Method for producing ketone derivatives

Abstract

One objective of the present invention is to provide a novel method for producing a ketone derivative. Provided is a method for producing a ketone derivative (I) represented by formula (I), the method comprising a step for forming a ketone derivative (I) by mixing: a thioester derivative (II) represented by formula (II); a Grignard reagent (III) represented by formula (III); and a copper salt.

Description

[Technical Field]

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

[0002] SGLT2 inhibitors are useful as antidiabetic drugs. "SGLT2" refers to sodium-glucose cotransporter-2. Examples of SGLT2 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-thiol), etc. are known.

[0003] As a method for producing an SGLT2 inhibitor, deprotection of the protecting group of a 1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor to synthesize canagliflozin has been proposed (see Patent Document 1). The 1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor is also called a C-arylhydroxyglycoxide derivative, and has attracted attention as an intermediate for producing SGLT-2 inhibitors (Patent Documents 1-2 and Non-Patent Documents 1-3).

[0004] Various methods for producing C-arylhydroxyglycoxide derivatives have been proposed, including a method in which an aryl group is added to a D-gluconolactone derivative by reacting with an aryllithium at an ultralow temperature of −78°C (Non-Patent Documents 1 and 3), a method in which an aryl group is added to a D-gluconolactone derivative by reacting with a turbo-Grignard reagent such as ArMgBr·LiCl (Ar represents an aryl group) at a low temperature of −20 to −10°C (Non-Patent Document 2), and a method in which an aryl group is added to a D-gluconolactone derivative by using a magnesium ate complex obtained from lithium tri-n-butylmagnesate (nBuMgLi) at a temperature of approximately −15°C (Patent Document 2). It has also been reported that coupling occurs when a thioester derivative is reacted with an organozinc reagent in the presence of a nickel catalyst, resulting in the production of a ketone derivative (Non-Patent Documents 4 and 5).

[0005] Furthermore, Remdesivir, represented by the following formula (VI'), is a compound that can be used as an antiviral drug. Remdesivir exhibits antiviral activity against single-stranded RNA viruses such as respiratory syncytial virus and coronavirus.

[0006] [ka]

[0007] Patent Document 3 discloses a method for producing remdesivir and its intermediates. Patent Document 3 describes that a hydroxynucleoside represented by the following formula (V') can be obtained by reacting a lactone represented by the following formula (I') with a bromopyrazole represented by the following formula (Ar'') at -78°C in the presence of chlorotrimethylsilane (TMSCl) and n-butyllithium. This hydroxynucleoside can be used as an intermediate for synthesizing remdesivir.

[0008] [ka] [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2010 / 043682 publication [Patent Document 2] WO2015 / 012110 publication [Patent Document 3] WO2012 / 012776 publication [Non-patent literature]

[0010] [Non-Patent Document 1] J.Med.Chem.2008,51,1145-1149 [Non-patent document 2] Org.Lett.2014,16,4090-4093 [Non-patent document 3] J.Org.Chem.1989,54, 610-612 [Non-patent document 4] Tetrahedron Letters 2002,43, 1039-1042 [Non-Patent Document 5] Chem.Eur.J.2018,24,8774-8778 Summary of the Invention [Problem to be solved by the invention]

[0011] All of the methods previously used to produce C-arylhydroxyglycoxide derivatives, remdesivir, or intermediates thereof require the use of expensive reagents under harsh low-temperature conditions, resulting in extremely high equipment and running costs, making it difficult to mass-produce the final drug substance at low cost. Therefore, there is a need for a method for producing ketone derivatives that enables the industrial production of C-arylhydroxyglycoxide derivatives, remdesivir, or intermediates thereof at low cost and efficiently.

[0012] An object of the present invention is to provide a novel method for producing a ketone derivative. [Means for solving the problem]

[0013] The present invention provides the following inventions. [1] Formula (I): [ka] [In the formula, W 1 and W 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. A method for producing a ketone derivative (I) represented by the following formula: The following formula (II): [ka] [In the formula, W 1 is as defined above, and W 3 represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group. a thioester derivative (II) represented by the formula: The following formula (IIIa): [ka] [In the formula, W 2 has the same meaning as defined above, and X represents a halogen atom. Grignard reagent (IIIa) represented by the formula: The following formula (IIIb): [ka] [In the formula, W 2 and X have the same meanings as defined above.] Grignard reagent (IIIb) represented by a Grignard reagent (III) selected from Copper salts, to form the ketone derivative (I). The method comprising: [2] The method according to [1], wherein in the step, the Grignard reagent (III) and the copper salt are mixed to form an organocopper reagent, and then the thioester derivative (II) is mixed therewith to bring the organocopper reagent and the thioester derivative (II) into contact with each other. [3] The method according to [1] or [2], wherein the amount of the copper salt used is 0.1 moles or more and 1 mole or less per mole of the Grignard reagent (III). [4] The method according to any one of [1] to [3], wherein in the step, the thioester derivative (II), the Grignard reagent (III), and the copper salt are mixed at a temperature in the range of 20°C or higher and 60°C or lower. [5]W 2 However, the carbon atoms on both sides of the carbon atom having a bond in the aryl group do not have a substituent, and the remaining carbon atoms are aryl groups which may have a substituent; or the carbon atoms or heteroatoms on both sides of the carbon atom having a bond in the heteroaryl group do not have a substituent, and the remaining carbon atoms or heteroatoms are heteroaryl groups which may have a substituent; In the step, the thioester derivative (II), the Grignard reagent (III), the copper salt, and a compound of the following formula (IV): [ka] [In the formula, W 4 represents a phenyl group having a substituent at at least one ortho-position and optionally having a substituent at the meta- and / or para-position; X 1represents a halogen atom.] and a Grignard reagent (IV) represented by the formula: [6] The method according to [5], wherein the amount of the Grignard reagent (IV) used is 0.01 mol or more and 1 mol or less per 1 mol of the Grignard reagent (III). [7] The method according to [5] or [6], wherein in the step, the Grignard reagent (III) and the copper salt are mixed, and then the Grignard reagent (IV) is mixed to form an organocopper reagent, and then the thioester derivative (II) is mixed therewith, and the organocopper reagent and the thioester derivative (II) are brought into contact with each other. [Effects of the Invention]

[0014] According to the present invention, a novel method for producing a ketone derivative is provided. The production method of the present invention enables inexpensive and efficient industrial production of a ketone derivative, and can significantly reduce equipment costs, running costs, etc. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows the molecular structure of [Ph2Cu][Mg2Br3(thf)6] using a 50% thermal ellipsoid. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention will be described below.

[0017] <Terminology> The following describes terms used in this specification. The following descriptions apply throughout this specification unless otherwise specified.

[0018] halogen atoms The halogen atom is selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0019] Alkyl group The linear alkyl group has usually 1 to 20 carbon atoms, and preferably 1 to 10. The linear alkyl group has usually 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The branched alkyl group has usually 3 to 20 carbon atoms, and preferably 3 to 10. The branched alkyl group has usually 3 to 8, 3 to 6, 3 to 5, or 3 to 4 carbon atoms.

[0020] Alkenyl group The number of carbon atoms in the linear alkenyl group is usually 1 to 20, and preferably 1 to 10. The number of carbon atoms in the linear alkenyl group is, for example, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. The number of carbon atoms in the branched alkenyl group is usually 3 to 20, and preferably 3 to 10. The number of carbon atoms in the branched alkenyl group is, for example, 3 to 8, 3 to 6, 3 to 5, or 3 to 4.

[0021] cycloalkyl group The cycloalkyl group usually has 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms.

[0022] Heterocycloalkyl Groups The heterocycloalkyl group contains, for example, one or two heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. The heterocycloalkyl group is, for example, a 4- to 7-membered heterocycloalkyl group. The heterocycloalkyl group preferably contains an oxygen atom as a heteroatom. Examples of the heterocycloalkyl group include a tetrahydrofuranyl group and a tetrahydropyranyl group. The heterocycloalkyl group is preferably a tetrahydrofuranyl group.

[0023] aryl group The aryl group is, for example, a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring group having 4 to 14 carbon atoms, preferably 6 to 14. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group is preferably a phenyl group.

[0024] Heteroaryl Groups The heteroaryl group contains, for example, one, two, or three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen atoms. The heteroaryl group is, for example, a monocyclic or bicyclic 4- to 10-membered, preferably 5- to 10-membered, aromatic heterocyclic group. The heteroaryl group is preferably a thienyl group, a benzothiophenyl group, a furyl group, a pyrrolyl group, an imidazolyl group, or a pyridyl group, and more preferably a thienyl group or a benzothiophenyl group.

[0025] Haloalkyl, haloaryl and haloheteroaryl groups The haloalkyl group, haloaryl group, and haloheteroaryl group are alkyl groups, aryl groups, and heteroaryl groups, respectively, having one or more halogen atoms, and the alkyl groups, aryl groups, and heteroaryl groups are as described above. The number of halogen atoms in the haloalkyl group, haloaryl group, or haloheteroaryl group is usually 1 to 3, preferably 1 to 2, and more preferably 1.

[0026] Alkylene, arylene and heteroarylene groups An alkylene group, an arylene group, and a heteroarylene group are divalent functional groups formed by removing one hydrogen atom from an alkyl group, an aryl group, and a heteroaryl group, respectively, and the alkyl group, the aryl group, and the heteroaryl group are as described above.

[0027] Haloalkylene, haloarylene, and haloheteroarylene groups A haloalkylene group, a haloarylene group, and a haloheteroarylene group are divalent functional groups formed by removing one hydrogen atom from a haloalkyl group, a haloaryl group, and a haloheteroaryl group, respectively. The haloalkyl group, the haloaryl group, and the haloheteroaryl group are as described above.

[0028] Arylalkyl group The arylalkyl group is an alkyl group having one or more aryl groups, and the explanations regarding the alkyl group and aryl group are as above. The number of aryl groups in the arylalkyl group is usually 1 to 3, preferably 1 or 2, and more preferably 1.

[0029] arylalkenyl group The arylalkenyl group is an alkenyl group having one or more aryl groups, and the explanations regarding alkenyl groups and aryl groups are as described above. The number of aryl groups in the arylalkenyl group is usually 1 to 3, preferably 1 or 2, and more preferably 1.

[0030] Alkylcarbonyl and arylcarbonyl groups The alkylcarbonyl group and the arylcarbonyl group are groups represented by the formula: -CO-alkyl group and the formula: -CO-aryl group, respectively, and the alkyl group and the aryl group are as described above.

[0031] Alkyloxy groups, haloalkyloxy groups, heterocycloalkyloxy groups, and arylalkyloxy groups The alkyloxy group, haloalkyloxy group, heterocycloalkyloxy group, and arylalkyloxy group are groups represented by the formula: -O-alkyl group, the formula: -O-haloalkyl group, the formula: -O-heterocycloalkyl group, and the formula: -O-arylalkyl group, respectively, and the alkyl group, haloalkyl group, heterocycloalkyl group, and arylalkyl group are as described above.

[0032] Alkylthio groups, haloalkylthio groups, heterocycloalkylthio groups, and arylalkylthio groups The alkylthio group, haloalkylthio group, heterocycloalkylthio group, and arylalkylthio group are groups represented by the formula: -S-alkyl group, the formula: -S-haloalkyl group, the formula: -S-heterocycloalkyl group, and the formula: -S-arylalkyl group, respectively, and the alkyl group, haloalkyl group, heterocycloalkyl group, and arylalkyl group are as described above.

[0033] Alkyloxycarbonyl group The alkyloxycarbonyl group is a group represented by the formula: -CO-O-alkyl, and the alkyl group is as described above. The number of carbon atoms in the alkyloxycarbonyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, and even more preferably 1 to 4.

[0034] Monoalkylamino group A monoalkylamino group has the formula: -NH(-Q 1 )[where, Q 1 represents an alkyl group.], and the explanation regarding the alkyl group is as above. Q 1 The alkyl group represented by the formula (I) preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, even more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms.

[0035] Dialkylamino group Dialkylamino groups have the formula: -N(-Q 2 )(-Q 3 )[where, Q 2 and Q 3 Each of Q independently represents an alkyl group. ], and the alkyl group is as described above. 2 or Q 3 The alkyl group represented by the formula (I) preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, even more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms.

[0036] Alicyclic amino group The alicyclic amino group is, for example, a 5- or 6-membered alicyclic amino group, and 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, and a piperidin-1-yl group. The alicyclic amino group may contain, in addition to the nitrogen atom having the bond of the alicyclic amino group, a heteroatom (for example, one heteroatom) independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. The alicyclic amino group is preferably a morpholino group.

[0037] Aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group and alicyclic aminocarbonyl group The aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group, and alicyclic aminocarbonyl group are groups represented by the formula: -CO-amino group, -CO-monoalkylamino group, -CO-dialkylamino group, and -CO-alicyclic amino group, respectively, and the explanations for the monoalkylamino group, dialkylamino group, and alicyclic amino group are as described above.

[0038] <Ketone Derivatives (I)> The ketone derivative (I) is a compound represented by the following formula (I). [ka]

[0039] In formula (I), W 1 and W 2 are each independently (1) an alkyl group which may have a substituent; (2) an alkenyl group which may have a substituent, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted heterocycloalkyl group, (5) an optionally substituted aryl group, (6) an optionally substituted heteroaryl group, (7) an arylalkyl group which may have a substituent, or (8) An arylalkenyl group which may have a substituent Represents.

[0040] The functional groups (1) to (8) will be explained below.

[0041] an alkyl group which may have a substituent The alkyl group is as described above. The alkyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0042] an optionally substituted alkenyl group The alkenyl group has been described above. The alkenyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0043] Optionally substituted cycloalkyl group The cycloalkyl group is as described above. The cycloalkyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0044] Optionally substituted heterocycloalkyl group The heterocycloalkyl group is as described above. The heterocycloalkyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0045] an optionally substituted aryl group; The aryl group has been described above. The aryl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0046] In the aryl group, the carbon atom having a bond to the aryl group (W in formula (I) 1 -CO- or W 2 The carbon atoms located on both sides of the carbon atom bonded to —CO— and the carbon atom bonded to Mg in formula (IIIa) or (IIIb) preferably have no substituents. The remaining carbon atoms may have substituents.

[0047] Optionally substituted heteroaryl group The heteroaryl group is as described above. The heteroaryl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0048] In the heteroaryl group, the carbon atom having the bond of the heteroaryl group (W in formula (I) 1 -CO- or W 2 The carbon atoms or hetero atoms located on both sides of the carbon atom bonded to —CO— and the carbon atom bonded to Mg in formula (IIIa) or (IIIb) preferably have no substituents. The remaining carbon atoms or hetero atoms may have substituents.

[0049] Optionally substituted arylalkyl group The arylalkyl group is as described above. The arylalkyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0050] an optionally substituted arylalkenyl group; The arylalkenyl group has been described above. The arylalkenyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0051] Substituent group α Substituent group α is composed of the following substituents. (α-1) halogen atom (α-2) nitrile group (α-3) nitro group (α-4) amino group (α-5) alkyl group (α-6) haloalkyl group (α-7) monoalkylamino group (α-8) dialkylamino group (α-9) Alicyclic amino group (α-10) alkyloxycarbonyl group (α-11) aminocarbonyl group (α-12) monoalkylaminocarbonyl group (α-13) Dialkylaminocarbonyl group (α-14) Alicyclic aminocarbonyl group (α-15) A hydroxy group which may be protected by a protecting group (α-16) A thio group which may be protected by a protecting group

[0052] Substituent group β The substituent group β is composed of the following substituents. (β-1) Substituent represented by formula (i) (β-2) Substituent represented by formula (ii)

[0053] The substituent groups α and β will be described below.

[0054] In (α-5) and (α-6), 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 to 2. In (α-6), the number of halogen atoms in the alkyl group is preferably 1 to 3, more preferably 1 to 2, and even more preferably 1.

[0055] a hydroxy group which may be protected by a protecting group The hydroxy-protecting group is preferably one that can protect the hydroxy group during the target reaction and can be cleaved from the hydroxy group after the target reaction is completed. Examples of the hydroxy-protecting group include alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, and aryl-type protecting groups. These protecting groups may have one or more halogen atoms.

