Method for producing c-arylglucoside derivative

Abstract

To provide a novel thioester derivative and a method for producing the same, a novel ketone derivative and a method for producing the same, a novel method for producing a C-arylhydroxyglucoside derivative, and a novel method for producing a C-arylglucoside derivative.SOLUTION: The present invention provides a thioester derivative (I) represented by the following formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to thioester derivatives and methods for producing the same, ketone derivatives and methods for producing the same, methods for producing C-aryl-hydroxyglycoside derivatives, and methods for producing C-arylglycoside derivatives. [Background technology]

[0002] SGLT2 inhibitors are useful as antidiabetic drugs. "SGLT2" stands for 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]oxyphenyl)methyl]phenyl}-D-glucitol), and ipragliflozin ((1S Examples include )-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid) and dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-thiol).

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

[0004] Various methods have been proposed for producing C-arylhydroxyglycoside derivatives. For example, methods include adding an aryl group to a D-gluconolactone derivative by reacting it with aryllithium at an ultra-low temperature of -78°C (Non-Patent Documents 1 and 3), adding an aryl group to a D-gluconolactone derivative by reacting it with a turbogrignard reagent such as ArMgBr·LiCl (Ar represents an aryl group) at a low temperature of -20 to -10°C (Non-Patent Document 2), and adding an aryl group to a D-gluconolactone derivative at a temperature of around -15°C using a magnesium ate complex obtained from lithium tri-n-butylmagnesate (nBu3MgLi) (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, yielding a ketone derivative (Non-Patent Documents 4 and 5).

[0005] Furthermore, remdesivir, represented by the following formula (X), is a compound that can be used as an antiviral drug. Remdesivir exhibits antiviral activity against single-stranded RNA viruses such as RSV 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 formula (XII) can be obtained by reacting a lactone represented by formula (XI) with a bromopyrazole represented by formula (Ar'') at -78°C in the presence of chlorotrimethylsilane (TMSCl) and n-butyllithium. This hydroxynucleoside can be used as an intermediate for the synthesis of remdesivir. Note that "Bn" represents a benzyl group.

[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 [Overview of the project] [Problems that the invention aims to solve]

[0011] The methods previously used to produce C-arylhydroxyglycoside derivatives, remdesivir, or their intermediates all require the use of expensive reagents under severe low-temperature conditions, resulting in extremely high equipment and running costs, making it difficult to mass-produce the final active pharmaceutical ingredient at low cost. Therefore, there is a need for thioester derivatives and their production methods, ketone derivatives and their production methods, C-arylhydroxyglycoside derivative production methods, and C-arylglycoside derivative production methods that will enable the industrial production of C-arylhydroxyglycoside derivatives, remdesivir, or their intermediates at low cost and in an efficient manner.

[0012] One objective of the present invention is to provide novel thioester derivatives and methods for producing the same, novel ketone derivatives and methods for producing the same, novel methods for producing C-aryl-hydroxyglycoside derivatives, and novel methods for producing C-arylglycoside derivatives. [Means for solving the problem]

[0013] This invention provides the following: [1] Formula (I): [ka] [In the formula, W 1 This 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. Each R independently represents an alkyl group which may have substituents. n represents either 1 or 2. A thioester derivative (I) represented by [formula].

[0014] [2] Formula (II) below: [ka] [In the formula, W 2 This 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. Each R independently represents an alkyl group which may have substituents. n represents either 1 or 2. A ketone derivative (II) represented by [formula].

[0015] A method for producing the thioester derivative (I) described in [3][1], In the presence of a base, Formula (III) below: [ka] [In the formula, W 1 R and n are synonymous with [1]. Thiol derivative (III) represented by, Formula (1): [ka] [In the formula, R is equivalent to the above.] A carboxylic acid anhydride represented by (1), The method comprising the step of contacting the thioester derivative (I) to produce the thioester derivative (I).

[0016] [4] Formula (2) below: [ka] [In the formula, W 1 This is synonymous with the above. Thiol(2) represented by, The following equation (3): [ka] [In the formula, W 3 This 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. X represents a halogen atom. Grignard reagent (3) represented by, Formula (IV): [ka] [In the formula, R and n are as defined above.] The acyl-protected lactone derivative (IV) represented by, The method according to [3], comprising the step of contacting the thiol derivative (III) to produce the thiol derivative (III).

[0017] [5] The method according to [4], wherein in the step of producing the thiol derivative (III) by contacting the thiol (2), the Grignard reagent (3), and the acyl-protected lactone derivative (IV), a magnesium thiolate is formed by the reaction of the thiol (2) and the Grignard reagent (3), and then the thiol derivative (III) is formed by the reaction of the magnesium thiolate and the acyl-protected lactone derivative (IV).

[0018] [6] The method according to [4] or [5], wherein the thioester derivative (I) is produced by contacting the thiol (2), the Grignard reagent (3), and the acyl-protected lactone derivative (IV) with the reaction mixture, without isolating the thiol derivative (III) from the reaction mixture, by adding the carboxylic acid anhydride (1) to the reaction mixture, thereby contacting the thiol derivative (III) with the carboxylic acid anhydride (1).

[0019] A method for producing the ketone derivative (II) described in [7][2], The thioester derivative (I) described in [1], The following formula (4a): [ka] [In the formula, W 2 This is synonymous with [2], where X represents a halogen atom. Grignard reagent (4a) represented by, Formula (4b) below: [ka] [In the formula, W 2 And X is synonymous with the above. Grignard reagent (4b) represented by A Grignard reagent (4) selected from, Copper salts and The method comprising the step of bringing into contact with the ketone derivative (II) to produce the ketone derivative (II).

[0020] [8] The method according to [7], wherein in the above step, the Grignard reagent (4) and the copper salt are brought into contact to form an organocopper reagent, and then the organocopper reagent is brought into contact with the thioester derivative (I) to produce the ketone derivative (II).

[0021] [9] The method according to [7] or [8], wherein the copper salt comprises at least one selected from the group consisting of copper(I) cyanide, copper(I) chloride, copper(I) acetate, and copper(I) thiophene-2-carboxylate.

[0022]

[10] The method according to any one of [7] to [9], wherein the copper salt is used in an amount of 1 mole to 3 moles per mole of the thioester derivative (I).

[0023]

[11] In the above process, the thioester derivative (I), the Grignard reagent (4), and the copper salt are contacted within a temperature range of -20°C or higher and 150°C or lower, according to the method described in any one of [7] to

[10] .

[0024]

[12] The following formula (V):

Chemical formula

[0025]

[13] The following formula (VI):

Chemical formula

[0026]

[14] The following equation (VII): [ka] [In the formula, W 2 This 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. n represents either 1 or 2. A method for producing a C-arylglycoside derivative (VII) represented by, The method comprising the step of producing the C-aryl-hydroxyglycoside derivative (V) by the method described in

[12] , and then contacting the obtained C-aryl-hydroxyglycoside derivative (V) with a silane compound to produce the C-arylglycoside derivative (VII). [Effects of the Invention]

[0027] The present invention provides a novel thioester derivative and a method for producing the same, a novel ketone derivative and a method for producing the same, a novel method for producing a C-aryl-hydroxyglycoside derivative, and a novel method for producing a C-arylglycoside derivative. The present invention enables inexpensive and efficient industrial production of thioester derivatives, ketone derivatives, C-aryl-hydroxyglycoside derivatives, and C-arylglycoside derivatives, and can significantly reduce raw material costs, equipment costs, running costs, etc. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows the 1H NMR spectrum (400 MHz, CDCl3, 30°C) of compound 2 obtained in Example 1. [Figure 2] Figure 2 shows the 13C{1H} NMR spectrum (100 MHz, CDCl3, 30°C) of compound 2 obtained in Example 1. [Figure 3] Figure 3 shows the ¹H NMR spectrum (400 MHz, CDCl3, 30°C) of compound 3 obtained in Example 2. [Figure 4] Figure 4 shows the 13C{1H} NMR spectrum (100 MHz, CDCl3, 30°C) of compound 3 obtained in Example 2. [Figure 5] Figure 5 shows the 19F{1H} NMR spectrum (376 MHz, CDCl3, 30°C) of compound 3 obtained in Example 2. [Figure 6A] Figure 6A shows the 19F{1H} NMR spectrum (376 MHz, DMSO-d6, 30°C) of compound 4 obtained in Example 11. [Figure 6B] This is a magnified view of the two peaks in Figure 6A. [Figure 7] Figure 7 shows the 1H NMR spectrum (400 MHz, DMSO-d6, 30°C) of compound 5 obtained in Example 12. [Figure 8] Figure 8 shows the 19F{1H} NMR spectrum (376 MHz, CDCl3, 30°C) of compound 5 obtained in Example 12. [Modes for carrying out the invention]

[0029] The present invention will be described below.

[0030] ≪Explanation of Terms≫ The following definitions of terms used in this specification are provided below. Unless otherwise specified, these definitions apply throughout this specification. Unless otherwise specified, the expression "value A to value B" means a range of values ​​greater than or equal to value A and less than or equal to value B.

[0031] halogen atom The halogen atom is selected from fluorine, chlorine, bromine, and iodine atoms.

[0032] alkyl group The number of carbon atoms in the alkyl group is, for example, 1 to 20, preferably 1 to 10 (for example, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2). The alkyl group may be linear or branched. The number of carbon atoms in a linear alkyl group is 1 or more, and the number of carbon atoms in a branched alkyl group is 3 or more.

[0033] Alkenyl group The number of carbon atoms in the alkenyl group is, for example, 2 to 20, preferably 2 to 10. The number of carbon atoms in the alkenyl group is, for example, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. The alkenyl group may be linear or branched. The number of carbon atoms in a linear alkenyl group is 2 or more, and the number of carbon atoms in a branched alkenyl group is 3 or more.

[0034] Cycloalkyl groups The number of carbon atoms in the cycloalkyl group is, for example, 3 to 10, preferably 3 to 8, and more preferably 3 to 6.

[0035] Heterocycloalkyl groups A heterocycloalkyl group contains, for example, one or two heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen atoms. A heterocycloalkyl group is, for example, a 4- to 7-membered ring heterocycloalkyl group. It is preferable that the heterocycloalkyl group contains an oxygen atom as a heteroatom. Examples of heterocycloalkyl groups include tetrahydrofuranyl groups and tetrahydropyranyl groups. A tetrahydrofuranyl group is preferred for the heterocycloalkyl group.

[0036] 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, more preferably 6 to 10 carbon atoms. Examples of aryl groups include phenyl groups and naphthyl groups. The aryl group is preferably a phenyl group.

[0037] heteroaryl group A heteroaryl group comprises, 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 aromatic heterocyclic group with 4 to 10 members, preferably 5 to 10 members. 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.

[0038] Haloalkyl groups, haloaryl groups, and haloheteraryl groups Haloalkyl groups, haloaryl groups, and haloheteroaryl groups are, respectively, alkyl groups, aryl groups, and heteroaryl groups having one or more halogen atoms, and the descriptions of alkyl groups, aryl groups, and heteroaryl groups are as described above. The number of halogen atoms in a haloalkyl group, haloaryl group, or haloheteroaryl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0039] Alkylene group, arylene group, and heteroarylene group Alkylene groups, arylene groups, and heteroarylene groups are divalent functional groups produced by removing one hydrogen atom from an alkyl group, an aryl group, and a heteroaryl group, respectively. The explanations of alkyl groups, aryl groups, and heteroaryl groups are as described above.

[0040] Haloalkylene group, haloarylene group, and haloheterarylene group Haloalkylene groups, haloarylene groups, and haloheteroarylene groups are divalent functional groups produced by removing one hydrogen atom from a haloalkyl group, a haloaryl group, and a haloheteroaryl group, respectively. The explanations of haloalkyl groups, haloaryl groups, and haloheteroaryl groups are as described above.

[0041] Arylalkyl groups An arylalkyl group is an alkyl group having one or more aryl groups, and the explanation of alkyl groups and aryl groups is as described above. The number of aryl groups in an arylalkyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0042] Aryl alkenyl group An 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 an arylalkenyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0043] Alkylcarbonyl group and arylcarbonyl group Alkylcarbonyl groups and arylcarbonyl groups are groups represented by the formulas: -CO-alkyl and -CO-aryl, respectively, and the explanations of alkyl and aryl groups are as described above.

[0044] Alkyloxy group, haloalkyloxy group, heterocycloalkyloxy group and arylalkyloxy group Alkyloxy groups, haloalkyloxy groups, heterocycloalkyloxy groups, and arylalkyloxy groups are groups represented by the formulas: -O-alkyl, -O-haloalkyl, -O-heterocycloalkyl, and -O-arylalkyl, respectively, and the explanations for alkyl, haloalkyl, heterocycloalkyl, and arylalkyl are as described above.

[0045] Alkylthio group, haloalkylthio group, heterocycloalkylthio group and arylalkylthio group Alkylthio groups, haloalkylthio groups, heterocycloalkylthio groups, and arylalkylthio groups are groups represented by the formulas: -S-alkyl, -S-haloalkyl, -S-heterocycloalkyl, and -S-arylalkyl, respectively, and the explanations for alkyl, haloalkyl, heterocycloalkyl, and arylalkyl groups are as described above.

[0046] Alkyloxycarbonyl group The alkyloxycarbonyl group is a group represented by the formula -CO-O-alkyl group, and the description of the alkyl group is as described above. The number of carbon atoms in the alkyl group contained in the alkyloxycarbonyl group is preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, and more preferably 1 to 4.

[0047] monoalkylamino group The monoalkylamino group is represented by the formula: -NH(-Q 1 )[where, Q 1 represents an alkyl group. It is a group represented by ], and the explanation of alkyl groups is as described above. Q 1 The number of carbon atoms in the alkyl group represented is preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, and more preferably 1 or 2.

[0048] dialkylamino group The dialkylamino group is represented by the formula: -N(-Q 2 )(-Q 3 )[where, Q 2 and Q 3 Each of these independently represents an alkyl group. The group represented by ] is as described above. Q 2 Or Q 3 The number of carbon atoms in the alkyl group represented is preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, and more preferably 1 or 2.

[0049] Alicyclic amino group The alicyclic amino group is, for example, a 5- or 6-membered alicyclic amino group. Examples of 5- or 6-membered alicyclic amino groups include morpholino groups, thiomorpholino groups, pyrrolidine-1-yl groups, pyrazolidine-1-yl groups, imidazolidine-1-yl groups, and piperidine-1-yl groups. In addition to the nitrogen atom having the alicyclic amino group bond, the alicyclic amino group may also contain a heteroatom (for example, one heteroatom) independently selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. The alicyclic amino group is preferably a morpholino group.

[0050] 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 formulas: -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.

[0051] Substituent group α The substituent group α consists 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 Hydroxyl groups that may be protected with an (α-15) protecting group (α-16) Thiol groups may be protected with a protecting group.

[0052] Substituent group β The substituent group β consists of the following substituents: (β-1) substituent represented by formula (i) (β-2) Substituents 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, more preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, and more preferably 1 or 2. In (α-6), the number of halogen atoms in the haloalkyl group is preferably 1 to 3, more preferably 1 or 2, and more preferably 1.

[0055] Hydroxyl groups that may be protected by protecting groups Preferably, the hydroxyl group protecting group can protect the hydroxyl group during the desired reaction and can be removed from the hydroxyl group after the reaction is complete. Examples of hydroxyl group protecting groups include alkylcarbonyl protecting groups, arylcarbonyl protecting groups, arylalkyl protecting groups, alkyl protecting groups, arylalkyloxyalkyl protecting groups, alkyloxyalkyl protecting groups, silyl protecting groups, oxycarbonyl protecting groups, acetal protecting groups, and aryl protecting groups. These protecting groups may have one or more halogen atoms.

[0056] Examples of alkylcarbonyl protecting groups include C2-C10 alkylcarbonyl groups which may have one or more substituents. Substituents can be selected from, for example, halogen atoms, nitro groups, cyano groups, phenyl groups, C1-C10 alkyl groups, preferably C1-C8, more preferably C1-C6, more preferably C1-C4 alkyloxy groups, C2-C11 alkyloxycarbonyl groups which may have one or more substituents, preferably C2-C9, more preferably C2-C7, more preferably C2-C5 alkyloxycarbonyl groups, etc. Examples of C2-C10 alkylcarbonyl groups which may have one or more substituents include acetyl groups, propanoyl groups, butanoyl groups, isopropanoyl groups, pivaloyl groups, etc. The alkylcarbonyl protecting group is preferably a C2-C5 alkylcarbonyl group, more preferably an acetyl group or a pivaloyl group, and more preferably an acetyl group.

[0057] Examples of arylcarbonyl protecting groups include arylcarbonyl groups having 7 to 11 carbon atoms, which may have one or more substituents. Specific examples of substituents are the same as for alkylcarbonyl protecting groups. Examples of arylcarbonyl groups having 7 to 11 carbon atoms, which may have one or more substituents, include benzoyl group, 4-nitrobenzoyl group, 4-methyloxybenzoyl group, 4-methylbenzoyl group, 4-tert-butylbenzoyl group, 4-fluorobenzoyl group, 4-chlorobenzoyl group, 4-bromobenzoyl group, 4-phenylbenzoyl group, and 4-methyloxycarbonylbenzoyl group.

