Method for producing ketone derivative

Abstract

To provide a method for producing a ketone derivative, the method enabling use of acid chloride derivatives other than aromatic acid chloride derivatives, in addition to aromatic acid chloride derivatives, as substrates.SOLUTION: The present invention provides a method for producing a ketone derivative, the method comprising a step of producing a ketone derivative by bringing an acid chloride derivative into contact with a Grignard reagent in the presence of a copper salt and a multidentate ligand. The multidentate ligand is a multidentate ligand that coordinates to Mg in the Grignard reagent, the multidentate ligand containing two or more donor atoms selected from oxygen atoms and nitrogen atoms.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Ketone derivatives are compounds useful as medical and agricultural chemicals, chemical materials, synthetic intermediates, and the like.

[0003] Patent Document 1 describes the following formula:

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0004]

[0005]

Table 1

[0006]

Table 2

Prior Art Documents

Non-Patent Literature

[0007]

Non-Patent Literature 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] The acid chloride derivatives used in Patent Document 1 were limited to aromatic acid chloride derivatives.

[0009] An object of the present invention is to provide a method for producing a ketone derivative capable of using, in addition to aromatic acid chloride derivatives, acid chloride derivatives other than aromatic acid chloride derivatives as substrates.

Means for Solving the Problems

[0010] The present invention includes the following inventions. [1] The following formula (I):

Chemical Formula

Chemical Formula

Chemical formula

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

[11] The process (S1) is the following process: (U1) A process of mixing the copper salt, the Grignard reagent (III), and the polydentate ligand to prepare a third mixture; and (U2) A process of mixing the third mixture and the acid chloride derivative (II) to produce the ketone derivative (I) The method according to any one of [1] to [8], comprising:

[12] The method is the following process: (S0) The following formula (II’):

Chemical formula

[11] , further comprising a process of contacting the carboxylic acid derivative (II’) represented by the formula with a chlorinating agent to produce the acid chloride derivative (II).

[13] In the process (S0), the method according to

[12] , wherein the carboxylic acid derivative (II’) and the chlorinating agent are contacted in the presence of a catalytic amount of N,N-dimethylformamide.

[14] The method according to

[12] or

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

Advantages of the Invention

[0011] According to the present invention, there is provided a method for producing a ketone derivative in which, in addition to an aromatic acid chloride derivative, an acid chloride derivative other than the aromatic acid chloride derivative can also be used as a substrate.

[0012] According to the present invention, by contacting the acid chloride derivative (II) and the Grignard reagent (III) in the presence of a copper salt and a polydentate ligand, it is possible to reduce the amount of copper salt used while achieving a high yield of the ketone derivative (I).

Embodiments for Carrying Out the Invention

[0013] The present invention will be described below. Two or more embodiments described in this specification can be combined, and combinations of two or more embodiments are also included in the present invention.

[0014] <<Explanation of Terms>> The terms used in this specification will be explained below. The following explanations apply throughout this specification unless otherwise specified. Note that the expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0015] Organic solvent Examples of the organic solvent include nitrile solvents such as acetonitrile and propionitrile; ether solvents such as tetrahydrofuran, 2-methyl-tetrahydrofuran, cyclopentyl methyl ether, dibutyl ether, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, and diglyme; 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; aliphatic hydrocarbon solvents such as hexane and heptane.

[0016] Halogen atom The halogen atom is selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0017] Alkyl group 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.

[0018] Alkenyl group The number of carbon atoms in 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 in the linear alkenyl group is 2 or more, and the number of carbon atoms in the branched alkenyl group is 3 or more.

[0019] Cycloalkyl group The number of carbon atoms in the cycloalkyl group is, for example, 3 to 10, preferably 3 to 8, and more preferably 3 to 6.

[0020] Heterocycloalkyl group A heterocycloalkyl group is a monocyclic saturated aliphatic heterocyclic group containing, 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. The saturated aliphatic heterocyclic group is an aliphatic heterocyclic group whose ring is constituted only by saturated bonds. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2. The number of members of the heterocycloalkyl group is, for example, 3 to 8 members, preferably 4 to 7 members, more preferably 5 to 7 members, and even more preferably 5 or 6 members. Examples of the heterocycloalkyl group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, those containing 1 to 4 nitrogen atoms, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, and the like. The heterocycloalkyl group preferably contains an oxygen atom as a heteroatom. Examples of the heterocycloalkyl group include an aziridinyl group, an oxiranyl group, a thiiranyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a tetrahydrothienyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an imidazolidinyl group, an oxazolidinyl group, a pyrazolidinyl group, a thiazolidinyl group, a tetrahydroisothiazolyl group, a tetrahydrooxazolyl group, a tetrahydroisoxazolyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a morpholinyl group, a thiomorpholinyl group (the sulfur atom on the ring may be oxidized), an azepanyl group, a diazepanyl group, an oxepanyl group, an azocanyl group, a diazocanyl group, and the like.

[0021] In one embodiment, the heterocycloalkyl group is selected from a tetrahydrofuranyl group and a tetrahydropyranyl group.

[0022] In one embodiment, the heterocycloalkyl group is a tetrahydrofuranyl group.

[0023] Aryl group The 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, more preferably 6 to 10 carbon atoms. The polycyclic is preferably a condensed ring type. Examples of the aryl group include a phenyl group, a naphthyl group, etc. The aryl group is preferably a phenyl group.

[0024] Heteroaryl group The heteroaryl group is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic heterocyclic group containing, 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. The polycyclic is preferably a condensed ring type. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2. The member number of the heteroaryl group is preferably 4 to 14 members, more preferably 5 to 10 members. Examples of the heteroaryl group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, those containing 1 to 4 nitrogen atoms, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, etc. The heteroaryl group is preferably a monocyclic or bicyclic 4- to 10-membered, preferably 5- to 10-membered aromatic heterocyclic group.

[0025] Examples of the monocyclic aromatic heterocyclic group include 5- to 7-membered monocyclic aromatic heterocyclic groups such as a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group (e.g., 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, etc.), a thiadiazolyl group (e.g., 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, etc.), a triazolyl group (e.g., 1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.), a tetrazolyl group, a triazinyl group, etc.

[0026] Examples of the condensed polycyclic aromatic heterocyclic group include 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as benzothiophenyl group, benzofuranyl group, benzimidazolyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzisothiazolyl group, benzotriazolyl group, imidazopyridinyl group, thienopyridinyl group, furopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyrazinyl group, imidazopyrimidinyl group, thienopyrimidinyl group, furopyrimidinyl group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, oxazolopyrimidinyl group, thiazolopyrimidinyl group, pyrazolotriazinyl group, naphtho[2,3-b]thienyl group, phenoxathiinyl group, indolyl group, isoindolyl group, 1H-indazolyl group, purinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, carbazolyl group, α-carbolinyl group, phenanthridinyl group, acridinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, etc.

[0027] In one embodiment, the heteroaryl group is selected from thienyl group, benzothiophenyl group, furyl group, pyrrolyl group, imidazolyl group and pyridyl group.

[0028] In one embodiment, the heteroaryl group is selected from thienyl group and benzothiophenyl group.

[0029] Haloalkyl group, haloaryl group and haloheteroaryl group The haloalkyl group, haloaryl group and haloheteroaryl group are an alkyl group, an aryl group and a heteroaryl group each having one or more halogen atoms, respectively, 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, more preferably 1.

[0030] Alkylene group, arylene group and heteroarylene group An alkylene group, an arylene group, and a heteroarylene group are each a divalent functional group formed by removing one hydrogen atom from an alkyl group, an aryl group, and a heteroaryl group, respectively. The descriptions of the alkyl group, the aryl group, and the heteroaryl group are as described above.

[0031] Haloalkylene group, haloarylene group and haloheteroarylene group A haloalkylene group, a haloarylene group, and a haloheteroarylene group are each a divalent functional group formed by removing one hydrogen atom from a haloalkyl group, a haloaryl group, and a haloheteroaryl group, respectively. The descriptions of the haloalkyl group, the haloaryl group, and the haloheteroaryl group are as described above.

[0032] Arylalkyl group An arylalkyl group is an alkyl group having one or more aryl groups. The descriptions of the alkyl group and the 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, more preferably 1.

[0033] Arylalkenyl group An arylalkenyl group is an alkenyl group having one or more aryl groups. The descriptions of the alkenyl group and the 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, more preferably 1.

[0034] Alkylcarbonyl group and arylcarbonyl group An alkylcarbonyl group and an arylcarbonyl group are groups represented by the formula: -CO-alkyl group and the formula: -CO-aryl group, respectively. The descriptions of the alkyl group and the aryl group are as described above.

[0035] Alkyloxy group, haloalkyloxy group, heterocycloalkyloxy group and arylalkyloxy group An alkyloxy group, a haloalkyloxy group, a heterocycloalkyloxy group, and an arylalkyloxy group are each a group represented by the formula: -O-alkyl group, the formula: -O-haloalkyl group, the formula: -O-heterocycloalkyl group, and the formula: -O-arylalkyl group, respectively. The descriptions of the alkyl group, the haloalkyl group, the heterocycloalkyl group, and the arylalkyl group are as described above.

[0036] Alkylthio group, haloalkylthio group, heterocycloalkylthio group and arylalkylthio group An alkylthio group, a haloalkylthio group, a heterocycloalkylthio group, and an arylalkylthio group are each a group represented by the formula: -S-alkyl group, the formula: -S-haloalkyl group, the formula: -S-heterocycloalkyl group, and the formula: -S-arylalkyl group, respectively. The descriptions of the alkyl group, the haloalkyl group, the heterocycloalkyl group, and the arylalkyl group are as described above.

[0037] Alkyloxycarbonyl group An alkyloxycarbonyl group is a group represented by the formula: -CO-O-alkyl group, and the description of the alkyl group is as described above. The number of carbon atoms of the alkyl group contained in the alkyloxycarbonyl 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, and still more preferably 1 or 2.

[0038] Amino group An amino group is a group (primary amino group) represented by the formula: -NH 2 as described above.

[0039] Monoalkylamino group A monoalkylamino group is a group represented by the formula: -NH(-Q 1 ) [wherein Q 1 represents an alkyl group.]. The description of the alkyl group is as described above. The number of carbon atoms of the alkyl group represented by Q 1 is preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 3, and still more preferably 1 or 2.