[0056] Examples of alkylcarbonyl-type protecting groups include alkylcarbonyl groups having 1 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, and even 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, and even more preferably 1 to 4 carbon atoms, and an alkyloxycarbonyl group having 2 to 11 carbon atoms, preferably 2 to 9 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably 2 to 5 carbon atoms. Examples of alkylcarbonyl groups having 1 to 10 carbon atoms, which may have one or more substituents, include an acetyl group, a propanoyl group, a butanoyl group, an isopropanoyl group, and a pivaloyl group. The alkylcarbonyl-type protecting group is preferably an alkylcarbonyl group having 1 to 5 carbon atoms, more preferably an acetyl group or a pivaloyl group, and even more preferably an acetyl group.

[0057] Examples of arylcarbonyl-type protecting groups include arylcarbonyl groups 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. Examples of arylcarbonyl groups having 6 to 10 carbon atoms which may have one or more substituents include benzoyl, 4-nitrobenzoyl, 4-methyloxybenzoyl, 4-methylbenzoyl, 4-tert-butylbenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-phenylbenzoyl, and 4-methyloxycarbonylbenzoyl groups.

[0058] Examples of arylalkyl-type protecting groups include arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting group. Examples of arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents include benzyl, 1-phenylethyl, diphenylmethyl, 1,1-diphenylethyl, naphthylmethyl, and trityl. The arylalkyl-type protecting group is preferably a benzyl group.

[0059] Examples of alkyl-type protecting groups include alkyl groups having 1 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl-type protecting group. The 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, an ethyl group, or a tert-butyl group, and even more preferably a methyl group.

[0060] Examples of the arylalkyloxyalkyl protecting group include arylalkyloxyalkyl groups such as an arylalkyloxymethyl group having 7 to 11 carbon atoms which may have one or more substituents, an arylalkyloxyethyl group having 7 to 11 carbon atoms which may have one or more substituents, and an arylalkyloxypropyl group having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl protecting group. Examples of the arylalkyloxyalkyl protecting group include 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.

[0061] Examples of the alkyloxyalkyl-type protecting group include alkyloxyalkyl groups such as an alkyloxymethyl group having 1 to 10 carbon atoms which may have one or more substituents, an alkyloxyethyl group having 1 to 10 carbon atoms which may have one or more substituents, and an alkyloxypropyl group having 1 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The alkyloxyalkyl-type protecting group is preferably an alkyloxymethyl group having 1 to 10 carbon atoms which may have one or more substituents, more preferably an alkyloxymethyl group having 1 to 5 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.

[0062] 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 10 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 substituent are the same as those of the alkylcarbonyl-type protecting group. 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.

[0063] Examples of oxycarbonyl-type protecting groups include alkyloxycarbonyl groups having 1 to 10 carbon atoms, which may have one or more substituents, alkenyloxycarbonyl groups having 2 to 10 carbon atoms, which may have one or more substituents, and arylalkyloxycarbonyl groups having 7 to 11 carbon atoms, which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The oxycarbonyl-type protecting group is preferably an alkyloxycarbonyl group having 1 to 5 carbon atoms, an alkenyloxycarbonyl group having 2 to 5 carbon atoms, or a benzyloxycarbonyl group, more preferably a methyloxymethyl group, an allyloxycarbonyl group, or a benzyloxycarbonyl group.

[0064] Examples of the acetal-type protecting group include a tetrahydrofuranyl group and a tetrahydropyranyl group.

[0065] The aryl-type protecting group includes, for example, an aryl group such as a phenyl group.

[0066] The hydroxy group protected with a protecting group is preferably a group represented by the formula: -OR. R 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 group represented by the formula: -OR preferably has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms. R is preferably an alkyl group, a heterocycloalkyl group, an alkylcarbonyl group, or an arylalkyl group, and more preferably an ethyl group, a tetrahydrofuranyl group, an acetyl group, or a benzyl group.

[0067] Optionally protected thiol group The thiol group-protecting group is preferably one that can protect the thiol group during the target reaction and can be detached from the thiol group after the target reaction is completed. Examples of the thiol group-protecting group include alkylcarbonyl-type protecting groups, arylcarbonyl-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups, acetal-type protecting groups, and aryl-type protecting groups. These protecting groups may have one or more halogen atoms. The explanation of these protecting groups is as above.

[0068] The thiol group protected with a protecting group is preferably a group represented by the formula: -SR, where R is as described above.

[0069] A substituent represented by formula (i) [ka]

[0070] In the above formula (i), R 11 , R 12 and R 13 each independently represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, or a hydroxy group which may be protected by a protecting group. The hydroxy group which may be protected by a protecting group is preferably a group represented by the above formula: -OR. a is 0 or more and 3 or less.

[0071] A substituent represented by formula (ii) [ka]

[0072] In the above formula (ii), V 10represents 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 alkylene group or haloalkylene group preferably has 1 to 10 carbon atoms, and more preferably has 1 to 8 carbon atoms. The arylene group, haloarylene group, heteroarylene group, or haloheteroarylene group preferably has 4 to 14 carbon atoms, and more preferably has 6 to 14 carbon atoms. V 10 is preferably an alkylene group, more preferably a methylene group or an ethylene group.

[0073] In the above formula (ii), b represents 0 or 1. Preferably, b is 1.

[0074] In the above 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. 10 is preferably a heteroarylene group, more preferably a 5-membered heteroarylene group containing a sulfur atom as a heteroatom.

[0075] In the above formula (ii), c represents 0 or 1. Preferably, c is 1.

[0076] In the above 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.

[0077] X 10The alkyl group, aryl group, or heteroaryl group represented by the formula (I) may have one or more substituents, and 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, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group, more preferably selected from a halogen atom, an alkyloxy group, and a heterocycloalkyloxy group having 1 to 3 carbon atoms, and even more preferably selected from a fluorine atom, an ethyloxy group, and a tetrahydrofuranyloxy group.

[0078] 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 containing an oxygen atom as a heteroatom, or an unsubstituted heteroaryl group, and more preferably a phenyl group having a fluorine atom, an ethyloxy group or a tetrahydrofuranyloxy group, or an unsubstituted benzothiophenyl group.

[0079] W 1 is preferably represented by the following formula (iii):

[0080] [ka]

[0081] In the above formula (iii), R 14 , R 15 and R 16 R each independently represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, an alkylcarbonyl group, an arylcarbonyl group, or an arylalkyl group. 14 and R 16 are preferably the same substituents, and R 15 is R 14 and R16 It is preferable that R is a different type of substituent from 14 and R 16 R is preferably an alkylcarbonyl group or an arylalkyl group, more preferably an acetyl group or a benzyl group, and more preferably a benzyl group. 15 is preferably an alkylcarbonyl group or an arylalkyl group, more preferably an acetyl group or a benzyl group, and even more preferably an acetyl group.

[0082] In the above formula (iii), d is 1 or more and 5 or less. d is preferably 2 or 3.

[0083] W 2 is preferably represented by the following formula (iv): [ka]

[0084] In the above 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 alkylene group preferably has 1 to 10 carbon atoms, and more preferably has 1 to 8 carbon atoms. The arylene group or heteroarylene group preferably has 4 to 14 carbon atoms, and more preferably has 6 to 14 carbon atoms.

[0085] Y 10 The alkylene group, arylene group, or heteroarylene group represented by the formula (I) may have one or more substituents, and the one or more substituents can be each independently 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, 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.

[0086] 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.

[0087] Y 10 is W 1 an arylene group in which the carbon atoms on both sides of the carbon atom bonded to —CO— have no substituents and the remaining carbon atoms have optionally substituted carbon atoms, or W 1 Preferably, the carbon atoms or heteroatoms located on both sides of the carbon atom bonded to —CO— have no substituents, and the remaining carbon atoms or heteroatoms are heteroarylene groups which may have substituents. 10 is W 1 It is more preferable that the phenylene group has no substituent at the ortho position relative to the carbon atom bonded to —CO—, and may have a substituent at the meta and / or para position.

[0088] In the above formula (iv), V 10 , W 10 , X 10 , b and c have the same meanings as in formula (ii).

[0089] Or W 2 is preferably represented by the following formula (vi). [ka]

[0090] In the above formula (vi), R 41 and R 42R each independently represent a hydrogen atom or an amino-protecting group. The amino-protecting group may be any of carbamate, acyl, amide, sulfonamide, phthaloyl, and other protecting groups. Examples of carbamate-based protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and allyloxycarbonyl. Examples of acyl-based protecting groups include acetyl, pivaloyl, and benzoyl. Examples of amide-based protecting groups include trifluoroacetyl. Examples of sulfonamide-based protecting groups include p-toluenesulfonyl and 2-nitrobenzenesulfonyl. The amino-protecting group is preferably an acyl- or amide-based protecting group. More preferably, the amino-protecting group is a pivaloyl or 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. 2 When the compound has the structure of formula (vi), it can be suitably used as an intermediate for remdesivir.

[0091] Examples of the ketone derivative (I) according to one embodiment include W 1 and W 2 and each independently represent an aryl group which may have a substituent, and specific examples thereof include the following compounds. [ka]

[0092] W 1 and W 2 Other specific examples of compounds in which each independently represents an aryl group which may have a substituent include the following compounds: t "Bu" represents a tert-butyl group, and "Ph" represents a phenyl group (the same applies throughout this specification).

[0093] [Table 1]

[0094] Among the compounds I-1 to I-17, the compounds I-1 to I-9, I-12 and I-13 are preferred.

[0095] An example of the ketone derivative (I) according to another embodiment is a ketone derivative (Ia) represented by the following formula (Ia). [ka]

[0096] Ar represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group, preferably an optionally substituted aryl group.

[0097] R 1 and R 2 each independently represents a hydroxy-protecting group or a hydrogen atom, R 3 and R 4 each independently represents a hydroxy-protecting group or a hydrogen atom, R 5 preferably represents a hydroxy protecting group, and R 1 and R 2 each independently represents a hydroxy-protecting group, R 3 and R 4 each independently represents a hydroxy-protecting group or a hydrogen atom, R 5 More preferably, represents a hydroxy protecting group.

[0098] R 1 and R 2Although R may be a hydrogen atom, it is preferably a hydroxy-protecting group from the viewpoint of efficiently forming the 6-membered ring compound of formula (IVa) described later. 1 and R 2 may be the same type of hydroxy-protecting group or different types of hydroxy-protecting groups, but from the viewpoint of efficient introduction and removal of the hydroxy-protecting group, they are preferably the same type of hydroxy-protecting group.

[0099] R 3 and R 4 Although R may be a hydrogen atom, it is preferably a hydroxy-protecting group from the viewpoint of efficiently forming the 6-membered ring compound of formula (IVa) described later. 3 and R 4 R may be the same type of hydroxy-protecting group or different types of hydroxy-protecting groups, but from the viewpoint of efficient introduction and removal of the hydroxy-protecting group, they are preferably the same type of hydroxy-protecting group. 3 and R 4 is R 1 and R 2 or R 1 and R 2 However, from the viewpoint of efficient introduction and removal of the hydroxyl group-protecting group, R 1 and R 2 It is preferable that the hydroxy-protecting group is the same type as that of the hydroxy-protecting group.

[0100] R 5 is R 1 and R 2 It is preferable that R is a hydroxy-protecting group of a different type from R. 5 When the hydroxy-protecting group represented by the formula (IVa) is removed, a hydroxy group is generated, which reacts with a carbonyl group in the same molecule to form a ring represented by the formula (IVa) described below. 1 and R 2 While retaining the hydroxy group protecting group represented by R 5 R 5It is preferable to select the type of hydroxy-protecting group represented by the following formula:

[0101] In one embodiment, R 5 is an acetyl group or a pivaloyl group, and R 1 and hydroxy-protecting groups represented by R 2 The hydroxy-protecting groups represented by the following formula (I) are each independently a methyl group, a benzyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.

[0102] In another embodiment, R 5 is a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, and R 1 and hydroxy-protecting groups represented by R 2 The hydroxy-protecting groups represented by the following formula (I) are each independently a methyl group, a benzyl group, an acetyl group, or a pivaloyl group.

[0103] R 5 is R 1 , R 2 , R 3 and R 4 It is preferable that the hydroxy protecting group is different from R 1 , R 2 , R 3 and R 4 is a benzyl group, R 5 is preferably a hydroxy protecting group other than a benzyl group (e.g., an acetyl group). 5 R 1 , R 2 , R 3 and R 4 By using a hydroxy protecting group different from -OR 1 , -OR 2 , -OR 3 and-OR 4 While maintaining -OR 5 can be eliminated, and the six-membered ring of formula (IVa) described below can be efficiently formed.

[0104] In one embodiment, R 5 is an acetyl group or a pivaloyl group, and R 1 , R 2 , R 3 and R 4 The hydroxy-protecting groups represented by the following formula (I) are each independently a methyl group, a benzyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.

[0105] In another embodiment, R 5 is a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, and R 1 , R 2 , R 3 and R 4 The hydroxy-protecting groups represented by the following formula (I) are each independently a methyl group, a benzyl group, an acetyl group, or a pivaloyl group.

[0106] The ketone derivative (Ia) can be, for example, R 1 ~R 5 are compounds in which each independently represents a hydroxy-protecting group, and Ar represents an aryl group which may have a substituent. Examples of such compounds include the following compounds. Note that "Ac" represents an acetyl group, and "Bn" represents a benzyl group (the same applies throughout this specification). [ka]

[0107] In the above compound, the phenyl group corresponding to Ar 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0108] From the viewpoint of using the ketone derivative (Ia) as a raw material for producing an SGLT-2 inhibitor or a derivative thereof, Ar is preferably the same as a functional group possessed by an SGLT-2 inhibitor or a functional group obtained by derivatizing a functional group possessed by an SGLT-2 inhibitor.

[0109] Here, canagliflozin (1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), empagliflozin (also known as "(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- SGLT-2 inhibitors, including dapagliflozin (also referred to as "(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-thiol"), have a functional group represented by the following formula (A):

[0110] Therefore, Ar is preferably a functional group represented by the following formula (A). [ka]

[0111] In formula (A), n represents an integer of 0 to 4. n is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. When n is 2 or more, n R a may be the same or different.

[0112] In formula (A), n R a can be independently selected from the substituent group α. aare 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.

[0113] In formula (A), Ar' is a group represented by the following formula (v). [ka]

[0114] In the above formula (v), W 10 , X 10 and c have the same meanings as in formula (ii).

[0115] In formula (A), Ar' is preferably a group represented by the following formula (Ar'-1), (Ar'-2) or (Ar'-3). [ka]

[0116] In formulae (Ar'-1), (Ar'-2) and (Ar'-3), p is an integer of 0 to 5. p is preferably an integer of 0 to 3, more preferably an integer of 0 to 2, and even more preferably 0 or 1.

[0117] In formulae (Ar'-1), (Ar'-2) and (Ar'-3), p R b can be each independently selected from Substituent Group α, an aryl group optionally having one or more substituents selected from Substituent Group α, and a heteroaryl group optionally having one or more substituents selected from Substituent Group α. bare preferably each independently selected from substituent group α and an aryl group optionally having one or more substituents selected from substituent group α. The one or more substituents selected from 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, and a heterocycloalkyloxy group having 1 to 3 carbon atoms, and even more preferably selected from a fluorine atom, an ethyloxy group, and a tetrahydrofuranyloxy group.

[0118] If p is 2 or more, p R b may be the same or different.

[0119] 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.

[0120] In formula (Ar'-2), p is preferably 0.

[0121] In formula (Ar'-3), p is preferably 1, and R bis 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.

[0122] When n is 1, Ar is preferably a group represented by the following formula (B). [ka]

[0123] In formula (B), R a and Ar' have the same meaning as in formula (A).

[0124] Ar is preferably a group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4): "Et" represents an ethyl group. [ka]

[0125] The ketone derivative (Ia) can be, for example, R 1 ~R 5 are compounds in which each independently represents a hydroxy-protecting group, and Ar represents a group represented by formula (Ar-1). Examples of such compounds include the following compounds. Note that "Ac" represents an acetyl group, and "Bn" represents a benzyl group. [ka]

[0126] An example of the ketone derivative (I) according to another embodiment is a ketone derivative (Ib) represented by the following formula (Ib). [ka]

[0127] In formula (Ib), R 1 , R 2 , R 3 , R 5 and Ar have the same meanings as above.