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

[0059] Examples of alkyl-type protecting groups include C1-C10 alkyl groups which may have one or more substituents. Specific examples of substituents are the same as those for alkylcarbonyl-type protecting groups. The alkyl-type protecting group is preferably a C1-C5 alkyl group which may have one or more substituents, more preferably a methyl group, an ethyl group, or a tert-butyl group, and more preferably a methyl group.

[0060] Examples of arylalkyloxyalkyl protecting groups include arylalkyloxyalkyl groups such as arylalkyloxymethyl groups having 8 to 12 carbon atoms that may have one or more substituents, arylalkyloxyethyl groups having 9 to 13 carbon atoms that may have one or more substituents, and arylalkyloxypropyl groups having 10 to 14 carbon atoms that may have one or more substituents. Specific examples of substituents are the same as for alkylcarbonyl protecting groups. Examples of arylalkyloxyalkyl protecting groups include benzyloxymethyl groups that may have one or more substituents, preferably benzyloxymethyl groups that may be substituted with a halogen atom, a nitro group, a cyano group, a methyl group, or a methyloxy group, and more preferably benzyloxymethyl groups.

[0061] Examples of alkyloxyalkyl protecting groups include alkyloxyalkyl groups such as a C2-C10 alkyloxymethyl group which may have one or more substituents, a C3-C10 alkyloxyethyl group which may have one or more substituents, and a C4-C10 alkyloxypropyl group which may have one or more substituents. Specific examples of substituents are the same as for alkylcarbonyl protecting groups. The alkyloxyalkyl protecting group is preferably a C2-C10 alkyloxymethyl group which may have one or more substituents, more preferably a C2-C6 alkyloxymethyl group which may have a halogen atom, a nitro group, a cyano group, a methyloxy group, or an ethyloxy group, and more preferably a methyloxymethyl group.

[0062] Examples of silyl protecting groups include silyl groups having a functional group selected from C1-C10 alkyl groups which may have one or more substituents, C7-C11 arylalkyl groups which may have one or more substituents, and C6-C10 aryl groups which may have one or more substituents. Specific examples of substituents are the same as for alkylcarbonyl protecting groups. The silyl protecting group is preferably a silyl group having a functional group selected from C1-C10 alkyl groups and C6-C10 aryl groups, more preferably a silyl group having a functional group selected from C1-C5 alkyl groups and phenyl groups, and more preferably a trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, or tert-butyldiphenylsilyl group.

[0063] Examples of oxycarbonyl protecting groups include C2-C10 alkyloxycarbonyl groups which may have one or more substituents, C3-C10 alkenyloxycarbonyl groups which may have one or more substituents, and C8-C12 arylalkyloxycarbonyl groups which may have one or more substituents. Specific examples of substituents are the same as for alkylcarbonyl protecting groups. Preferably, the oxycarbonyl protecting group is a C2-C6 alkyloxycarbonyl group, a C3-C6 alkenyloxycarbonyl group or benzyloxycarbonyl group, and more preferably a methyloxymethyl group, an allyloxycarbonyl group or a benzyloxycarbonyl group.

[0064] Examples of acetal protecting groups include tetrahydrofuranyl groups and tetrahydropyranyl groups.

[0065] Examples of aryl protecting groups include aryl groups such as the phenyl group.

[0066] The hydroxyl group protected by the protecting group is preferably a group represented by the formula -OQ. Q represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, a heterocycloalkyl group, an alkylcarbonyl group, an arylcarbonyl group, or an arylalkyl group. The number of carbon atoms in the group represented by the formula -OQ is preferably 1 to 10, more preferably 1 to 8. Q 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] Thiol groups that may not be protected by a protecting group It is preferable that the thiol protecting group can protect the thiol group during the desired reaction and can be removed from the thiol group after the reaction is complete. Examples of thiol protecting groups include alkylcarbonyl protecting groups, arylcarbonyl protecting groups, arylalkyl protecting groups, alkyl protecting groups, arylalkyloxyalkyl protecting groups, alkyloxyalkyl protecting groups, silyl protecting groups, oxycarbonyl protecting groups, acetal protecting groups, and aryl protecting groups. These protecting groups may have one or more halogen atoms. A description of these protecting groups is provided above.

[0068] The thiol group protected by the protecting group is preferably a group represented by the formula -SQ. The explanation for Q is as described above.

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

[0070] In equation (i), R 11 , R 12 and R 13Each of these independently represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, or a hydroxyl group that may be protected by a protecting group. The hydroxyl group that may be protected by a protecting group is preferably a group represented by the above formula:-OQ. a is between 0 and 3.

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

[0072] In equation (ii), V 10 This represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond, or a carbonyl group. The number of carbon atoms in the alkylene group or haloalkylene group is preferably 1 to 10, and more preferably 1 to 8. The number of carbon atoms in the arylene group, haloarylene group, heteroarylene group, or haloheteroarylene group is preferably 4 to 14, and more preferably 6 to 14. V 10 It is preferably an alkylene group, and more preferably a methylene group or an ethylene group.

[0073] In formula (ii), b represents either 0 or 1. It is preferable that b is 1.

[0074] In equation (ii), W 10 W represents an alkylene group, haloalkylene group, arylene group, haloarylene group, heteroarylene group, haloheteroarylene group, ester bond, ether bond, or carbonyl group. 10 It is preferably a heteroarylene group, more preferably a five-membered ring heteroarylene group containing a sulfur atom as a heteroatom, and even more preferably a thienylene group.

[0075] In formula (ii), c represents either 0 or 1. It is preferable that c is 1.

[0076] In equation (ii), X 10 This represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

[0077] X 10 The alkyl, aryl, or heteroaryl group represented by may have one or more substituents, and each of the one or more substituents can be independently selected from substituent group α. The one or more substituents are preferably independently selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio groups, haloalkylthio groups, heterocycloalkyloxy groups, and heterocycloalkylthio groups, more preferably selected from halogen atoms, C1-C3 alkyloxy groups, and heterocycloalkyloxy groups, and more preferably selected from fluorine atoms, ethyloxy groups, and tetrahydrofuranyloxy groups.

[0078] X 10 It is preferably an aryl group or heteroaryl group which may have substituents, more preferably an aryl group having a halogen atom, a C1-C3 alkyloxy group 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] ≪Thioester derivatives (I)≫ The thioester derivative (I) is represented by the following formula (I).

[0080] [ka]

[0081] In equation (I), n represents either 1 or 2.

[0082] In formula (I), R independently represents an alkyl group which may have substituents. The description of alkyl groups is as described above. Alkyl groups may be linear or branched, but linear is preferred. The number of carbon atoms in the alkyl group is preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3. Alkyl groups may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents can 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.

[0083] In formula (I), when n=1, the four R groups may be different, but it is preferable that they be the same from the viewpoint of efficient introduction and removal of the hydroxyl group protecting group represented by formula -CO-R. In one embodiment, all four R groups are methyl groups.

[0084] In formula (I), when n=2, the five R groups may be different, but it is preferable that they be the same from the viewpoint of efficient introduction and removal of the hydroxyl group protecting group represented by formula -CO-R. In one embodiment, all five R groups are methyl groups.

[0085] In equation (I), W 1 teeth, (1) an alkyl group which may have a substituent, (2) an alkenyl group which may have a substituent, (3) Cycloalkyl groups which may have substituents, (4) A heterocycloalkyl group which may have a substituent, (5) Aryl group which may have a substituent, (6) A heteroaryl group which may have a substituent, (7) an arylalkyl group which may have a substituent, or (8) Aryl alkenyl group which may have a substituent It represents.

[0086] The following describes the functional groups (1) to (8).

[0087] alkyl groups which may have substituents The description of alkyl groups is as described above. Alkyl groups may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents can 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.

[0088] Alkenyl groups which may have substituents The description of the alkenyl group is as 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 can 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.

[0089] cycloalkyl groups which may have substituents The description of cycloalkyl groups is as described above. Cycloalkyl groups may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents can 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.

[0090] Heterocycloalkyl groups which may have substituents The description of heterocycloalkyl groups is as described above. Heterocycloalkyl groups may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents can 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.

[0091] aryl group which may have substituents The description of the aryl group is as 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 can 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.

[0092] Optional heteroaryl group The description of 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 can 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.

[0093] Arylalkyl groups which may have substituents The description of arylalkyl groups is as described above. An arylalkyl group may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. Each of the one or more substituents can be independently selected from substituent groups α and β. Alternatively, one or more substituents may be selected from substituent group α and one or more substituents may be selected from substituent group β.

[0094] arylalkenyl group which may have a substituent The description of the arylalkenyl group is as 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 can 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.

[0095] In one embodiment, W in formula (I)1 This is an alkyl group which may have substituents, preferably an alkyl group having 1 to 20 carbon atoms which may have substituents, more preferably an alkyl group having 1 to 16 carbon atoms which may have substituents, and more preferably an alkyl group having 1 to 12 carbon atoms which may have substituents.

[0096] In one embodiment, the thioester derivative (I) is a thioester derivative (Ia) represented by the following formula (Ia). The thioester derivative (Ia) is an example of a thioester derivative (I) where n=2.

[0097] [ka]

[0098] In equation (Ia), R 1 ~R 5 Each of these independently represents a hydroxyl group protecting group represented by the formula -CO-R. R is synonymous with formula (I). 1 ~R 5 Although they may be different hydroxyl protecting groups, it is preferable that they be the same hydroxyl protecting group from the viewpoint of efficient introduction and removal of the hydroxyl protecting group. In one embodiment, R 1 ~R 5 These are all acetyl groups.

[0099] In equation (Ia), W 1 This is synonymous with equation (I). In one embodiment, W in equation (Ia) 1 This is an alkyl group which may have substituents, preferably an alkyl group having 1 to 20 carbon atoms which may have substituents, more preferably an alkyl group having 1 to 16 carbon atoms which may have substituents, and more preferably an alkyl group having 1 to 12 carbon atoms which may have substituents. 1 Examples of thioester derivatives (Ia) in which the alkyl group may have substituents include the following compounds. Note that "Ac" represents an acetyl group (the same applies throughout this specification).

[0100] [Chemical formula]

[0101] In the above compound, -C 1 corresponding to W 12 H 25 may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents can each independently be selected from substituent 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.

[0102] In the above compound, -C 1 corresponding to W 12 H 25 can be changed to another alkyl group. Examples of the other alkyl group include -C 10 H 21 , -C 11 H 23 and the like. 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 can each independently be selected from substituent groups α and β. One or more substituents may be selected from substituent group α and one or more substituents may be selected from substituent group β.

[0103] In another embodiment, the thioester derivative (I) is a thioester derivative (Ib) represented by the following formula (Ib). The thioester derivative (Ib) is an example of the thioester derivative (I) where n = 1.

[0104] [Chemical formula]

[0105] R 1 , R 2 , R 3 , R 5 and W 1is synonymous with formula (Ia).

[0106] ≪Ketone derivative (II)≫ The ketone derivative (II) is represented by the following formula (II).

[0107] [Chemical formula]

[0108] In formula (II), R and n are synonymous with formula (I). Therefore, the above description regarding R and n also applies to R and n in formula (II).

[0109] In formula (II), when n = 1, the four Rs may be different, but from the perspective of efficient introduction and removal of the hydroxy group protecting group represented by the formula: -CO-R, it is preferable that they are the same. In one embodiment, all four Rs are methyl groups.

[0110] In formula (II), when n = 2, the five Rs may be different, but from the perspective of efficient introduction and removal of the hydroxy group protecting group represented by the formula: -CO-R, it is preferable that they are the same. In one embodiment, all five Rs are methyl groups.

[0111] In formula (II), W 2 is (1) an alkyl group which may have a substituent, (2) an alkenyl group which may have a substituent, (3) a cycloalkyl group which may have a substituent, (4) a heterocycloalkyl group which may have a substituent, (5) an aryl group which may have a substituent, (6) a heteroaryl group which may have a substituent, (7) an arylalkyl group which may have a substituent, or, (8) an arylalkenyl group which may have a substituent represents.

[0112] Functional groups (1) to (8) are synonymous with those in formula (I), and the above explanation regarding functional groups (1) to (8) also applies to functional groups (1) to (8) in formula (II).

[0113] In the functional group (5) (i.e., an aryl group which may have substituents), the carbon atom having the bond of the aryl group (i.e., in formula (II), -CO-(-CO-W) 2 In the above, the carbon atoms adjacent to the carbon atom bonded to the -CO- atom are preferably unsubstituted. The remaining carbon atoms may have substituents.

[0114] In the functional group (6) (i.e., a heteroaryl group which may have substituents), the carbon atom having the bond of the heteroaryl group (i.e., in formula (II), -CO-(-CO-W) 2 In the above, the carbon atoms or heteroatoms adjacent to the carbon atom bonded to -CO- are preferably unsubstituted. The remaining carbon atoms or heteroatoms may have substituents.

[0115] W 2 is, W 1 It may be the same as, or it may be different from, it may be.

[0116] W 2 It is preferable that it is represented by the following formula (iv).

[0117] [ka]

[0118] In equation (iv), Y 10 This represents an optionally substituted alkylene group, an optionally substituted arylene group, or an optionally substituted heteroarylene group. The alkylene group preferably has 1 to 10 carbon atoms, and more preferably 1 to 8 carbon atoms. The arylene group or heteroarylene group preferably has 4 to 14 carbon atoms, and more preferably 6 to 14 carbon atoms.

[0119] Y 10 The alkylene group, arylene group or heteroarylene group represented by may have one or more substituents, and the one or more substituents can each be independently selected from the substituent group α. The one or more substituents are each preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group and a haloalkylthio group, and more preferably from a halogen atom, an alkyl group having 1 to 3 carbon atoms and an alkyloxy group having 1 to 3 carbon atoms.

[0120] 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.

[0121] Y 10 is an arylene group in which the carbon atoms adjacent to both sides of the carbon atom bonded to -CO- (the -CO- in -CO-W 2 do not have substituents, and the remaining carbon atoms may have substituents, or a heteroarylene group in which the carbon atoms or heteroatoms adjacent to both sides of the carbon atom bonded to -CO- (the -CO- in -CO-W 2 do not have substituents, and the remaining carbon atoms or heteroatoms may have substituents. Y 10 is preferably a phenylene group in which the ortho position to the carbon atom bonded to -CO- (the -CO- in -CO-W 2 does not have a substituent, and the meta position and / or para position may have substituents.

[0122] In formula (iv), V 10 、W 10 、X 10 、b and c are each synonymous with formula (ii).

[0123] Or, W 2It is preferable that it be expressed by the following formula (vi).

[0124] [ka]

[0125] In equation (vi), R 41 and R 42 Each of these independently represents a protecting group for a hydrogen atom or an amino group. Any protecting group can be used for the amino group, including carbamate, acyl, amide, sulfonamide, and phthaloyl groups. Examples of carbamate protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and allyloxycarbonyl groups. Examples of acyl protecting groups include acetyl, pivaloyl, and benzoyl groups. Examples of amide protecting groups include trifluoroacetyl. Examples of sulfonamide protecting groups include p-toluenesulfonyl and 2-nitrobenzenesulfonyl groups. The protecting group for the amino group is preferably an acyl or amide group. It is more preferable that the protecting group for the amino group is a pivaloyl or trifluoroacetyl group. 41 and R 42 These may be bonded to each other to form protecting groups for amino groups such as phthaloyl groups. 2 If it has the structure of formula (vi), it can be suitably used as an intermediate for remdesivir.

[0126] The ketone derivative (II) includes the ketone derivative (IIA) represented by the following formula (IIA). The ketone derivative (IIA) corresponds to the ketone derivative (II) where n=2.

[0127] [ka]

[0128] In equation (IIA), W2 and R is synonymous with formula (II), and m represents 2.

[0129] In one embodiment, the ketone derivative (II) is a ketone derivative (IIa) represented by the following formula (IIa). The ketone derivative (IIa) is an example of the ketone derivative (II) where n = 2 (i.e., the ketone derivative (IIA)).

[0130]

Chemical formula

[0131] In formula (IIa), R 1 ~R 5 each independently represents a hydroxy group protecting group represented by the formula: -CO-R. R is synonymous with the above. R 1 ~R 5 may be different hydroxy group protecting groups, but from the viewpoint of efficient introduction and removal of the hydroxy group protecting group, it is preferably the same hydroxy group protecting group. In one embodiment, R 1 ~R 5 are all acetyl groups.

[0132] In formula (IIa), W 2 is synonymous with formula (II). In one embodiment, W in formula (IIa) 2 is an aryl group which may have a substituent. Examples of the ketone derivative (IIa) where W 2 is an aryl group which may have a substituent include, for example, the following compounds. Note that "Ac" represents an acetyl group (the same applies throughout this specification).

[0133]

Chemical formula

[0134] In the above compounds, W 2The corresponding phenyl 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 can 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.