[0040] Dialkylamino group The dialkylamino group is a group represented by the formula: -N(-Q 2 )(-Q 3 ) [wherein Q 2 and Q 3 each independently represents an alkyl group. The description of the alkyl group is as above. The carbon number of the alkyl group represented by Q 2 or Q 3 is preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 3, and still more preferably 1 or 2.

[0041] Alicyclic amino group The alicyclic amino group is, for example, a 5- or 6-membered alicyclic amino group. Examples of the 5- or 6-membered alicyclic amino group 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, and the like. The alicyclic amino group may contain a heteroatom (for example, one heteroatom) independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the nitrogen atom having a bond of the alicyclic amino group.

[0042] In one embodiment, the alicyclic amino group is a morpholino group.

[0043] Aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group and alicyclic aminocarbonyl group The aminocarbonyl group, the monoalkylaminocarbonyl group, the dialkylaminocarbonyl group, and the alicyclic aminocarbonyl group are groups represented by the formula: -CO-amino group, the formula: -CO-monoalkylamino group, the formula: -CO-dialkylamino group, and the formula: -CO-alicyclic amino group, respectively. The descriptions of the monoalkylamino group, the dialkylamino group, and the alicyclic amino group are as above.

[0044] Substituent "May have a substituent" means that it may have one or more substituents. One or more substituents preferably means 1 to 3 substituents, more preferably 1 or 2 substituents.

[0045] Substituent group α Substituent group α is composed of the following substituents. (α-1) A halogen atom (α-2) A nitrile group (α-3) A nitro group (α-4) An amino group (α-5) An alkyl group (α-6) A haloalkyl group (α-7) A monoalkylamino group (α-8) A dialkylamino group (α-9) An alicyclic amino group (α-10) An alkyloxycarbonyl group (α-11) An aminocarbonyl group (α-12) A monoalkylaminocarbonyl group (α-13) A dialkylaminocarbonyl group (α-14) An alicyclic aminocarbonyl group (α-15) A hydroxy group which may be protected by a protecting group (α-16) A thiol group which may be protected by a protecting group

[0046] Substituent group β Substituent group β is composed of the following substituents. (β-1) A substituent represented by formula (i) (β-2) A substituent represented by formula (ii)

[0047] Hereinafter, substituent groups α and β will be described.

[0048] (α-5) In the case of an alkyl group, the number of carbon atoms 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.

[0049] In (α-6), the number of carbon atoms in 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 in the haloalkyl group is preferably 1 to 3, more preferably 1 or 2, still more preferably 1.

[0050] (α-15) Hydroxy group which may be protected by a protecting group The hydroxy group protecting group preferably can protect the hydroxy group when carrying out the target reaction and can be removed from the hydroxy group after completion of the target reaction. Examples of the hydroxy group protecting group include 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 alkyloxyalkyl type protecting group, a silyl type protecting group, an oxycarbonyl type protecting group, an acetal type protecting group, an aryl type protecting group, etc. These protecting groups may have one or more halogen atoms.

[0051] Examples of the alkylcarbonyl type protecting group include an alkylcarbonyl group having 2 to 10 carbon atoms which may have one or more substituents. The substituents can be selected from, for example, 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 alkyloxy 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 alkyloxycarbonyl 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. Examples of the alkylcarbonyl group having 2 to 10 carbon atoms which may have one or more substituents include an acetyl group, a propanoyl group, a butanoyl group, an isopropanoyl group, a pivaloyl group, etc. The alkylcarbonyl type protecting group is preferably an alkylcarbonyl group having 2 to 5 carbon atoms, more preferably an acetyl group or a pivaloyl group, still more preferably an acetyl group.

[0052] Examples of the arylcarbonyl type protecting group include an arylcarbonyl group having 7 to 11 carbon atoms which may have one or more substituents, and the like. Specific examples of the substituent are the same as those of the alkylcarbonyl type protecting group. Examples of the arylcarbonyl group having 7 to 11 carbon atoms which may have one or more substituents include a benzoyl group, 4-nitrobenzoyl group, 4-methoxybenzoyl group, 4-methylbenzoyl group, 4-tert-butylbenzoyl group, 4-fluorobenzoyl group, 4-chlorobenzoyl group, 4-bromobenzoyl group, 4-phenylbenzoyl group, 4-methoxycarbonylbenzoyl group, and the like.

[0053] Examples of the arylalkyl type protecting group include an arylalkyl group having 7 to 11 carbon atoms which may have one or more substituents, and the like. Specific examples of the substituent are the same as those of the alkylcarbonyl type protecting group. Examples of the arylalkyl group having 7 to 11 carbon atoms which may have one or more substituents include a benzyl group, 1-phenylethyl group, diphenylmethyl group, 1,1-diphenylethyl group, naphthylmethyl group, trityl group, and the like. The arylalkyl type protecting group is preferably a benzyl group.

[0054] Examples of the alkyl type protecting group include an alkyl group having 1 to 10 carbon atoms which may have one or more substituents, and the like. 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 group having 1 to 5 carbon atoms which may have one or more substituents, more preferably a methyl group, ethyl group, tert-butyl group, and even more preferably a methyl group.

[0055] Examples of arylalkyloxyalkyl-type protecting groups include arylalkyloxyalkyl groups such as an arylalkyloxymethyl group having 8 to 12 carbon atoms which may have one or more substituents, an arylalkyloxyethyl group having 9 to 13 carbon atoms which may have one or more substituents, and an arylalkyloxypropyl group having 10 to 14 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting groups. The arylalkyloxyalkyl-type protecting group is, for example, a benzyloxymethyl group which may have one or more substituents, preferably a benzyloxymethyl group which may be substituted with a halogen atom, a nitro group, a cyano group, a methyl group or a methyloxy group, and more preferably a benzyloxymethyl group.

[0056] Examples of alkyloxyalkyl-type protecting groups include alkyloxyalkyl groups such as an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, an alkyloxyethyl group having 3 to 10 carbon atoms which may have one or more substituents, and an alkyloxypropyl group having 4 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 groups. The alkyloxyalkyl-type protecting group is preferably an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, more preferably an alkyloxymethyl group having 2 to 6 carbon atoms which may have a halogen atom, a nitro group, a cyano group, a methyloxy group or an ethyloxy group, and even more preferably a methyloxymethyl group.

[0057] Examples of silyl-type protecting groups include silyl groups having a functional group selected from an alkyl group having 1 to 10 carbon atoms which may have one or more substituents, an arylalkyl group having 7 to 11 carbon atoms which may have one or more substituents, and an aryl group 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 groups. The silyl-type protecting group is preferably a silyl group having a functional group selected from an alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 10 carbon atoms, more preferably a silyl group having a functional group selected from an alkyl group having 1 to 5 carbon atoms and a phenyl group, and even more preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group.

[0058] Examples of oxycarbonyl-type protecting groups include an alkyloxycarbonyl group having 2 to 10 carbon atoms which may have one or more substituents, an alkenyloxycarbonyl group having 3 to 10 carbon atoms which may have one or more substituents, an arylalkyloxycarbonyl group having 8 to 12 carbon atoms which may have one or more substituents, and the like. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting groups. The oxycarbonyl-type protecting group is preferably an alkyloxycarbonyl group having 2 to 6 carbon atoms, an alkenyloxycarbonyl group having 3 to 6 carbon atoms or a benzyloxycarbonyl group, more preferably a methyloxymethyl group, an allyloxycarbonyl group or a benzyloxycarbonyl group.

[0059] Examples of acetal-type protecting groups include a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.

[0060] Examples of aryl-type protecting groups include aryl groups such as a phenyl group.

[0061] The hydroxy group protected by a protecting group is preferably a group represented by the formula: -O-Q. Q represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, a heterocycloalkyl group, an alkylcarbonyl group, an arylcarbonyl group or an arylalkyl group. The number of carbon atoms in the group represented by the formula: -O-Q is preferably from 1 to 10, more preferably from 1 to 8. Q is preferably an alkyl group, a heterocycloalkyl group, an alkylcarbonyl group or an arylalkyl group, more preferably an ethyl group, a tetrahydrofuranyl group, an acetyl group or a benzyl group.

[0062] (α-16) Thiol group which may be protected by a protecting group The thiol group protecting group preferably can protect the thiol group when carrying out the target reaction and can be removed from the thiol group after completion of the target reaction. Examples of the thiol group protecting group include 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 alkyloxyalkyl type protecting group, a silyl type protecting group, an oxycarbonyl type protecting group, an acetal type protecting group, an aryl type protecting group and the like. These protecting groups may have one or more halogen atoms. The description of these protecting groups is as described above.

[0063] The thiol group protected by a protecting group is preferably a group represented by the formula: -S-Q. The description of Q is as described above.

[0064] (β-1) Substituent represented by formula (i)

Chemical formula

[0065] In formula (i), R 11 , R 12 and R 13Each independently represents a hydroxy group which may be protected by an alkyl group, a haloalkyl group, an aryl group, a haloaryl group or a protecting group. The hydroxy group which may be protected by a protecting group is preferably a group represented by the above formula: -O-Q. a is 0 or more and 3 or less.

[0066] (β-2) Substituent represented by formula (ii)

Chemical formula

[0067] 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 preferably 1 to 10, more preferably 1 to 8 respectively. The number of carbon atoms of the arylene group and the haloarylene group is preferably 4 to 14, more preferably 6 to 14 respectively. The number of carbon atoms of the heteroarylene group and the haloheteroarylene group is preferably 4 to 14 respectively. V 10 is preferably an alkylene group, more preferably a methylene group or an ethylene group.

[0068] In formula (ii), b represents 0 or 1. b is preferably 1.

[0069] 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 5-membered heteroarylene group containing a sulfur atom as a heteroatom, and even more preferably thienylene.

[0070] In formula (ii), c represents 0 or 1. It is preferable that c is 1.

