Grignard reagent (IIIb) represented by the following formula (IIIb) in the presence of a copper salt and a polydentate ligand to produce the ketone derivative (I); The polydentate ligand is a polydentate ligand that coordinates with Mg in the Grignard reagent (III) and is a polydentate ligand containing two or more donor atoms selected from oxygen atoms and nitrogen atoms, [Chemical formula 1] In formula (I), R 1 and R 2 each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent, [Chemical formula 2] In formula (II), R 1 has the same meaning as above, [Chemical formula 3] R 2 MgX (IIIa) In formula (IIIa), R 2 has the same meaning as above, X represents a halogen atom, [Chemical formula 4] R 2 MgX·LiCl (IIIb) In formula (IIIb), the meanings of R 2 and X are the same as those described above.

2. The method according to claim 1, wherein The polydentate ligand is a polydentate ligand represented by the following formula (IV) or a polydentate ligand represented by the following formula (VI), [Chemical formula 5] L 1 -L 2 -L 3 (IV) In formula (IV), L 1 and L 3 each independently represents an amino group which may have a substituent, an alkyloxy group which may have a substituent, or a group represented by the following formula (V). [Chemical formula 6] In formula (V), R 100 Expression: -[(Y 1 ) a -Z 1 ) b -(Y 1 ) c - the divalent group shown Y 1 Each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent. Z 1 each independently represents an ether group or an imino group which may have a substituent a represents an integer of 1 or more, b represents an integer of 0 or more, c represents an integer of 1 or more; L 2 Expression: -[(Y 2 )d - Z 2 ) e -(Y 2 ) f - the divalent group shown Y 2 Each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent, Z 2 each independently represents an ether group or an imino group which may have a substituent d represents an integer of 1 or more, e represents an integer of 1 or more, f represents an integer of 1 or more; [Chemical formula 7] In formula (VI), R 200 represents an alkyl group which may have substituents R 300 Expression: -[(Y 3 ) g -Z 3 ) h -(Y 3 ) i - the divalent group shown Y 3 Each independently represents a methylene group which may have a substituent, or a phenylene group which may have a substituent, Z 3 each independently represents an ether group or an imino group which may have a substituent g represents an integer of 1 or more, h represents an integer of 1 or more, i represents an integer of 1 or more.

3. The method according to claim 2, wherein, The polydentate ligand is selected from polydentate ligands represented by the following formulas (A) to (F), [Table 1] 4. The method according to claim 3, wherein The polydentate ligand is the polydentate ligand represented by the formula (A).

5. The method according to any one of claims 1 to 4, wherein, The copper salt is selected from copper(I) cyanide, copper(I) chloride, copper(I) bromide, copper(I) iodide, and copper(I) thiophene-2-carboxylate.

6. The method according to any one of claims 1 to 4, wherein, The amount of the Grignard reagent (III) used is 0.5 to 3 moles relative to 1 mole of the acyl chloride derivative (II).

7. The method according to any one of claims 1 to 4, wherein The amount of the copper salt used is 0.005 to 2 moles relative to 1 mole of the Grignard reagent (III).

8. The method according to any one of claims 1 to 4, wherein, The amount of the polydentate ligand used is 0.05 to 3 moles relative to 1 mole of the Grignard reagent (III).

9. The method according to any one of claims 1 to 4, wherein, Step (S1) includes the following steps: Step (T1) of mixing the acyl chloride derivative (II) and the copper salt to prepare a first mixture; Step (T2) of mixing the Grignard reagent (III) and the polydentate ligand to prepare a second mixture; and Step (T3) of mixing the first mixture and the second mixture to produce the ketone derivative (I).

10. The method according to claim 9, wherein, In step (T3), the second mixture is added dropwise to the first mixture.

11. The method according to any one of claims 1 to 4, wherein, Step (S1) includes the following steps: Step (U1) of mixing the copper salt, the Grignard reagent (III), and the polydentate ligand to prepare a third mixture; and Step (U2) of mixing the third mixture and the acyl chloride derivative (II) to produce the ketone derivative (I).

12. The method according to any one of claims 1 to 4, wherein The method further includes the following step: Step (S0) of contacting a carboxylic acid derivative (II’) represented by the following formula (II’) with a chlorinating agent to produce the acyl chloride derivative (II), [Chemical formula 8] In formula (II’), the meaning of R 1 is the same as described above.

13. The method according to claim 12, wherein, In the step (S0), the carboxylic acid derivative (II') is brought into contact with the chlorinating agent in the presence of a catalytic amount of N,N-dimethylformamide.

14. The method according to claim 12, wherein, The chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphoryl chloride and phosphorus pentachloride.

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