[0135] W in equations (II), (IIA), or (IIa) 2 From the viewpoint of using ketone derivatives (II), (IIA), or (IIa) as raw materials for the manufacture of SGLT-2 inhibitors or their derivatives, it is preferable that the functional group is identical to that of the SGLT-2 inhibitor or is a functional group derived from the functional group of the SGLT-2 inhibitor.

[0136] Here, 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-[( SGLT-2 inhibitors, including 1-benzothiophene-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid and dapagliflozin ((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).

[0137] Therefore, W in equations (II), (IIA), or (IIa) 2 Preferably, it is a functional group represented by the following formula (A).

[0138] [ka]

[0139] In formula (A), d represents an integer from 0 to 4. d is preferably from 1 to 3, more preferably 1 or 2, and even more preferably 1. When d is 2 or more, the d R a may be the same or different.

[0140] In formula (A), the d R a can each independently be selected from the substituent group α. The d R a 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.

[0141] In formula (A), Ar’ is a group represented by the following formula (v).

[0142]

Chemical formula

[0143] In formula (v), W 10 , X 10 and c are each synonymous with formula (ii).

[0144] In formula (A), Ar’ is preferably a group represented by the following formula (Ar’-1), (Ar’-2), or (Ar’-3).

[0145]

Chemical formula

[0146] In formula (Ar’-1), (Ar’-2), and (Ar’-3), p is an integer from 0 to 5. p is preferably an integer from 0 to 3, more preferably an integer from 0 to 2, and even more preferably 0 or 1.

[0147] In equations (Ar'-1), (Ar'-2), and (Ar'-3), p R b Each of these can be independently selected from substituent group α, an aryl group which may have one or more substituents selected from substituent group α, and a heteroaryl group which may have one or more substituents selected from substituent group α. p R b It is preferable that each substituent is independently selected from substituent group α and an aryl group which may have one or more substituents selected from substituent group α. The one or more substituents selected from substituent group α are preferably independently selected from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, haloalkyloxy groups, alkylthio groups, haloalkylthio groups, heterocycloalkyloxy groups and heterocycloalkylthio groups, more preferably selected from halogen atoms, C1-C3 alkyl groups, C1-C3 alkyloxy groups and heterocycloalkyloxy groups, and more preferably selected from fluorine atoms, ethyloxy groups and tetrahydrofuranyloxy groups.

[0148] If p is 2 or greater, then p R b They may be the same or they may be different.

[0149] In equation (Ar'-1), p is preferably 1, and R b Preferably, the phenyl group is a phenyl group which may have substituents, more preferably a phenyl group which has a halogen atom, and more preferably a phenyl group which has a fluorine atom. The position to which the unsubstituted or substituted phenyl group is attached is preferably the 2nd position of the thiophene ring. In the case of a phenyl group which has a halogen atom, the position to which the halogen atom is attached is preferably the 4th position of the benzene ring.

[0150] In equation (Ar'-2), p is preferably 0.

[0151] In formula (Ar'-3), p is preferably 1, and R bPreferably, the alkyloxy group is a optionally substituted alkyloxy group or an optionally substituted heterocycloalkyloxy group. The optionally substituted alkyloxy group is preferably a C1-C3 alkyloxy group, and more preferably a methoxy group or an ethoxy group. The optionally substituted heterocycloalkyloxy group is preferably a tetrahydrofuranyloxy group. The position to which the optionally substituted alkyloxy group or the optionally substituted heterocycloalkyloxy group is attached is preferably at position 4 of the benzene ring.

[0152] When d=1, the functional group represented by formula (A) is preferably the group represented by formula (B) below.

[0153] [ka]

[0154] In equation (B), R a And Ar' are synonymous with equation (A).

[0155] The group represented by formula (A) or (B) is preferably a group represented by the following formulas (Ar-1), (Ar-2), (Ar-3), or (Ar-4). Note that "Et" represents an ethyl group (this is the same throughout this specification).

[0156] [ka]

[0157] Ketone derivatives (II), (IIA), or (IIa) are, for example, W 2 However, it is a compound with a group represented by formula (Ar-1). Examples of such compounds include the following compounds. Note that "Ac" represents an acetyl group (this is the same throughout this specification).

[0158] [ka]

[0159] In another embodiment, ketone derivative (II) is ketone derivative (IIb) represented by the following formula (IIb). Ketone derivative (IIb) is an example of ketone derivative (II) where n=1.

[0160] [ka]

[0161] In equation (IIb), R 1 , R 2 , R 3 , R 5 and W 2 This is equivalent to equation (IIa).

[0162] ≪Thiol derivatives (III)≫ Thiol derivative (III) is represented by the following formula (III).

[0163] [ka]

[0164] In equation (III), W 1 , R and n are equivalent to equation (I). Therefore, W 1 The above explanation regarding R and n is based on W in equation (III). 1 This also applies to R and n.

[0165] In formula (III), when n=1, the three R groups may be different, but it is preferable that they be the same from the viewpoint of efficient introduction and removal of the hydroxyl protecting group represented by formula -CO-R. In one embodiment, all three R groups are methyl groups.

[0166] In formula (III), when n=2, the four R groups may be different, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxyl group protecting group represented by formula -CO-R. In one embodiment, all four R groups are methyl groups.

[0167] In one embodiment, the thiol derivative (III) is a thiol derivative (IIIa) represented by the following formula (IIIa). The thiol derivative (IIIa) is an example of a thiol derivative (III) where n=2.

[0168] [ka]

[0169] In equation (IIIa), R 1 ~R 4 This is equivalent to equation (Ia). Therefore, R 1 ~R 4 The above explanation regarding R in equation (IIIa) 1 ~R 4 This also applies to...

[0170] In equation (IIIa), R 1 ~R 4 Although they may be different hydroxyl protecting groups, it is preferable that they be the same hydroxyl protecting group from the viewpoint of efficient introduction and removal of the hydroxyl protecting group. In one embodiment, R 1 ~R 4 These are all acetyl groups.

[0171] In another embodiment, thiol derivative (III) is thiol derivative (IIIb) represented by the following formula (IIIb). Thiol derivative (IIIb) is an example of thiol derivative (III) where n=1.

[0172] [ka]

[0173] In equation (IIIb), R 1 ~R 3 This is equivalent to equation (Ib). Therefore, R 1 ~R 3 The above explanation regarding R in equation (IIIb) 1 ~R 3 This also applies to...

[0174] In equation (IIIb), R 1 ~R 3 Although they may be different hydroxyl protecting groups, it is preferable that they be the same hydroxyl protecting group from the viewpoint of efficient introduction and removal of the hydroxyl protecting group. In one embodiment, R 1 ~R 3 These are all acetyl groups.

[0175] ≪Acyl-protected lactone derivatives (IV)≫ Acyl-protected lactone derivatives (IV) are represented by the following formula (IV).

[0176] [ka]

[0177] In equation (IV), R and n are equivalent to those in equation (I). Therefore, the above explanation regarding R and n also applies to R and n in equation (IV).

[0178] In formula (IV), when n=1, the three R groups may be different, but it is preferable that they be the same from the viewpoint of efficient introduction and removal of the hydroxyl group protecting group represented by formula -CO-R. In one embodiment, all three R groups are methyl groups.

[0179] In formula (IV), when n=2, the four R groups may be different, but it is preferable that they be the same from the viewpoint of efficient introduction and removal of the hydroxyl protecting group represented by formula -CO-R. In one embodiment, all four R groups are methyl groups.

[0180] In one embodiment, the acyl-protected lactone derivative (IV) is an acyl-protected lactone derivative (IVa) represented by the following formula (IVa). The acyl-protected lactone derivative (IVa) is an example of an acyl-protected lactone derivative (IV) having n=2 (i.e., a 6-membered ring).

[0181] [ka]

[0182] In equation (IVa), R is equivalent to equation (IV).

[0183] ≪C-aryl-hydroxyglycoside derivative (V)≫ The C-aryl-hydroxyglycoside derivative (V) is represented by the following formula (V).

[0184] [ka]

[0185] In equation (V), W 2 And n are equivalent to equation (II). Therefore, W 2 The above explanation regarding and n is related to W in equation (V). 2 This also applies to n.

[0186] R 100 As will be described later, this is a group determined by the acid used when producing the C-aryl-hydroxyglycoside derivative (V). Specifically, R 100 This is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group. The optionally substituted alkyl group and optionally substituted aryl group in formula (V) are synonymous with those in formula (I), and the above description of functional groups (1) and (5) also applies to the optionally substituted alkyl group and optionally substituted aryl group in formula (V). 100Preferably, is a hydrogen atom, a methyl group, a phenyl group, or a methylphenyl group, and more preferably a methyl group.

[0187] In one embodiment, the C-aryl-hydroxyglycoside derivative (V) is a C-aryl-hydroxyglycoside derivative (Va) represented by the following formula (Va). The C-aryl-hydroxyglycoside derivative (Va) has n=2 (i.e., a 6-membered ring), and R 100 This is an example of a C-aryl-hydroxyglycoside derivative (V) in which is a hydrogen atom. In formula (Va), W 2 This is equivalent to equation (V).

[0188] [ka]

[0189] In other embodiments, the C-aryl-hydroxyglycoside derivative (V) is a C-aryl-hydroxyglycoside derivative (Vb) represented by the following formula (Vb). The C-aryl-hydroxyglycoside derivative (Vb) has n=2 (i.e., a 6-membered ring), and R 100 R 101 This is an example of a C-aryl-hydroxyglycoside derivative (V). 101 R is a group other than a hydrogen atom, in other words, an alkyl group which may have substituents, or an aryl group which may have substituents. 101 is preferably a methyl group, a phenyl group, or a methylphenyl group, and more preferably a methyl group. In formula (Vb), W 2 This is equivalent to equation (V).

[0190] [ka]

[0191] ≪C-arylglycoside derivative (VI)≫ The C-aryl glycoside derivative (VI) is represented by the following formula (VI).

[0192] [ka]

[0193] In equation (VI), W 2 This is equivalent to equation (II), where m represents 2. Therefore, W 2 The above explanation regarding W in equation (VI) 2 This also applies to...

[0194] In one embodiment, the C-arylglycoside derivative (VI) is a C-arylglycoside derivative (VIa) represented by the following formula (VIa). In formula (VIa), W 2 This is equivalent to equation (VI).

[0195] [ka]

[0196] ≪C-arylglycoside derivative (VII)≫ The C-arylglycoside derivative (VII) is represented by the following formula (VII).

[0197] [ka]

[0198] In equation (VII), W 2 And n are equivalent to equation (II). W 2 The above explanation regarding and n is based on W in equation (VI). 2 This also applies to n.

[0199] In one embodiment, the C-arylglycoside derivative (VII) is a C-arylglycoside derivative (VIIa) represented by the following formula (VIIa). The C-arylglycoside derivative (VIIa) is an example of a C-arylglycoside derivative (VII) with n=2 (i.e., a 6-membered ring). In formula (VIIa), W 2 This is equivalent to equation (VII).

[0200] [ka]

[0201] <<Lactone derivative (VIII)>> The lactone derivative (VIII) is represented by the following formula (VIII).

[0202] [ka]

[0203] In equation (VIII), n is equivalent to n in equation (I). Therefore, the above explanation for n also applies to n in equation (VIII).

[0204] In one embodiment, lactone derivative (VIII) is a lactone derivative (VIIIa) represented by the following formula (VIIIa). Lactone derivative (VIIIa) is an example of lactone derivative (VIII) having n=2 (i.e., a 6-membered ring).

[0205] [ka]

[0206] ≪Carboxylic Acid Anhydride (1)≫ Carboxylic acid anhydride (1) is represented by the following formula (1).

[0207] [ka]

[0208] In equation (1), R is equivalent to that in equation (I). Therefore, the above explanation of R also applies to R in equation (1).

[0209] In formula (1), the two R groups may be different, but it is preferable that they be the same from the viewpoint of efficient introduction and removal of the hydroxyl group protecting group represented by formula -CO-R. In one embodiment, both R groups are methyl groups. That is, the carboxylic acid anhydride (1) in one embodiment is acetic anhydride.

[0210] The R in formula (1) may be different from the R in formula (III), but it is preferable that they be the same. In one embodiment, both the R in formula (1) and the R in formula (III) are methyl groups.

[0211] ≪Thiol (2)≫ Thiol (2) is represented by the following formula (2).

[0212] [ka]

[0213] In equation (2), W 1 This is equivalent to equation (I). Therefore, W 1 The above explanation regarding W in equation (2) 1 This also applies to...

[0214] ≪Grignard Reagent (3)≫ Grignard reagent (3) is represented by the following formula (3).

[0215] [ka]

[0216] In equation (3), W 3 teeth, (1) an alkyl group which may have a substituent, (2) an alkenyl group which may have a substituent, (3) Cycloalkyl groups which may have substituents, (4) A heterocycloalkyl group which may have a substituent, (5) Aryl group which may have a substituent, (6) A heteroaryl group which may have a substituent, (7) an arylalkyl group which may have a substituent, or (8) Aryl alkenyl group which may have a substituent It represents.

[0217] Functional groups (1) to (8) are synonymous with formula (I), and the above explanation regarding functional groups (1) to (8) also applies to functional groups (1) to (8) in formula (3).

[0218] In functional group (5) (i.e., an aryl group which may have substituents), it is preferable that the carbon atoms adjacent to the carbon atom having the aryl bond (i.e., the carbon atom bonded to Mg in formula (3)) are unsubstituted. The remaining carbon atoms may have substituents.

[0219] In functional group (6) (i.e., a heteroaryl group which may have substituents), it is preferable that the carbon atoms or heteroatoms located on either side of the carbon atom having the heteroaryl bond (i.e., the carbon atom bonded to Mg in formula (3)) are unsubstituted. The remaining carbon atoms or heteroatoms may have substituents.

[0220] W 3 is, W 1 and / or W 2 It may be the same as, or it may be different from, it may be.

[0221] In formula (3), X represents a halogen atom. The halogen atom is preferably selected from a chlorine atom, a bromine atom, and an iodine atom, more preferably from a chlorine atom and a bromine atom, and more preferably from a chlorine atom.

[0222] In one embodiment, W in formula (3) 3 This is an alkyl group which may have substituents. The description of alkyl groups is as described above. Alkyl groups may be linear or branched, but linear is preferred. The number of carbon atoms in the alkyl group is preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3. Alkyl groups may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents can each 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.

[0223] In another embodiment, W in formula (3) 3 This is an aryl group which may have substituents. The description of the aryl group is as described above. The number of carbon atoms in the aryl group is preferably 6 to 14, more preferably 6 to 10. The aryl group is, for example, a phenyl group. 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 can each 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.

[0224] W 3 Examples of Grignard reagents (3) in which the alkyl group is included are alkylmagnesium bromide and alkylmagnesium chloride, of which alkylmagnesium chloride is preferred.

[0225] Examples of alkylmagnesium bromides include methylmagnesium bromide, ethylmagnesium bromide, n-propylmagnesium bromide, isopropylmagnesium bromide, n-butylmagnesium bromide, and isobutylmagnesium bromide.

[0226] Examples of alkylmagnesium chlorides include methylmagnesium chloride, ethylmagnesium chloride, n-propylmagnesium chloride, isopropylmagnesium chloride, n-butylmagnesium chloride, and isobutylmagnesium chloride.

[0227] W 3 Examples of Grignard reagents (3) in which the group is an aryl group include arylmagnesium bromide and arylmagnesium chloride, of which arylmagnesium chloride is preferred.

[0228] Examples of arylmagnesium bromides include phenylmagnesium bromide.

[0229] Examples of aryl magnesium chlorides include phenylmagnesium chloride.

[0230] ≪Grignard Reagent (4)≫ The Grignard reagent (4) is selected from Grignard reagent (4a) represented by the following formula (4a) and Grignard reagent (4b) represented by the following formula (4b).

[0231] [ka]

[0232] [ka]

[0233] In equations (4a) and (4b), W 2 This is equivalent to equation (II). That is, in equations (4a) and (4b), W 2 teeth, (1) an alkyl group which may have a substituent, (2) an alkenyl group which may have a substituent, (3) Cycloalkyl groups which may have substituents, (4) A heterocycloalkyl group which may have a substituent, (5) Aryl group which may have a substituent, (6) A heteroaryl group which may have a substituent, (7) an arylalkyl group which may have a substituent, or (8) Aryl alkenyl group which may have a substituent Represents W 2 The above explanation regarding W in equations (4a) and (4b) 2 This also applies to...

[0234] In functional group (5) (i.e., an aryl group which may have substituents), it is preferable that the carbon atoms adjacent to the carbon atom having the aryl bond (i.e., the carbon atom bonded to Mg in formula (4a) or (4b)) are unsubstituted. The remaining carbon atoms may have substituents.

[0235] In functional group (6) (i.e., a heteroaryl group which may have substituents), it is preferable that the carbon atoms or heteroatoms located on either side of the carbon atom having the heteroaryl bond (i.e., the carbon atom bonded to Mg in formula (4a) or (4b)) are unsubstituted. The remaining carbon atoms or heteroatoms may have substituents.