[0128] <Thioester derivatives (II)> The thioester derivative (II) is a compound represented by the following formula (II). [ka]

[0129] In formula (II), W 1 is the same as above, and W 3 teeth, an alkyl group which may have a substituent, an alkenyl group which may have a substituent; an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group; an optionally substituted heteroaryl group, an arylalkyl group which may have a substituent, or an optionally substituted arylalkenyl group; The explanations regarding the optionally substituted alkyl group, the optionally substituted alkenyl group, the optionally substituted cycloalkyl group, the optionally substituted heterocycloalkyl group, the optionally substituted aryl group, the optionally substituted heteroaryl group, the optionally substituted arylalkyl group, and the optionally substituted arylalkenyl group are as described above.

[0130] W 3 is W 1 and / or W 2 It may be the same as or different from.

[0131] The thioester derivative (II) may be a commercially available product or may be prepared according to a conventional method.

[0132] In one embodiment, W 1 is an alkyl group which may have a substituent. 1 is preferably an alkyl group which may have a hydroxy group which may be protected by a protecting group, and more preferably an alkyl group which has a hydroxy group which may be protected by a protecting group. An example of the thioester derivative (II) according to this embodiment is a thioester derivative (IIa) represented by the following formula (IIa): [ka]

[0133] In formula (IIa), R 1 ~R 5 and W 3 is synonymous with the above.

[0134] In one embodiment, W 3 is an alkyl group which may have a substituent. 3 is more preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 16 carbon atoms which may have a substituent, and even more preferably an alkyl group having 1 to 12 carbon atoms which may have a substituent. Examples of the thioester derivative (IIa) according to this embodiment include the following compounds. In addition, "Ac" represents an acetyl group, and "Bn" represents a benzyl group. [ka]

[0135] In the above compound, W 3 Corresponding to -C 10 H 21 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0136] In the above compound, W 3 Corresponding to -C 10 H 21 can be changed to other alkyl groups. Examples of other alkyl groups include -C 12 H 25 The other alkyl group 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 be independently selected from substituent groups α and β. One or more substituents may be selected from substituent group α, and one or more substituents may be selected from substituent group β.

[0137] An example of the thioester derivative (II) according to another embodiment is a thioester derivative (IIb) represented by the following formula (IIb). [ka]

[0138] In the above formula (IIb), R 1 , R 2 , R 3 , R 5 and W 3 is synonymous with the above.

[0139] <Method of producing thioester derivatives> The thioester derivative (II) can be obtained, for example, by the following method.

[0140] The following formula (V): [ka] and a lactone derivative (V) represented by the following formula (1): [ka] In the presence of trialkylaluminum, a thiol (1) represented by the following formula (II-i): [ka] A hydroxyl group-containing compound (II-i) represented by the following formula can be obtained.

[0141] Furthermore, by protecting the hydroxyl group of this hydroxyl group-containing compound (II-i), a compound of the following formula (II-ii): [ka] A thioester derivative (II-ii) represented by the following formula can be obtained.

[0142] In formula (V), R 1 , R 2 and R 3 has the same meaning as above. e is 1 or more and 4 or less.

[0143] As the lactone derivative (V), a commercially available product may be used, or one synthesized by a known method may be used.

[0144] In equation (1), W 3 is synonymous with the above.

[0145] The thiol (1) may be a commercially available product or may be synthesized by a known method. The thiol (1) preferably includes at least one selected from the group consisting of 1-decanethiol and 1-dodecanethiol.

[0146] In formula (II-i), R 1 , R 2 , R 3 , W3 and e have the same meanings as above.

[0147] In formula (II-ii), R 1 , R 2 , R 3 , R 5 , W 3 and e have the same meanings as above.

[0148] The amount of thiol (1) is, for example, 0.5 to 10 moles, preferably 1 to 5 moles, more preferably 1 to 2 moles, per mole of lactone derivative (V). The molar amount of thiol (1) is preferably greater than the molar amount of lactone derivative (V).

[0149] The trialkylaluminum serves as a reactant and preferably includes at least one selected from the group consisting of trimethylaluminum, triethylaluminum, and tripropylaluminum, and more preferably includes trimethylaluminum.

[0150] The amount of trialkylaluminum is, for example, 1 to 10 moles, preferably 1 to 5 moles, more preferably 1 to 3 moles, per mole of lactone derivative (V). The molar amount of trialkylaluminum is preferably greater than the molar amount of lactone derivative (V).

[0151] The amount of trialkylaluminum is, for example, 1 mole or more and 2 moles or less, preferably 1 mole or more and 1.5 moles or less, more preferably 1 mole or more and 1.1 moles or less, relative to 1 mole of thiol (1).

[0152] In the contact of lactone derivative (V) with thiol (1) in the presence of trialkylaluminum, the contact temperature is, for example, from -30°C to 80°C, preferably from -10°C to 40°C, and more preferably from -10°C to 10°C. The contact time is, for example, from 30 minutes to 120 hours, preferably from 1 hour to 100 hours, and more preferably from 30 hours to 90 hours. It is preferable that lactone derivative (V) and thiol (1) are stirred while being maintained at the above contact temperature during the contact time. This reaction is preferably carried out under an inert atmosphere such as argon.

[0153] The lactone derivative (V) and thiol (1) are preferably contacted in the presence of a first reaction solvent. When using the first reaction solvent, the lactone derivative (V) and thiol (1) are preferably contacted by the following method. First, the lactone derivative (V), thiol (1), and trialkylaluminum are mixed with the first reaction solvent to prepare a lactone derivative solution, a thiol solution, and a trialkylaluminum solution, respectively. Next, the trialkylaluminum solution is added to the thiol solution at a rate of, for example, 0.1 mL to 10 mL per minute, and the mixture is stirred for 1 minute to 1 hour. The lactone derivative solution is added to the stirred mixture at a rate of 0.1 mL to 10 mL per minute, and the mixture is stirred for 20 minutes to 3 hours.

[0154] In the lactone derivative solution, the amount of the first reaction solvent per 1 g of lactone derivative (V) is preferably 1 mL or more and 10 mL or less. In the thiol solution, the amount of the first reaction solvent per 1 g of thiol (1) is preferably 1 mL or more and 15 mL or less. The concentration of the trialkylaluminum solution is preferably 0.1 mol / L or more and 5 mol / L or less.

[0155] The first reaction solvent may be, for example, at least one selected from the group consisting of acetonitrile, propionitrile, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diglyme, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, butyl acetate, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane. The first reaction solvent may preferably be methylene chloride, toluene, hexane, or a mixture thereof, more preferably methylene chloride.

[0156] The hydroxyl group-containing compound (II-i) obtained by the reaction of the lactone derivative (V) with the thiol (1) is preferably isolated by the following method.

[0157] First, a quenching liquid such as ice-cold water is added to the reaction solution to terminate the reaction. Next, it is preferable to add a Bronsted acid to the reaction solution after the addition of the quenching liquid. This can prevent the hydroxyl-containing compound (II-i) from cyclizing and changing to the structure of the lactone derivative (V). The present inventors have found that the hydroxyl-containing compound (II-i) obtained using a lactone derivative (V) having five or fewer ring members as a substrate is more likely to change to the structure of the substrate than the hydroxyl-containing compound obtained using a lactone derivative (V) having six or more ring members as a substrate. To address this issue, we have found that adjusting the pH of the reaction solution to an acidic level can prevent the cyclization of the hydroxyl-containing compound (II-i) and increase its yield.

[0158] The amount of the Bronsted acid is, for example, 1 mole or more, preferably 3 moles or more, more preferably 5 moles or more relative to 1 mole of the lactone derivative (V). There is no particular upper limit to the amount of the Bronsted acid, but, according to one example, it is 30 moles or less.

[0159] The Bronsted acid may be, for example, at least one selected from the group consisting of hydrogen halide, sulfuric acid (H2SO4), carbonic acid, acetic acid, oxalic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid. The hydrogen halide may be, for example, hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr), or hydrogen iodide (HI). The Bronsted acid is preferably at least one selected from the group consisting of hydrogen chloride, hydrogen bromide, and sulfuric acid. An acidic solution in which a Bronsted acid is dissolved in water may also be used.

[0160] When 1N hydrochloric acid is used as the Bronsted acid, the amount thereof is preferably 10 mL or more and 30 mL or less per 1 g of the lactone derivative (V).

[0161] Next, the reaction solution to which the Bronsted acid has been added is stirred to separate into an aqueous layer and an organic layer. After the organic layer is extracted, the same type of solvent as the solvent listed as the first reaction solvent is added to the aqueous layer, and the organic layer and aqueous layer are separated again. The organic layer is extracted and combined with the previously extracted organic layer to obtain a total organic layer. The total organic layer is washed with water, brine, etc., and then dried using sodium sulfate, etc., to obtain a residue containing the product of hydroxyl group-containing compound (II-i).

[0162] The structure of the hydroxyl group-containing compound (II-i) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis.

[0163] Next, the hydroxyl group of the hydroxyl group-containing compound (II-i) thus obtained is protected to obtain a thioester derivative (II-ii). The method for protecting the hydroxyl group is not particularly limited, and known methods can be used. For example, the hydroxyl group-containing compound (II-i) is reacted with a protecting group introduction reagent in the presence of an acid or a basic reagent in an inert solvent to introduce a hydroxyl group-protecting group R 5 This reaction is preferably carried out under an inert atmosphere such as argon.

[0164] The protecting group introduction reagent is R 5 Examples of the protecting group introducing reagent include ester-type protecting group introducing agents such as acetic anhydride, pivalic anhydride, acetyl chloride, and pivaloyl chloride; aryl alkyl ether-type protecting group introducing agents such as benzyl bromide; alkyl ether-type protecting group introducing agents such as iodomethane; silyl-type protecting group introducing agents such as trimethylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilyl chloride; and oxycarbonyl-type protecting group introducing agents such as bis(tert-butyloxycarbonyloxy)oxide. Among these, ester-type protecting group introducing agents such as acetic anhydride, pivalic anhydride, acetyl chloride, and pivaloyl chloride are preferred, and acetic anhydride is more preferred.

[0165] Examples of acidic reagents include inorganic acids such as acetic acid and hydrogen bromide, and organic acids such as p-toluenesulfonic acid and phthalic acid. Examples of basic reagents include organic amines such as triethylamine, 4-dimethylaminopyridine (DMAP), diazabicycloundecene (DBU), and diethylaniline, with triethylamine, 4-dimethylaminopyridine (DMAP), or a mixture thereof being preferred.

[0166] The amount of the acidic reagent used is not particularly limited, but is, for example, 0.1 to 1000 mol, preferably 1 to 5 mol, relative to 1 mol of the lactone derivative (V).The amount of the basic reagent used is not particularly limited, but is, for example, 0.001 to 10 mol, preferably 0.01 to 2 mol, relative to 1 mol of the lactone derivative (V).

[0167] The solvent used is preferably an organic solvent, and examples thereof include polar aprotic solvents such as acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diglyme, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, and butyl acetate; nonpolar solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane, or combinations thereof, with methylene chloride, toluene, or a mixed solvent thereof being preferred.

[0168] The amount of the solvent used is not particularly limited, but is, for example, 1 to 1000 mL, preferably 1 to 100 mL, per 1 g of lactone derivative (V).

[0169] The reaction temperature is not particularly limited, but is usually -30 to 100°C, preferably -30 to 40°C, more preferably -10 to 40°C, and even more preferably 0 to 30°C.

[0170] The hydroxyl-protecting group R on the hydroxyl-containing compound (II-i) 5 The thioester derivative (II-ii) obtained by the introduction of the formula (II-ii) is preferably isolated by the following method.

[0171] First, a quenching liquid such as water is added to the reaction solution to terminate the reaction. The reaction solution to which the quenching liquid has been added is stirred to separate into an aqueous layer and an organic layer. After extracting the organic layer, a solvent of the same type as the solvent listed as the first reaction solvent is added to the aqueous layer, and the organic layer and aqueous layer are separated again. The organic layer is extracted and combined with the previously extracted organic layer to obtain a total organic layer. The total organic layer is washed with water, brine, etc., and then dried using sodium sulfate, etc., to obtain a residue containing the product thioester derivative (II-ii).

[0172] The structure of the thioester derivative (II-ii) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopic analysis.

[0173] <Grignard reagent (III)> Grignard reagent (III) is The following formula (IIIa): [ka] Grignard reagent (IIIa) represented by the formula: The following formula (IIIb): [ka] Grignard reagent (IIIb) represented by is selected from.

[0174] In formulas (IIIa) and (IIIb), W 2 has the same meaning as above, and X represents a halogen atom, which is preferably selected from a chlorine atom, a bromine atom, and an iodine atom.

[0175] As the Grignard reagent (III), one of Grignard reagent (IIIa) and Grignard reagent (IIIb) may be selected, or both may be selected. When both are selected, a mixture of both may be added to the reaction system, or both may be added separately to the reaction system.

[0176] The Grignard reagent (IIIa) may be a commercially available product or may be prepared according to a conventional method.

[0177] From the viewpoint of improving the reaction rate, the Grignard reagent (III) preferably contains a Grignard reagent (IIIb), which is also called a turbo Grignard reagent.

[0178] The Grignard reagent (IIIb) may be a commercially available product or may be prepared by a conventional method. The Grignard reagent (IIIb) may be prepared, for example, by reacting magnesium with a compound of the formula: W in the presence of a lithium salt in a reaction vessel purged with an inert gas (e.g., nitrogen, argon, etc.). 2 X [where W 2and X has the same meaning as above.] in an organic solvent.

[0179] The Grignard reagent (IIIb) can be prepared by reacting a Noschel-Hauser base represented by the formula: TMPMgX·LiY (wherein TMP represents 2,2,6,6-tetramethylpiperidine) with a compound represented by the formula: W 2 It may also be produced by reacting a compound represented by —H with the compound represented by —H. [ka]

[0180] <Copper salts> Examples of copper salts include copper(I) chloride (CuCl), copper(II) chloride (CuCl2), copper(I) bromide (CuBr), copper(II) bromide (CuBr2), copper(I) cyanide (CuCN), copper(I) 3-methylsalicylate, mesitylene copper(I) (MesCu), isopropoxy copper(I) (iPrOCu), copper(I) iodide (CuI), copper(II) iodide (CuI2), copper(I) acetate (CuOAc), copper(II) acetate (Cu(OAc)2), copper(II) sulfate (CuSO4), copper(I) oxide (Cu2O), copper(II) oxide (CuO), copper(I) pivalate (CuOPiv), copper(II) pivalate (Cu(OPiv)2), and copper salts containing sulfur (S). The valence of the copper atom contained in the copper salt is usually monovalent or divalent, but is preferably monovalent. Copper salts in which the copper atom is monovalent have excellent catalytic activity. Among copper salts in which the copper atom is monovalent, CuCl, CuI, or CuBr are particularly preferred. CuCl, CuI, and CuBr have particularly excellent catalytic activity. Examples of copper salts containing sulfur (S) include copper(I) thiophene-2-carboxylate. S has a high affinity for Cu, and in copper salts, S easily coordinates with Cu. This coordination activates Cu and increases the yield.

[0181] <Method for producing ketone derivative (I)> The method for producing the ketone derivative (I) comprises the step of mixing the thioester derivative (II), the Grignard reagent (III), and a copper salt to form the ketone derivative (I).

[0182] By mixing the thioester derivative (II), the Grignard reagent (III), and a copper salt, the ketone derivative (I) can be obtained in high yield. The inventors speculate that this is due to the formation of an anionic complex represented by the following formula (10). That is, it is believed that the oxidative addition of the carbon-sulfur bond of the thioester derivative (II) is promoted by the anionic complex (10), rather than the neutral complex. [ka]

[0183] When mixing the thioester derivative (II), the Grignard reagent (III), and the copper salt, it is preferable to mix the Grignard reagent (III) with the copper salt to form an organocopper reagent, and then mix the thioester derivative (II) to bring the organocopper reagent into contact with the thioester derivative (II), thereby obtaining the ketone derivative (I) in high yield.