[0071] 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, aryl group, and heteroaryl group may each be unsubstituted or may have one or more substituents. The one or more substituents may each independently be selected from substituent group α. The one or more substituents may each independently preferably be selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group, more preferably be selected from a halogen atom, an alkyloxy group having 1 to 3 carbon atoms, and a heterocycloalkyloxy group, and even more preferably be selected from a fluorine atom, an ethyloxy group, and a tetrahydrofuranyloxy group. The heterocycloalkyloxy group preferably contains an oxygen atom as a heteroatom. The number of substituents that the alkyl group, aryl group, and heteroaryl group may each have is preferably 1 to 3, more preferably 1 or 2.

[0072] 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 alkyloxy group having 1 to 3 carbon atoms, or a heterocycloalkyloxy group, or an unsubstituted heteroaryl group, and even more preferably a phenyl group having a fluorine atom, an ethyloxy group, or a tetrahydrofuranyloxy group, or an unsubstituted benzothiophenyl group. The heterocycloalkyloxy group preferably contains an oxygen atom as a heteroatom.

[0073] ≪Ketone Derivative (I)≫ The ketone derivative (I) is represented by the following formula (I).

[0074] [Chemical formula]

[0075] In formula (I), R 1 and R 2 are each independently (1) an alkyl group which may have a substituent, (2) an alkenyl group which may have a substituent, (3) a cycloalkyl group which may have a substituent, (4) a heterocycloalkyl group which may have a substituent, (5) an aryl group which may have a substituent, (6) a heteroaryl group which may have a substituent, (7) an arylalkyl group which may have a substituent, or (8) an arylalkenyl group which may have a substituent represents.

[0076] Hereinafter, functional groups (1) to (8) will be described.

[0077] (1) Alkyl group which may have a substituent The description of the alkyl group is as above. 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. The one or more substituents may each independently be 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, the one or more substituents are each 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. In one embodiment, the one or more substituents are each 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 alkyloxy group having 1 to 3 carbon atoms, and a haloalkyloxy group having 1 to 3 carbon atoms. In one embodiment, the one or more substituents are each independently selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0078] (2) Alkenyl group which may have a substituent The description of the alkenyl group is as above. The alkenyl group may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of functional group (1).

[0079] (3) Cycloalkyl group which may have a substituent The description of the cycloalkyl group is as above. The cycloalkyl group may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of functional group (1).

[0080] (4) Heterocycloalkyl group which may have a substituent The description of the heterocycloalkyl group is as above. The heterocycloalkyl group may be unsubstituted or may have one or more substituents. The description of the substituents is the same as that of functional group (1).

[0081] (5) Aryl group which may have a substituent The description of the aryl group is as above. The aryl group 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).

[0082] (6) Heteroaryl group which may have a substituent The description of the heteroaryl group is as above. The heteroaryl group 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).

[0083] (7) Arylalkyl group which may have a substituent The description of the arylalkyl group is as above. The arylalkyl group 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).

[0084] (8) Arylalkenyl group which may have a substituent The description of the arylalkenyl group is as above. The arylalkenyl group 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).

[0085] In the functional group (5) (i.e., an aryl group which may have a substituent), the carbon atoms adjacent to the carbon atom having the bond of the aryl group (i.e., the carbon atom bonded to -CO- in the formula (I)) preferably do not have a substituent. The remaining carbon atoms may have a substituent.

[0086] In the functional group (6) (i.e., a heteroaryl group which may have a substituent), the carbon atoms or heteroatoms adjacent to the carbon atom having the bond of the heteroaryl group (i.e., the carbon atom bonded to -CO- in the formula (I)) preferably do not have a substituent. The remaining carbon atoms or heteroatoms may have a substituent.

[0087] In one embodiment, R 1 is the functional group (1), and R 2is one of the functional groups (1) to (8). R 1 and R 2 are both the functional group (1), R 1 and R 2 may be the same or different.

[0088] In one embodiment, R 1 is the functional group (2), and R 2 is one of the functional groups (1) to (8). R 1 and R 2 are both the functional group (2), R 1 and R 2 may be the same or different.

[0089] In one embodiment, R 1 is the functional group (3), and R 2 is one of the functional groups (1) to (8). R 1 and R 2 are both the functional group (3), R 1 and R 2 may be the same or different.

[0090] In one embodiment, R 1 is the functional group (4), and R 2 is one of the functional groups (1) to (8). R 1 and R 2 are both the functional group (4), R 1 and R 2 may be the same or different.

[0091] In one embodiment, R 1 is the functional group (5), and R 2 is one of the functional groups (1) to (8). R 1 and R 2 are both the functional group (5), R 1 and R 2 may be the same or different.

[0092] In one embodiment, R 1 is a functional group (6), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (6), R 1 and R 2 may be the same or different.

[0093] In one embodiment, R 1 is a functional group (7), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (7), R 1 and R 2 may be the same or different.

[0094] In one embodiment, R 1 is a functional group (8), and R 2 is any one of the functional groups (1) to (8). When both R 1 and R 2 are the functional group (8), R 1 and R 2 may be the same or different.

[0095] 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 (for example, R 2 ) is the functional group (5) or (6), preferably the functional group (5), more preferably a phenyl group which may have a substituent.

[0096] In one embodiment, R 1 and R 2is, independently of each other, 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), even more preferably functional group (1) or (3), and most preferably functional group (1).

[0097] In one embodiment, R 1 and R 2 are, independently of each other, functional group (5) or (6), preferably functional group (5), and more preferably a phenyl group which may have a substituent.

[0098] R 1 and R 2 Examples of the ketone derivative (I) in which one of them is an alkyl group which may have a substituent and the other is an aryl group which may have a substituent include the following compounds.

[0099]

Chemical formula

[0100] R 1 and R 2 Examples of the ketone derivative (I) in which R and R are each independently an aryl group which may have a substituent include the following compounds.

[0101]

Chemical formula

[0102] R 1 and R 2 Examples of the ketone derivative (I) in which one of them is a cycloalkyl group which may have a substituent and the other is an aryl group which may have a substituent include the following compounds.

[0103]

Chemical formula

[0104] In one embodiment, R 1 and R 2 one of them (for example, R 2 ) is a functional group represented by the following formula (iv).

[0105]

Chemical formula

[0106] In formula (iv), Y 10 represents an alkylene group which may have a substituent, an arylene group which may have a substituent, or a heteroarylene group which may have a substituent. 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. The alkylene group, arylene group and heteroarylene group may each be unsubstituted or may have one or more substituents. The one or more substituents may each independently be selected from the substituent group α. The one or more substituents are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy 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 alkyloxy group having 1 to 3 carbon atoms. The number of substituents that the alkylene group, arylene group and heteroarylene group may each have is preferably 1 to 3, more preferably 1 or 2.

[0107] Y 10 is preferably an arylene group having a substituent, 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.

[0108] Y 10The carbon atoms adjacent to both sides of the carbon atom bonded to -CO- in formula (I) have no substituents, and the remaining carbon atoms may have substituents, which is an arylene group, or the carbon atoms or heteroatoms adjacent to both sides of the carbon atom bonded to -CO- in formula (I) have no substituents, and the remaining carbon atoms or heteroatoms may have substituents, which is preferably a heteroarylene group. Y 10 is more preferably a phenylene group in which the ortho position to the carbon atom bonded to -CO- in formula (I) has no substituent, and the meta position and / or para position may have substituents.

[0109] In formula (iv), V 10 , W 10 , X 10 , b and c are respectively synonymous with formula (ii).

[0110] In one embodiment, one of R 1 and R 2 (for example, R 2 ) is a functional group represented by the following formula (vi).

[0111]

Chemical formula

[0112] 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. may be used. Examples of the carbamate-based protecting group include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an allyloxycarbonyl group, etc. Examples of the acyl-based protecting group include an acetyl group, a pivaloyl group, a benzoyl group, etc. Examples of the amide-based protecting group include a trifluoroacetyl group, etc. Examples of the sulfonamide-based protecting group include a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, etc. 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 a pivaloyl group or a trifluoroacetyl group. 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. When R 2 has the structure of formula (vi), the ketone derivative (I) can be preferably used as an intermediate of remdesivir.

[0113] 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), and most preferably the functional group (1), and the other (for example, R 2 ) is a functional group represented by the above formula (iv) or a functional group represented by the above formula (vi).

[0114] Examples of the ketone derivative (I) in which R 1 is an alkyl group which may have a substituent include, for example, a ketone derivative (Ia) represented by the following formula (Ia).

[0115]

Chemical formula

[0116] In formula (Ia), n represents 1 or 2.

[0117] In formula (Ia), each R independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. The explanations for 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, even more preferably 1 to 6, even more preferably 1 to 4, and even more preferably 1 to 3. The aryl group is preferably a phenyl group. The alkyl group and the aryl group may each be unsubstituted or may have one or more substituents. The number of substituents that the alkyl group and the aryl group may each have is preferably 1 to 3, and 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 be selected from substituent group α and one or more substituents may be selected from substituent group β. One or more substituents are each independently preferably 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 selected 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, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0118] 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 group protecting group represented by the formula: -CO-R. In one embodiment, the four Rs are all methyl groups. In one embodiment, the four Rs are all phenyl groups.

[0119] In formula (Ia), when n = 2, the five Rs may be different, but from the viewpoint of efficient introduction and removal of a hydroxy group protecting group represented by the formula: -CO-R, they are preferably the same. In one embodiment, the five Rs are all methyl groups. In one embodiment, the five Rs are all phenyl groups.

[0120] Examples of the ketone derivative (Ia) include the following compounds. Note that "Ac" represents an acetyl group.

[0121]

Chemical formula

[0122] In one embodiment, R in formula (Ia) 2 is a functional group represented by the above formula (iv) or a functional group represented by the above formula (vi).

[0123] In one embodiment, R in formula (I) or (Ia) 2 is the same as the functional group possessed by the SGLT-2 inhibitor or a functional group derived from the functional group possessed by the SGLT-2 inhibitor. Thereby, the ketone derivative (I) or (Ia) can be used as a raw material for producing an SGLT-2 inhibitor or a derivative thereof.

[0124] SGLT-2 inhibitors are useful as antidiabetic agents. Note that "SGLT-2" means sodium-glucose cotransporter-2. Examples of SGLT-2 inhibitors include canagliflozin (1-(β-D-glycopyranosyl)-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-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol), etc.