[0236] In formulas (4a) and (4b), X represents a halogen atom. The halogen atom is preferably selected from chlorine, bromine, and iodine atoms, more preferably from chlorine and bromine atoms, and more preferably from bromine atoms. X in formulas (4a) and (4b) may be the same as or different from X in formula (3).

[0237] Method for producing thioester derivative (I) The thioester derivative (I) can be produced by a method that includes the step of contacting the thiol derivative (III) and the carboxylic acid anhydride (1) in the presence of a base to produce the thioester derivative (I).

[0238] In one embodiment, the thioester derivative (I) is the thioester derivative (Ia). The thioester derivative (Ia) can be produced by a method that includes the step of contacting the thiol derivative (IIIa) with the carboxylic acid anhydride (1) in the presence of a base to produce the thioester derivative (Ia).

[0239] In another embodiment, thioester derivative (I) is thioester derivative (Ib). Thioester derivative (Ib) can be produced by a method that includes the step of contacting thiol derivative (IIIb) and carboxylic acid anhydride (1) in the presence of a base to produce thioester derivative (Ib).

[0240] The thiol derivative (III) and carboxylic acid anhydride (1) may be commercially available products or may be manufactured according to conventional methods.

[0241] When thiol derivative (III) and carboxylic acid anhydride (1) are brought into contact in the presence of a base, the hydroxyl group contained in thiol derivative (III) is protected by a hydroxyl protecting group represented by the formula -CO-R, yielding thioester derivative (I).

[0242] Contact between the thiol derivative (III) and the carboxylic acid anhydride (1) is preferably carried out in a solvent. Contact can be achieved by mixing the thiol derivative (III) and the carboxylic acid anhydride (1) in a solvent. The solvent is preferably an organic solvent. Examples of solvents include polar aprotic solvents such as 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, and butyl acetate; and nonpolar solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane. One solvent may be used alone, or a combination of two or more solvents may be used. The solvents are preferably THF, tert-butyl methyl ether, methylene chloride, toluene, or a mixture thereof.

[0243] The amount of solvent used is, for example, 1 to 200 mL, preferably 2 to 100 mL, per 1 g of thiol derivative (III).

[0244] The contact between the thiol derivative (III) and the carboxylic acid anhydride (1) is carried out in the presence of a base. The amount of carboxylic acid anhydride (1) used is, for example, 0.1 to 10 moles, preferably 0.2 to 5 moles, and more preferably 0.5 to 3 moles, per mole of thiol derivative (III).

[0245] Examples of bases include triethylamine, pyridine, 4-dimethylaminopyridine (4-DMAP), N,N-diisopropylethylamine (DIEA), imidazole, diazabicycloundecene (DBU), diethylaniline and other organic amines, sodium acetate, and Schottenbaumann conditions.

[0246] The amount of base used is, for example, 0.1 to 10 moles, preferably 0.2 to 5 moles, and more preferably 0.3 to 3 moles, per mole of thiol derivative (III).

[0247] When contacting the thiol derivative (III) with the carboxylic acid anhydride (1), the contact temperature (reaction temperature) is, for example, -30 to 100°C, preferably -10 to 80°C, more preferably 0 to 50°C, and the contact time (reaction time) is, for example, 0.1 to 24 hours, preferably 0.5 to 17 hours, more preferably 0.5 to 5 hours. The contact environment is preferably an inert atmosphere, and more preferably an argon atmosphere or a nitrogen atmosphere.

[0248] The obtained thioester derivative (I) can be isolated by the following method.

[0249] First, a quenching solution (e.g., water, aqueous HCl solution, etc.) is added to the reaction mixture to stop the reaction. The reaction mixture with the added quenching solution is stirred to separate it into an aqueous layer and an organic layer. After extracting the organic layer, an organic solvent is added to the aqueous layer to separate it again into an organic layer and an aqueous layer. The organic layer is extracted and combined with the previously extracted organic layer to obtain the total organic layer. The total organic layer is washed with a washing solution (e.g., water, aqueous HCl solution, saturated NaHCO3 aqueous solution, saline solution, etc.), and then dried using sodium sulfate or the like to obtain a residue containing the thioester derivative (I) product.

[0250] Examples of organic solvents that can be added to the aqueous layer include acetonitrile, propionitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 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. One organic solvent may be used alone, or two or more organic solvents may be used in combination. The organic solvent is preferably methylene chloride, toluene, hexane, or a mixture thereof, and more preferably methylene chloride.

[0251] The structure of thioester derivative (I) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0252] A method for producing the thioester derivative (I) may include a step of producing the thiol derivative (III). In this case, after the step of producing the thiol derivative (III), a step of producing the thioester derivative (I) is carried out by contacting the thiol derivative (III) with the carboxylic acid anhydride (1).

[0253] Thiol derivative (III) can be produced by contacting thiol (2) with acyl-protected lactone derivative (IV) in the presence of trialkylaluminum, and then contacting the resulting compound with carboxylic acid anhydride (1). The compound produced by contacting thiol (2) with acyl-protected lactone derivative (IV) in the presence of trialkylaluminum contains a hydroxyl group. This hydroxyl group is protected by a hydroxyl group protecting group represented by the formula -CO-R upon reaction with carboxylic acid anhydride (1), thereby yielding thiol derivative (III). Trialkylaluminum acts as a reactant. Examples of trialkylaluminum include trimethylaluminum, triethylaluminum, and trippropylaluminum. For details on the reaction conditions between thiol(2) and acyl-protected lactone derivative(IV) in the presence of trialkylaluminum, please refer to International Publication No. 2020 / 129899, ​​Tiffany Malinky Gierasch, Zhangjie Shi, and Gregory L. Verdine, “Extensively Stereodiversified Scaffolds for Use in Diversity-Oriented Library Synthesis,” ORGANIC LETTERS, 2003, Vol. 5, No. 5, 621-624, etc.

[0254] However, trialkylaluminum compounds such as trimethylaluminum, which have been conventionally used as reactants, are highly flammable and require careful handling. Therefore, it is preferable to produce thiol derivative (III) by contacting thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV). Grignard reagent (3) has lower flammability compared to trialkylaluminum compounds such as trimethylaluminum, so relatively little attention is required to the environment in which it is used. Therefore, when using Grignard reagent (3), thiol derivative (III) can be produced more efficiently compared to when using trialkylaluminum compounds such as trimethylaluminum, and consequently, large-scale production of thiol derivative (III) can be achieved.

[0255] In one embodiment, the thiol derivative (III) is the thiol derivative (IIIa). The thiol derivative (IIIa) can be produced by contacting the thiol (2), the Grignard reagent (3), and the acyl-protected lactone derivative (IVa).

[0256] The thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) may be commercially available or may be manufactured according to conventional methods.

[0257] Examples of thiol(2) include ethanethiol, t-butyl mercaptan, thiophenol, benzyl mercaptan, 1-decanethiol, and 1-dodecanethiol.

[0258] The amount of thiol(2) used is, for example, 0.5 to 4 moles, preferably 0.7 to 3 moles, and more preferably 0.9 to 2 moles, per mole of acyl-protected lactone derivative(IV). It is preferable that the amount of thiol(2) is greater than the amount of acyl-protected lactone derivative(IV).

[0259] Grignard reagent (3) acts as a reagent to react the acyl-protected lactone derivative (IV) with thiol (2) after ring opening. One type of Grignard reagent (3) may be used alone, or two or more types of Grignard reagent (3) may be used in combination.

[0260] When thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) are brought into contact, preferably, magnesium thiolate is formed by the reaction of thiol (2) and Grignard reagent (3), and then thiol derivative (III) is formed by the reaction of magnesium thiolate with acyl-protected lactone derivative (IV). That is, when thiol (2) and Grignard reagent (3) react, hydrocarbon (W) is formed as shown in the following formula. 3 H) and magnesium thiolate (XMgSW 1It is thought that the following are produced. Then, when the produced magnesium thiolate reacts with the acyl-protected lactone derivative (IV), it is thought that the thiol derivative (III) is produced.

[0261] [ka]

[0262] The amount of Grignard reagent (3) used per mole of thiol (2) is, for example, 0.1 to 1 mole, preferably 0.3 to 1 mole, and more preferably 0.5 to 1 mole.

[0263] The amount of Grignard reagent (3) used per mole of acyl-protected lactone derivative (IV) is, for example, 0.1 to 1 mole, preferably 0.3 to 1 mole, and more preferably 0.5 to 1 mole.

[0264] Note that "amount of Grignard reagent (3)" refers to the amount of one type of Grignard reagent (3) if one type is used, and the total amount of two or more types of Grignard reagent (3) if two or more types are used. The same applies to the amounts of other substances.

[0265] When thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) are brought into contact, the contact temperature (reaction temperature) is, for example, -30 to 50°C, preferably -20 to 40°C, more preferably -10 to 30°C, and the contact time (reaction time) is, for example, 0.1 to 5 hours, preferably 0.2 to 4 hours, more preferably 0.5 to 3 hours. The contact environment is preferably an inert atmosphere, and more preferably an argon atmosphere or a nitrogen atmosphere.

[0266] Contact between thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) is preferably carried out in a solvent. By mixing thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) in a solvent, contact between thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) can be achieved. The solvent is preferably an organic solvent. Examples of solvents include methylene chloride, chlorobenzene, tetrahydrofuran (THF), diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, toluene, xylene, mesitylene, hexane, and heptane. One solvent may be used alone, or two or more solvents may be used in combination. The solvent is preferably THF, dibutyl ether, 2-methyltetrahydrofuran, or a mixture thereof.

[0267] The amount of solvent used is, for example, 0.5 to 100 mL, preferably 2 to 50 mL, per 1 g of acyl-protected lactone derivative (IV).

[0268] When contacting thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) in a solvent, the order of addition of thiol (2), Grignard reagent (3), acyl-protected lactone derivative (IV), and solvent is not particularly limited. For example, thiol (2) and solvent can be added to the acyl-protected lactone derivative (IV), and then Grignard reagent (3) can be added. Grignard reagent (3) can be added, for example, by dropwise addition.

[0269] The thiol derivative (III) may be isolated from the reaction mixture obtained by contacting thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) and then used in the reaction with carboxylic acid anhydride (1), or it may be used in the reaction with carboxylic acid anhydride (1) without being isolated from the reaction mixture.

[0270] In one embodiment, a thioester derivative (I) is produced by contacting thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) with a reaction mixture, without isolating thiol derivative (III) from the mixture. This is done by adding carboxylic acid anhydride (1) to the reaction mixture, thereby contacting thiol derivative (III) with carboxylic acid anhydride (1). In this embodiment, the amount of carboxylic acid anhydride (1) used is, for example, 0.5 to 10 moles, preferably 0.8 to 5.0 moles, and more preferably 1.0 to 3.0 moles, per mole of acyl-protected lactone derivative (IV). In this embodiment, since the Grignard reagent (3) contained in the reaction mixture acts as a base, there is no need to add a base to the reaction mixture. That is, according to this embodiment, thioester derivative (I) can be produced by contacting thiol derivative (III) and carboxylic acid anhydride (1) under the presence of Grignard reagent (3).

[0271] The resulting thiol derivative (III) can be isolated, for example, by the following method.

[0272] First, a quenching solution such as ice-cold water is added to the reaction mixture to stop the reaction. Next, it is preferable to add Brønsted acid to the reaction mixture after the addition of the quenching solution. This suppresses the cyclization of thiol derivative (III) to the structure of acyl-protected lactone derivative (IV). In particular, thiol derivative (III) obtained using acyl-protected lactone derivative (IV) having a 5-membered ring as a substrate is more prone to changing to the substrate structure compared to thiol derivative (III) obtained using acyl-protected lactone derivative (IV) having a 6-membered ring as a substrate. To address this problem, the cyclization of thiol derivative (III) can be suppressed by making the pH of the reaction mixture acidic, thereby increasing the yield.

[0273] The amount of Brønsted acid is, for example, 1 mole or more, preferably 3 moles or more, and more preferably 5 moles or more, per mole of acyl-protected lactone derivative (IV). There is no particular upper limit to the amount of Brønsted acid, but for example, it is 30 moles or less.

[0274] Examples of Brønsted acids include hydrogen halides, sulfuric acid (H2SO4), carbonic acid, acetic acid, oxalic acid, citric acid, trifluoroacetic acid (TFA), methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid. One type of Brønsted acid may be used alone, or two or more types of Brønsted acids may be used in combination. Examples of hydrogen halides include hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr), and hydrogen iodide (HI). Examples of Brønsted acids include hydrogen chloride, hydrogen bromide, and sulfuric acid. An acidic solution obtained by dissolving a Brønsted acid in water may also be used.

[0275] When using 1M hydrochloric acid as the Brønsted acid, the amount is preferably 10 to 30 mL per 1 g of acyl-protected lactone derivative (IV).

[0276] Next, the reaction mixture to which Brønsted acid has been added is stirred to separate it into an aqueous layer and an organic layer. After extracting the organic layer, an organic solvent is added to the aqueous layer to separate it again into an organic layer and an aqueous layer. The organic layer is extracted and combined with the previously extracted organic layer to obtain the total organic layer. The total organic layer is washed with a washing solution (e.g., water, aqueous HCl solution, saturated aqueous NaHCO3 solution, saline solution, etc.) and then dried using sodium sulfate or the like to obtain a residue containing the thiol derivative (III) product.

[0277] Examples of organic solvents that can be added to the aqueous layer include acetonitrile, propionitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 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. One organic solvent may be used alone, or two or more organic solvents may be used in combination. The organic solvent is preferably methylene chloride, toluene, hexane, or a mixture thereof, and more preferably methylene chloride.

[0278] The structure of thiol derivative (III) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0279] If the method for producing thioester derivative (I) includes a step of producing thiol derivative (III) by contacting thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV), the method for producing thioester derivative (I) may also include a step of producing acyl-protected lactone derivative (IV). In this case, the step of producing thiol derivative (III) by contacting thiol (2), Grignard reagent (3), and acyl-protected lactone derivative (IV) is performed after the step of producing acyl-protected lactone derivative (IV).

[0280] Acyl-protected lactone derivative (IV) can be produced by contacting lactone derivative (VIII) with carboxylic acid anhydride (1) in the presence of Brønsted acid.

[0281] When lactone derivative (VIII) is brought into contact with carboxylic acid anhydride (1) in the presence of Brønsted acid, the hydroxyl group contained in lactone derivative (VIII) is protected by a hydroxyl group protecting group represented by the formula -CO-R, yielding acyl-protected lactone derivative (IV).

[0282] In one embodiment, the acyl-protected lactone derivative (IV) is the acyl-protected lactone derivative (IVa). The acyl-protected lactone derivative (IVa) can be produced by contacting the lactone derivative (VIIIa) with a carboxylic acid anhydride (1) in the presence of a Brønsted acid.

[0283] The amount of carboxylic acid anhydride (1) used is, for example, 1 to 200 moles, preferably 1 to 100 moles, and more preferably 1 to 50 moles, per mole of lactone derivative (VIII).

[0284] Contact between the lactone derivative (VIII) and the carboxylic acid anhydride (1) may be carried out without a solvent, but it is preferable to carry out the contact in a solvent. Contact between the lactone derivative (VIII) and the carboxylic acid anhydride (1) can be achieved by mixing them in a solvent. The solvent is preferably an organic solvent. Examples of solvents include tetrahydrofuran (THF), methylene chloride, toluene, ethyl acetate, dioxane, and t-butyl methyl ether. One solvent may be used alone, or a combination of two or more solvents may be used. The solvents are preferably methylene chloride, toluene, or a mixture thereof. Examples of Brønsted acids include trifluoroacetic acid (TFA), sulfuric acid, and methanesulfonic acid, with TFA and sulfuric acid being preferred.

[0285] The amount of solvent used is, for example, 0 to 100 mL, preferably 0 to 50 mL, and more preferably 0 to 10 mL, per 1 g of lactone derivative (VIII).

[0286] The amount of Brønsted acid used is, for example, 0.1 to 100 mL, preferably 0.5 to 50 mL, and more preferably 1 to 30 mL, per 1 g of lactone derivative (VIII).

[0287] The contact between the lactone derivative (VIII) and the carboxylic acid anhydride (1) may be carried out in the presence of a base.

[0288] Specific examples of bases are similar to the specific examples of bases used when contacting thiol derivative (III) with carboxylic acid anhydride (1).

[0289] The amount of base used is, for example, 0 to 10 moles, preferably 0.1 to 5 moles, and more preferably 0.5 to 3 moles, per mole of lactone derivative (VIII).

[0290] When the lactone derivative (VIII) and the carboxylic acid anhydride (1) are brought into contact, the contact temperature (reaction temperature) is, for example, -10 to 50°C, preferably -5 to 40°C, more preferably 0 to 30°C, and the contact time (reaction time) is, for example, 0.1 to 10 hours, preferably 1 to 8 hours, more preferably 2 to 5 hours. The contact environment is preferably an inert atmosphere, and more preferably an argon atmosphere or a nitrogen atmosphere.