[0184] The amount of copper salt used is preferably 0.1 mol or more and 1 mol or less per mol of Grignard reagent (III). By using the copper salt in this range relative to Grignard reagent (III), the formation of the complex (10) tends to proceed smoothly. The amount of copper salt used is more preferably 0.3 mol or more and 0.9 mol or less, and even more preferably 0.4 mol or more and 0.8 mol or less, relative to 1 mol of Grignard reagent (III). In one example, the amount of copper salt used is 0.5 mol or more and 0.9 mol or less, and in another example, 0.6 mol or more and 0.8 mol or less, relative to 1 mol of Grignard reagent (III).

[0185] When the Grignard reagent (III) contains the Grignard reagent (IIIb), the amount of the copper salt used is usually 0.1 mol to 1 mol, preferably 0.3 mol to 0.9 mol, more preferably 0.4 mol to 0.8 mol, relative to 1 mol of the Grignard reagent (IIIb). Alternatively, when the Grignard reagent (III) contains the Grignard reagent (IIIb), the amount of the copper salt used is, for example, 0.4 mol to 0.92 mol, for example, 0.5 mol to 0.82 mol, for example, 0.6 mol to 0.72 mol, relative to 1 mol of the Grignard reagent (IIIb).

[0186] The amount of copper salt used is usually 0.1 to 10 moles, preferably 0.5 to 5 moles, more preferably 0.6 to 3 moles, and even more preferably 1 to 3 moles, per mole of thioester derivative (II).

[0187] The amount of Grignard reagent (III) used is usually 1 to 10 moles, preferably 1 to 5 moles, more preferably 1.05 to 4 moles, and even more preferably 1.5 to 4 moles, per mole of thioester derivative (II). The amount of Grignard reagent (III) used does not need to be an excessive amount relative to the amount of thioester derivative (II) used.

[0188] When both the Grignard reagent (IIIa) and the Grignard reagent (IIIb) are selected as the Grignard reagent (III), the amount of the Grignard reagent (IIIb) is, for example, 10% by mass or more and 90% by mass or less based on the total mass of the Grignard reagent (IIIa) and the Grignard reagent (IIIb).

[0189] Examples of the solvent used when mixing the thioester derivative (II), the Grignard reagent (III), and the copper salt include tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, methylene chloride, toluene, xylene, hexane, and heptane. One solvent may be used alone, or two or more solvents may be combined and used as a mixed solvent. The solvent is preferably THF, toluene, or a mixed solvent thereof.

[0190] The amount of the solvent used is usually 1 mL or more and 100 mL or less, preferably 2 mL or more and 50 mL or less, per 1 g of the thioester derivative (II).

[0191] The temperature during mixing of the thioester derivative (II), the Grignard reagent (III), and the copper salt is typically within the range of −10° C. to 100° C. According to one embodiment of the method, the Grignard reagent (III) is used, so the ketone derivative (I) can be produced even under relatively high temperature conditions. This reduces the equipment costs associated with temperature control compared to methods requiring ultralow temperatures below −10° C. for the synthesis of the ketone derivative (I), enabling more inexpensive industrial production of the ketone derivative (I). The temperature during mixing is preferably within the range of 10° C. to 80° C., more preferably 20° C. to 60° C. Within this temperature range, the yield of the ketone derivative (I) tends to be higher.

[0192] The time for mixing the thioester derivative (II), the Grignard reagent (III) and the copper salt is usually 0.5 to 72 hours, preferably 1 to 48 hours.

[0193] When the thioester derivative (II), the Grignard reagent (III), and the copper salt are mixed, the following formula (III-I): [ka] [In the formula, W 2and X have the same meanings as above.] An organozinc compound (III-I) represented by the formula: The following formula (III-II): [ka] [In the formula, W 2 has the same meaning as above.] One or both of the organozinc compounds (III-II) represented by the formula: may be used in combination with the Grignard reagent (III) and the copper salt. The organozinc compounds (III-I) and (III-II) are used in combination with the thioester derivative (II) by attaching a group W to the thioester derivative (II). 2 It can be used as a reagent for introducing

[0194] However, when mixing the thioester derivative (II), the Grignard reagent (III), and the copper salt, it is preferable to use as little of either the organozinc compound (III-I) or the organozinc compound (III-II) as possible. The presence of the organozinc compound (III-I) or the organozinc compound (III-II) tends to decrease the yield of the ketone derivative (I). The total amount of the organozinc compound (III-I) and the organozinc compound (III-II) used is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 1% by mass or less, based on the mass of the thioester derivative (II). The lower limit is zero.

[0195] The organic zinc compound (III-I) may be, for example, an aryl zinc halide (in the formula (III-I), W 2 is an aryl group and X is a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom), alkyl zinc halides (compounds in which W 2 is an alkyl group and X is a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom).

[0196] As the organic zinc compound (III-II), for example, diaryl zinc (in the formula (III-II), W 2is an aryl group), dialkyl zinc (in formula (III-II), 2 is an alkyl group).

[0197] The organozinc compound (III-I) and the organozinc compound (III-II) may be commercially available products or may be produced according to a conventional method.

[0198] The organozinc compound (III-I) and / or the organozinc compound (III-II) may be used together with a lithium salt such as lithium chloride. The organozinc compound (III-I) may form a complex with a lithium salt. The complex of the organozinc compound (III-I) and a lithium salt can be represented by the following formula (III-Ia): [ka]

[0199] In formula (III-Ia), W 2 and X have the same meanings as above.

[0200] <Grignard reagent (IV)> W 2 is a carbon atom having a bond to an aryl group (W in formula (I) 1 -CO- or W 2 The carbon atoms on both sides of the carbon atom bonded to —CO—, the carbon atom bonded to Mg in formula (IIIa) or (IIIb) have no substituent, and the remaining carbon atoms are carbon atoms having a bond to an aryl group or heteroaryl group (W in formula (I)) which may have a substituent. 1 -CO- or W 2 In the case where the carbon atoms or hetero atoms located on both sides of the carbon atom bonded to —CO— and the carbon atom bonded to Mg in formula (IIIa) or (IIIb) have no substituents, and the remaining carbon atoms or hetero atoms are heteroaryl groups which may have a substituent, the method for producing the ketone derivative (I) comprises the step of: [ka] Grignard reagent (IV) represented by the following formula may also be used:

[0201] In the above formula (IV), W 4 represents a phenyl group having a substituent at at least one ortho-position and optionally having a substituent at the meta- and / or para-position; X 1 represents a halogen atom.

[0202] Grignard reagent (IV) can be used together with one or both of Grignard reagents (IIIa) and (IIIb). In this case, a mixture of one or both of Grignard reagents (IIIa) and (IIIb) and Grignard reagent (IV) may be added to the reaction system, or one or both of Grignard reagents (IIIa) and (IIIb) and Grignard reagent (IV) may be added separately to the reaction system.

[0203] In addition to the Grignard reagent (III) and the Grignard reagent (IV), other Grignard reagents may be used. In this case, the total amount of the Grignard reagent (III) and the Grignard reagent (IV) is preferably 80% by mass or more, and may be 100% by mass, based on the total mass of the Grignard reagent (III), the Grignard reagent (IV), and the other Grignard reagents.

[0204] When the Grignard reagent (IV) is used, the ketone derivative (I) can be formed by mixing the thioester derivative (II), the Grignard reagent (III), a copper salt, and the Grignard reagent (IV).

[0205] When mixing the thioester derivative (II), the Grignard reagent (III), the copper salt, and the Grignard reagent (IV), it is preferable to mix the Grignard reagent (III) with the copper salt, then mix the Grignard reagent (IV) to form an organocopper reagent, and then mix the thioester derivative (II) to bring the organocopper reagent into contact with the thioester derivative (II), thereby obtaining the ketone derivative (I) in high yield.

[0206] The compound represented by the following formula (III') is W 2 However, the carbon atoms on both sides of the carbon atom having a bond of the aryl group (the carbon atom bonding to Mg) have no substituents, and the remaining carbon atoms are aryl groups which may have a substituent; or the carbon atoms or heteroatoms on both sides of the carbon atom having a bond of the heteroaryl group (the carbon atom bonding to Mg) have no substituents, and the remaining carbon atoms or heteroatoms are heteroaryl groups which may have a substituent.

[0207] [ka]

[0208] In formula (III'), the carbon atoms on both sides of the carbon atom bonded to MgX, i.e., the ortho positions, have no substituents. The meta positions relative to the carbon atom bonded to MgX are R 21 and R 23 The para position to the carbon atom bonded to MgX is R 22 R 21 , R 22 and R 23 are each independently a hydrogen atom or a substituent selected from substituent groups α and β. f is 0 or 1.

[0209] The compound represented by the following formula (IV') is an example of a Grignard reagent (IV), and will be referred to as W 4 Details will be explained below.

[0210] [ka]

[0211] In formula (IV'), R 31 , R 32 , R 33 , R 34 and R 35Each independently represents a hydrogen atom or a substituent. 1 R bonded to the meta position relative to the carbon atom bonded to 31 and R 35 At least one of R is a substituent. 31 and R 35 It is preferred that both of the groups are substituents.

[0212] The substituent is, for example, an alkyl group, an arylalkyl group, a halogen group, a nitrile group, a dialkylamino group, an alkyloxy group, an arylalkyloxy group, an alkylthio group, or an arylalkylthio group. The number of carbon atoms in the alkyl group, alkyloxy group, or alkylthio group is preferably 1 to 10. The number of carbon atoms in the dialkylamino group is preferably 2 to 10. The number of carbon atoms in the arylalkyl group, arylalkyloxy group, or arylalkylthio group is preferably 5 to 14, and more preferably 7 to 14.

[0213] The substituent is preferably an alkyl group, more preferably a methyl group. 4 Preferred specific examples include a 2,4,6-trimethylphenyl group and a 2,6-dimethylphenyl group.

[0214] The method using Grignard reagent (IV) can increase the yield of ketone derivative (I). The inventors believe that the reason for this is as follows. First, Grignard reagents (IIIa) and (IIIb) are 2 The carbon atoms on both sides of the carbon atom bonded to Mg are unsubstituted aryl groups, or the carbon atoms or heteroatoms on both sides of the carbon atom bonded to Mg are unsubstituted heteroaryl groups. Grignard reagent (IV) is a compound in which W 4is a phenyl group in which at least one of the carbon atoms adjacent to the carbon atom bonded to Mg has a substituent. When such Grignard reagents (IIIa) and / or (IIIb) are used with Grignard reagent (IV), it is believed that an anionic complex represented by the following formula (11) is formed. In such complex (11), W 4 has a substituent at at least one ortho position, which causes steric hindrance and results in -SW 3 From -W 4 This inhibits the substitution reaction to -SW 3 From -W 2 As a result, the yield of the ketone derivative (I) per Grignard reagent (IIIa) and (IIIb) used is higher than when the complex (10) is used. In addition, the ortho-position substituent has an electron-donating effect, which allows the W 2 Furthermore, the reactivity of W, which is not subjected to the reaction, can be increased. 4 By introducing W into the reactant (organic copper reagent), 2 This allows reducing the amount of Grignard reagent required to generate

[0215] [ka]

[0216] In the method using Grignard reagent (IV), -SW in thioester derivative (II) 3 From -W 2 Since this can promote the substitution reaction to the above, the amounts of copper salt and Grignard reagent (III) can be relatively reduced.

[0217] The amount of copper salt used is, for example, 0.1 mol to 10 mol, preferably 0.5 mol to 5 mol, and more preferably 0.5 mol to 2 mol, relative to 1 mol of Grignard reagent (III).

[0218] The amount of copper salt used is, for example, 0.1 to 10 moles, preferably 0.5 to 5 moles, and more preferably 0.5 to 2 moles, relative to 1 mole of Grignard reagent (IV). In another example, the amount of copper salt used is 1 to 3 moles relative to 1 mole of Grignard reagent (IV).

[0219] The amount of copper salt used is, for example, 0.1 to 10 moles, more preferably 0.5 to 5 moles, and even more preferably 0.5 to 1.4 moles, relative to 1 mole of the thioester derivative (II).

[0220] The amount of Grignard reagent (III) used is, for example, 0.1 to 10 moles, preferably 0.5 to 5 moles, more preferably 0.5 to 1.4 moles, per mole of thioester derivative (II).

[0221] The amount of Grignard reagent (IV) used is, for example, 0.01 mol or more and 1 mol or less, preferably 0.01 mol or more and 0.8 mol or less, more preferably 0.1 mol or more and 0.8 mol or less, relative to 1 mol of Grignard reagent (III).

[0222] The amount of Grignard reagent (IV) used is, for example, 0.1 to 10 moles, preferably 0.1 to 5 moles, more preferably 0.1 to 1.0 mole, per mole of thioester derivative (II).

[0223] The reaction solvent, reaction conditions, etc. are the same as those in the above-mentioned method for producing the ketone derivative (I).

[0224] Hereinafter, the case where the thioester derivative (IIa) is used as the thioester derivative (II) will be described.

[0225] When the thioester derivative (IIa) is used as the thioester derivative (II), the ketone derivative (Ia) can be obtained by mixing the thioester derivative (IIa), the Grignard reagent (III), and a copper salt. The reaction scheme is as follows: [ka]

[0226] From the obtained ketone derivative (Ia), R 5 By removing the hydroxy-protecting group represented by the following formula (IVa), a compound (IVa) represented by the following formula (IVa) can be obtained.

[0227] [ka]

[0228] R 5 The hydroxy-protecting group represented by the formula (Ia) can be removed by a conventional method depending on the type of the group. For example, the ketone derivative (Ia) can be reacted with an acidic or basic reagent in an inert solvent to give R 5 Examples of the acidic reagent include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and hydrogen bromide, and organic acids such as trifluoroacetic acid, trichloroacetic acid, p-toluenesulfonic acid, formic acid, and phthalic acid. Examples of the basic reagent include fluorides such as tetra-n-butylammonium fluoride, ammonium fluoride, ammonium bifluoride, and hydrofluoric acid, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and aqueous ammonia.

[0229] The thioester derivative (IIa), Grignard reagent (III), and copper salt may be mixed to form a ketone derivative (Ia), and then the ketone derivative (Ia) separated from the reaction system may be reacted with an acidic or basic reagent to obtain compound (IVa). Alternatively, the thioester derivative (IIa), Grignard reagent (III), and copper salt may be mixed to form a ketone derivative (Ia), and then an acidic or basic reagent may be added to the reaction system without separating the ketone derivative (Ia) from the reaction system to obtain compound (IVa). In the latter case, since there is no need to separate the ketone derivative (Ia) from the reaction system, compound (IVa) can be obtained efficiently. The reaction conditions for the latter case are described below. The solvent used when mixing the thioester derivative (IIa), Grignard reagent (III), and copper salt is preferably tetrahydrofuran (THF) or the like. It is preferable to use a basic reagent, and the basic reagent is preferably sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, sodium hydroxide, ammonia, or the like. The amount of the basic reagent used is usually 0.001 to 10 mol, preferably 0.01 to 8 mol, per 1 mol of the ketone derivative (Ia). The amount of the solvent used is usually 1 to 500 mL or less, preferably 3 to 200 mL, per 1 g of the ketone derivative (Ia). The temperature when reacting the ketone derivative (Ia) with the basic reagent is usually -20 to 120°C, preferably -10 to 100°C. The time for reacting the ketone derivative (Ia) with the basic reagent is usually 0.1 to 48 hours, preferably 0.5 to 24 hours.

[0230] The thioester derivative (IIa) may be commercially available or may be prepared according to the following reaction scheme. [ka]

[0231] The thioester derivative (IIa) is represented by the following formula (VI): [ka] Compound (VI) represented by The following formula (VII): [ka] and a compound (VII) represented by the following formula (VIII): [ka] After obtaining compound (VIII) represented by The hydroxy group in compound (VIII) can be replaced by R 5 It can be obtained by protecting with a hydroxy group-protecting group represented by the following formula:

[0232] Compound (VI) and compound (VII) may be commercially available products or may be produced according to a conventional method.