[0125] SGLT-2 inhibitors including canagliflozin, empagliflozin, ipragliflozin and dapagliflozin have a functional group represented by the following formula (A).

[0126] In one embodiment, R in formula (I) or (Ia) 2 is a functional group represented by the following formula (A).

[0127] 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), even more preferably functional group (1) or (3), and most preferably functional group (1), and R 2 is a functional group represented by the following formula (A).

[0128]

Chemical formula

[0129] In formula (A), d represents an integer from 0 to 4. d is preferably from 1 to 3, more preferably 1 or 2, and even more preferably 1. When d is 2 or more, the d R a s may be the same or different.

[0130] In formula (A), the d R a s may each independently be selected from the substituent group α. The d R a s are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy 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 alkyloxy group having 1 to 3 carbon atoms.

[0131] In formula (A), Ar’ is a functional group represented by the following formula (v).

[0132]

Chemical formula

[0133] In formula (v), W 10 , X 10 and c are each synonymous with formula (ii).

[0134] In formula (A), Ar’ is preferably a functional group represented by the following formula (Ar’-1), (Ar’-2), or (Ar’-3).

[0135]

Chemical formula

[0136] In formulas (Ar’-1), (Ar’-2), and (Ar’-3), p is an integer from 0 to 5. p is preferably an integer from 0 to 3, more preferably an integer from 0 to 2, and even more preferably 0 or 1.

[0137] In formulas (Ar’-1), (Ar’-2), and (Ar’-3), p Rs b may each independently be selected from a 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. The p Rs b are preferably each independently selected from a 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 each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy 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 alkyloxy group having 1 to 3 carbon atoms, and a heterocycloalkyloxy group, and even more preferably selected from a fluorine atom, an ethyloxy group, and a tetrahydrofuranyloxy 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.

[0138] When p is 2 or more, the p Rs b may be the same or different.

[0139] In formula (Ar’-1), p is preferably 1, and R b is preferably a phenyl group which may have a substituent, more preferably a phenyl group having a halogen atom, and even more preferably a phenyl group having a fluorine atom. The position to which the unsubstituted or substituted phenyl group is bonded is preferably the 2-position of the thiophene ring. In the phenyl group having a halogen atom, the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.

[0140] In formula (Ar’-2), p is preferably 0.

[0141] In formula (Ar’-3), p is preferably 1, and R b is preferably an alkyloxy group which may have a substituent or a heterocycloalkyloxy group which may have a substituent. The alkyloxy group which may have a substituent is preferably an alkyloxy group having 1 to 3 carbon atoms, more preferably a methoxy group or an ethoxy group. The heterocycloalkyloxy group which may have a substituent is preferably a tetrahydrofuranyloxy group. The position to which the alkyloxy group which may have a substituent or the heterocycloalkyloxy group which may have a substituent is bonded is preferably the 4-position of the benzene ring.

[0142] When d = 1, the functional group represented by formula (A) is preferably a functional group represented by the following formula (B).

[0143]

Chemical formula

[0144] In formula (B), R a and Ar’ have the same meanings as in formula (A).

[0145] The functional group represented by formula (A) or (B) is preferably a functional group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4). Here, "Et" represents an ethyl group.

[0146]

Chemical formula

[0147] In one embodiment, R 2 in formula (I) or (Ia) is a compound which is a functional group represented by formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4).

[0148] In one embodiment, R 1is 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), even more preferably the functional group (1) or (3), and most preferably the functional group (1), and R 2 is a compound having a functional group represented by the formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4).

[0149] ≪Acid chloride derivative (II)≫ The acid chloride derivative (II) is represented by the following formula (II).

[0150]

Chemical formula

[0151] In formula (II), R 1 has the same meaning as in formula (I). R 1 The above description regarding 1 also applies to R in formula (II).

[0152] 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), even more preferably the functional group (1) or (3), and most preferably the functional group (1).

[0153] In one embodiment, R 1 is the functional group (5) or (6), preferably the functional group (5), and more preferably a phenyl group which may have a substituent.

[0154] When R in formula (II) 1 is an alkyl group which may have a substituent, examples of the acid chloride derivative (II) include an acid chloride derivative (IIa) represented by the following formula (IIa).

[0155]

Chemical formula

[0156] In formula (IIa), n represents 1 or 2.

[0157] In formula (IIa), R is synonymous with formula (Ia). The above description regarding R also applies to R in formula (IIa).

[0158] In formula (IIa), when n = 1, the four Rs may be different, but from the viewpoint of efficient introduction and removal of the hydroxy group protecting group represented by the formula: -CO-R, it is preferable that they are the same. In one embodiment, the four Rs are all methyl groups. In one embodiment, the four Rs are all phenyl groups.

[0159] In formula (IIa), when n = 2, the five Rs may be different, but from the viewpoint of efficient introduction and removal of the hydroxy group protecting group represented by the formula: -CO-R, it is preferable that they are the same. In one embodiment, the five Rs are all methyl groups. In one embodiment, the five Rs are all phenyl groups.

[0160] Examples of the acid chloride derivative (IIa) include the following compounds. Note that "Ac" represents an acetyl group.

[0161]

Chemical formula

[0162] The acid chloride derivative (II) can be produced by contacting a carboxylic acid derivative (II') represented by the following formula (II') with a chlorinating agent.

[0163]

Chemical formula

[0164] In formula (II'), R 1 is synonymous with formula (I). R 1The above description regarding R in formula (II’) 1 is also applicable.

[0165] When R in formula (II’) 1 is an alkyl group which may have a substituent, examples of the carboxylic acid derivative (II’) include carboxylic acid derivatives (IIa’) represented by the following formula (IIa’).

[0166]

Chemical formula

[0167] In formula (IIa’), n represents 1 or 2.

[0168] In formula (IIa’), R is synonymous with formula (Ia). The above description regarding R is also applicable to R in formula (IIa’).

[0169] In formula (IIa’), when n = 1, the four Rs may be different, but from the viewpoint of efficient introduction and removal of the hydroxy group protecting group represented by the formula: -CO-R, it is preferably the same. In one embodiment, the four Rs are all methyl groups. In one embodiment, the four Rs are all phenyl groups.

[0170] In formula (IIa’), when n = 2, the five Rs may be different, but from the viewpoint of efficient introduction and removal of the hydroxy group protecting group represented by the formula: -CO-R, it is preferably the same. In one embodiment, the five Rs are all methyl groups. In one embodiment, the five Rs are all phenyl groups.

[0171] Examples of the carboxylic acid derivative (IIa’) include the following compounds. Note that "Ac" represents an acetyl group.

[0172]

Chemical formula

[0173] The carboxylic acid derivative (II') and the chlorinating agent may each be a commercially available product or may be produced according to a conventional method.

[0174] Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc. Among these, thionyl chloride and oxalyl chloride are preferred, and oxalyl chloride is more preferred.

[0175] The amount of the chlorinating agent used is preferably 0.2 to 10 moles, more preferably 0.5 to 5 moles, and even more preferably 1 to 3 moles per 1 mole of the carboxylic acid derivative (II').

[0176] The temperature at which the carboxylic acid derivative (II') and the chlorinating agent are contacted is preferably -10 to 50°C, more preferably 0 to 40°C, and even more preferably 0 to 35°C.

[0177] The time for contacting the carboxylic acid derivative (II') and the chlorinating agent is preferably 0.5 to 48 hours, more preferably 1 to 24 hours, and even more preferably 1 to 8 hours.

[0178] The contact between the carboxylic acid derivative (II') and the chlorinating agent can be carried out under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0179] The contact of the carboxylic acid derivative (II’) with the chlorinating agent is preferably carried out in a solvent. By mixing the carboxylic acid derivative (II’) and the chlorinating agent in a solvent, the carboxylic acid derivative (II’) and the chlorinating agent can be brought into contact with each other. As the solvent, it is preferable to use an organic solvent. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane and heptane, and more preferably dichloromethane.

[0180] 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 per 1 g of the carboxylic acid derivative (II’).

[0181] 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). By mixing the carboxylic acid derivative (II’), the chlorinating agent and DMF in a solvent, the carboxylic acid derivative (II’) and the chlorinating agent can be brought into contact with each other in the presence of DMF. By bringing the carboxylic acid derivative (II’) and the chlorinating agent into contact with each other in the presence of a catalytic amount of DMF, the acid chloride derivative (II) can be produced under milder conditions.

[0182] The amount of DMF used is preferably 0.005 to 0.1 mol, more preferably 0.0075 to 0.1 mol, and even more preferably 0.01 to 0.1 mol per 1 mol of the carboxylic acid derivative (II’).

[0183] The above conditions regarding the contact of the carboxylic acid derivative (II’) with the chlorinating agent can be appropriately combined.

[0184] The obtained acid chloride derivative (II) may be isolated according to a conventional method such as silica gel column chromatography and then used in the next step, or it may be used in the next step without isolation. For example, the obtained acid chloride derivative (II) may be used in the next step as an unpurified concentrated residue.

[0185] The structure of the acid chloride derivative (II) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis.

[0186] ≪Grignard reagent (III)≫ 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). The Grignard reagent (IIIb) is called a turbo Grignard reagent.

[0187]

Chemical formula

[0188]

Chemical formula

[0189] In formulas (IIIa) and (IIIb), R 2 is synonymous with formula (I). The above description regarding R 2 also applies to R 2 in formulas (IIIa) and (IIIb).

[0190] In one embodiment, R 2 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), even more preferably the functional group (1) or (3), and most preferably the functional group (1).

[0191] In one embodiment, R 2is a functional group (5) or (6), preferably functional group (5), more preferably a phenyl group which may have a substituent.

[0192] In one embodiment, R 2 is a functional group having a β-carbon to which a hydrogen atom is bonded. The β-carbon is a carbon atom adjacent to the α-carbon (i.e., the carbon atom having the bond of R 2 ). Examples of the functional group having a β-carbon to which a hydrogen atom is bonded include an ethyl group, a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a cyclopentylidene group, a cyclohexylidene group, etc., which 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 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. One or more substituents may each independently be selected from, for example, an alkyloxy group, a phenoxy group, a phenylthio group, a nitro group, an ester group, a halogen group, an alkylthio group, a dialkylamino group, etc.