[0291] The acyl-protected lactone derivative (IV) may be isolated from the reaction mixture obtained by contacting the lactone derivative (VIII) with the carboxylic acid anhydride (1) in the presence of a Brønsted acid and then used in the reaction with thiol (2) and Grignard reagent (3), or it may be used in the reaction with thiol (2) and Grignard reagent (3) without isolation from the reaction mixture. For example, the acyl-protected lactone derivative (IV) may be concentrated by adding a solvent such as toluene to the reaction mixture obtained by contacting the lactone derivative (VIII) with the carboxylic acid anhydride (1) in the presence of a Brønsted acid and evaporating the volatile brønsted acid and carboxylic acid anhydride (1). The concentrate can then be used as is (i.e., without isolating the acyl-protected lactone derivative (IV) from the concentrate) in the reaction with thiol (2) and Grignard reagent (3).

[0292] In one embodiment, a step is performed to produce a thiol derivative (III) by contacting a lactone derivative (VIII) with a carboxylic acid anhydride (1) in the presence of a Brønsted acid, and without isolating the acyl-protected lactone derivative (IV) from the reaction mixture obtained, by adding a thiol (2) and a Grignard reagent (3) to the reaction mixture, thereby contacting the thiol (2) and the Grignard reagent (3) with the acyl-protected lactone derivative (IV). Then, without isolating the thiol derivative (III) from the obtained reaction mixture, a step is performed to produce a thioester derivative (I) by adding a carboxylic acid anhydride (1) to the reaction mixture, thereby contacting the thiol derivative (III) with the carboxylic acid anhydride (1). In this embodiment, the total amount of carboxylic acid anhydride (1) used (the sum of the amount of carboxylic acid anhydride (1) used in the production of acyl-protected lactone derivative (IV) and the amount of carboxylic acid anhydride (1) used in the production of thioester derivative (I)) is, for example, 1 to 200 moles, preferably 1 to 100 moles, and more preferably 1 to 50 moles, per mole of lactone derivative (VIII).

[0293] Method for producing ketone derivative (II) The ketone derivative (II) can be produced by a method that includes the step of contacting a thioester derivative (I), a Grignard reagent (4) selected from Grignard reagent (4a) and Grignard reagent (4b), and a copper salt to produce the ketone derivative (II).

[0294] In one embodiment, the ketone derivative (II) is the ketone derivative (IIa). The ketone derivative (IIa) can be produced by a method that includes the step of contacting the thioester derivative (Ia), a Grignard reagent (4) selected from Grignard reagent (4a) and Grignard reagent (4b), and a copper salt to produce the ketone derivative (IIa).

[0295] In another embodiment, ketone derivative (II) is ketone derivative (IIb). Ketone derivative (IIb) can be produced by a method comprising the step of contacting a thioester derivative (Ib) with a Grignard reagent (4) selected from Grignard reagent (4a) and Grignard reagent (4b) and a copper salt to produce ketone derivative (IIb).

[0296] As Grignard reagent (4), either Grignard reagent (4a) or Grignard reagent (4b) may be selected, or both may be selected. If both are selected, a mixture of both may be added to the reaction system, or they may be added to the reaction system separately.

[0297] Grignard reagent (4a) may be a commercially available product or may be manufactured according to conventional methods.

[0298] Grignard reagent (4) preferably contains Grignard reagent (4b) from the viewpoint of improving the reaction rate. Grignard reagent (4b) is called turboGrignard reagent.

[0299] Grignard reagent (4b) may be a commercially available product or may be manufactured by conventional methods. Grignard reagent (4b) may be prepared, for example, in a reaction vessel substituted with an inactivating gas (e.g., nitrogen, argon, etc.) in the presence of a lithium salt, with magnesium and formula: W 2 X [where W 2 And X is the same as above. It can be produced by reacting a halogen organic compound represented by ] in an organic solvent.

[0300] Furthermore, Grignard reagent (4b) is prepared according to a known method described in Angew Chem.Int.Ed2006,45,2958, etc., using a Noschel-Hauser base represented by the formula:TMPMgX·LiY [wherein TMP represents 2,2,6,6-tetramethylpiperidine] and the formula:W 2 It may also be produced by reacting it with a compound represented by -H.

[0301] [ka]

[0302] 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, copper(I) mesitylene (MesCu), copper(I) isopropoxy (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).

[0303] Examples of copper salts containing sulfur (S) include copper(I) thiophene-2-carboxylate (CuTC). S has a high affinity for Cu, and in copper salts, S readily coordinates to Cu. This coordination activates Cu, increasing the yield.

[0304] The valency of copper atoms in copper salts is usually monovalent or divalent, but preferably monovalent. Copper salts with monovalent copper atoms exhibit excellent catalytic activity. Among copper salts with monovalent copper atoms, CuCN, CuCl, CuI, CuBr, CuOAc, and CuTC exhibit particularly excellent catalytic activity. Therefore, copper salts are preferably CuCN, CuCl, CuI, CuBr, CuOAc, or CuTC, and more preferably CuCN, CuCl, CuOAc, or CuTC.

[0305] Ketone derivative (II) can be obtained in high yield by contacting thioester derivative (I), Grignard reagent (4), and copper salt. The inventors speculate that this is because an anionic complex (10) represented by formula (10) or an anionic complex (11) represented by formula (11) below is formed. That is, it is thought that the oxidative addition of the carbon-sulfur bond of thioester derivative (I) is promoted in the anionic complex (10) or (11), which is not neutral.

[0306] [ka]

[0307] [ka]

[0308] Furthermore, it is believed that anionic complex (10) is formed when a copper salt other than CuCN (e.g., CuCl, CuBr, CuI, CuOAc, etc.) is used, and anionic complex (11) is formed when CuCN is used as the copper salt.

[0309] The amount of copper salt used is preferably 0.1 to 1 mole, more preferably 0.3 to 0.9 moles, and more preferably 0.4 to 0.8 moles per mole of Grignard reagent (4). By setting the amount of copper salt used relative to Grignard reagent (4) within the above range, the formation of the anionic complex (10) or (11) tends to proceed smoothly. In one example, the amount of copper salt used is 0.5 to 0.9 moles per mole of Grignard reagent (4), and in another example, it is 0.6 to 0.8 moles.

[0310] When Grignard reagent (4) contains Grignard reagent (4b), the amount of copper salt used is, for example, 0.1 to 1 mole, preferably 0.3 to 0.9 moles, and more preferably 0.4 to 0.8 moles, per mole of Grignard reagent (4b). Alternatively, when Grignard reagent (4) contains Grignard reagent (4b), the amount of copper salt used is, in one example, 0.4 to 0.92 moles, in another example, 0.5 to 0.82 moles, and in yet another example, 0.6 to 0.72 moles, per mole of Grignard reagent (4b).

[0311] The amount of copper salt used is, for example, 0.1 to 10 moles, preferably 0.5 to 5 moles, and more preferably 1 to 3 moles, per mole of thioester derivative (I).

[0312] The amount of Grignard reagent (4) used is, for example, 1 to 10 moles, preferably 1 to 5 moles, and more preferably 1.5 to 4 moles, per mole of thioester derivative (I). The amount of Grignard reagent (4) used does not need to be in excess of the amount of thioester derivative (I) used.

[0313] When both Grignard reagent (4a) and Grignard reagent (4b) are selected as Grignard reagent (4), the amount of Grignard reagent (4b) is, for example, 10 to 90% by mass based on the total mass of Grignard reagent (4a) and Grignard reagent (4b).

[0314] Contact between the thioester derivative (I), the Grignard reagent (4), and the copper salt is preferably carried out in a solvent. By mixing the thioester derivative (I), the Grignard reagent (4), and the copper salt in a solvent, contact can be achieved. The solvent is preferably an organic solvent. Examples of solvents include tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, methylene chloride, toluene, xylene, hexane, and heptane. One solvent may be used, or two or more solvents may be used in combination. The solvent is preferably THF, toluene, or a mixture thereof.

[0315] The amount of solvent used is, for example, 1 to 100 mL, preferably 2 to 50 mL, per 1 g of thioester derivative (I).

[0316] When contacting the thioester derivative (I), Grignard reagent (4), and copper salt, the contact temperature (reaction temperature) is, for example, -20 to 150°C, preferably -10 to 120°C, more preferably 0 to 70°C, and more preferably 0 to 50°C. By using Grignard reagent (4), ketone derivative (II) can be produced even under relatively high temperature conditions. Therefore, compared to methods that require ultra-low temperatures below -10°C for the synthesis of ketone derivative (II), equipment costs related to temperature control can be suppressed, and cheaper industrial production of ketone derivative (II) can be realized. In addition, when the contact temperature (reaction temperature) is within the above temperature range, the yield of ketone derivative (II) tends to be higher.

[0317] When the thioester derivative (I), Grignard reagent (4), and copper salt are brought into contact, the contact time (reaction time) is, for example, 0.5 to 72 hours, preferably 1 to 48 hours.

[0318] When contacting the thioester derivative (I), Grignard reagent (4), and copper salt, it is preferable to first contact the Grignard reagent (4) with the copper salt to form an organocopper reagent, then mix in the thioester derivative (I), and finally contact the organocopper reagent with the thioester derivative (I). This allows for obtaining the ketone derivative (II) in high yield.

[0319] When the Grignard reagent (4) is brought into contact with the copper salt, the contact temperature (reaction temperature) is, for example, -20 to 150°C, preferably -10 to 100°C, more preferably 0 to 50°C, and the contact time (reaction time) is, for example, 0.1 to 5 hours, preferably 0.2 to 2 hours, more preferably 0.5 to 1 hour.

[0320] When an organocopper reagent is brought into contact with a thioester derivative (I), the contact temperature (reaction temperature) is, for example, -20 to 150°C, preferably -10 to 100°C, and more preferably 0 to 50°C, and the contact time (reaction time) is, for example, 0.1 to 5 hours, preferably 0.2 to 2 hours, and more preferably 0.5 to 1 hour.

[0321] When contacting the thioester derivative (I), the Grignard reagent (4), and the copper salt, the following formula (5a): [ka] An organozinc compound represented by (5a), and Formula (5b): [ka] One or both of the organozinc compounds (5b) represented by the formula may be used in combination with the Grignard reagent (4) and the copper salt. Organozinc compounds (5a) and organozinc compounds (5b) have a W group in the thioester derivative (I). 2 It can be used as a reagent for introducing [the substance].

[0322] In equations (5a) and (5b), W 2 This is equivalent to equation (II). Therefore, W 2The above explanation regarding W in equations (5a) and (5b) 2 This also applies to...

[0323] In formula (5a), X represents a halogen atom. The halogen atom is preferably selected from a chlorine atom, a bromine atom, and an iodine atom, more preferably from a chlorine atom and a bromine atom, and more preferably from a bromine atom. X in formula (5a) may be the same as or different from X in formulas (4a) and (4b).

[0324] When mixing the thioester derivative (I), the Grignard reagent (4), and the copper salt, it is preferable to use as little organozinc compound (5a) and organozinc compound (5b) as possible. The presence of organozinc compound (5a) and organozinc compound (5b) tends to reduce the yield of ketone derivative (II). The total amount of organozinc compound (5a) and organozinc compound (5b) used is preferably 10% by mass or less, more preferably 5% by mass or less, and more preferably 1% by mass or less, based on the mass of thioester derivative (I). The lower limit is zero.

[0325] Examples of organozinc compounds (5a) include aryl zinc halides (in formula (5a), W 2 A compound in which is an aryl group and X is a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom), alkyl zinc halide (in formula (5a), W 2 Examples include compounds in which is an alkyl group and X is a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom.

[0326] Examples of organozinc compounds (5b) include diarylzinc (in formula (5b), W 2 Compounds in which is an aryl group), dialkylzinc (in formula (5b), W 2 Examples include compounds in which the alkyl group is.

[0327] The organozinc compounds (5a) and (5b) may be commercially available products or may be manufactured according to conventional methods.

[0328] The organozinc compound (5a) and / or organozinc compound (5b) may be used together with a lithium salt, such as lithium chloride. The organozinc compound (5a) may form a complex with the lithium salt. The complex of organozinc compound (5a) and lithium salt can be represented, for example, by the following formula (5c).

[0329] [ka]

[0330] In equation (5c), W 2 And X is equivalent to equation (5a).

[0331] W 2 However, carbon atoms having an aryl bond (in formula (II), -CO- (i.e., -CO-W) 2 W that binds with -CO- in 2 The carbon atoms adjacent to the carbon atom (the carbon atom bonded to Mg in formula (4a) or (4b)) are unsubstituted, and the remaining carbon atoms may have substituents on an aryl group or a heteroaryl group bond (in formula (II), -CO- (i.e., -CO-W) 2 W that binds with -CO- in 2 In an embodiment in which the carbon atoms or heteroatoms adjacent to the carbon atom (the carbon atom bonded to Mg in formula (4a) or (4b)) are unsubstituted, and the remaining carbon atoms or heteroatoms are heteroaryl groups which may have substituents, the method for producing the ketone derivative (II) is as follows: formula (6): [ka] A Grignard reagent (6) represented by the formula may also be used.

[0332] In equation (6), W 4This represents a phenyl group having a substituent at least at one ortho position and possibly having substituents at the meta and / or para positions.

[0333] In equation (6), X 1 X represents a halogen atom. The halogen atom is preferably selected from chlorine, bromine, and iodine atoms, more preferably selected from chlorine and bromine atoms, and more preferably a bromine atom. X in formula (6) 1 X in equations (4a) and (4b) may be the same as or different from X.

[0334] Grignard reagent (6) can be used together with one or both of Grignard reagents (4a) and (4b). In this case, a mixture of one or both of Grignard reagents (4a) and (4b) and Grignard reagent (6) may be added to the reaction system, or Grignard reagents (4a) and (4b) and Grignard reagent (6) may be added separately to the reaction system.

[0335] In addition to Grignard reagent (4) and Grignard reagent (6), other Grignard reagents may be used. In this case, the total amount of Grignard reagent (4) and Grignard reagent (6) is preferably 80% by mass or more, and may be 100% by mass, based on the total mass of Grignard reagent (4), Grignard reagent (6), and other Grignard reagents.

[0336] When using Grignard reagent (6), ketone derivative (II) can be produced by contacting thioester derivative (I), Grignard reagent (4), copper salt, and Grignard reagent (6).

[0337] The compound represented by the following formula (4') is W 2However, an example of a Grignard reagent (4a) or (4b) is an aryl group in which the carbon atoms adjacent to the carbon atom having an aryl bond (the carbon atom bonded to Mg) are unsubstituted, and the remaining carbon atoms may have substituents, or the carbon atoms or heteroatoms adjacent to the carbon atom having a heteroaryl bond (the carbon atom bonded to Mg) are unsubstituted, and the remaining carbon atoms or heteroatoms may have substituents.

[0338] [ka]

[0339] In formula (4'), the carbon atoms adjacent to the carbon atom bonded to MgX, i.e., the ortho position, are unsubstituted. The meta position relative to the carbon atom bonded to MgX is R 21 and R 23 It has the following: The para position relative to the carbon atom bonded to MgX is R 22 It has R 21 , R 22 and R 23 Each of these is independently a hydrogen atom or a substituent selected from substituent groups α and β. f is either 0 or 1.

[0340] The compound represented by the following formula (6') is an example of a Grignard reagent (6), and hereafter referred to as W 4 I will explain the details.

[0341] [ka]

[0342] In equation (6'), R 31 , R 32 , R 33 , R 34 and R 35 Each of these independently represents a hydrogen atom or a substituent. MgX 1 R bonded to the meta position of the carbon atom that is bonded to it. 31 and R 35At least one of them is a substituent. 31 and R 35 It is preferable that both are substituents.

[0343] Substituents include, for example, alkyl groups, arylalkyl groups, halogen groups, nitrile groups, dialkylamino groups, alkyloxy groups, arylalkyloxy groups, alkylthio groups, or arylalkylthio groups. The number of carbon atoms in the alkyl group, dialkylamino group, alkyloxy group, or alkylthio group is preferably 1 to 10. The number of carbon atoms in the arylalkyl group, arylalkyloxy group, or arylalkylthio group is preferably 5 to 14.

[0344] The substituent is preferably an alkyl group, and more preferably a methyl group. 4 Preferred specific examples include the 2,4,6-trimethylphenyl group (mesityl group) and the 2,6-dimethylphenyl group (2,6-xylyl group).

[0345] Using Grignard reagent (6) can further increase the yield of ketone derivative (II). The inventors speculate that this is because Grignard reagents (4a) and (4b) are W 2 However, it is a compound in which the carbon atoms adjacent to the carbon atom bonded to Mg are unsubstituted aryl groups, or the carbon atoms or heteroatoms adjacent to the carbon atom bonded to Mg are unsubstituted heteroaryl groups. Grignard reagent (6) is W 4 However, at least one of the carbon atoms adjacent to the carbon atom bonded to Mg is a phenyl group with a substituent. Therefore, it is thought that when Grignard reagent (4a) and / or (4b) and Grignard reagent (6) are used, an anionic complex (12) represented by the following formula (12) is formed. In anionic complex (12), W 4 Since it has a substituent at least one ortho position, steric hindrance occurs, -SW 1 From -W 4 The substitution reaction to -SW is inhibited. 1From -W 2 The substitution reaction to is promoted. As a result, the yield of ketone derivative (II) per unit amount of Grignard reagents (4a) and (4b) can be increased compared to when anionic complex (10) or (11) is used. In addition, the substituent at the ortho position has an electron-donating effect. 2 This can increase the reactivity of the reaction. Furthermore, the W that is not used in the reaction 4 By introducing it into the reactant (organocopper reagent), the reaction actually occurs. 2 This allows for a reduction in the amount of Grignard reagent used to generate the reaction.