[0233] Introduction of a hydroxy-protecting group into the hydroxy group in compound (VIII) can be carried out according to a conventional method depending on the type of the hydroxy-protecting group. For example, the hydroxy-protecting group can be introduced by reacting compound (VIII) with a protecting group-introducing reagent in the presence of an acid or a base reagent in an inert solvent. Examples of protecting group introduction reagents include ester-type protecting group introduction agents such as acetic anhydride, pivalic anhydride, acetyl chloride, and pivaloyl chloride; aryl alkyl ether-type protecting group introduction agents such as benzyl bromide; alkyl ether-type protecting group introduction agents such as iodomethane; silyl-type protecting group introduction agents such as trimethylsilyl chloride, N-trimethylsilylimidazole, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilyl chloride; and oxycarbonyl-type protecting groups such as bis(tert-butyloxycarbonyloxy)oxide. Preferred are ester-type protecting group introduction agents such as acetic anhydride, pivalic anhydride, acetyl chloride, and pivaloyl chloride, and more preferably acetic anhydride. Examples of acidic reagents include inorganic acids such as acetic acid and hydrogen bromide, and organic acids such as p-toluenesulfonic acid and phthalic acid. Examples of basic reagents include organic amines such as triethylamine, 4-dimethylaminopyridine (DMAP), diazabicycloundecene (DBU), and diethylaniline.

[0234] The reaction of compound (VI) with compound (VII) is preferably carried out in the presence of compound (IX) represented by the following formula (IX): Compound (IX) may be a commercially available aluminum catalyst, or may be prepared according to a conventional method.

[0235] [ka]

[0236] In formula (IX), R c and R dR each independently represents a halogen atom, an optionally substituted alkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group. c and R d are preferably each independently an alkyl group, an aryl group, or an arylalkyl group.

[0237] In formula (IX), q represents an integer of 0 to 3, and r represents an integer of 0 to 3, provided that q+r=3. In a preferred embodiment, one of q and r represents 0, and the other represents 3.

[0238] Compound (IVa) can be used as a raw material to produce compound (XI) represented by the following formula (XI), ie, a β-C-aryl glycoside derivative. [ka]

[0239] A known reduction reaction can be used to convert Compound (IVa) to Compound (XI). Examples of the reduction method include a reduction method using triethylsilane in the presence of boron trifluoride diethyl ether complex (BF3·OEt2), and a reaction method with a Lewis acid such as BF3·OEt2, boron trifluoride tetrahydrofuran (BF3·THF), or aluminum chloride in the presence of a silane compound such as triethylsilane, triisopropylsilane, or tetramethyldisiloxane.

[0240] The resulting compound (XI) can be used as it is or as a compound having the formula R 1 , R 2 , R 3 or R 4 When is a hydroxy-protecting group, it can be deprotected as desired and used as a β-C-aryl glycoside derivative. [Example]

[0241] Example 1 Compound 2 was produced from Compound 1 by carrying out the reaction shown in the following formula. Note that "Ph" represents a phenyl group. The same applies hereinafter. [ka]

[0242] To a suspension of CuI (35.8 mg, 0.188 mmol, 0.75 equiv.) in dry THF (2 mL), PhMgBr (0.85 M THF solution) (0.330 mL, 0.281 mmol, 1.1 equiv.) was added dropwise over 5 min and stirred for 10 min. At this stage, the organocopper reagent was generated. To the resulting organocopper reagent, a solution of S-decyl 4-methylbenzothioate (73.1 mg, 0.250 mmol, 1.0 equiv.) in THF (2 mL) was added dropwise over 5 min, followed by stirring at 25 °C for 1 h. After completion of the reaction, the reaction was quenched with 1 mL of 1N aqueous HCl. A fixed amount of triphenylmethane (internal standard) in ethyl acetate (3 mL) was added to the reaction mixture, followed by stirring. A sample for gas chromatography was prepared by short-pad silica gel filtration (ethyl acetate), and analyzed by gas chromatography to determine the yield.

[0243] The conditions for the gas chromatography analysis are as follows. Instrument: GC-2014 (SHIMADSU GAS CHROMATOGRAPH) Column: SH-Rtx-50 (length: 30.0 m, inner diameter: 0.25 mm, film thickness: 0.25 μm, medium polar column)

[0244] ·Analysis conditions Injection volume: 1.0 μL Column oven temperature program (total program time: 15 min)

[0245] [Table 2]

[0246] [Table 3]

[0247] The yield was determined from integral ratios using triphenylmethane (manufactured by Aldrich, 25 g) as an internal standard. The results are shown in Table 4. The yield of Compound 2 in Example 1 was 89%.

[0248] The physical properties of Compound 2 were as follows: 1 H NMR (400MHz, CDCl3, 30℃) δ 7.80-7.77(m,2H),7.73-7.71(m,2H),7.59-7.55(m,1H),7.49-7.45(m,2H),7.29-7.27(m,2H),2.44(s,3H). 13 C NMR (100MHz, CDCl3, 30℃) δ 196.6,143.4,138.2,135.1,132.3,130.5,130.1,129.1,128.4,21.8.

[0249] <Example 2> The same procedure as in Example 1 was carried out, except that CuI was changed to 0.25 equivalents. The results are shown in Table 4. The yield of compound 2 in Example 2 was 48%.

[0250] Example 3 The same procedure as in Example 1 was carried out, except that CuI was changed to 0.50 equivalents. The results are shown in Table 4. The yield of compound 2 in Example 3 was 63%.

[0251] Example 4 The same procedure as in Example 1 was carried out, except that CuI was changed to 1.0 equivalent. The results are shown in Table 4. The yield of compound 2 in Example 4 was 33%.

[0252] <Comparative Example 1> The same procedure as in Example 1 was carried out, except that CuI was not used. The results are shown in Table 4. The yield of the ketone derivative (1) in Comparative Example 1 was 0%.

[0253] [Table 4]

[0254] <Reference Example 1 (Production of Compound 1)> Compound 1 was produced by carrying out the reaction shown in the following formula. [ka]

[0255] A 20 mL suspension of p-toluic acid (1.43 g, 10.5 mmol) in methylene chloride was prepared in an 80 mL Schlenk flask. The suspension was cooled to 0 °C, and then 4-dimethylaminopyridine (122 mg, 1.00 mmol), 1-decanethiol (2.08 mL, 10.0 mmol), and N,N'-dicyclohexylcarbodiimide (2.17 g, 10.5 mmol) were added. The mixture was stirred at 0 °C for 30 minutes, then warmed to room temperature and stirred overnight. After completion of the reaction, the suspension was filtered, and the filtrate was washed with 1 M aqueous HCl, saturated aqueous sodium bicarbonate, and saturated brine (50 mL each), dried over Na2SO4, and concentrated under reduced pressure. The concentrated residue was purified by silica column chromatography (n-hexane, followed by ethyl acetate / n-hexane = 1:20) to give compound 1 (2.73 g, 93%). 1 H NMR(400MHz, CDCl3, 30℃) δ 7.86(d,J=8.1Hz,2H),7.23(d,J=8.0Hz,2H),3.05(t,J=7.3Hz,2H),2.40(s,3H),1.66(qu int, J=7.4Hz, 2H), 1.42 (quint, J=7.1Hz, 2H), 1.35-1.26 (m, 12H), 0.88 (t, J=6.8Hz, 3H). 13C NMR (100MHz, CDCl3, 30℃) δ 191.9,170.1,144.1,135.0,129.4,127.4,32.0,29.8,29.7,29.66,29.5,29.3,29.1,22.8,21.8,14.2. HRMS:[M+H] + C 18 H 29 OS calculated value 293.1934; measured value 293.1938.

[0256] <Reference Example 2 (Synthesis of Alcohol)> The reaction shown in the following formula was carried out to produce an alcohol. [ka]

[0257] A 20 mL Schlenk flask was charged with 4-methylbenzophenone (196 mg, 1.00 mmol) in THF (4.0 mL). PhMgBr (0.85 M THF solution) (1.3 mL, 1.11 mmol) was added dropwise, followed by refluxing at 80 °C for 1 h. The reaction was quenched with 1 M aqueous HCl (5 mL). Ethyl acetate (10 mL) was added, and the organic layer was washed with 1 M aqueous HCl (5 mL x 2) and saturated brine (5 mL x 1). The washed organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column chromatography (ethyl acetate / n-hexane = 1:20 to 1:10) to give the alcohol (243 mg, 89%). 1 H NMR (400MHz, CDCl3, 30℃) δ 7.31-7.23(m,10H),7.12(q,J=8.2Hz,4H),2.76(s,1H),2.33(s,3H). 13 C NMR (100MHz, CDCl3, 30℃) δ 147.2,144.2,137.0,128.7,128.0,127.99,127.3,82.0,21.1.

[0258] <Example 5> Compound 5 was produced from compound 4 by carrying out the reaction shown in the following formula. Note that "Ac" represents an acetyl group, and "Bn" represents a benzyl group. The same applies below. [ka]

[0259] To a suspension of CuI (35.8 mg, 0.188 mmol, 0.75 equiv.) in dry THF (2 mL), PhMgBr (0.85 M THF solution) (0.330 mL, 0.281 mmol, 1.1 equiv.) was added dropwise over 5 min and stirred for 10 min. At this stage, the organocopper reagent was generated. To this organocopper reagent, a THF solution (2 mL) of the thioester derivative (189 mg, 0.250 mmol, 1.0 equiv.) was added dropwise over 5 min, followed by stirring at room temperature for 20 h. After completion of the reaction, the reaction was quenched with 1 mL of 1N aqueous HCl. Ethyl acetate (10 mL) was added to the reaction mixture, which was then washed with 3 portions of 1N aqueous HCl (5 mL each) and saturated brine (5 mL each). The washed organic layer was dried over Na2SO4 and concentrated under reduced pressure. The concentrated residue was purified by silica column chromatography (ethyl acetate / n-hexane = 1:20 → 1:5) to obtain the ketone (compound 5) (71.8 mg, 44%) and the thioester (compound 4) (99.4 mg, 53%).

[0260] The physical properties of the ketone body (compound 5) were as follows: 1 H NMR (400 MHz, CDCl3, 30°C) δ 7.92(dd,J=8.3,1.1Hz,2H),7.49-7.45(m,1H),7.36-7.14(m,20H),7.05-7.0 2(m,2H),5.28(dt,J=5.4,3.5Hz,1H),4.89(d,J=4.2Hz,1H),4.67-4.41(m,7H ),4.31(d,J=10.8Hz,1H),4.21(dd,J=6.9,4.3Hz,1H),4.07(dd,J=6.9,3.5Hz ,1H),3.87(dd,J=10.2,5.4Hz,1H),3.63(dd,J=10.2,5.5Hz,1H),1.97(s,3H). 13C NMR(100MHz, CDCl3, 30℃) δ 199.0,170.1,138.5,138.0,137.9,137.2,136.2,133.2,129.1,128.9,128.6,128.5,128.4,128.36,128.3,1 28.2,128.0,127.9,127.8,127.81,127.6,127.56,82.8,80.5,79.7,75.4,74.7,73.3,73.2,72.7,68.0,21.2.

[0261] The physical properties of the thioester (compound 4) were as follows: 1 H NMR(400MHz, CDCl3, 30℃) δ 7.42-7.21(m,20H),5.17-5.14(m,1H),4.81-4.42(m,8H),4.25(d,J=4.4Hz,1H),4.01-3.95(m,2H),3.82(dd,J=10.7,4.2Hz,1H),3. 65(dd,J=10.6,5.7Hz,1H),2.84(t,J=7.4Hz,2H),1.96(s,3H),1.56(quint,J=7.4Hz,2H),1.37-1.26(m,14H),0.88(t,J=6.9Hz,3H). 13 C NMR(100MHz, CDCl3, 30℃) δ 202.0,170.1,138.6,138.2,138.1,137.2,128.7,128.6,128.5,128.46,128.43,128.3,128.2,128.1,128.0,127.9,127.8,127. 7,127.6,126.7,85.6,80.4,78.5,75.8,74.7,74.6,73.3,73.0,68.2,32.0,29.7,29.6,29.4,29.3,29.1,28.5,22.8,21.2,14.2.

[0262] Example 6 Compound 7 was produced from Compound 6 by carrying out the reaction shown in the following formula. [ka]

[0263] Preparation of 0.25 M ArMgBr LiCl THF solution LiCl (32.0 mg, 0.755 mmol, 1.01 equiv.) was dried under vacuum at 100 °C for 1 h and then added to THF (1.3 mL) to form a solution. A 2.0 M solution of iPrMgCl in THF (0.4 mL, 0.8 mmol, 1.07 equiv.) was then added while cooling to 0 °C. (Note: "iPr" stands for isopropyl group). A solution of ArI (2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (306 mg, 0.750 mmol, 1.0 equiv.) in THF (1.3 mL) was then slowly added dropwise at 0 °C and the mixture was stirred at room temperature for 1 h. TLC confirmed that ArI had been consumed and ArMgBr·LiCl had been produced, which was then used in the next reaction.

[0264] ketonization reaction To a suspension of CuI (71.4 mg, 0.375 mmol, 1.5 equiv.) in dry THF (0.5 mL), a 0.25 M solution of ArMgBr·LiCl in THF (2.25 mL, 0.563 mmol, 2.3 equiv.) was added dropwise over 5 min and stirred for 10 min. To this solution, a solution of compound 6 (189 mg, 0.250 mmol, 1.0 equiv.) in THF (1.5 mL) was added dropwise over 5 min and stirred at 40 °C for 20 h. The reaction was monitored by TLC (ethyl acetate / n-hexane = 1:5). After completion of the reaction, the mixture was quenched with 1 M aqueous HCl (1 mL). Ethyl acetate (10 mL) was added to the quenched reaction mixture, which was washed with 1 M aqueous HCl (5 mL x 3) and brine (5 mL x 1). The organic layer was dried over Na2SO4. The mixture was purified by silica column chromatography (ethyl acetate / n-hexane = 1:20 to 1:5) to give the corresponding ketone (compound 7) in a 76% yield (164 mg, yellow oil) and the thioester (compound 6) in a 19% recovery (35.2 mg, yellow oil).

[0265] The physical properties of the ketone body (compound 7) were as follows: 1H NMR(400MHz, CDCl3, 30℃) δ 7.89(d,J=1.3Hz,1H),7.76(dd,J=7.9,1.7Hz,1H),7.38-7.27(m,9H),7.24-7.11(m,11 H),7.07-7.02(m,3H),7.00-6.94(m,3H),6.54(d,J=3.6Hz,1H),5.27(q,J=4.7Hz,1H), 4.88(d,J=4.6Hz,2H),4.70-4.35(m,9H),4.21(dd,J=6.5,4.7Hz,1H),4.05-4.02(m,3H ),3.85(dd,J=10.4,5.0Hz,1H),3.62(dd,J=10.4,5.6Hz,1H),2.33(s,3H),1.96(s,3H). 13 C{ 1 H}NMR(100MHz, CDCl3, 30℃) δ 198.5,170.1,142.7,142.6,138.6,138.1,138.0,137.4,134.6,130.7,130.3,128.8,128.6,128.43,128.4,128.3,128.2,128.0,12 7.9,127.8,127.6,127.3,127.2,126.3,122.9,115.9,115.7,83.0,80.7,79.5,75.5,74.7,73.3,73.2,72.8,68.1,34.2,21.2,19.9.

[0266] Example 7 Compound 7 was produced from compound 8 by carrying out the reaction shown in the following formula. [ka]

[0267] First, a 0.25 M THF solution of ArMgBr·LiCl was prepared using a method similar to that described in Example 6. To a suspension of CuCl (27.2 mg, 0.275 mmol, 1.1 equiv.) in dry THF (1.00 mL), a 0.25 M THF solution of ArMgCl·LiCl (1.10 mL, 0.275 mmol, 1.1 equiv.) was added dropwise over 5 min and stirred for 10 min to obtain a suspension. To this suspension, a 1.0 M THF solution of RMgBr (2,6-dimethylphenylmagnesium bromide) (0.140 mmol, 0.56 equiv.) in THF (0.140 mL) was added and stirred for an additional 10 min to obtain the organocopper reagent.