[0193] 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 even more preferably a bromine atom.

[0194] ≪Copper salt≫ Examples of the copper salt include copper(I) chloride (CuCl), copper(II) chloride (CuCl2), copper(I) bromide (CuBr), copper(II) bromide (CuBr2), copper(I) iodide (CuI), copper(II) iodide (CuI2), copper(I) cyanide (CuCN), copper(I) 3-methylsalicylate, copper(I) mesitylene (MesCu), copper(I) isopropoxide (iPrOCu), copper(I) tert-butoxide (CuO tExamples of the copper salts include copper(I) acetate (CuOAc), copper(II) acetate (Cu(OAc)₂), copper(I) sulfate (Cu₂SO₄), copper(II) sulfate (CuSO₄), copper(I) oxide (Cu₂O), copper(II) oxide (CuO), copper(I) pivalate (CuOPiv), copper(II) pivalate (Cu(OPiv)₂), copper salts containing sulfur (S), and the like.

[0195] Examples of the copper salts containing sulfur (S) include copper(I) thiophene-2-carboxylate (CuTC), and the like. S has a high affinity for Cu, and in the copper salt, S is likely to coordinate to Cu. Due to this coordination, Cu is activated, and a high yield of the ketone derivative (I) can be achieved.

[0196] 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.

[0197] The valence of the copper atom contained in the copper salt is usually monovalent or divalent, preferably monovalent. The copper salt with a monovalent copper atom has excellent catalytic activity. Among the copper salts with a monovalent copper atom, CuCN, CuCl, CuBr, CuI, and CuTC have particularly excellent catalytic activity. Therefore, the copper salt is preferably selected from CuCN, CuCl, CuBr, CuI, and CuTC.

[0198] ≪Multidentate ligand≫ The multidentate ligand used in the present invention is a multidentate ligand that coordinates to Mg in the Grignard reagent (III) and contains two or more donor atoms selected from oxygen atoms and nitrogen atoms.

[0199] The donor atom is also called a coordinating atom. A multidentate ligand with two donor atoms is called a bidentate ligand, a multidentate ligand with three donor atoms is called a tridentate ligand, a multidentate ligand with four donor atoms is called a tetradentate ligand, and a multidentate ligand with n donor atoms is called an n-dentate ligand.

[0200] 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.

[0201] 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 a multidentate ligand represented by the following formula (IV) or a multidentate ligand represented by the following formula (VI), and more preferably a multidentate ligand represented by the formula (IV).

[0202]

Chemical formula

[0203]

Chemical formula

[0204] Hereinafter, the multidentate ligand represented by the formula (IV) will be described.

[0205] <Multidentate ligand represented by formula (IV)>

[0206] 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).

[0207]

Chemical formula

[0208] Hereinafter, the amino group which may have a substituent, the alkyloxy group which may have a substituent, and the group represented by the formula (V) will be described.

[0209] Amino group which may have a substituent The amino group which may have a substituent is a primary amino group, a secondary amino group or a tertiary amino group.

[0210] The primary amino group is represented by the formula: -NH2. The secondary amino group is represented by the formula: -NHR 10 and is represented by the formula: -NR 10 R 20 and is represented by the formula:

[0211] R 10 and R 20 each independently represent 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.

[0212] 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.

[0213] [Alkyl group which may have a substituent] The description of the alkyl group is as above. The number of carbon atoms in the alkyl 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, and even 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. The one or more substituents can each independently be selected from substituent group α. The one or more substituents are each independently preferably 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 selected 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, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0214] [Cycloalkyl group which may have a substituent] The description of the cycloalkyl group is as above. 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. The one or more substituents can each independently be selected from substituent group α. The one or more substituents are each independently preferably 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 selected 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, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0215] [Aryl group which may have a substituent] The description of the aryl group is as 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. The one or more substituents can each independently be selected from substituent group α. The one or more substituents are each independently preferably 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 selected 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, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0216] [Optionally substituted arylalkyl group] The description of the arylalkyl group is as 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. The one or more substituents can each independently be selected from substituent group α. The one or more substituents are each independently preferably 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 selected 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, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0217] The secondary amino group and the tertiary amino group may be an aliphatic amino group or an aromatic amino group, but an aliphatic amino group is preferred. Examples of the aliphatic amino group include a secondary amino group which is an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and a tertiary amino group in which both R 10 and R 10 are an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, etc. Examples of the aromatic amino group include a secondary amino group which is an aryl group which may have a substituent or an arylalkyl group which may have a substituent, and a tertiary amino group in which at least one of R 20 and R 10 is an aryl group which may have a substituent or an arylalkyl group which may have a substituent, etc. 10 and R 20

[0218] Examples of the secondary amino group include aliphatic amino groups such as N-methylamino group, N-ethylamino group, N-propylamino group, N-isopropylamino group, etc., and aromatic amino groups such as N-phenylamino group (anilino group), etc. The secondary amino group is preferably a monoalkylamino group. The description of the monoalkylamino group is as above.

[0219] Examples of the tertiary amino group include aliphatic amino groups such as N,N-dimethylamino group, N,N-diethylamino group, N,N-methylethylamino group, N,N-dipropylamino group, N,N-diisopropylamino group, etc., and aromatic amino groups such as N,N-diphenylamino group, etc. The tertiary amino group is preferably a dialkylamino group. The description of the dialkylamino group is as above.

[0220] The amino group which may have a substituent is preferably a tertiary amino group, more preferably a dialkylamino group, and even more preferably a dimethylamino group.

[0221] Alkyloxy group which may have a substituent ​The description of the alkyloxy group is as above. The number of carbon atoms in the alkyloxy group is preferably from 1 to 10, more preferably from 1 to 8, still more preferably from 1 to 6, still more preferably from 1 to 4, still more preferably from 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 from 1 to 3, more preferably 1 or 2. The one or more substituents can each independently be selected from the substituent group α. The one or more substituents can each independently preferably be 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, and 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.

[0222] 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.

[0223] Group represented by formula (V) In formula (V), R 100 represents a divalent group represented by the formula: -[(Y 1 ) a -Z 1 ) b -(Y 1 ) c -.

[0224] Y 1 each independently represents a methylene group which may have a substituent or a phenylene group which may have a substituent.

[0225] Hereinafter, the methylene group which may have a substituent and the phenylene group which may have a substituent will be described.

[0226] [A methylene group which may have a substituent] The methylene group (-CH2-) may be unsubstituted or may have one or more substituents. The number of substituents is 1 or 2. Each of the one or more substituents can be independently selected from the substituent group α. Each of the one or more substituents is 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, and even 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.

[0227] [A phenylene group which may have a substituent] 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. Each of the one or more substituents can be independently selected from the substituent group α. Each of the one or more substituents is 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, and even 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.

[0228] Formula: -[(Y 1 ) a -Z 1 b -(Y 1 ) c - with a plurality of Y 1 ​When it appears (that is, when b is an integer of 1 or more, c is an integer of 1 or more, or b is 0 and c is an integer of 2 or more), a plurality of Y 1 may be the same group or different groups.

[0229] From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Y 1 is preferably all methylene groups. When all of Y 1 are methylene groups, R 100 is a divalent group represented by the formula: -[(CH2) a -Z 1 b -(CH2) c -.

[0230] In formula (V), Z 1 each independently represents an ether group or an imino group which may have a substituent.

[0231] Hereinafter, the ether group and the imino group which may have a substituent will be described.

[0232] [Ether group] The ether group is a divalent group represented by -O-.

[0233] [Imino group which may have a substituent] 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 each independently preferably 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 selected 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, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms and an alkyloxy group having 1 to 3 carbon atoms.

[0234] ​ Formula: -[(Y 1 ) a -Z 1 ) b -(Y 1 ) c - When a plurality of Z 1 appear (that is, when b is 2 or more), the plurality of Z 1 may be the same group or different groups.

[0235] From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, Z 1 are all preferably an ether group or an imino group, and more preferably an ether group.

[0236] Z 1 In the embodiment where all are ether groups, Y 1 are all preferably methylene groups. When all of Y 1 are methylene groups, R 100 is a divalent group represented by the formula: -[(CH2) a -O] b -(CH2) c -.

[0237] Z 1 In the embodiment where all are imino groups, Y 1 are all preferably methylene groups. When all of Y 1 are methylene groups, R 100 is a divalent group represented by the formula: -[(CH2) a -NH] b -(CH2) c -.

[0238] a represents an integer of 1 or more. a is, for example, an integer of 1 or more and 6 or less. From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of 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.

[0239] b represents an integer of 0 or more. b is, for example, an integer of 0 or more and 5 or less. From the viewpoint of more effectively realizing 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.

[0240] c represents an integer of 1 or more. c is, for example, an integer of 1 or more and 6 or less. From the viewpoint of more effectively realizing 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.

[0241] From the viewpoint of more effectively realizing 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.

[0242] In the embodiment where both a and c are 2, from the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Y 1 is preferably all methylene groups. Y 1 When all are methylene groups, R 100 is a divalent group represented by the formula: -[(CH2)2-Z 1 b -(CH2)2-.

[0243] Y 1 is a methylene group, and in the embodiment where both a and c are 2, from the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, Z 1 is preferably all ether groups or imino groups, and more preferably ether groups. Z 1 When all are ether groups, R 100 is a divalent group represented by the formula: -[(CH2)2-O] b -(CH2)2-. When all Z 1 are imino groups, R 100 is a divalent group represented by the formula: -[(CH2)2-NH]​b It is a divalent group represented by -(CH2)2-.

[0244] Y 1 are all methylene groups, and Z 1 are all ether groups. In the embodiment where both a and c are 2, from the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, b is preferably 1 or 2, and 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-.

[0245] Y 1 are all methylene groups, and Z 1 are all imino groups. In the embodiment where both a and c are 2, from the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, b is preferably 1 or 2, and 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-.

[0246] From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, R 100 is the formula: -[(CH2)2-O] b -(CH2)2-, or the formula: -[(CH2)2-NH] bIt is preferably a divalent group represented by -(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-, and even more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-.

[0247] R 100 When it is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, the group represented by the formula (V) is a morpholino group.

[0248] 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 even more preferably a dimethylamino group.