[0346] [ka]

[0347] Furthermore, using Grignard reagent (6), the -SW of thioester derivative (I) 1 From -W 2 Because the substitution reaction can be promoted, the amounts of copper salt and Grignard reagent (4) can be reduced relatively.

[0348] When using Grignard reagent (6), the amount of copper salt used is, for example, 0.1 moles to 10 moles per mole of Grignard reagent (4), preferably 0.5 moles to 5 moles, and more preferably 0.5 moles to 2 moles.

[0349] When using Grignard reagent (6), the amount of copper salt used is, for example, 0.1 moles to 10 moles per mole of Grignard reagent (6), preferably 0.5 moles to 5 moles, and more preferably 0.5 moles to 2 moles. For example, the amount of copper salt used is 1 mole to 3 moles per mole of Grignard reagent (6).

[0350] When using Grignard reagent (6), the amount of copper salt used is, for example, 0.1 moles to 10 moles per mole of thioester derivative (I), more preferably 0.5 moles to 5 moles, and even more preferably 0.5 moles to 1.4 moles.

[0351] When using Grignard reagent (6), the amount of Grignard reagent (4) used is, for example, 0.1 moles to 10 moles, preferably 0.5 moles to 5 moles, and more preferably 0.5 moles to 1.4 moles, per mole of thioester derivative (I).

[0352] When using Grignard reagent (6), the amount of Grignard reagent (6) used is, for example, 0.01 moles or more and 1 mole or less, preferably 0.01 moles or more and 0.8 moles or less, and more preferably 0.1 moles or more and 0.8 moles or less, per mole of Grignard reagent (4).

[0353] When using Grignard reagent (6), the amount of Grignard reagent (6) used is, for example, 0.1 moles to 10 moles, preferably 0.1 moles to 5 moles, and more preferably 0.1 moles to 1.0 mole, per mole of thioester derivative (I).

[0354] Other conditions (solvent, reaction temperature, reaction time, etc.) when using Grignard reagent (6) are the same as described above.

[0355] When contacting the thioester derivative (I), Grignard reagent (4), copper salt, and Grignard reagent (6), it is preferable to first contact Grignard reagent (4) with the copper salt, then Grignard reagent (6) to form an organocopper reagent, and then mix in the thioester derivative (I) and contact the organocopper reagent with the thioester derivative (I). This allows for obtaining the ketone derivative (II) in high yield.

[0356] The contact temperature (reaction temperature) and contact time (reaction time) when contacting the Grignard reagent (4) with the copper salt are the same as described above.

[0357] When Grignard reagent (4) is brought into contact with the copper salt, and then Grignard reagent (6) is brought into contact, the contact temperature (reaction temperature) is, for example, -20 to 150°C, preferably -10 to 100°C, more preferably 0 to 70°C, and the contact time (reaction time) is, for example, 0.1 to 5 hours, preferably 0.2 to 3 hours, more preferably 0.5 to 2 hours.

[0358] The contact temperature (reaction temperature) and contact time (reaction time) when contacting the organocopper reagent with the thioester derivative (I) are the same as described above.

[0359] When CuCN is used as the copper salt, using too much Grignard reagent (6) may reduce the yield of the ketone derivative (II). Therefore, when CuCN is used as the copper salt, the amount of Grignard reagent (6) used is preferably 1 mole or less, more preferably 0.5 moles or less, and more preferably 0.1 moles or less per mole of Grignard reagent (4), and preferably 1 mole or less, more preferably 0.5 moles or less, and more preferably 0.1 moles or less per mole of thioester derivative (I). When CuCN is used as the copper salt, the lower limit of the amount of Grignard reagent (6) used is zero.

[0360] Method for producing C-aryl-hydroxyglycoside derivative (V) The C-aryl-hydroxyglycoside derivative (V) can be produced by a method that includes the steps of contacting a ketone derivative (II) with a base to remove the hydroxyl protecting group represented by formula -CO-R from the ketone derivative (II), and then further contacting it with an acid to produce the C-aryl-hydroxyglycoside derivative (V).

[0361] In one embodiment, the C-aryl-hydroxyglycoside derivative (V) is the C-aryl-hydroxyglycoside derivative (Va) or (Vb). The C-aryl-hydroxyglycoside derivative (Va) or (Vb) can be produced by a method comprising the steps of contacting a ketone derivative (IIa) with a base to remove the hydroxyl protecting group represented by formula:-CO-R from the ketone derivative (IIa), and then further contacting it with an acid to produce the C-aryl-hydroxyglycoside derivative (Va) or (Vb). 100 Types (in formula (Va), hydrogen atom; in formula (Vb), R 101 ) is determined by the acid used in the production of the C-aryl-hydroxyglycoside derivative (V).

[0362] C-aryl-hydroxyglycoside derivative (V) is, in formula (IIa), R 5 The acetyl group is R 1 ~R 4 From ketone derivatives where the protecting group is a hydroxyl group other than an acetyl group (e.g., a benzyl group), 5 The hydroxyl protecting group represented by is removed, then cyclized, and then R 1 ~R 4 It can also be produced by removing the hydroxyl protecting group represented by . However, in this case, R 5 The process involves the removal of the hydroxyl protecting group represented by and the cyclization process, and R 1 ~R 4A step of removing the hydroxyl protecting group represented by formula:-CO-R is required. In contrast, a method that includes the step of contacting the ketone derivative (II) with a base to remove the hydroxyl protecting group represented by formula:-CO-R from the ketone derivative (II), and then further contacting it with an acid to produce the C-aryl-hydroxyglycoside derivative (V) is performed. In this method, all hydroxyl protecting groups represented by formula:-CO-R are removed from the ketone derivative (II), and then a cyclization step is performed by reaction with the acid. Therefore, there is no need to perform a step of removing the hydroxyl protecting group after the cyclization step. Thus, the C-aryl-hydroxyglycoside derivative (V) can be obtained from the ketone derivative (II) in a simple and efficient manner.

[0363] Examples of bases include alkali metal alkoxides, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and cesium hydroxide. Examples of alkali metal alkoxides include sodium methoxide, potassium methoxide, sodium t-butoxide, and potassium t-butoxide.

[0364] The amount of base used is, for example, 0.01 to 50 moles, preferably 0.1 to 20 moles, and more preferably 0.5 to 10 moles, per mole of ketone derivative (II).

[0365] Contact between the ketone derivative (II) and the base is preferably carried out in a solvent. The ketone derivative (II) and the base can be brought into contact by mixing them in a solvent. The solvent is preferably water, an organic solvent, or a mixture thereof. Examples of solvents include methanol, ethanol, isopropanol (IPA), t-butanol, tetrahydrofuran (THF), methylene chloride, chloroform, acetonitrile, and water.

[0366] The amount of solvent used is, for example, 0.5 to 100 mL, preferably 1 to 80 mL, and more preferably 2 to 50 mL, per 1 g of ketone derivative (II).

[0367] When contacting a ketone derivative (II) with a base, the contact temperature (reaction temperature) is, for example, -20 to 100°C, preferably -10 to 70°C, more preferably 0 to 50°C, and the contact time (reaction time) is, for example, 0.1 to 24 hours, preferably 0.2 to 17 hours, more preferably 0.5 to 8 hours. The contact environment is preferably an inert atmosphere, and more preferably an argon atmosphere or a nitrogen atmosphere.

[0368] After removing the hydroxyl protecting group represented by formula -CO-R from the ketone derivative (II), the deprotected ketone derivative (II) can be cyclized by contacting it with an acid to produce the C-aryl-hydroxyglycoside derivative (V).

[0369] Examples of acids include hydrochloric acid, sulfuric acid, alkyl sulfonic acids such as methyl sulfonic acid, and aryl sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid. The acid is preferably methyl sulfonic acid.

[0370] R in equation (V) 100 Types (in formula (Va), hydrogen atom; in formula (Vb), R 101 ) is determined by the acid used in the production of the C-aryl-hydroxyglycoside derivative (V). Specifically, if the acid is hydrochloric acid or sulfuric acid, R in formula (V) 100 R is a hydrogen atom, and the acid is given by formula: 100 -SO3H (in the formula, R 100 If it is an alkyl sulfonic acid represented by (where represents an alkyl group which may have substituents), then R in formula (V) 100 is an alkyl group which may have substituents, and the acid is of formula:R 100 -SO3H (in the formula, R 100 If it is an aryl sulfonic acid represented by (where represents an aryl group which may have substituents), then R in formula (V) 100 is an aryl group which may have substituents. More specifically, when the acid is methylsulfonic acid, R in formula (V) 100R is a methyl group, and when the acid is p-toluenesulfonic acid, R in formula (V) 100 R is a methylphenyl group, and when the acid is benzenesulfonic acid, R in formula (V) 100 It is a phenyl group.

[0371] The amount of acid used is, for example, 0.01 to 100 moles, preferably 0.1 to 50 moles, and more preferably 0.5 to 10 moles, per mole of ketone derivative (II).

[0372] Contact between the deprotected ketone derivative (II) and the acid is preferably carried out in a solvent. The deprotected ketone derivative (II) and the acid can be brought into contact by mixing them in a solvent. The solvent is preferably water, an organic solvent, or a mixture thereof. Examples of solvents include methanol, ethanol, isopropanol (IPA), t-butanol, tetrahydrofuran (THF), methylene chloride, chloroform, acetonitrile, and water.

[0373] When the deprotected ketone derivative (II) is brought into contact with an acid, the contact temperature (reaction temperature) is, for example, -20 to 60°C, preferably -10 to 50°C, more preferably 0 to 40°C, and the contact time (reaction time) is, for example, 0.5 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 17 hours. The contact environment is preferably an inert atmosphere, and more preferably an argon atmosphere or a nitrogen atmosphere.

[0374] When producing a C-aryl-hydroxyglycoside derivative (Vb) by contacting a deprotected ketone derivative (II) with an acid to cyclize the deprotected ketone derivative (II), at least one intermediate selected from the group consisting of a 5-membered ring C-arylglycoside derivative (VIa) and a 6-membered ring C-aryl-hydroxyglycoside derivative (Va) may be produced.

[0375] Among the C-aryl-hydroxyglycoside derivatives (V), the C-aryl-hydroxyglycoside derivative (V) with n=2 (i.e., a 6-membered ring) is particularly useful.

[0376] The obtained C-aryl-hydroxyglycoside derivative (V) may be isolated by silica gel column chromatography or used in the next step as an unpurified concentrated residue.

[0377] The structure of the C-aryl-hydroxyglycoside derivative (V) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0378] A method for producing the C-aryl-hydroxyglycoside derivative (V) may include a step of producing the ketone derivative (II). In this case, after the step of producing the ketone derivative (II), the ketone derivative (II) is brought into contact with a base to remove the hydroxyl protecting group represented by the formula -CO-R from the ketone derivative (II), and then further contact with an acid to produce the C-aryl-hydroxyglycoside derivative (V).

[0379] The ketone derivative (II) can be produced by a method that includes the step of contacting the thioester derivative (I), the Grignard reagent (4), and the copper salt to produce the ketone derivative (II). A description of this method is as described above.

[0380] If a method for producing a C-aryl-hydroxyglycoside derivative (V) includes a step of producing a ketone derivative (II) by contacting a thioester derivative (I), a Grignard reagent (4), and a copper salt, the ketone derivative (II) may be isolated from the reaction mixture obtained by contacting the thioester derivative (I), the Grignard reagent (4), and the copper salt, and then contacted with a base, or the base may be added to the reaction mixture and contacted with the base without isolating the ketone derivative (II) from the reaction mixture. In the latter case, since it is not necessary to isolate the ketone derivative (II) from the reaction mixture obtained by contacting the thioester derivative (I), the Grignard reagent (4), and the copper salt, the C-aryl-hydroxyglycoside derivative (V) can be produced efficiently.

[0381] Method for producing C-aryl-hydroxyglycoside derivatives (VI) The C-aryl-hydroxyglycoside derivative (VI) can be produced by a method that includes the step of contacting a ketone derivative (IIA) with lipase to produce the C-aryl-hydroxyglycoside derivative (VI).

[0382] In one embodiment, the C-aryl-hydroxyglycoside derivative (VI) is the C-aryl-hydroxyglycoside derivative (VIa). The C-aryl-hydroxyglycoside derivative (VIa) can be produced by a method that includes the step of contacting the ketone derivative (IIa) with lipase to produce the C-aryl-hydroxyglycoside derivative (VIa).

[0383] Examples of lipases include lipases derived from microorganisms, and lipases derived from animal or plant tissues or cells, but among these, lipases derived from microorganisms are preferred. Lipases can be obtained from microbial cells, animal or plant tissues or cells, etc., according to conventional methods.

[0384] The microorganisms from which lipase originates may be wild-type strains, mutant strains, or those induced by genetic engineering techniques such as genetic recombination. Examples of microorganisms from which lipase originates include those of the genera Penicillium, Mucor, Pseudomonas, Humicola, Aspergillus, Candida, and Serratia. More specifically, examples include Penicillium cyclopium, Mucor javanicus, Mucor miehei, Pseudomonas fluorescens, Pseudomonas cepasia, Humicola lanuginosa, Aspergillus niger, Candida cylindracea, Candida antarctica, and Serratia marcescens.

[0385] Lipase can be used, for example, in the form of purified enzyme or partially purified enzyme (crudely purified enzyme). If it is a lipase derived from a microorganism, it may be used in the form of microbial cells, cultures, or processed products thereof (e.g., culture supernatant, cell lysates, cell extracts, etc.). If it is a lipase derived from animal or plant tissue or cells, it may be used in the form of tissue or cell extracts, etc.

[0386] Lipase may be used in the form of an immobilized enzyme. Immobilization can be carried out according to conventional methods using a carrier such as carrageenan gel, polyacrylamide, alginate gel, agar gel, Celite, or photocrosslinkable resin.

[0387] The lipase used may be a commercially available lipase. Examples of commercially available lipases include Lipase G (manufactured by Amano Pharmaceutical, origin: Penicillium cyclopium), Lipase M (manufactured by Amano Pharmaceutical, origin: Mucor javanicus), Lipase P (manufactured by Amano Pharmaceutical, origin: Pseudomonas fluorescens), Lipase CE (manufactured by Amano Pharmaceutical, origin: Fumicola lanuginosa), Novozim 388 (manufactured by Novo National Pharmaceutical, origin: Mucor miehei), Novozim IM (manufactured by Novo National Pharmaceutical, origin: Mucor miehei), Lipase A (manufactured by Sigma-Industrial Pharmaceuticals, origin: Aspergillus niger), Novozim 435 (manufactured by Novo National Pharmaceutical, origin: Candida antarctica), Lipase SP523 (manufactured by Novo National Pharmaceutical, origin: Fumicola sp.), and Lipase SP524 (manufactured by Novo National Pharmaceutical, origin: Mucor Examples include Miehei, lipase SP525 (manufactured by Novo National Corporation, origin: Candida antarctica), lipase SP526 (manufactured by Novo National Corporation, origin: Candida antarctica), etc., but among these, Novozyme 435 is preferred.

[0388] The amount of lipase used per gram of ketone derivative (IIA) is, for example, an amount having an olive oil degrading activity of 1 to 100,000 U, preferably 50 to 50,000 U, and more preferably 100 to 20,000 U. The olive oil degrading activity can be determined according to a fat digestion capacity test method that measures the amount of fatty acids that increase with the cleavage of ester bonds when lipase acts on olive oil ("Medical Research" 11 [3] (1980) pp. 505-506).

[0389] Contact between the ketone derivative (IIA) and lipase is preferably carried out in a solvent. The ketone derivative (IIA) and lipase can be brought into contact by mixing them in a solvent. The solvent is preferably water, an organic solvent, or a mixture thereof. Examples of solvents include acetonitrile, propionitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, diisopropyl ether, dimethoxyethane, diglyme, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, heptane, and water. A single solvent may be used, or a mixture containing two or more solvents may be used. The solvent is preferably acetonitrile, ethanol, water, or a mixture thereof.

[0390] The contact between the ketone derivative (IIA) and lipase is preferably carried out at a pH at which the lipase can exhibit enzymatic activity (lipase activity), and more preferably at the optimal pH of the lipase. When the contact between the ketone derivative (IIA) and lipase is carried out in a solvent, the pH of the solvent used when contacting the ketone derivative (IIA) and lipase is preferably at a pH at which the lipase can exhibit enzymatic activity (lipase activity), and more preferably at the optimal pH of the lipase. The pH at which the lipase can exhibit enzymatic activity (lipase activity) is, for example, 6 to 10, preferably 6.5 to 10, and more preferably 7 to 9.