[0268] A THF solution (2.00 mL) of compound 8 (196 mg, 0.250 mmol, 1.0 equiv.) was added dropwise to the organocopper reagent over 5 min and then stirred at 40 °C for 20 h. After completion of the reaction, the reaction mixture was quenched with 1 M aqueous HCl (1 mL). Ethyl acetate (10 mL) was added to the quenched reaction mixture, which was then washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1). The organic layer was then dried over Na2SO4. The dried organic layer was purified by silica column chromatography (ethyl acetate:n-hexane = 1:20 to 1:5). The yield of the ketone derivative (compound 7) was 66% (143 mg), and the yield of compound 8 was 32% (62.6 mg). Although as much as possible was separated by silica column chromatography, compound 9, which could be generated as a by-product, was not observed. Furthermore, no signal corresponding to compound 9 was observed in the NMR spectrum.

[0269] Example 8 The same procedure as in Example 7 was carried out, except that the use of RMgBr was omitted and the amount of CuCl used was changed to 0.75 equivalents. As a result, the yield of the ketone derivative (compound 7) was 44%.

[0270] Example 9 Compound 7 was produced from compound 8 by carrying out the reaction shown in the following formula. [ka]

[0271] Preparation of 0.5 M ArMgBr LiCl THF solution LiCl (42.4 mg, 1.00 mmol) was dried under vacuum at 100°C for 1 hour, and THF (0.500 mL) was added to form a solution. Then, a 2.0 M THF solution of iPrMgCl (0.500 mL, 1.00 mmol) was added while cooling at 0°C. Next, a THF (1.00 mL) solution of ArI (2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, 408 mg, 1.00 mmol) was slowly added dropwise at 0°C, followed by stirring at room temperature for 1 hour.

[0272] ketonization reaction To a suspension of CuCl (49.5 mg, 0.500 mmol, 2.0 equiv.) in dry THF (1.00 mL), a 0.5 M solution of ArMgBr·LiCl in THF (1.5 mL, 0.750 mmol, 3.0 equiv.) was added dropwise over 5 min and stirred for 10 min. To this solution, a solution of compound 8 (196 mg, 0.250 mmol, 1.0 equiv.) in THF (1.5 mL) was added dropwise over 5 min and stirred at 80 °C for 20 h. After completion of the reaction, the mixture was quenched with 1 M aqueous HCl (1 mL). After quenching, ethyl acetate (10 mL) was added to the reaction mixture, which was washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1). The organic layer was dried over Na2SO4. The mixture was purified by silica column chromatography (ethyl acetate / n-hexane = 1:20 to 1:5) to obtain the corresponding ketone (compound 7) in a 50% yield (109 mg) and the thioester (compound 8) in an 8% recovery (15.4 mg).

[0273] Example 10 Compound 7 was produced from compound 8 by carrying out the reaction shown in the following formula. [ka]

[0274] First, a 0.25 M THF solution of ArMgBr·LiCl was prepared using a method similar to that described in Example 6. To a suspension of CuCl (49.5 mg, 0.500 mmol, 2.0 equiv.) in dry THF (2.00 mL), a 0.25 M THF solution of ArMgCl·LiCl (3.00 mL, 0.750 mmol, 3.0 equiv.) was added dropwise over 5 min and stirred for 10 min. To this solution, a THF solution of compound 8 (196 mg, 0.250 mmol, 1.0 equiv.) in THF (3.00 mL) was added dropwise over 5 min and stirred at 40 °C for 20 h. After completion of the reaction, the mixture was quenched with 1 M aqueous HCl (1 mL). After quenching, ethyl acetate (10 mL) was added to the reaction mixture, which was then washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1). The organic layer was dried over Na2SO4. The dried organic layer was purified by silica column chromatography (ethyl acetate:n-hexane = 1:20 to 1:5). As a result, the yield of the ketone derivative (compound 7) was 88% (190 mg), and the yield of compound 8 was 6% (11.3 mg).

[0275] Example 11 Compound 7 was produced from compound 8 by carrying out the reaction shown in the following formula. [ka]

[0276] Preparation of 0.25M ArMgBr THF solution Mg (18.2 mg, 0.750 mmol, 2.0 equivalents) was activated by adding THF (0.500 mL) and 1,2-dibromoethane (0.05 mL). Then, a solution of ArBr (2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, 135 mg, 0.375 mmol, 1.00 equivalents) in THF (1.00 mL) was slowly added dropwise, while taking care not to generate heat, and the mixture was stirred at room temperature for 3 hours.

[0277] ketonization reaction To a suspension of CuCl (18.6 mg, 0.188 mmol, 0.75 equiv.) in dry THF (1.00 mL), a 0.25 M THF solution of ArMgBr (1.10 mL, 0.275 mmol, 1.1 equiv.) was added dropwise over 5 minutes and stirred for 10 minutes. To this solution, a THF solution of compound 8 (196 mg, 0.250 mmol, 1.0 equiv.) in THF (2.00 mL) was added dropwise over 5 minutes and then stirred at 80 °C for 20 hours. After completion of the reaction, the mixture was quenched with 1 M aqueous HCl (1 mL). After quenching, ethyl acetate (10 mL) was added to the reaction mixture, which was washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1), and the organic layer was dried over Na2SO4. The mixture was purified by silica column chromatography (ethyl acetate / n-hexane = 1:20 to 1:5) to obtain the corresponding ketone (compound 7) in a 42% yield (90.2 mg) and the thioester (compound 8) in a 51% recovery (100 mg).

[0278] Example 12 Preparation of thioester derivatives The reaction shown in the following formula was carried out to produce a thioester derivative (II-iia) from the following lactone derivative (Ia) via a hydroxyl group-containing derivative (II-ia). [ka]

[0279] A 1-decanethiol solution was prepared by adding 0.89 g (5.1 mmol) of 1-decanethiol to 20 mL of anhydrous dichloromethane. A 2 M trimethylaluminum solution was prepared by dissolving trimethylaluminum in hexane. A lactone derivative (Ia) solution was prepared by dissolving 2.09 g (5 mmol) of lactone derivative (Ia) in 10 mL of anhydrous dichloromethane.

[0280] To the 1-decanethiol solution cooled to 0°C, 2.5 mL of 2 M trimethylaluminum solution (trimethylaluminum: 5 mmol) was added dropwise over 10 minutes and stirred for 20 minutes to obtain a mixture. The lactone derivative (Ia) solution was slowly added to this mixture over 20 minutes and stirred for 2 hours to obtain a reaction mixture. 30 mL of dichloromethane was added to this reaction mixture, and then the mixture was slowly poured into a 500 mL beaker containing 20 mL of ice-cold water. While stirring, 40 mL of 1 N hydrochloric acid was slowly added to the stirred reaction mixture in the beaker, rapidly separating the reaction mixture into organic and aqueous layers. After extracting the organic layer, 30 mL of ice-cold dichloromethane was added to the aqueous layer, separating the organic and aqueous layers, and the organic layer was extracted. This procedure was repeated two more times. All organic layers were mixed to obtain the combined organic layer. The combined organic layer was washed with water and then brine, and then dried over sodium sulfate to obtain a residue.

[0281] Nuclear magnetic resonance (NMR) spectroscopic analysis confirmed that this residue contained the hydroxyl group-containing compound represented by the above formula (II-ia).

[0282] Next, 3 g (5 mmol) of this residue was dissolved in 30 mL of anhydrous dichloromethane to prepare a solution of hydroxyl-containing compound (II-ia). Under an argon atmosphere, 1.5 mL (15.9 mmol) of acetic anhydride was added to this solution of hydroxyl-containing compound (II-ia), which had been cooled to 0°C. Then, 13 mg (2 mol%) of 4-dimethylaminopyridine (DMAP) was added and stirred for 5 minutes. 2.2 mL (15 mmol) of triethylamine was added to the stirred solution, which was then stirred at room temperature for 6 hours under an argon atmosphere to obtain a reaction solution. The reaction was quenched by adding 30 mL of water, and the reaction solution was separated into an organic layer and an aqueous layer. After extracting the organic layer, 30 mL of dichloromethane was added to the aqueous layer, separating the organic layer and the aqueous layer, and the organic layer was extracted. This procedure was repeated two more times. All organic layers were mixed to obtain the combined organic layer. The combined organic layer was washed with 30 mL of water and 30 mL of brine, followed by drying over sodium sulfate, to obtain a residue. The residue was purified by silica gel column chromatography to obtain a transparent liquid thioester derivative (II-iia). A mixed solvent of ethyl acetate and hexane was used for the silica gel column chromatography. The volume ratio of the mixed solvent was ethyl acetate:hexane = 1:20 to 2:20.

[0283] The amount of thioester derivative (II-iia) was 2.67 g, and the yield from lactone derivative (I) was 84%. The NMR spectroscopic analysis results of thioester derivative (II-iia) were as follows.

[0284] 1H NMR (400MHz, CDCl3) δ=7.38-7.18(m,15H),5.31(dt,J=6.6,3.9Hz,1H),4.77(d,J=11.7Hz,1H) ,4.65-4.56(m,2H),4.53(d,J=4.4Hz,1H),4.50(d,J=5.2Hz,1H),4.40(d,J =12.1Hz,1H),4.24-4.16(m,2H),3.70(d,J=3.9Hz,2H),2.94-2.79(m,2H), 1.98(s,3H),1.61-1.51(m,2H),1.38-1.19(m,14H),0.88(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ=200.66,169.86,138.27,137.80,137.14,128.50,128.45,128.41,128.16,128.08,128.04,127.84,127.84,127.71,83.9 7,79.29,73.92,73.55,73.22,71.42,68.43,32.02,29.67,29.62,29.50,29.43,29.27,29.16,28.45,22.81,21.34,14.23. HRMS: [M+H] + C 38 H 51 O6S Calculated value 635.3406; Measured value 635.3403.

[0285] ketonization reaction The compound (9) was produced from the thioester derivative (II-iia) by the reaction shown in the following formula. [ka]

[0286] To a suspension of CuCl (18.6 mg, 0.188 mmol, 0.75 equiv.) in dry THF (3.00 mL), a 0.85 M PhMgBr THF solution (0.330 mL, 0.281 mmol, 1.1 equiv.) was added dropwise over 5 min and stirred for 10 min. To this solution, a THF solution (2.00 mL) of the thioester derivative (II-iia) (166 mg, 0.261 mmol, 1.0 equiv.) was added dropwise over 5 min, followed by stirring at 40 °C for 20 h. After completion of the reaction, the reaction was quenched with 1 M aqueous HCl (1 mL). Ethyl acetate (10 mL) was added to the quenched reaction solution, which was then washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1). The organic layer was then dried over Na2SO4. The mixture was purified by silica column chromatography (ethyl acetate / n-hexane = 1:20 to 1:5) to obtain the corresponding ketone (compound (9)) in a 43% yield (60.4 mg) and the thioester derivative (II-iia) in a 55% recovery (91.0 mg).

[0287] The physical properties of the ketone body (compound (9)) were as follows: 1 H NMR (400MHz, CDCl3, 30℃) δ 7.87(d,J=7.2Hz,2H),7.52(t,J=7.4Hz,1H),7.38-7.15(m,15H),6.99-6.97(m,2H),5.49(q,J=4.8Hz,1H),4.87(d,J =6.7Hz,1H),4.64(d,J=11.6Hz,1H),4.54-4.34(m,5H),4.20(dd,J=6.6,4.6Hz,1H),3.74-3.73(m,2H),1.96(s,3H).

[0288] Example 13 Compound 7 was produced from compound 8 by carrying out the reaction shown in the following formula. [ka]

[0289] Preparation of 0.25 M ArMgBr LiCl THF solution LiCl (21.2 mg, 0.500 mmol, 1.00 equiv.) was dried under vacuum at 100 °C for 1 hour and then added to THF (0.750 mL) to form a solution. A 2.0 M solution of iPrMgCl in THF (0.250 mL, 0.500 mmol, 1.00 equiv.) was then added while cooling to 0 °C. (Note: "iPr" stands for isopropyl group). A solution of ArI (2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (204 mg, 0.500 mmol, 1.00 equiv.) in THF (1.00 mL) was then slowly added dropwise at 0 °C, followed by stirring at room temperature for 1 hour. TLC confirmed that ArI had been consumed and ArMgBr·LiCl had been produced, which was then used in the next reaction.

[0290] ketonization reaction To a suspension of CuCl (37.1 mg, 0.375 mmol, 1.5 equiv) in dry THF (1.50 mL), a 0.25 M solution of ArMgCl·LiCl in THF (1.50 mL, 0.375 mmol, 1.5 equiv) was added dropwise over 5 min and stirred for 10 min to obtain a suspension. To this suspension, a 1.0 M solution of RMgBr (2,6-dimethylphenylmagnesium bromide) (0.188 mmol, 0.75 equiv) in THF (0.188 mL) was added and stirred for an additional 10 min to obtain the organocopper reagent.

[0291] A THF solution (1.00 mL) of compound 8 (196 mg, 0.250 mmol, 1.0 equiv.) was added dropwise to the organocopper reagent over 5 min and then stirred at 40 °C for 20 h. After completion of the reaction, the mixture was quenched with 1 M aqueous HCl (1 mL). Ethyl acetate (10 mL) was added to the quenched reaction mixture, which was then washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1). The organic layer was then dried over Na2SO4. The dried organic layer was purified by silica column chromatography (ethyl acetate:n-hexane = 1:20 to 1:5). The yield of the ketone derivative (compound 7) was 92% (198 mg), and the yield of compound 8 was 8% (16.1 mg).

[0292] Example 14 The same procedure as in Example 13 was carried out, except that the amount of CuCl, ArMgBr·LiCl, and RMgBr was changed to 2.0 equivalents, 2.0 equivalents, and 1.0 equivalent, respectively. As a result, the yield of the ketone derivative (compound 7) was 91% (196 mg), and the yield of compound 8 was 4% (8.6 mg).

[0293] Example 15 Compound 7 was produced from compound 8 by carrying out the reaction shown in the following formula. [ka]

[0294] Preparation of 0.25M ArMgBr THF solution Magnesium (24.3 mg, 1.00 mmol, 2.00 equiv.) was activated by adding THF (1.00 mL) and 1,2-dibromoethane (0.05 mL). To this was added a THF solution (1.00 mL) of BMB (2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene: 181 mg, 0.500 mmol, 1.00 equiv.) slowly dropwise. The mixture was then stirred at 80°C for 3 hours to prepare a 0.25 M THF solution of ArMgBr.

[0295] Preparation of 0.25M MesMgBr THF solution Magnesium (24.3 mg, 1.00 mmol, 2.00 equiv.) was activated by adding THF (1.00 mL) and 1,2-dibromoethane (0.05 mL). To this was added a THF solution (1.00 mL) of 2-bromomesitylene (99.5 mg, 0.500 mmol, 1.00 equiv.) slowly, while taking care not to generate heat. The mixture was then stirred at room temperature for 3 hours to prepare a 0.25 M THF solution of MesMgBr.

[0296] ketonization reaction To a suspension of CuCl (27.2 mg, 0.275 mmol, 1.1 equiv) in THF (1.50 mL), a 0.25 M solution of ArMgCl in THF (1.10 mL, 0.275 mmol, 1.1 equiv) was added dropwise over 5 min and stirred for 10 min to obtain a suspension. To this suspension, a 0.25 M solution of MesMgBr (0.138 mmol, 0.55 equiv) in THF (0.550 mL) was added and stirred for an additional 10 min to obtain the organocopper reagent.

[0297] A THF solution (1.00 mL) of compound 8 (196 mg, 0.250 mmol, 1.0 equiv.) was added dropwise to the organocopper reagent over 5 min and then stirred at 40 °C for 20 h. After completion of the reaction, the mixture was quenched with 1 M aqueous HCl (1 mL). Ethyl acetate (10 mL) was added to the quenched reaction mixture, which was then washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1). The organic layer was then dried over Na2SO4. The dried organic layer was purified by silica column chromatography (ethyl acetate:n-hexane = 1:20 to 1:5). The yield of the ketone derivative (compound 7) was 56% (120 mg), and the yield of compound 8 was 43% (85.0 mg).

[0298] Example 16A Compound 10 was produced from Compound 8 by carrying out the reaction shown in the following formula. [ka]

[0299] Preparation of 0.25M ArMgBr THF solution Magnesium (48.6 mg, 2.00 mmol, 2.0 equiv.) was activated with THF (2.00 mL) and 1,2-dibromoethane (0.05 mL), and then a THF solution (2.00 mL) of BMB (2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, 361 mg, 1.00 mmol, 1.00 equiv.) was slowly added dropwise. After the addition was complete, the mixture was stirred at 80°C for 3 hours.