[0249] 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, even more preferably an alkyloxy group having 1 to 3 carbon atoms, and most preferably a methyloxy group.

[0250] In one embodiment, L 1 and L 3 are each independently a group represented by the formula (V). The group represented by the formula (V) is preferably a morpholino group.

[0251] In the formula (IV), L 2 is the formula: -[(Y 2 ) d -Z 2 e -(Y 2 ) f ​represents a divalent group represented by -.

[0252] Hereinafter, the divalent group represented by the formula: -[(Y 2 ) d -Z 2 e -(Y 2 ) f - will be described.

[0253] 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 . The description of Y 1 applies to Y 2 as well, unless otherwise specified.

[0254] In the formula: -[(Y 2 ) d -Z 2 e -(Y 2 ) f The plurality of Y 2 appearing in - may be the same group or different groups.

[0255] From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, it is preferable that all of Y 2 are methylene groups. When all of Y 2 are methylene groups, L 2 is a divalent group represented by the formula: -[(CH2) d -Z 2 e -(CH2) f -.

[0256] 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 . The description of Z 1 ​​​The description regarding Z 2 also applies, unless otherwise specified.

[0257] Formula: -[(Y 2 ) d -Z 2 e -(Y 2 ) f - When a plurality of Z 2 appear (that is, when e is 2 or more), the plurality of Z 2 may be the same group or different groups.

[0258] From the perspective of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, all of Z 2 are preferably all ether groups or imino groups, and more preferably ether groups.

[0259] Z 2 In the embodiment where all are ether groups, from the perspective of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, all of Y 2 are preferably all methylene groups. When all of Y 2 are methylene groups, L 2 is a divalent group represented by the formula: -[(CH2) d -O] e -(CH2) f -.

[0260] Z 2 In the embodiment where all are imino groups, from the perspective of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, all of Y 2 are preferably all methylene groups. When all of Y 2 are methylene groups, L 2 is a divalent group represented by the formula: -[(CH2) d -NH] e -(CH2) f -.

[0261] ​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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] In the 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, Y 2 is preferably all methylene groups. Y 2 When all are methylene groups, L 2 is a divalent group represented by the formula: -[(CH2)2-Z 2 e -(CH2)2-.

[0266] 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, Z 2 ​All are preferably an ether group or an imino group, more preferably an ether group. Z 2 When all of them are ether groups, L 2 is a divalent group represented by the formula: -[(CH2)2 - O] e -(CH2)2-. Z 2 When all of them are imino groups, L 2 is a divalent group represented by the formula: -[(CH2)2 - NH] e -(CH2)2-.

[0267] Y 2 When all of them are methylene groups and Z 2 When all of them are ether groups and d and f are both 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-.

[0268] Y 2 When all of them are methylene groups and Z 2 When all of them are imino groups and d and f are both 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-.

[0269] L 1 and L 3In an embodiment where each is 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 realizing a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, L 2 is 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- is 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- is more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2- is still more preferably a divalent group.

[0270] L 1 and L 3 In an embodiment where each is independently an alkyloxy group which may have a substituent (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), from the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of the copper salt used, L 2 is 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- is preferably a divalent group represented by the formula: -[(CH2)2-O] e -(CH2)2- is more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, or a divalent group represented by the formula: -(CH2)2-O-(CH2)2-O-(CH2)2- is more preferably a divalent group.

[0271] L 1 and L 3In an embodiment in which each is independently 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 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- is 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-; more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2-; and even more preferably a divalent group represented by the formula: -(CH2)2-O-(CH2)2-, or the formula: -(CH2)2-NH-(CH2)2-.

[0272] Hereinafter, the polydentate ligand represented by the formula (VI) will be described.

[0273] <Polydentate ligand represented by the formula (VI)> In the formula (VI), R 200 represents an alkyl group which may have a substituent.

[0274] The description of the alkyl group is as described above. The number of carbon atoms in the alkyl 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 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. The one or more substituents can each independently be selected from the substituent group α. The one or more substituents can each independently preferably be 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, and even 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.

[0275] In formula (VI), R 300 represents a divalent group represented by the formula: -[(Y 3 ) g -Z 3 ) h -(Y 3 ) i -.

[0276] Each Y 3 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 . The description of Y 1 applies to Y 3 as well, unless otherwise specified.

[0277] In the formula: -[(Y 3 ) g -Z 3 ) h -(Y 3 ) i -, the plurality of Y 3They may be the same group or different groups.

[0278] 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. Y 3 When all of Y 300 is the divalent group represented by the formula: -[(CH2) g -Z 3 h -(CH2) i -.

[0279] Z 3 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 . The description of Z 1 applies to Z 3 as well, unless otherwise specified.

[0280] In the case where a plurality of Z 3 appear in the formula: -[(Y g ) 3 -Z h 3 -(Y i ) 3 - (that is, when h is 2 or more), the plurality of Z 3 may be the same group or different groups.

[0281] 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 imino groups, and more preferably ether groups.

[0282] Z 3 In the embodiment where all of Z 3 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, Y 3 ​​When all are methylene groups, R 300 is a divalent group represented by the formula: -[(CH2) g -O] h -(CH2) i -.

[0283] Z 3 In the embodiment where all are imino groups, from the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, Y 3 are preferably all methylene groups. When all of Y3 are methylene groups, R 300 is a divalent group represented by the formula: -[(CH2) g -NH] h -(CH2) i -.

[0284] 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 realizing a high yield of the ketone derivative (I) and reducing the amount of 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.

[0285] h represents an integer of 1 or more. h is, for example, an integer of 1 or more and 5 or less. From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of 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.

[0286] i represents an integer of 1 or more. i is, for example, an integer of 1 or more and 6 or less. From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of 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.

[0287] From the viewpoint of more effectively realizing a high yield of the ketone derivative (I) and reducing the amount of copper salt used, g and i are preferably the same integer, and more preferably both are 2.

[0288] 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. Y 3 When all of Y are methylene groups, R 300 is a divalent group represented by the formula: -[(CH2)2-Z 3 h -(CH2)2-.

[0289] Y 3 In the embodiment where all of Y are 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 imino groups, and more preferably ether groups. Z 3 When all of Z are ether groups, R 300 is a divalent group represented by the formula: -[(CH2)2-O] h -(CH2)2-. Z 3 When all of Z are imino groups, R 300 is a divalent group represented by the formula: -[(CH2)2-NH] h -(CH2)2-.

[0290] Y 3 In the embodiment where all of Y are methylene groups and all of Z are 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 3 is 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-. 300 is a divalent group represented by the formula: -(CH2)2-O-(CH2)2-O-(CH2)2-.

[0291] Y 3 In the embodiment where all of Y are methylene groups and all of Z 3 ​In the embodiment where all of them are imino 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 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-.

[0292] 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, even more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group. R 300 is a divalent group represented by the formula: -[(CH2)2-O] h -(CH2)2-, or a divalent group represented by the formula: -[(CH2)2-NH] h -(CH2)2- is preferable, and 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- is more preferable, and a divalent group represented by the formula: -(CH2)2-O-(CH2)2- is even more preferable.

[0293] Preferable specific examples of the polydentate ligand are as follows.

[0294]

Table 4

[0295] The polydentate ligands (A) to (E) are specific examples of the polydentate ligand represented by the formula (IV), and the polydentate ligand (F) is a specific example of the polydentate ligand represented by the formula (VI).

[0296] 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.

[0297] ≪Production method of ketone derivative (I)≫ The production method of the ketone derivative (I) according to the present invention comprises the following steps: (S1) A step of contacting an acid chloride derivative (II) with a Grignard reagent (III) in the presence of a copper salt and a multidentate ligand to produce a ketone derivative (I) including.

[0298] The multidentate ligand used in the present invention is a multidentate ligand that coordinates to Mg in the Grignard reagent (III) and contains two or more donor atoms selected from oxygen atoms and nitrogen atoms.

[0299] By contacting the acid chloride derivative (II) with the Grignard reagent (III) in the presence of a copper salt and a multidentate ligand, it is possible to reduce the amount of the copper salt used while achieving a high yield of the ketone derivative (I). It is considered that the multidentate ligand suppresses the reactivity of the Grignard reagent (III), thereby suppressing the formation of an alcohol (for example, R 1 -C(-OH)(-R 2 )(-R 2 )) as a by-product, and it is possible to reduce the amount of the copper salt used while achieving a high yield of the ketone derivative (I). In addition, the organocopper reagent formed by the contact of the Grignard reagent (III) and the copper salt is also considered to be involved in achieving a high yield of the ketone derivative (I) and reducing the amount of the copper salt used.

[0300] The acid chloride derivative (II), the Grignard reagent (III), the copper salt, and the multidentate ligand may each be a commercially available product or may be produced according to a conventional method.

[0301] The acid chloride derivative (II) can be produced, for example, by bringing a carboxylic acid derivative (II') into contact with a chlorinating agent.

[0302] The method for producing the ketone derivative (I) according to the present invention includes the following steps: (S0) A step of producing an acid chloride derivative (II) by bringing a carboxylic acid derivative (II') into contact with a chlorinating agent may further be included. Step (S0) is carried out before step (S1), and the acid chloride derivative (II) produced in step (S0) is used in step (S1).

[0303] 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 mole of the acid chloride derivative (II). As the Grignard reagent (III), either one of the Grignard reagents (IIa) or (IIb) may be used, or both of the Grignard reagents (IIa) and (IIb) may 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). The "amount of the Grignard reagent (III) used" means the amount of the one kind of Grignard reagent used when one kind of Grignard reagent is used, and means the total amount of the two or more kinds of Grignard reagents used when two or more kinds of Grignard reagents are used.

[0304] From the perspective of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of copper salt used, the amount of copper salt used is preferably 0.005 to 2 moles, more preferably 0.01 to 1 mole, even more preferably 0.02 to 0.5 mole, and even 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 may be used alone, or two or more kinds of copper salts may be used in combination. The "amount of copper salt used" means the amount of the one kind of copper salt used when one kind of copper salt is used, and means the total amount of the two or more kinds of copper salts used when two or more kinds of copper salts are used.

[0305] From the perspective of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of 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.