[0391] The solvent used when contacting the ketone derivative (IIA) with lipase may contain a buffer solution to adjust and / or maintain the pH of the solvent. Examples of buffer solutions include phosphate buffer.

[0392] The amount of solvent used is, for example, 1 to 100 mL, preferably 3 to 70 mL, and more preferably 4 to 50 mL, per 1 g of ketone derivative (IIA).

[0393] When a ketone derivative (IIA) is brought into contact with lipase, the contact temperature (reaction temperature) is, for example, 0 to 80°C, preferably 10 to 50°C, more preferably 15 to 40°C, and the contact time (reaction time) is, for example, 1 to 48 hours, preferably 2 to 24 hours, more preferably 5 to 20 hours.

[0394] The obtained C-aryl-hydroxyglycoside derivative (VI) may be isolated by silica gel column chromatography, or it may be used in the next step as an unpurified concentrated residue.

[0395] The structure of the C-aryl-hydroxyglycoside derivative (VI) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0396] Method for producing C-arylglycoside derivatives (VII) C-arylglycoside derivative (VII) can be produced by a method that includes the step of contacting C-aryl-hydroxyglycoside derivative (V) with a silane compound to produce C-arylglycoside derivative (VII).

[0397] In one embodiment, the C-arylglycoside derivative (VII) is the C-arylglycoside derivative (VIIa). The C-arylglycoside derivative (VIIa) can be produced by a method that includes the step of contacting the C-aryl-hydroxyglycoside derivative (Va) or (Vb) with a silane compound to produce the C-arylglycoside derivative (VIIa).

[0398] A method for producing C-arylglycoside derivative (VII) may include a step of producing C-aryl-hydroxyglycoside derivative (V). In this case, after the step of producing C-aryl-hydroxyglycoside derivative (V), a step of producing C-arylglycoside derivative (VII) is carried out by contacting C-aryl-hydroxyglycoside derivative (V) with a silane compound.

[0399] The C-aryl-hydroxyglycoside derivative (V) can be produced by a method comprising the steps of contacting a ketone derivative (II) with a base to remove the hydroxyl protecting group represented by formula -CO-R from the ketone derivative (II), and then further contacting it with an acid to produce the C-aryl-hydroxyglycoside derivative (V). A description of this method is as described above.

[0400] Silane compounds act as reducing agents. Therefore, when C-aryl-hydroxyglycoside derivative (V) is brought into contact with a silane compound, the reduction reaction of C-aryl-hydroxyglycoside derivative (V) proceeds, yielding C-arylglycoside derivative (VII).

[0401] Examples of silane compounds include triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane, and tetramethyldisiloxane. From the viewpoint of reactivity and cost, the silane compound is preferably trimethoxyhydrosilane, triethoxyhydrosilane, or tetramethyldisiloxane, and more preferably tetramethyldisiloxane.

[0402] The amount of silane compound used is preferably 1 to 10 moles, more preferably 1 to 5 moles, and more preferably 1 to 3 moles per mole of C-aryl-hydroxyglycoside derivative (V), in order to allow the reaction to proceed sufficiently.

[0403] Contact between the C-aryl-hydroxyglycoside derivative (V) and the silane compound is preferably carried out in the presence of a Lewis acid.

[0404] Examples of Lewis acids include BF3·Et2O (boron trifluoride diethyl ether complex), BF3·THF (boron trifluoride tetrahydrofuran), AlCl3, ZnCl2, FeCl3, and titanium compounds. Of these, titanium compounds are preferred. By using titanium compounds, the reduction reaction of the C-aryl-hydroxyglycoside derivative (V) can be carried out rapidly at low temperatures, and the target C-arylglycoside derivative (VII) can be obtained with high selectivity and high yield.

[0405] Examples of known titanium compounds include those in which titanium is 0-valent, 2-valent, 3-valent, or 4-valent states, and any of these titanium compounds may be used. Examples of titanium compounds include 4-valent titanium salts or solvates thereof such as triisopropoxytitanium(IV) monochloride, diisopropoxytitanium(IV) dichloride, monoisopropoxytitanium(IV) monochloride, titanium(IV) chloride, titanium(IV) bromide, titanium(IV) iodide, and titanium(IV) oxide; 3-valent titanium salts or solvates thereof such as titanium(III) chloride and titanium(III) bromide; 4-valent titanium salts or solvates thereof such as titanium(II) chloride; and 0-valent titanium such as metallic Ti or its solvates. Examples of solvates include those coordinated with solvents such as water and tetrahydrofuran.

[0406] Titanium compounds are given by formula:TiR c r (OR d ) s [In the formula, R c is a halogen atom, and R d R is a substituted or unsubstituted alkyl group, and r and s are integers from 0 to 4 satisfying r+s=3 or 4. Preferably, it is a trivalent or tetravalent titanium salt or its solvate represented by ]. c It is preferably a chlorine atom, a bromine atom, or an iodine atom, R d It is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 to 3 carbon atoms.

[0407] The titanium compound is preferably titanium(IV) triisopropoxymonochloride, titanium(IV) diisopropoxydichloride, titanium(IV) monoisopropoxytrichloride, titanium(IV) chloride, titanium(III) chloride, and more preferably titanium(IV) chloride. Titanium(IV) chloride is preferred because it has a low melting point and is liquid at room temperature, making it easy to handle and inexpensive.

[0408] The amount of Lewis acid used is, for example, 0.1 to 3 moles, preferably 0.5 to 2 moles, and more preferably 1 to 1.5 moles, per mole of C-aryl-hydroxyglycoside derivative (V). When a titanium compound is used, the amount of titanium compound used is, for example, 0.05 to 10 moles, preferably 0.1 to 7 moles, and more preferably 1 to 5 moles, per mole of C-aryl-hydroxyglycoside derivative (V).

[0409] Contact between the C-aryl-hydroxyglycoside derivative (V) and the silane compound is preferably carried out in a solvent. The solvent is preferably an organic solvent. Examples of solvents include aliphatic nitriles such as acetonitrile and propionitrile, ethers such as tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, and diglyme, ketones such as acetone, methyl ethyl ketone, and diethyl ketone, acetic acid esters such as methyl acetate, ethyl acetate, and butyl acetate, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, and chlorobenzene, aromatic hydrocarbons such as toluene and xylene, and aliphatic hydrocarbons such as hexane and heptane. One solvent may be used alone, or two or more solvents may be used in combination. The solvent is preferably acetonitrile, methylene chloride, or a mixture thereof. These are aprotic polar solvents and are preferred because they are less susceptible to silane reduction.

[0410] The amount of solvent used is, for example, 1 to 100 mL, preferably 1 to 50 mL, and more preferably 2 to 20 mL, per 1 g of C-aryl-hydroxyglycoside derivative (V).

[0411] When contacting a C-aryl-hydroxyglycoside derivative (V) with a silane compound, the contact temperature (reaction temperature) is, for example, in the range of -100°C to 100°C, more preferably -78°C to 50°C, and more preferably -60°C to 10°C, and the contact time (reaction time) is, for example, 10 minutes to 48 hours, preferably 0.5 to 24 hours, and more preferably 1 to 17 hours.

[0412] The reaction atmosphere is not particularly limited, but it is preferable to use an inert gas atmosphere or an air atmosphere to suppress the inclusion of moisture.

[0413] The reaction system may be under atmospheric pressure, pressurized pressure, or reduced pressure, but of these, it is preferable to carry out the reaction under atmospheric pressure.

[0414] C-arylglycoside derivative (VII) can be obtained by reduction reaction. The product obtained by reduction reaction may be a mixture of β-C-arylglycoside derivative (hereinafter sometimes referred to as "β-form") and α-C-arylglycoside derivative (hereinafter sometimes referred to as "α-form"). When a titanium compound is used as the Lewis acid, β-C-arylglycoside derivatives can be produced with high selectivity and high yield, resulting in a high proportion of the β-form in the product.

[0415] It is preferable to remove the obtained C-arylglycoside derivative (VII) from the reaction system. For example, C-arylglycoside derivative (VII) can be removed from the reaction system by adding water to the reaction solution, then contacting it with a poorly water-soluble organic solvent such as ethyl acetate, toluene, tert-butyl methyl ether, or methylene chloride, and extracting C-arylglycoside derivative (VII) with the poorly water-soluble organic solvent.

[0416] The obtained C-arylglycoside derivative (VII) can be further purified using known methods such as column separation and recrystallization. However, it is difficult to separate the β-isomer from the α-isomer by column purification using silica gel columns, etc. Therefore, the usefulness of the present invention, which can produce β-C-arylglycoside derivatives with high selectivity and high yield, is extremely high.

[0417] The obtained C-arylglycoside derivative (VII) can be suitably used as an SGLT2 inhibitor or a synthetic intermediate thereof, which is useful as an antidiabetic drug.

[0418] The structure of the C-arylglycoside derivative (VII) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy. [Examples]

[0419] [Example 1] Production of acetyl-protected thioester derivatives Compound 2 was produced from Compound 1 (D-(+)-glucono-1,5-lactone) by carrying out the reaction shown in the following formula. Note that "Ac" represents an acetyl group, i "Pr" represents an isopropyl group. The same applies below.

[0420] [ka]

[0421] Compound 1 (1.78 g, 10.0 mmol, 1.00 equivalent) was mixed with acetic anhydride (10.0 mL, 106 mmol, 10.6 equivalents) and trifluoroacetic acid (TFA) (1.00 mL, 13.1 mmol, 1.31 equivalents), and the reaction mixture was stirred at room temperature for 3 hours. After removing all volatile substances using toluene (10 mL x 3), 1-dodecanethiol (3.00 mL, 12.6 mmol, 1.26 equivalents) and tetrahydrofuran (THF) (50.0 mL) were added to the residue. To the resulting mixture, iA THF solution of PrMgCl (2M, 6.30 mL, 12.6 mmol, 1.26 equivalents) was added dropwise over 5 minutes at 0°C. After stirring for 1 hour, acetic anhydride (1.40 mL, 14.8 mmol, 1.48 equivalents) was added at 0°C, and the reaction mixture was stirred at room temperature for a further 1 hour. The reaction was quenched with 1N aqueous HCl (10 mL), then ethyl acetate (50 mL) was added, and the organic layer was washed with 1N aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried using sodium sulfate, and the solvent was removed by vacuum evacuation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10:1) to obtain compound 2 as a colorless oil in 91% yield (5.36 g).

[0422] The NMR spectroscopy results for compound 2 were as follows: 1 1H NMR (400MHz, CDCl3, 30℃) δ 5.67(dd,J=5.5,3.8Hz,1H),5.48(d,J=3.7Hz,1H),5.45(t,J=5.7Hz,1H),5.03 (dt,J=5.7,4.6,Hz,1H),4.30(dd,J=12.2,4.5Hz,1H),4.13(dd,J=12.1,5.5Hz ,1H),2.87(dt,J=7.4,3.8,1H),2.24(s,3H),2.10(s,3H),2.09(s,3H),2.05(s ,3H),2.04(s,3H),1.57-1.50(m,2H),1.34-1.25(m,18H),0.88(t,J=6.8Hz,3H) 13 C{ 1 H} NMR(100MHz, CDCl3, 30℃) δ 196.0,170.5,169.8,169.81,169.7,169.3,76.2,69.7,69.1,68.8,61.5,32.0, 29.7,29.6,29.5,29.2,29.18,28.9,28.88,22.8,20.8,20.75,20.7,20.5,14.2

[0423] Compound 2 1Figure 1 shows the 1H NMR spectrum (400 MHz, CDCl3, 30°C) of compound 2. 13 C{ 1 The H} NMR spectrum (100 MHz, CDCl3, 30°C) is shown in Figure 2.

[0424] [Example 2] Production of acetyl-protected ketone bodies Compound 3 was prepared from Compound 2 by carrying out the reaction shown in the following formula. Note that "Mes" represents a mesityl group. The same procedure applies below.

[0425] [ka]

[0426] Preparation of a 0.25M ArMgBr solution in THF To magnesium flakes (48.6 mg, 2.00 mmol, 2.00 equivalents), THF (2.00 mL) and 1,2-dibromoethane (0.05 mL) were added to activate the mixture. Then, a THF solution (2.00 mL) of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (BMB) (361 mg, 1.00 mmol, 1.00 equivalent) was added. After refluxing at 80°C for 3 hours, the resulting solution was used for the ketonation reaction.

[0427] Preparation of a 0.25M MesMgBr solution in THF To magnesium flakes (48.6 mg, 2.00 mmol, 2.00 equivalents), THF (2.00 mL) and 1,2-dibromoethane (0.05 mL) were added to activate the mixture. Then, a THF solution (2.00 mL) of 2-bromomesitylene (200 mg, 1.00 mmol, 1.00 equivalent) was added. After refluxing at 80°C for 3 hours, the resulting solution was used for the ketonation reaction.

[0428] Ketonement reaction To a THF solution (1.25 mL) of CuCN (33.6 mg, 0.375 mmol, 1.50 equivalents), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalents) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution (0.750 mL, 0.188 mmol, 0.750 equivalents) of 0.25 M MesMgBr was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (1.5 mL) of compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) was added, and the reaction mixture was refluxed at 80°C for 20 hours. To the reaction mixture, saturated aqueous NaHCO3 (1 mL) and ethyl acetate (5 mL) were added to quench the reaction, and the mixture was then filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with saturated NaHCO3 aqueous solution (5 mL) and saline solution (5 mL), and dried using sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a yellow oily substance in 51% yield (85.3 mg).

[0429] The NMR spectroscopic analysis results for compound 3 were as follows: 1 H NMR(400MHz, CDCl3, 30℃) δ 7.81(d,J=1.7Hz,1H),7.73(dd,J=7.9,1.9Hz,1H),7.49-7.45(m,2H),7.28(d,J=8.0Hz,1H ),7.04-7.00(m,3H),6.66(d,J=3.6Hz,1H),6.10(d,J=5.1Hz,1H),5.73(t,J=4.8Hz,1H),5. 49(dd,J=6.8,4.3,Hz,1H),5.14-5.10(m,1H),4.31(dd,J=12.4,3.0Hz,1H),4.17(s,2H),4. 08(dd,J=12.4,5.9Hz,1H),2.38(s,3H),2.13(s,3H),2.04(s,6H),2.03(s,3H),1.94(s,3H) 13 C{ 1H} NMR(100MHz, CDCl3, 30℃) δ 192.8,170.8,170.0,169.8,169.7,169.6,162.3(d, 1 J C-F =245.2Hz),143.6,142.4,142.0,139.1,133.3,131.1,130.9(d, 4 J C-F =3.6Hz),129.8,127.3(d, 3 J C-F =7.7Hz),127.28,126.4,122.9,115.9(d, 2 J C-F =21.9Hz),72.6,69.5,68.9,68.88,61.9,34.1,20.9,20.8,20.6,20.57,20.5,20.0 19 F{ 1 H} NMR(376MHz, CDCl3, 30℃) δ -116.1HRMS(FAB + )m / z C 34 H 35 FO 11 S ([M] + Calculated value: 670.1884 Measured value: 670.1888

[0430] Compound 3 1 Figure 3 shows the 1H NMR spectrum (400 MHz, CDCl3, 30°C) of compound 3. 13 C{ 1 Figure 4 shows the H} NMR spectrum (100 MHz, CDCl3, 30°C) of compound 3. 19 F{ 1 The H NMR spectrum (376 MHz, CDCl3, 30°C) is shown in Figure 5.

[0431] [Example 3] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0432] [ka]

[0433] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 2.

[0434] Ketonement reaction To a THF solution (2.00 mL) of CuCl (24.8 mg, 0.250 mmol, 1.00 equivalent), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalent) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (1.5 mL) of compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) was added, and the reaction mixture was refluxed at 80°C for 20 hours. To the reaction mixture, a 1 M aqueous solution (1 mL) and ethyl acetate (5 mL) were added to quench the reaction, and then the mixture was filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with a 1 M aqueous solution (5 mL), a saturated aqueous solution (5 mL) of NaHCO3 and saline solution (5 mL), and dried over sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a yellow oily substance in a yield of 23% (38.5 mg).

[0435] The NMR spectroscopic analysis results of compound 3 obtained in Example 3 were consistent with the data obtained in Example 2.

[0436] [Example 4] Production of acetyl-protected ketone bodies Compound 3 was prepared from Compound 2 by carrying out the reaction shown in the following formula. Note that "2,6-Xylyl" represents the 2,6-xylyl group. The same applies hereafter.

[0437] [ka]

[0438] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 2.

[0439] Preparation of a 0.25M 2,6-XylylMgBr solution in THF 48.6 mg, 2.00 mmol, 2.00 equivalents of cut magnesium were activated with THF (2.00 mL) and 1,2-dibromoethane (0.05 mL), and then 2.00 mL of a THF solution of 2,6-xylyl bromide (185 mg, 1.00 mmol, 1.00 equivalent) was added. After refluxing at 80°C for 3 hours, the resulting solution was used for the ketonation reaction.