[0300] Preparation of 0.25M MesMgBr THF solution Magnesium (48.6 mg, 2.00 mmol, 2.0 equiv.) was activated with THF (2.00 mL) and 1,2-dibromoethane (0.05 mL), and then a THF solution (2.00 mL) of 2-bromomesitylene (200 mg, 1.00 mmol, 1.00 equiv.) was slowly added dropwise, taking care not to generate heat. After the addition was complete, the mixture was stirred at 80°C for 3 hours.

[0301] Preparation of copper reagent To a THF suspension (1.25 mL) of CuCl (37.1 mg, 0.375 mmol, 1.5 equiv.), a 0.25 M THF solution of ArMgBr (1.50 mL, 0.375 mmol, 1.5 equiv.) was added dropwise over 5 minutes and stirred for 10 minutes. A 0.25 M THF solution of 2-mesitylmagnesium bromide (0.750 mL, 0.188 mmol, 0.75 equiv.) was added and stirred for an additional 10 minutes. The entire THF suspension of the copper reagent was used in the reaction.

[0302] Compound 8 was dissolved in THF (1.50 mL) and added dropwise to the prepared THF suspension of copper reagent over 5 minutes at room temperature. The mixture was then stirred at 40 °C for 20 hours. After cooling to room temperature, a methanol solution (5.00 mL) of sodium methoxide (67.5 mg, 1.25 mmol, 5.0 equiv.) was added to the reaction mixture, which was then stirred at 60 °C for 6 hours. The reaction was quenched with 1 M aqueous HCl (1 mL), and ethyl acetate (10 mL) was added. The mixture was washed with 1 M aqueous HCl (5 mL × 3) and brine (5 mL × 1), and the organic layer was dried over Na2SO4. The mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:10 to 1:3) to obtain compound 10 in 69% yield (141 mg, yellow oil).

[0303] Example 16B Compound 10 was produced from Compound 8 by carrying out the reaction shown in the following formula. [ka]

[0304] Preparation of 0.25M ArMgBr THF solution Magnesium (48.6 mg, 2.00 mmol, 2.0 equiv.) was activated with THF (2.00 mL) and 1,2-dibromoethane (0.05 mL), and then a THF solution (2.00 mL) of BMB (2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, 361 mg, 1.00 mmol, 1.00 equiv.) was slowly added dropwise. After the addition was complete, the mixture was stirred at 80°C for 3 hours.

[0305] Preparation of copper reagent A 0.25 M ArMgBr solution in THF (1.50 mL, 0.375 mmol, 1.5 equiv.) was added dropwise over 5 minutes to a 1.81 mL suspension of CuCl (37.1 mg, 0.375 mmol, 1.5 equiv.) in 1M Aldrich 425508-100 mL, 0.188 mL, 0.188 mmol, 0.75 equiv. in 1M 2,6-xylylmagnesium bromide in THF (Aldrich 425508-100 mL, 0.188 mL, 0.188 mmol, 0.75 equiv.) in 1M Aldrich 425508-100 mL, 0.188 mL, 0.188 mmol, 0.75 equiv. ...) in 1M Aldrich 425508-100 mL, 0.188 mL, 0.188 mmol, 0.75 equiv. in 1M Aldrich 425508-100 mL, 0.188 mL, 0.188 mmol, 0.

[0306] Lactol synthesis Compound 8 was dissolved in THF (1.50 mL) and added dropwise to the prepared THF suspension of copper reagent over 5 minutes at room temperature. The mixture was then stirred at 40°C for 20 hours. After cooling to room temperature, a methanol solution (5.00 mL) of sodium methoxide (67.5 mg, 1.25 mmol, 5.0 equiv.) was added to the reaction mixture, which was then stirred at 60°C for 6 hours. The reaction was quenched with 1M aqueous HCl (1 mL), and ethyl acetate (10 mL) was added. The mixture was washed with 1M aqueous HCl (5 mL × 3) and brine (5 mL × 1), and the organic layer was dried over Na2SO4. The mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:10 to 1:3) to obtain compound 10 in a 77% yield (157 mg, yellow oil).

[0307] Compound 10 obtained in Examples 16A and 16B 1 The 1 H NMR data was as follows: 1H NMR(400MHz, CDCl3, 30℃) δ 7.52(d,J=1.8Hz,1H),7.45(dd,J=7.8,1.9Hz,1H),7.38-7.28(m,10H),7.26-7.15(m,11H),7.00-6. 94(m,5H),6.61(d,J=3.6Hz,1H),4.89-4.86(m,3H),4.67(d,J=8.4Hz,1H),4.64(d,J=9.8Hz,1H),4. 54(d,J=12.4Hz,1H),4.38(d,J=10.6Hz,1H),4.18-4.03(m,4H),3.94(d,J=10.6Hz,1H),3.88-3.82( m,2H),3.72(dd,J=11.1,1.8Hz,1H),3.60(dd,J=9.3,0.8Hz,1H),3.06(d,J=0.9Hz,1H),2.33(s,3H).

[0308] Example 17 Compound 12a was produced from compound 11a by carrying out the reaction shown in the following formula: Similarly, compounds 12b to 12k were produced from compounds 11b to 11k, respectively.

[0309] [ka]

[0310] [ka]

[0311] [ka]

[0312] Preparation of thioesters (compounds 11a-11k) The reaction shown in the following formula was carried out to produce the target thioester. [ka]

[0313] N,N'-Dicyclohexylcarbodiimide (DCC) (1.05 equiv.) was added to a dichloromethane (DCM) suspension containing the corresponding carboxylic acid (1.05 equiv.), thiol (1.00 equiv.), and 4-dimethylaminopyridine (DMAP) (0.100 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature (rt) for 15 h. After completion of the reaction, the precipitate was removed by filtration through Celite, and the filtrate was washed with 1 M aqueous HCl, saturated aqueous sodium bicarbonate, and saturated brine. After evaporation of the solvent, the crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1:30 → 1:2) to obtain the desired thioester.

[0314] Compound 11a was obtained as a white solid (3.04 g, 8.03 mmol, yield 72%). The analytical results of compound 11a were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.11(d,J=8.6Hz,2H,ArH),8.01(d,J=8.6Hz,2H,ArH),4.41(q,J=7.1Hz,2H,OCH2CH3),3.09(t,J=7.3Hz,2H,SCH2), 1.69(quint,J=7.1Hz,2H,SCH2CH2),1.43-1.26(m,21H,SCH2CH2(CH2)9CH3+OCH2CH3),0.88(t,J=6.6Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.7,165.8,140.6,134.5,129.9,127.2,61.6,32.0,29.8,29.74,29.69,29.60,29.55,29.5,29.3,29.1,22.8,14.4,14.2.

[0315] Compound 11b was obtained as a white solid (1.47 g, 3.62 mmol, yield 89%). The analytical results of Compound 11b were as follows. 1H NMR (400MHz,CDCl3,30℃) δ 8.05-7.97(m,4H,ArH),3.08(t,J=7.2Hz,2H,SCH2),1.68(quint,J=7.5Hz,2H,SCH2CH2),1.61(s,9H, t Bu),1.43(m,2H,SCH2CH2CH2),1.30-1.26(m,16H,SCH2CH2CH2(CH2)8CH3),0.88(t,J=6.7Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.8,164.9,140.3,136.1,129.7,127.5,127.1,81.9,32.0,29.74,29.69,29.60,29.56,29.46,29.4,29.3,29.1,28.3,22.8,14.2. IR (neat KBr, ν / cm -1 ) 2952,2915,2871,2850,1728,1657,1607,1542. HRMS (FAB + ) m / z C 40 H 49 O3S ([M+H] + ) Calculated value 406.2542 Measured value 407.2616. Melting point: 50.8-52.0℃.

[0316] Compound 11c was obtained as a white solid (6.20 g, 17.0 mmol, yield 85%). The analytical results of compound 11c were as follows. 1H NMR (400MHz, CDCl3, 30℃) δ 8.10(d,J=8.0Hz,2H,ArH),8.01(d,J=8.0Hz,2H,ArH),3.94(s,3H,OCH3),3.09(t,J=8.0Hz,2H,SCH2),1.68(quint,J=8.0 Hz,2H,SCH2CH2),1.41-1.43(m,2H,SCH2CH2CH2),1.26-1.30(m,16H,SCH2CH2CH2(CH2)8CH3),0.88(t,J=6.0Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.7,166.3,140.7,134.2,129.9,127.2,66.2,56.1,52.6,52.2,32.0,29.7,29.7,29.6,29.5,29.5,29.3,29.0,22.8,14.2. IR (neat KBr, ν / cm -1 ) 2952,2917,2850,1715,1656. HRMS (FAB + ) m / z C 24 H 49 O3S ([M+H] + ) Calculated value 364.2072 Measured value 365.2151. Melting point: 68.3-70.7℃.

[0317] Compound 11d was obtained as a white solid (1.25 g, 2.98 mmol, yield 92%). The analytical results of compound 11d were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.01(d,J=8.2Hz,2H,ArH),7.47(d,J=8.2Hz,2H,ArH),3.77-3.40(m,8H,morpholine),3.08(t,J=8.0Hz,2H,SCH2),1.68(qui nt,J=8.0Hz,2H,SCH2CH2),1.43-1.40(m,2H,SCH2CH2CH2),1.26(m,16H,SCH2CH2CH2(CH2)8CH3),0.88(t,J=6.0Hz,3H,S(CH2)11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.5,169.3,139.9,138.4,127.6,127.4,66.9,48.2,42.7,32.0,29.73,29.69,29.60,29.57,29.5,29.4,29.3,29.0,22.8,14.2. IR (neat KBr, ν / cm -1 ) 2951,2917,2849,1661,1920,1604. HRMS (FAB + ) m / z C 40 H 49 NO3S ([M+H] + ) Calculated value 419.2494 Measured value 420.2571. Melting point: 75.9-77.1℃.

[0318] Compound 11e was obtained as a white solid (0.792 g, 2.39 mmol, yield 80%). The analytical results of Compound 11e were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.05(d,J=8.5Hz,2H,ArH),7.75(d,J=8.4Hz,2H,ArH),3.10(t,J=7.3Hz,2H,SCH2),1.69(quint,J=7.1Hz,2H,SC H2CH2),1.43-1.41(m,2H,SCH2CH2CH2),1.32-1.26(m,16H,SCH2CH2CH2(CH2)8CH3),0.88(t,J=6.6Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 190.9,140.5,132.6,127.8,118.0,116.6,32.0,29.74,29.67,29.64,29.58,29.5,29.2,29.0,22.8,14.2. IR (neat KBr, ν / cm -1) 2952,2915,2870,2851,1658,1623,1560,1542. HRMS (FAB + ) m / z C 24 H 49 NOS ([M+H] + ) Calculated value 331.1970 Measured value 332.2047. Melting point: 50.6-53.1℃.

[0319] Compound 11f was obtained as a white solid (0.887 g, 2.73 mmol, yield 91%). The analytical results of Compound 11f were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.02-7.98(m,2H,ArH),7.14-7.10(m,2H,ArH),3.07(t,J=7.3Hz,2H,SCH2),1.67(quint,J =7.0Hz,2H,SCH2CH2),1.43-1.27(m,18H,SCH2CH2(CH2)9CH3),0.89(t,J=6.6Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 190.7,166.0(d,J C-F =253Hz), 133.8, 129.8(d,J C-F =10Hz), 115.7(d,J C-F =22Hz),32.0,29.76,29.75,29.70,29.67,29.6,29.5,29.32,29.27,29.1,22.8,14.2. 19 F{ 1 H} NMR (376MHz, CDCl3, 30℃) δ -105.2.

[0320] Compound 11g was obtained as a white solid (0.702g, 2.06mmol, yield 69%). The analytical results of compound 11g were as follows. 1H NMR (400MHz, CDCl3, 30℃) δ 7.91(d,J=8.4Hz,2H,ArH),7.42(d,J=8.4Hz,2H,ArH),3.07(t,J=7.4Hz,2H,SCH2),1.67(quin t,J=7.2Hz,2H,SCH2CH2),1.43-1.27(m,18H,SCH2CH2(CH2)9CH3),0.89(t,J=6.3Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.2,139.8,135.9,129.1,128.8,32.2,29.91,29.85,29.8,29.6,29.5,29.4,29.2,23.0,14.4.

[0321] Compound 11h was obtained as a white solid (0.996 g, 2.58 mmol, yield 87%). The analytical results of Compound 11h were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.83(d,J=8.6Hz,2H,ArH),7.58(d,J=8.6Hz,2H,ArH),3.07(t,J=7.3Hz,2H,SCH2),1.67(quint,J=7.1Hz,2H, SCH2CH2),1.42-1.40(m,2H,SCH2CH2CH2),1.26(m,16H,SCH2CH2CH2(CH2)8CH3),0.88(t,J=6.6Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.3,136.2,132.0,128.8,128.3,32.0,29.74,29.73,29.68,29.59,29.58,29.5,29.34,29.25,29.0,22.8,14.2.

[0322] Compound 11i was obtained as a white solid (1.23 g, 2.84 mmol, yield 95%). The analytical results of compound 11i were as follows. 1H NMR (400MHz, CDCl3, 30℃) δ 7.81(d,J=8.5Hz,2H,ArH),7.68(d,J=8.6Hz,2H,ArH),3.07(t,J=7.3Hz,2H,SCH2),1.67(quint,J=7.0Hz,2H, SCH2CH2),1.42-1.40(m,2H,SCH2CH2CH2),1.27(m,16H,SCH2CH2CH2(CH2)8CH3),0.89(t,J=6.6Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 191.3,137.8,136.6,128.5,100.7,31.8,29.6,29.5 4, 29.49, 29.41, 29.38, 29.3, 29.11, 29.06, 28.8, 22.6, 14.0. IR (neat KBr, ν / cm -1 ) 2952,2915,2869,2847,1651,1578,1559,1541,1508. HRMS (FAB + ) m / z C 24 H 49 OSI ([M+H] + ) Calculated value 432.0984 Measured value 433.1055. Melting point: 47.6-48.6℃.

[0323] Compound 11j was obtained as a white solid (0.955 g, yield 51%). The analytical results of Compound 11j were as follows. 1H NMR (400MHz, CDCl3, 30℃) δ 7.80(d,J=3.8Hz,1H,thiophene),7.60(d,J=4.9Hz,1H,thiophene),7.10(d,J=4.0Hz,1H,thiophene),3.07(t,J=7.3Hz,2H,SCH2),1 .67(quint,J=7.0Hz,2H,SCH2CH2),1.42-1.40(m,2H,SCH2CH2CH2),1.27(m,16H,SCH2CH2CH2(CH2)8CH3),0.88(t,J=6.6Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 184.3,142.6,132.4,130.9,127.9,32.0,29.78,29.76,29.74,29.70,29.6,29.5,29.4,29.3,29.0,22.8,14.2.

[0324] Compound 11k was obtained as a colorless liquid (2.55 g, yield 85%). The analytical results of compound 11k were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.30-7.25(m,2H,ArH),7.21-7.17(m,3H,ArH),2.98(t,J=7.2Hz,2H,SCH2),2.89-2.83(m,4H,PhCH2CH 2),1.55(quint,J=7.2Hz,2H,SCH2CH2),1.26(m,18H,SCH2CH2(CH2)9CH3),0.89(t,J=7.0Hz,3H,S(CH2) 11 CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 198.8,140.3,128.6,128.4,126.4,45.7,32.1,31.6,29.78,29.76,29.71,28.67,29.6,29.5,29.3,29.1,28.9,22.8,14.2.

[0325] Ketonization reaction (preparation of compounds 12a to 12k) To a THF suspension (2 mL) of CuTC (copper(I) thiophene-2-carboxylate, 0.250 mmol, 47.7 mg, 1.0 equiv.), a 0.52 M THF solution of PhMgBr (0.325 mmol, 0.625 mL, 1.3 equiv.) was added dropwise over 5 minutes, followed by stirring at room temperature for 10 minutes. At this stage, the organocopper reagent was generated. The resulting organocopper reagent was added dropwise over 5 minutes to a THF solution (2 mL) of the thioester obtained above (0.250 mmol, 1.0 equiv.), and the reaction mixture was stirred at 30°C for 1 hour. After completion of the reaction, the reaction was quenched with 1 M aqueous HCl (1 mL). The yield was calculated using the following method.