[0306] From the perspective of more effectively achieving a high yield of the ketone derivative (I) and reducing the amount of the multidentate ligand used, the amount of the multidentate ligand used is preferably 0.05 to 3 moles, more preferably 0.5 to 2 moles, even more preferably 0.8 to 1.5 moles, and even more preferably 0.9 to 1.2 moles, per 1 mole of the Grignard reagent (III). As the multidentate ligand, one kind of multidentate ligand may be used alone, or two or more kinds of multidentate ligands may be used in combination. The "amount of multidentate ligand used" means the amount of the one kind of multidentate ligand used when one kind of multidentate ligand is used, and means the total amount of the two or more kinds of multidentate ligands used when two or more kinds of multidentate ligands are used.

[0307] 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 selected from the multidentate ligands (A) to (E), more preferably selected from the multidentate ligands (A) to (D), even more preferably selected from the multidentate ligands (A) and (C), and most preferably the multidentate ligand (A).

[0308] When the acid chloride derivative (II) and the Grignard reagent (III) are contacted in the presence of the copper salt and the multidentate ligand, the temperature is preferably -50 to 50°C, more preferably -30 to 30°C, and even more preferably -20 to 20°C. When the temperature is within the above range, the yield of the ketone derivative (I) tends to be higher.

[0309] When the acid chloride derivative (II) and the Grignard reagent (III) are contacted in the presence of the copper salt and the multidentate ligand, the time is preferably 0.5 to 24 hours, more preferably 1 to 17 hours, and even more preferably 1 to 8 hours.

[0310] The contact between the acid chloride derivative (II) and the Grignard reagent (III) in the presence of the copper salt and the multidentate ligand can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0311] The contact of the acid chloride derivative (II) with the Grignard reagent (III) in the presence of a copper salt and a polydentate ligand is preferably carried out in a solvent. In the presence of a copper salt and a polydentate ligand, the acid chloride derivative (II) and the Grignard reagent (III) can be brought into contact with each other in the presence of a copper salt and a polydentate ligand by mixing them in a solvent. As the solvent, it is preferable to use an organic solvent. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane and toluene.

[0312] 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 per 1 g of the acid chloride derivative (II).

[0313] As long as the contact of the acid chloride derivative (II) with the Grignard reagent (III) is carried out in the presence of a copper salt and a polydentate ligand, the addition order of the acid chloride derivative (II), the Grignard reagent (III), the copper salt and the polydentate ligand is not particularly limited.

[0314] In the first embodiment, step (S1) is the following steps: (T1) A step of mixing the acid chloride derivative (II) and the copper salt to prepare a first mixture; (T2) A step of mixing the Grignard reagent (III) and the polydentate ligand to prepare a second mixture; and (T3) A step of mixing the first mixture and the second mixture to produce the ketone derivative (I) It includes. 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 more effectively achieved. According to the first embodiment, a reduction in the amount of the copper salt used can be more effectively achieved than in the second embodiment described later.

[0315] <Step (T1)> When mixing the acid chloride derivative (II) and the copper salt, the copper salt may be added to the acid chloride derivative (II) and mixed, or the acid chloride derivative (II) may be added to the copper salt and mixed.

[0316] The temperature when mixing the acid chloride derivative (II) and the copper salt is preferably -30 to 0 °C, more preferably -25 to -5 °C, and even more preferably -20 to -10 °C.

[0317] The time for mixing the acid chloride derivative (II) and 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.

[0318] The mixing of the acid chloride derivative (II) and the copper salt can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0319] The mixing of the acid chloride derivative (II) and the copper salt is preferably carried out in a solvent. As the solvent, it is preferable to use an organic solvent. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0320] 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 per 1 g of the acid chloride derivative (II).

[0321] The above conditions regarding the mixing of the acid chloride derivative (II) and the copper salt can be appropriately combined.

[0322] <Step (T2)> When mixing the Grignard reagent (III) and the polydentate ligand, the polydentate ligand may be added to the Grignard reagent (III) for mixing, or the Grignard reagent (III) may be added to the polydentate ligand for mixing.

[0323] The temperature when 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.

[0324] 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.

[0325] The mixing of the Grignard reagent (III) and the polydentate ligand can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0326] The mixing of Grignard reagent (III) and the multidentate ligand is preferably carried out in a solvent. As the solvent, an organic solvent is preferably used. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane and toluene.

[0327] The amount of the solvent used is preferably 1 to 50 mL, more preferably 2 to 30 mL, and even more preferably 5 to 20 mL per 1 g of Grignard reagent (III).

[0328] The above conditions regarding the mixing of Grignard reagent (III) and the multidentate ligand can be appropriately combined.

[0329] <Step (T3)> When mixing the first mixture and the second mixture, the second mixture may be added to the first mixture for mixing, or the first mixture may be added to the second mixture for mixing.

[0330] When adding one of the first mixture and the second mixture to the other, the addition can be carried out dropwise. From the viewpoint of effectively (preferably completely) carrying out the conversion from Grignard reagent (III) to the organocopper reagent, it is preferable to add the second mixture dropwise to the first mixture.

[0331] The temperature when mixing the first mixture and the second mixture is preferably -50 to 50 °C, more preferably -30 to 30 °C, and even more preferably -20 to 20 °C.

[0332] 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 even more preferably 1 to 8 hours.

[0333] The mixing of the first mixture and the second mixture can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0334] When mixing the first mixture and the second mixture, a solvent contained in the first mixture and a solvent other than the solvent contained in the second mixture (hereinafter referred to as "additional solvent") may be added. As the additional solvent, it is preferable to use an organic solvent. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are the same as above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane and toluene.

[0335] In the second embodiment, step (S1) is the following steps: (U1) A step of mixing a copper salt, a Grignard reagent (III) and a polydentate ligand to prepare a third mixture; and (U2) A step of mixing the third mixture and an acid chloride derivative (II) to produce a ketone derivative (I) is included. 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 more effectively realized.

[0336] <Step (U1)> When mixing a copper salt, a Grignard reagent (III) and a polydentate ligand, after adding the Grignard reagent (III) to the copper salt, the polydentate ligand may be added and mixed, or after adding the polydentate ligand to the copper salt, the Grignard reagent (III) may be added and mixed.

[0337] The addition of the Grignard reagent (III) and the polydentate ligand can be carried out dropwise. From the viewpoint of effectively (preferably completely) carrying out the conversion from the Grignard reagent (III) to the organocopper reagent, it is preferable to add the polydentate ligand dropwise after adding the Grignard reagent (III) dropwise to the copper salt.

[0338] The temperature at the time of 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.

[0339] 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.

[0340] The mixing of the copper salt, the Grignard reagent (III), and the polydentate ligand can be carried out, for example, under an inert atmosphere (for example, under an argon atmosphere or a nitrogen atmosphere).

[0341] The mixing of the copper salt, the Grignard reagent (III), and the polydentate ligand is preferably carried out in a solvent. As the solvent, it is preferable to use an organic solvent. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are as described above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane, and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, and toluene.

[0342] 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 per 1 g of the polydentate ligand.

[0343] When mixing a copper salt, a Grignard reagent (III), and a multidentate ligand in an organic solvent, the Grignard reagent (III) may be added to the organic solvent containing the copper salt, followed by adding the multidentate ligand and mixing, or the multidentate ligand may be added to the organic solvent containing the copper salt, followed by adding the Grignard reagent (III) and mixing.

[0344] The above conditions regarding the mixing of the copper salt, the Grignard reagent (III), and the multidentate ligand can be appropriately combined.

[0345] <Step (U2)> When mixing the third mixture and the acid chloride derivative (II), the acid chloride derivative (II) may be added to the third mixture and mixed, or the third mixture may be added to the acid chloride derivative (II) and mixed.

[0346] When adding one of the third mixture and the acid chloride derivative (II) to the other, the addition can be carried out by dropping.

[0347] The temperature when mixing the third mixture and the acid chloride derivative (II) is preferably -50 to 50 °C, more preferably -30 to 30 °C, and even more preferably -20 to 0 °C.

[0348] The mixing time of the third mixture and the acid chloride derivative (II) is preferably 0.5 to 24 hours, more preferably 1 to 17 hours, and even more preferably 1 to 5 hours.

[0349] The mixing of the third mixture and the acid chloride derivative (II) can be carried out, for example, under an inert atmosphere (e.g., under an argon atmosphere or a nitrogen atmosphere).

[0350] When mixing the third mixture and the acid chloride derivative (II), a solvent other than the solvent contained in the third mixture (hereinafter referred to as "additional solvent") may be added. As the additional solvent, it is preferable to use an organic solvent. One kind of organic solvent may be used alone, or a mixed solvent of two or more kinds of organic solvents may be used. Specific examples of the organic solvent are the same as above. The organic solvent is preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, dichloromethane, toluene, xylene, hexane and heptane, and more preferably selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane and toluene.

[0351] The above conditions regarding the contact of the acid chloride derivative (II) and the Grignard reagent (III) in the presence of a copper salt and a polydentate ligand can be appropriately combined.

[0352] The obtained ketone derivative (I) can be isolated by the following method.

[0353] First, a quenching solution (for example, water, aqueous HCl solution, etc.) is added to the reaction solution to stop the reaction. The reaction solution to which the quenching solution has been added is stirred and separated into an aqueous layer and an organic layer. After extracting the organic layer, an organic solvent is added to the aqueous layer and separated 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. The total organic layer is washed with a washing solution (for example, water, aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, etc.) and then dried using sodium sulfate or the like to obtain a residue containing the ketone derivative (I).

[0354] Specific examples of the organic solvent added to the aqueous layer are as described above. One kind of organic solvent may be used, or two or more kinds of organic solvents may be used in combination. The organic solvent is preferably selected from ethyl acetate, toluene, t-butyl methyl ether, dichloromethane and chloroform.

[0355] The ketone derivative (I) can be purified according to conventional methods such as silica gel column chromatography.

[0356] The structure of the ketone derivative (I) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

Examples

[0357] <Example 1> Compound 3a was produced from Compound 1a and Compound 2a according to the following reaction formula. Compound 1a is 3,3-dimethylbutanoyl chloride, and Compound 2a is PhMgBr (where Ph represents a phenyl group).