[0440] Ketonement reaction To a THF solution (1.25 mL) of CuCl (37.1 mg, 0.375 mmol, 1.50 equivalents), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalents) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution (0.750 mL, 0.188 mmol, 0.750 equivalents) of 0.25 M 2,6-XylylMgBr was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (1.5 mL) of compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) was added, and the reaction mixture was then heated at 40°C for 20 hours. To the reaction mixture, 1 mL of 1 M aqueous HCl and 5 mL of ethyl acetate were added to quench the reaction, and then the mixture was filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with 5 mL of 1 M aqueous HCl, 5 mL of saturated aqueous NaHCO3, and 5 mL of brine, and dried over sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a yellow gum-like substance in 17% yield (29.0 mg).

[0441] The NMR spectroscopy results of compound 3 obtained in Example 4 were consistent with the data obtained in Example 2.

[0442] [Example 5] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0443] [ka]

[0444] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 2.

[0445] Preparation of a 0.25M MesMgBr solution in THF A 0.25 M MesMgBr THF solution was prepared in the same manner as in Example 2.

[0446] Ketonement reaction To a THF solution (1.25 mL) of CuCl (37.1 mg, 0.375 mmol, 1.50 equivalents), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalents) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution (0.750 mL, 0.188 mmol, 0.750 equivalents) of 0.25 M MesMgBr was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (1.5 mL) of compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) was added, and the reaction mixture was refluxed at 80°C for 20 hours. To the reaction mixture, a 1 M aqueous HCl solution (1 mL) and ethyl acetate (5 mL) were added to quench the reaction, and the mixture was then filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with 1 M HCl aqueous solution (5 mL), saturated NaHCO3 aqueous solution (5 mL), and saline solution (5 mL), and dried using sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a yellow oily substance in 39% yield (65.2 mg).

[0447] The NMR spectroscopy results of compound 3 obtained in Example 5 were consistent with the data obtained in Example 2.

[0448] [Example 6] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0449] [ka]

[0450] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 2.

[0451] Preparation of a 0.25M MesMgBr solution in THF A 0.25 M MesMgBr THF solution was prepared in the same manner as in Example 2.

[0452] Ketonement reaction To a THF solution (1.25 mL) of CuCl (37.1 mg, 0.375 mmol, 1.50 equivalents), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalents) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution (0.750 mL, 0.188 mmol, 0.750 equivalents) of 0.25 M MesMgBr was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) and a THF solution (1.5 mL) of LiCl (53.0 mg, 1.25 mmol, 5.00 equivalents) were added, and the reaction mixture was refluxed at 80°C for 20 hours. To the reaction mixture, 1 mL of 1 M aqueous HCl and 5 mL of ethyl acetate were added to quench the reaction, and then the mixture was filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with 5 mL of 1 M aqueous HCl, 5 mL of saturated aqueous NaHCO3, and 5 mL of brine, and dried over sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a yellow oil in 45% yield (75.1 mg).

[0453] The NMR spectroscopy results of compound 3 obtained in Example 6 were consistent with the data obtained in Example 2.

[0454] [Example 7] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0455] [ka]

[0456] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 2.

[0457] Preparation of a 0.25M MesMgBr solution in THF A 0.25 M MesMgBr THF solution was prepared in the same manner as in Example 2.

[0458] Ketonement reaction To a THF solution (1.25 mL) of CuOAc (46.0 mg, 0.375 mmol, 1.50 equivalents), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalents) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution (0.750 mL, 0.188 mmol, 0.750 equivalents) of 0.25 M MesMgBr was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (1.5 mL) of compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) was added, and the reaction mixture was refluxed at 80°C for 20 hours. To the reaction mixture, a 1 M aqueous HCl solution (1 mL) and ethyl acetate (5 mL) were added to quench the reaction, and the mixture was then filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with 5 mL of 1 M HCl aqueous solution, 5 mL of saturated NaHCO3 aqueous solution, and 5 mL of saline solution, and dried using sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a pale yellow gum-like substance in 21% yield (35.1 mg).

[0459] The NMR spectroscopic analysis results of compound 3 obtained in Example 7 were consistent with the data obtained in Example 2.

[0460] [Example 8] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0461] [ka]

[0462] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 2.

[0463] Preparation of a 0.25M MesMgBr solution in THF A 0.25 M MesMgBr THF solution was prepared in the same manner as in Example 2.

[0464] Ketonement reaction To a THF solution (1.25 mL) of CuTC (71.5 mg, 0.375 mmol, 1.50 equivalents) of copper(I) thiophene-2-carboxylate (CuTC), a THF solution (1.50 mL, 0.375 mmol, 1.50 equivalents) was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution (0.750 mL, 0.188 mmol, 0.750 equivalents) of 0.25 M MesMgBr was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (1.5 mL) of compound 2 (148 mg, 0.250 mmol, 1.00 equivalent) was added, and the reaction mixture was refluxed at 80°C for 20 hours. To the reaction mixture, 1 mL of 1 M aqueous HCl and 5 mL of ethyl acetate were added to quench the reaction, and then the mixture was filtered through a Celite pad using ethyl acetate (10 mL x 3). The organic layer was washed with 5 mL of 1 M aqueous HCl, 5 mL of saturated aqueous NaHCO3, and 5 mL of brine, and dried over sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a yellow gum-like substance in 25% yield (41.8 mg).

[0465] The NMR spectroscopy results of compound 3 obtained in Example 8 were consistent with the data obtained in Example 2.

[0466] [Example 9] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0467] [ka]

[0468] Preparation of a 0.25M ArMgBr solution in THF To magnesium flakes (122 mg, 5.00 mmol, 2.00 equivalents), THF (2.00 mL) and 1,2-dibromoethane (0.05 mL) were added to activate the mixture. Then, a THF solution (8.00 mL) of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (BMB) (903 mg, 2.50 mmol, 1.00 equivalent) was added. After refluxing at 80°C for 3 hours, the resulting solution was used for the ketonation reaction.

[0469] Preparation of a 0.25M MesMgBr solution in THF 60.8 mg, 2.50 mmol, 2.00 equivalents of cut magnesium were activated with THF (2.00 mL) and 1,2-dibromoethane (0.05 mL), and then 3.00 mL of a THF solution of 2-bromomesitylene (249 mg, 1.25 mmol, 1.00 equivalent) was added. After refluxing at 80°C for 3 hours, the solution was used for the ketonation reaction.

[0470] Ketonement reaction To a THF solution of CuCN (134 mg, 1.50 mmol, 1.50 equivalents) (5.00 mL), a THF solution of 0.25 M ArMgBr (6.00 mL, 1.50 mmol, 1.50 equivalents) was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a THF solution of 0.25 M MesMgBr (3.00 mL, 0.750 mmol, 0.750 equivalents) was added, and the reaction mixture was stirred at room temperature for another 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution of compound 2 (591 mg, 1.00 mmol, 1.00 equivalent) (6.0 mL) was added, and the reaction mixture was refluxed at 40°C for 40 hours. The reaction was quenched by adding saturated NaHCO3 aqueous solution (5 mL) and ethyl acetate (20 mL) to the reaction mixture, and then filtered through a Celite pad using ethyl acetate (20 mL x 3). The organic layer was washed with saline solution (5 mL) and dried using sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as an orange oil in 55% yield (369 mg).

[0471] The NMR spectroscopy results of compound 3 obtained in Example 9 were consistent with the data obtained in Example 2.

[0472] [Example 10] Production of acetyl-protected ketone bodies Compound 3 was produced from Compound 2 by carrying out the reaction shown in the following formula.

[0473] [ka]

[0474] Preparation of a 0.25M ArMgBr solution in THF A 0.25 M ArMgBr THF solution was prepared in the same manner as in Example 9.

[0475] Ketonement reaction To a THF solution (8.00 mL) of CuCN (134 mg, 1.50 mmol, 1.50 equivalents), a THF solution (6.00 mL, 1.50 mmol, 1.50 equivalents) of 0.25 M ArMgBr was added, and the reaction mixture was stirred at room temperature for 10 minutes. To the resulting organocopper reagent (cuprate agent), a THF solution (6.0 mL) of compound 2 (591 mg, 1.00 mmol, 1.00 equivalent) was added, and the reaction mixture was refluxed at 40°C for 20 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (5 mL) and ethyl acetate (20 mL), and then filtered through a Celite pad using ethyl acetate (20 mL x 3). The organic layer was washed with saline solution (20 mL) and dried over sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3 → 1 / 1) to obtain compound 3 as a pale yellow gum-like substance in 59% yield (399 mg).

[0476] The NMR spectrum of compound 3 obtained in Example 10 was consistent with the data obtained in Example 2.

[0477] [Example 11] Production of C-aryl-hydroxyglycoside derivatives Compound 4 was produced from Compound 3 by carrying out the reaction shown in the following formula.

[0478] [ka]

[0479] Preparation of 0.1M phosphate buffer (pH 8.5) NaH2PO4 (0.477 mmol, 57.2 mg) and Na2HPO4·7H2O (9.52 mmol, 2.55 g) were dissolved in water (100 mL).

[0480] Deacetylation of compound 3 Novozim 435 (≧5000 U / g, 3.00 g) was added to a mixture of acetonitrile solution (3.00 mL) of compound 3 (115 mg, 0.171 mmol) and 0.1 M phosphate buffer (pH 8.5) (12 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through a Celite pad using ethyl acetate (15 mL x 3). The organic layer was washed with saturated NaHCO3 aqueous solution (15 mL) and saline solution (15 mL). The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum evacuation. The residue was purified by preparative thin-layer chromatography (ethyl acetate / n-hexane = 1 / 2) to obtain compound 4 as a white solid in 38% yield (30.2 mg).

[0481] The NMR spectroscopic analysis results for compound 4 were as follows: 1 H NMR(400MHz,DMSO-d6,30℃) δ 7.95-7.93(m,3H),7.63-7.47(m,4H),7.14(dd,J=15.3,10.1Hz,1H),6.93-6.86(m,1H),6.30 -6.16(m,3H),5.76(d,J=15.4Hz,1H),4.37-4.12(m,1H),3.65-3.55(m,3H),2.23-2.12(m,3H) 19 F{ 1 H}NMR(376MHz,DMSO-d6,30℃)δ-117.3,-117.5

[0482] Compound 4 19 F{ 1 The ¹H NMR spectra (376 MHz, DMSO-d6, 30°C) are shown in Figures 6A and 6B. Figure 6B is a magnified view of the two peaks shown in Figure 6A.

[0483] [Example 12] Production of C-aryl-hydroxyglycoside derivatives Compound 5 was produced from Compound 3 by carrying out the reaction shown in the following formula.

[0484] [ka]

[0485] A methanol solution (5.00 mL) of compound 3 (168 mg, 0.250 mmol, 1.0 equivalent) was mixed with a methanol solution of sodium methoxide (28% by mass, Aldrich, code No.: 28-3391-5, 0.05 mL, 0.250 mmol, 1.00 equivalent) and stirred at 0°C for 5 hours. Then, 1 equivalent of hydrochloric acid (1 mL) and ethyl acetate (10 mL) were added to quench the reaction. The organic layer was washed with brine (5 mL) and dried over sodium sulfate. After removing the solvent by vacuum, methanol (5 mL) and methylsulfonic acid (24.0 mg, 0.250 mmol, 1.00 equivalent) were added to the residue and stirred at 40°C for 18 hours. Saturated sodium bicarbonate (1 mL) and ethyl acetate (10 mL) were added to quench the reaction. The organic layer was washed with brine (5 mL) and dried over sodium sulfate. After removing the solvent by vacuum evacuation, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 2 → 1 / 1) to obtain compound 5 as a brown gum-like substance in a yield of 17% (20.7 mg).

[0486] The NMR spectroscopy analysis results for compound 5 were as follows: 1 H NMR(400MHz,DMSO-d6,30℃) δ 7.78-7.72(m,1H)7.62-7.55(m,2H),7.38-7.14(m,5H),6.89-657(m,1H),5.54(t,J=6.0Hz,1H),4.52(d,J=5.9Hz,1H ),4.37-4.22(m,2H),4.19-4.09(m,2H),4.04-3.92(m,1H),3.88-3.74(m,1H),3.63-3.60(m,1H),3.31-3.19(m,4H), 2.91-2.89(m,1H),2.39-2.27(m,4H) 19 F{ 1 H}NMR(376MHz,DMSO-d6,30℃) δ -117.3,-117.4.

[0487] Compound 5 1 Figure 7 shows the 1H NMR spectrum (400 MHz, DMSO-d6, 30°C) of compound 5. 19 F{ 1 The H NMR spectrum (376 MHz, CDCl3, 30°C) is shown in Figure 8.

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, R each independently represents an alkyl group which may have a substituent; n represents 1 or 2. A thioester derivative (I) represented by the following formula:

2. The following formula (II): 【Chemistry 2】 [In the formula, W ２ 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, R each independently represents an alkyl group which may have a substituent; n represents 1 or 2. Ketone derivative (II) represented by the formula:

3. A method for producing the thioester derivative (I) according to claim 1, comprising the steps of: In the presence of a base, The following formula (III): 【Chemistry 3】 [In the formula, W １ , R and n have the same meanings as in claim 1. a thiol derivative (III) represented by the formula: The following formula (1): 【Chemistry 4】 [In the formula, R has the same meaning as defined above.] A carboxylic acid anhydride (1) represented by the formula: to produce the thioester derivative (I).

4. The following formula (2): 【Chemistry 5】 [In the formula, W １ has the same meaning as above.] and a thiol (2) represented by the formula: The following formula (3): 【Chemistry 6】 [In the formula, 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, X represents a halogen atom. A Grignard reagent (3) represented by The following formula (IV): 【Chemistry 7】 [In the formula, R and n are as defined above.] and an acyl-protected lactone derivative (IV) represented by the formula: to produce the thiol derivative (III).

5. The method according to claim 4, wherein in the step of producing the thiol derivative (III) by contacting the thiol (2), the Grignard reagent (3), and the acyl-protected lactone derivative (IV), a magnesium thiolate is formed by the reaction of the thiol (2) with the Grignard reagent (3), and then the thiol derivative (III) is formed by the reaction of the magnesium thiolate with the acyl-protected lactone derivative (IV).

6. The method according to claim 4 or 5, wherein the step of producing the thioester derivative (I) by contacting the thiol derivative (III) with the carboxylic acid anhydride (1) is carried out by adding the carboxylic acid anhydride (1) to a reaction mixture obtained by contacting the thiol (2), the Grignard reagent (3), and the acyl-protected lactone derivative (IV) without isolating the thiol derivative (III) from the reaction mixture.

7. A method for producing the ketone derivative (II) according to claim 2, comprising the steps of: The thioester derivative (I) according to claim 1, The following formula (4a): 【Chemistry 8】 [In the formula, W ２ has the same meaning as in claim 2, and X represents a halogen atom. A Grignard reagent (4a) represented by the formula: The following formula (4b): 【Chemistry 9】 [In the formula, W ２ and X have the same meanings as defined above.] Grignard reagent (4b) represented by a Grignard reagent (4) selected from Copper salts, to produce the ketone derivative (II).

8. 8. The method according to claim 7, wherein in the step, the Grignard reagent (4) is contacted with the copper salt to form an organocopper reagent, and then the organocopper reagent is contacted with the thioester derivative (I) to produce the ketone derivative (II).

9. 8. The method of claim 7, wherein the copper salt comprises at least one selected from the group consisting of copper(I) cyanide, copper(I) chloride, copper(I) acetate, and copper(I) thiophene-2-carboxylate.

10. The method according to any one of claims 7 to 9, wherein the copper salt is used in an amount of 1 mole to 3 moles per mole of the thioester derivative (I).

11. The method according to any one of claims 7 to 9, wherein in the step, the thioester derivative (I), the Grignard reagent (4), and the copper salt are contacted at a temperature in the range of -20°C to 150°C.

12. The following formula (V): 【Chemistry 10】 [In the formula, W ２ 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, R １００ represents a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent, n represents 1 or 2. A method for producing a C-aryl-hydroxyglycoside derivative (V) represented by the following formula: The method according to claim 2, comprising the step of contacting the ketone derivative (II) with a base to remove the hydroxy-protecting group represented by the formula: -CO-R from the ketone derivative (II), and then further contacting the ketone derivative (II) with an acid to produce the C-aryl-hydroxyglycoside derivative (V).

13. The following formula (VI): 【Chemistry 11】 [In the formula, W ２ 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, m represents 2. A method for producing a C-aryl-hydroxyglycoside derivative (VI) represented by the following formula: The following formula (IIA): 【Chemistry 12】 [In the formula, W ２ and m are as defined above, Each R independently represents an alkyl group which may have a substituent. The method comprises a step of contacting a ketone derivative (IIA) represented by the following formula with a lipase to produce the C-aryl-hydroxyglycoside derivative (VI).

14. The following formula (VII): 【Chemistry 13】 [In the formula, W ２ 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, n represents 1 or 2. A method for producing a C-aryl glycoside derivative (VII) represented by the following formula: The method according to claim 12, further comprising the step of producing the C-aryl-hydroxyglycoside derivative (V) by the method according to claim 12, and then contacting the obtained C-aryl-hydroxyglycoside derivative (V) with a silane compound to produce the C-arylglycoside derivative (VII).

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