[0326] [yield] The yield was calculated from the proton integral ratio between the internal standard (triphenylmethane) and the product. After adding the internal standard triphenylmethane, the sample was prepared by removing metal salts with short pad silica (ethyl acetate), distilling off the solvent under reduced pressure, and dissolving the residue in deuterated chloroform.

[0327] Compound 12a was obtained as a colorless oil (52.1 mg, 0.205 mmol, yield 82%). The analytical results of compound 12a were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.15(d,J=8.2Hz,2H,ArH),7.83(d,J=8.2Hz,2H,ArH),7.80(d,J=7.5Hz,2H,ArH),7.61(t,J=7.3Hz ,1H,ArH),7.49(t,J=7.6Hz,2H,ArH),4.42(q,J=7.1Hz,2H,OCH2),1.42(t,J=7.2Hz,3H,OCH2CH3). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 196.1,165.9,141.4,137.2,133.7,133.0,130.2,129.8,129.6,128.6,61.5,14.4.

[0328] Compound 12b was obtained as a colorless oil (56.7 mg, 0.201 mmol, yield 81%). The analytical results of compound 12b are as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.09(d,J=8.3Hz,2H,ArH),7.81(d,J=8.0Hz,2H,ArH),7.79(d,J=6.8Hz,2H,ArH),7.61(t,J=7.3Hz,2H,ArH),7.49(t,J=7.8Hz,2H,ArH),1.62(s,9H,O t Bu). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 196.1,164.9,140.9,137.1,135.2,132.8,130.1,129.6,129.3,128.4,81.8,28.1.

[0329] Compound 12c was obtained as a white solid by recycling HPLC (49.3 mg, purity 93%, 0.190 mmol, yield 76%). The analytical results of compound 12c are as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 8.15(d,J=8.4Hz,2H,ArH),8.15(d,J=8.0Hz,2H,ArH),8.15(d,J=8.0Hz,2H,A rH),7.61(t,J=7.4Hz,1H,ArH),7.49(t,J=7.4Hz,2H,ArH),3.96(s,3H,OMe). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 196.0,166.3,141.3,137.0,132.9,130.1,129.7,129.5,128.4,52.4.

[0330] Compound 12d was obtained as a colorless oil (62.3 mg, 0.211 mmol, yield 84%). The analytical results of compound 12d were as follows. 1H NMR (400MHz, CDCl3, 30℃) δ 7.85-7.79(m,4H,ArH),7.63-7.59(m,1H,ArH),7.53-7.47(m,4H,ArH),3.78-3.45(m,8H,morpholine). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 196.0,169.5,139.1,139.0,137.2,133.0,130.3,130.2,128.6,127.1,67.0,48.1,42.8.

[0331] Compound 12e was obtained as a white solid (41.0 mg, 0.198 mmol, yield 79%). The analytical results of compound 12e were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.88(d,J=8.3Hz,2H,ArH),7.79(m,4H,ArH),7.65(t,J=7.3Hz,2H,ArH),7.52(t,J=7.7Hz,2H,ArH). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 195.1,141.4,136.5,133.4,132.3,130.4,130.2,128.8,118.1,115.8.

[0332] Compound 12f was obtained as a colorless oil (41.8 mg, 0.209 mmol, yield 84%). The analytical results of Compound 12f are as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.86-7.83(m,2H,ArH),7.77(d,J=7.3Hz,2H,ArH),7.59(t,J=7.4Hz,1H,ArH),7.49(t,J=7.8Hz,2H,ArH),7.16(t,J=8.6Hz,2H,ArH). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 195.2,165.3(d,J C-F=252Hz), 137.5, 133.8(d,J C-F =3Hz), 132.6(d,J C-F =9Hz),132.4,129.8,128.3,115.4(d,J C-F =22Hz). 19 F{ 1 H} NMR (376MHz, CDCl3, 30℃) δ -106.0.

[0333] Compound 12g was obtained as a white solid (49.0 mg, 0.226 mmol, yield 91%). The analytical results of compound 12g were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.78(d,J=6.4Hz,2H,ArH),7.76(d,J=8.3Hz,2H,ArH),7.60(t,J=7.3Hz,1H,ArH),7.49(t,J=7.8Hz,2H,ArH),7.46(d,J=8.4Hz,2H,ArH). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 195.4,138.9,137.3,135.9,132.6,131.4,129.9,128.6,128.4.

[0334] Compound 12h was obtained as a white solid (57.2 mg, 0.219 mmol, yield 88%). The analytical results of compound 12h were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.77(d,J=7.1Hz,2H,ArH),7.68(d,J=8.6Hz,2H,ArH),7.63(d,J=8.5Hz,2H,ArH),7.59(d,J=7.4Hz,1H,ArH),7.49(t,J=7.5Hz,2H,ArH). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 195.7,137.4,136.5,132.8,131.8,131.7,130.1,128.5,127.6.

[0335] Compound 12i was obtained as a white solid (59.6 mg, 0.193 mmol, yield 77%). The analytical results of compound 12i are as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.85(d,J=8.4Hz,2H,ArH),7.77(d,J=7.2Hz,2H,ArH),7.60(t,J=7.4Hz,1H,ArH),7.53-7.47(m,4H,ArH). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 196.0,137.7,137.3,137.1,132.8,131.6,130.1,128.5,100.2.

[0336] Compound 12j was obtained as a yellow oil (34.3 mg, 0.182 mmol, yield 73%). The analytical results of compound 12j were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.87(d,J=7.4Hz,2H,ArH),7.72(d,J=5.0Hz,1H,thiophene),7.66(d,J=3.8Hz,1H,thiophene e),7.59(t,J=7.2Hz,1H,ArH),7.50(t,J=7.8Hz,2H,ArH),7.16(t,J=4.0Hz,1H,thiophene). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 188.3,143.8,138.3,134.9,134.3,132.4,129.3,128.5,128.1.

[0337] Compound 12k was obtained as a white solid (37.8 mg, 0.180 mmol, yield 72%). The analytical results of compound 12k were as follows. 1H NMR (400MHz, CDCl3, 30℃) δ 7.95(d,J=7.5Hz,2H,ArH),7.54(t,J=7.4Hz,2H,ArH),7.44(t,J=7.7Hz,2H,ArH),7.31-7.27(m,3 H,ArH),7.21-7.17(m,2H,ArH),3.29(t,J=7.7Hz,2H,PhCH2CH2),3.07(t,J=7.7Hz,2H,PhCH2CH2). 13 C{ 1 H} NMR (100MHz, CDCl3, 30℃) δ 199.3,141.4,137.0,133.2,128.7,128.65,128.6,128.55,128.4,128.2,126.3,40.6,30.3.

[0338] Example 18 The reaction shown in the following formula was optimized.

[0339] [ka]

[0340] In Example 18a, 1.3 equivalents of PhMgBr were used per equivalent of CuCl, and the reaction time was 3 hours. That is, the amount of CuCl per mole of PhMgBr was 0.77 moles. In Example 18b, 1.6 equivalents of PhMgBr were used per equivalent of CuCl, and the reaction time was 3 hours. That is, the amount of CuCl per mole of PhMgBr was 0.63 moles. In Example 18c, 1.3 equivalents of PhMgBr were used per equivalent of CuTC (copper(I) thiophene-2-carboxylate), and the reaction time was 3 hours. In Example 18d, 1.3 equivalents of PhMgBr were used per equivalent of CuTC, and the reaction time was 1 hour.

[0341] In Examples 18a to 18d, the yields of compounds 12a and 13 were determined in the same manner as in Example 17. The results are shown in Table 5.

[0342] [Table 5]

[0343] From the results shown in Table 5, the optimal ratio of copper salt to Grignard reagent (equivalents of copper salt: equivalents of Grignard reagent) was determined to be 1:1.3. Furthermore, CuTC showed higher activity than CuCl, and although the by-product of compound 13 was observed, compound 12a was obtained in a higher yield. Furthermore, by shortening the reaction time from 3 hours to 1 hour, compound 12a was obtained in a higher yield.

[0344] Example 19 [Ph 2 Cu][Mg 2 Br 3 (thf) 6 Preparation of The reaction shown in the following formula was carried out to prepare [Ph2Cu][Mg2Br3(thf)6]. 2CuCl+3PhMgBr→[Ph2Cu][Mg2Br3(thf)6]+PhCu+MgCl2

[0345] A 0.9 M PhMgBr solution in THF (4.17 mL, 3.75 mmol, 1.5 equiv.) was added to a THF solution (5.73 mL) of CuCl (248 mg, 2.50 mmol, 1.0 equiv.). After stirring at room temperature for 1 h, a yellow-green suspension was obtained. Toluene (30 mL) was added, and the mixture was heated to 120 °C. After the solution turned dark green, insoluble material was removed by filtration. The filtrate was then slowly cooled to room temperature. The crystals obtained by crystallization from toluene / THF = 3 / 1 were washed with toluene (1 mL × 3) and THF (1 mL × 3), and [PhCu][MgBr(thf)6] was obtained as green cubic crystals in 59% yield (693 mg). The crystals obtained were suitable for single-crystal X-ray structural analysis (Figure 1). Figure 1 shows the molecular structure of [PhCu][MgBr(thf)] as a 50% thermal ellipsoid, with hydrogen atoms omitted for clarity.

[0346] Example 20 [Ph 2 Cu][Mg 2 Br 3 (thf) 6 Comparative experiments on the reactivity of [ka]

[0347] Preparation of 0.5M CuPh THF suspension A 0.9 M PhMgBr solution in THF (11.1 mL, 10.0 mmol, 1.00 equiv.) was added dropwise to a 20.0 mL solution of CuBr (1.43 g, 10.0 mmol, 1.00 equiv.) at 0 °C. After stirring at room temperature for 2 hours, the supernatant was removed by filtration. The residue was washed with THF (10 mL x 3) and dried under vacuum. THF (20 mL) was added to obtain a 0.5 M suspension of CuPh in THF.

[0348] Schemes (a) to (d) were carried out using a J-young tube, and scheme (e) was carried out using a 20 mL J-young Schlenk flask.

[0349] Scheme (a) To a solution of [PhCu][MgBr(thf)] (11.7 mg, 12.5 μmol, 0.500 equiv. or 23.5 mg, 25.0 μmol, 1.00 equiv.) in THF-d8 (0.250 mL) was added a solution of compound 14 (S-butyl thiobenzoate, 4.63 μL, 25.0 μmol, 1.00 equiv.) in THF-d8 (0.250 mL). The reaction mixture was heated at 30 °C for 3 h, and the reaction mixture was 1 H NMR analysis was performed directly. The yield of compound 15 was determined by the reaction of S-butyl thiobenzoate with CuS. n When calculated from the integral ratio of -SCH2- with butyl, it was 50% when [Ph2Cu][Mg2Br3(thf)6] was 0.500 equivalents, and nearly 100% (quant.) when [Ph2Cu][Mg2Br3(thf)6] was 1.00 equivalents.

[0350] Scheme (b) A 0.5M suspension of CuPh in THF (50.0 μL, 25.0 μmol, 1.00 equiv.) was added to a J-young tube, and the THF was removed by vacuum pumping. THF-d8 (0.250 mL) was added, followed by a THF-d8 solution (0.250 mL) of compound 14 (S-butyl thiobenzoate, 4.63 μL, 25.0 μmol, 1.00 equiv.). The reaction mixture was heated at 30°C for 3 hours, and the solubility of the reaction mixture was confirmed. 1 H NMR analysis was performed directly. The yield of compound 15 was determined by the reaction of S-butyl thiobenzoate with CuS. n The amount was determined to be trace based on the integral ratio of -SCH2- to butyl.

[0351] Scheme (c) A 0.5M THF suspension of CuPh (25.0 μL, 12.5 μmol, 0.500 equiv.) was added to a J-young tube, and the THF was removed by vacuum. A THF-d8 solution (0.250 mL) of [PhCu][MgBr(thf)] (11.7 mg, 12.5 μmol, 0.500 equiv.) was added, followed by a THF-d8 solution (0.250 mL) of compound 14 (S-butyl thiobenzoate, 4.63 μL, 25.0 μmol, 1.00 equiv.). The reaction mixture was heated at 30°C for 3 hours, and the THF of the reaction mixture was removed. 1 H NMR analysis was performed directly. The yield of compound 15 was determined by the reaction of S-butyl thiobenzoate with CuS. n The integral ratio of butyl -SCH2- was calculated to be 90%.

[0352] Scheme (d) A 0.5M THF suspension of CuPh (25.0 μL, 12.5 μmol, 0.500 equiv.) was added to a J-young tube, and the THF was removed by vacuum. A THF-d8 solution (0.250 mL) of [PhCu][MgBr(thf)] (11.7 mg, 12.5 μmol, 0.500 equiv.) was added, followed by a THF-d8 solution (0.250 mL) of compound 16 (ethyl benzoate, 3.58 μL, 25.0 μmol, 1.00 equiv.). The reaction mixture was heated at 30°C for 3 hours, and the THF of the reaction mixture was removed.1 H NMR analysis was carried out directly and no compound 15 was detected.

[0353] Scheme (e) To a THF solution (3.15 mL) of [PhCu][MgBr(thf)] (70.4 mg, 0.0750 mmol, 30.0 mol%), a 0.5 M suspension of CuPh in THF (0.350 mL, 0.175 mmol, 0.700 equiv.) was added, followed by a THF solution (1.50 mL) of compound 17 (94.6 mg, 0.250 mmol, 1.00 equiv.). The reaction mixture was heated at 30 °C for 3 h, after which the reaction was quenched by the addition of 1 M aqueous HCl (1 mL). The metal complex was removed by filtration through a silica gel pad eluted with ethyl acetate. The yield of compound 18 was determined to be 84% by gas chromatography using triphenylethane (PhCH) as an internal standard.

Claims

1. The following formula (I): 【Chemical 1】 [In the formula, W １ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group; W ２ represents an aryl group in which the carbon atoms on both sides of the carbon atom having a bond in an aryl group have no substituents and the remaining carbon atoms may have a substituent, or a heteroaryl group in which the carbon atoms or heteroatoms on both sides of the carbon atom having a bond in a heteroaryl group have no substituents and the remaining carbon atoms or heteroatoms may have a substituent.] A method for producing a ketone derivative (I) represented by the following formula: The following formula (II): 【Chemistry 2】 [In the formula, W １ has the same meaning as above, and W ３ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted arylalkyl group, or an optionally substituted arylalkenyl group.] a thioester derivative (II) represented by the formula: The following formula (IIIa): 【Chemistry 3】 [In the formula, W ２ has the same meaning as defined above, and X represents a halogen atom. a Grignard reagent (IIIa) represented by The following formula (IIIb): 【Chemistry 4】 [In the formula, W ２ and X have the same meanings as defined above.] Grignard reagent (IIIb) represented by a Grignard reagent (III) selected from Copper salts, The following formula (IV): 【Chemistry 5】 [In the formula, W 4 represents a phenyl group which has a substituent at at least one ortho position and may have a substituent at the meta and / or para position, and X 1 represents a halogen atom.] a Grignard reagent (IV) represented by at a temperature in the range of 20°C to 60°C to form the ketone derivative (I). The method comprising:

2. 2. The method according to claim 1, wherein the amount of the copper salt used is 0.1 mol or more and 2 mol or less relative to 1 mol of the Grignard reagent (III), and the amount of the Grignard reagent (IV) used is 0.1 mol or more and 1 mol or less relative to 1 mol of the Grignard reagent (III).

3. 3. The method according to claim 1 or 2, wherein in the step, the Grignard reagent (III) and the copper salt are mixed, and then the Grignard reagent (IV) is mixed to form an organocopper reagent, and then the thioester derivative (II) is mixed therewith to bring the organocopper reagent and the thioester derivative (II) into contact with each other.

4. W ３ The method according to any one of claims 1 to 3, wherein represents an alkyl group which may have a substituent.

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