[0358]

Chemical formula

[0359] The oven-dried Schlenk tube was heated three times for 5 minutes at 3-minute intervals using a hot air blower under vacuum, and argon was backfilled three 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.

[0360] To another Schlenk tube containing 0.5 mL of THF, at 0 °C, after adding compound 2a (1 M THF solution, 1 equivalent, 0.5 mmol, 0.0906 g, 0.5 mL), bis(2-dimethylaminoethyl) ether (1 equivalent, 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 suspension of CuCl and compound 1a prepared above at -15 °C, and the reaction was continued for 2 hours. The completion of the reaction was confirmed by TLC. After adding water (5 mL) to quench the reaction, it was extracted 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 purified compound 3a as a colorless liquid (0.0633 g, yield 72%).

[0361] The analysis results of the obtained compound 3a are shown below. 1 H NMR (500 MHz, CDCl3) δ 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). 13 C NMR (126 MHz, CDCl3) δ 200.3, 138.4, 132.6, 128.3, 128.1, 49.9, 31.2, 29.9.

[0362] <Comparative Example 1> Compound 3a was produced from compound 1a and compound 2a according to the following reaction formula. Note that Comparative Example 1 is different from Example 1 in that no copper salt was used.

[0363]

Chemical formula

[0364] The Schlenk tube dried in an oven was heated three times for 5 minutes at 3 - minute intervals using a hot - air blower under vacuum, and argon was back - filled three times each time. After returning to room temperature and 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.

[0365] To another oven - dried Schlenk tube containing 0.5 mL of THF, at 0 °C, compound 2a (1 M THF solution, 1 equivalent, 0.5 mmol, 0.0906 g, 0.5 mL) was slowly added dropwise, then bis(2 - dimethylaminoethyl) ether (1 equivalent, 0.5 mmol, 0.0801 g) was slowly 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 continued for 4 hours. The completion of the reaction was confirmed by TLC. After adding water (5 mL) to quench the reaction, it was extracted 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 purified compound 3a as a colorless liquid (0.0228 g, yield 26%).

[0366] The analysis results of the obtained compound 3a are shown below. 1 H NMR(500MHz,CDCl3)δ 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). 13 C NMR(126MHz,CDCl3)δ 200.3,138.4,132.6,128.3,128.1,49.9,31.2,29.9.

[0367] <Example 2> According to the following reaction formula, compound 3b was produced from compound 1b and compound 2b. Compound 1b is benzoyl chloride, and compound 2b is EtMgBr (where Et represents an ethyl group).

[0368]

Chem.

[0369] The Schlenk tube dried in an oven was heated three times for 5 minutes at 3 - minute intervals using a hot - air blower under vacuum, and argon was backfilled three times each time. After returning to room temperature, CuCl (20 mol% (= 0.2 eq), 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 eq, 0.5 mmol, 0.070 g) was slowly added.

[0370] To another Schlenk tube containing 0.5 mL of THF, at 0 °C, compound 2b (1 M THF solution, 1 eq, 0.5 mmol, 0.066 g, 0.5 mL) was added, then bis(2 - dimethylaminoethyl)ether (1 eq, 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 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), it was extracted 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 / 25) to obtain purified compound 3b as a colorless liquid (0.0569 g, yield 85%).

[0371] The analysis results of the obtained compound 3b are shown below. 1 H NMR (301 MHz, CDCl3) δ 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). 1313C NMR (76 MHz, CDCl3) δ 200.7, 136.8, 132.8, 128.4, 127.8, 31.6, 8.1.

[0372] <Comparative Example 2> Compound 3b was produced from Compound 1b and Compound 2b according to the following reaction formula. Note that Comparative Example 2 differs from Example 2 in that bis(2-dimethylaminoethyl) ether was not used.

[0373]

Chemical formula

[0374] The oven-dried Schlenk tube was heated three times for 5 minutes at 3-minute intervals using a hot air blower under vacuum, 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. To the resulting reaction mixture, Compound 1b (1 equivalent, 0.5 mmol, 0.070 g) was slowly added, 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), it was extracted 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 purified Compound 3b as a colorless liquid (0.0164 g, yield 23%).

[0375] The analysis results of the obtained Compound 3b are shown below. 1 1H NMR (300 MHz, CDCl3) δ 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). 13 13C NMR (76 MHz, CDCl3) δ 200.78, 136.88, 132.81, 128.49, 127.91, 31.71, 8.17.

[0376] <Example 3> Compound 3b was produced from Compound 1b and Compound 2b according to the following reaction formula. Example 3 is different from Example 2 in that the amount of copper salt used was increased to 1 equivalent.

[0377]

Chemical formula

[0378] The oven-dried Schlenk tube was heated three times for 5 minutes at 3-minute intervals using a hot air blower under vacuum, 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. 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 obtained 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), it was extracted 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 purified Compound 3b as a colorless liquid (0.0498 g, yield 74%).

[0379] The analysis results of the obtained Compound 3 are shown below. 11H NMR (300 MHz, CDCl3) δ 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). 13 13C NMR (76 MHz, CDCl3) δ 200.78, 136.88, 132.81, 128.49, 127.91, 31.71, 8.17.

[0380] <Reference Example 1> Compound 3c was produced from Compound 1b and Compound 2a according to the following reaction formula.

[0381] [Chemical formula]

[0382] The oven-dried Schlenk tube was heated three times for 5 minutes at 3-minute intervals using a hot air blower under vacuum, 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. To the resulting reaction mixture, Compound 1b (1 equivalent, 0.5 mmol, 0.070 g) was slowly added, and the mixture was further stirred for 1.5 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), the mixture was extracted 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 purified Compound 3c as a white solid (0.0795 g, yield 87%).

[0383] The analysis results of the obtained Compound 3c are shown below. 11H NMR (500 MHz, CDCl3) δ 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). 13 13C NMR (126 MHz, CDCl3) δ 196.62, 137.44, 132.31, 129.92, 128.15.

[0384] <Reference Example 2> Compound 3d was produced from Compound 1c and Compound 2a according to the following reaction formula. Compound 1c is 2-cyclopentylacetyl chloride.

[0385]

Chemical Formula

[0386] The oven-dried Schlenk tube was heated three times at 5-minute intervals for 5 minutes each using a hot air blower under vacuum, 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. To the resulting reaction mixture, Compound 1c (1 equivalent, 0.5 mmol, 0.0733 g) was slowly added, and the mixture was further stirred for 2 hours. The completion of the reaction was confirmed by TLC. After quenching the reaction by adding water (5 mL), the mixture was extracted 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 purified Compound 3d as a colorless liquid (0.0789 g, yield 84%).

[0387] The analysis results of the obtained Compound 3d are shown below. 11H NMR (500 MHz, CDCl3) δ 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). 13 13C NMR (126 MHz, CDCl3) δ 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): 【Chemical Formula 1】 [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.] The method comprising the following steps: The method comprising the following steps: (S1) In the presence of a copper salt and a polydentate ligand, An acid chloride derivative (II) represented by the following formula (II): 【Chemical 2】 [wherein, R １ is as defined above.] And, A Grignard reagent (IIIa) represented by the following formula (IIIa): 【Chemical Formula 3】 [wherein, R ２ is as defined above, and X represents a halogen atom.] And, A Grignard reagent (IIIb) represented by the following formula (IIIb): 【Chemical Formula 4】 [wherein, R ２ and X are as defined above.] A Grignard reagent (III) selected from the group consisting of: Contacting to produce the ketone derivative (I), The polydentate ligand is a polydentate ligand that coordinates to Mg in the Grignard reagent (III) and contains two or more donor atoms selected from oxygen atoms and nitrogen atoms. The method.

2. The polydentate ligand is The following formula (IV): [Wherein, 【Chemical Formula 5】 (Wherein, 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 the following formula (V): 【Chemical Formula 6】 a represents an integer of 1 or more, R １００ represents a divalent group represented by the formula: -[(Y １ ) ａ -Z １ - ｂ -(Y １ ) ｃ -, and 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 b represents an integer of 0 or more, c represents an integer of 1 or more.) Represents a group represented by, d represents an integer of 1 or more, L ２ represents a divalent group represented by the formula: -[((Y ２ )) ｄ -Z ２ ｅ -(Y ２ )) ｆ -.​ 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 e represents an integer of 1 or more, f represents an integer of 1 or more.] Is a polydentate ligand represented by, or The following formula (VI): [Wherein, [Chemical Formula 7] g represents an integer of 1 or more, R ２００ represents an alkyl group which may have a substituent, R ３００ represents a divalent group represented by the formula: -[(Y ３ ) ｇ -Z ３ - ｈ -(Y ３ ) ｉ -, and 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, h represents an integer of 1 or more, i represents an integer of 1 or more.] Is a polydentate ligand represented by. The method according to claim 1.

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

4. 【Table 1】 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 per 1 mole of the acid 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 per 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 per 1 mole of the Grignard reagent (III).

9. The step (S1) is the following step: (T1) A step of mixing the acid chloride derivative (II) and the copper salt to prepare a first mixture; ​ Step (T2): preparing a second mixture by mixing the Grignard reagent (III) and the multidentate ligand; and Step (T3): mixing the first mixture and the second mixture to produce the ketone derivative (I). The method according to any one of claims 1 to 4, comprising these steps. **Claim 10** The method according to claim 9, wherein in step (T3), the second mixture is added dropwise to the first mixture. **Claim 11** The step (S1) is the following step: Step (U1): preparing a third mixture by mixing the copper salt, the Grignard reagent (III), and the multidentate ligand; and Step (U2): mixing the third mixture and the acid chloride derivative (II) to produce the ketone derivative (I). The method according to any one of claims 1 to 4, comprising these steps. **Claim 12** The method further comprises the following step: Step (S0): contacting a carboxylic acid derivative (II') represented by the following formula (II') with a chlorinating agent to produce the acid chloride derivative (II). 【Chemical 8】 [wherein, R １ is as defined above.] The method according to any one of claims 1 to 4, further comprising this step. **Claim 13** The method according to claim 12, wherein in step (S0), the carboxylic acid derivative (II') and the chlorinating agent are contacted in the presence of a catalytic amount of N,N-dimethylformamide. **Claim 14** The method according to claim 12, wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride.

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