Method for producing compounds such as c-aryl hydroxyglycoside derivatives

Abstract

To provide a method for producing compounds such as C-aryl-hydroxyglycoside derivatives with high yield.SOLUTION: A method for producing a compound (III) represented by formula (III) comprises a step of bringing a compound (I) represented by formula (I) into contact with an alkylsulfonic acid in a solvent containing an alcohol.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for producing a compound such as a C-aryl hydroxyglycoside derivative. [Background technology]

[0002] SGLT-2 inhibitors are useful as antidiabetic drugs. In addition, "SGLT-2" means sodium-glucose cotransporter-2. Examples of SGLT-2 inhibitors include canagliflozin (1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), empagliflozin ((1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol), ipragliflozin ((1S )-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid), dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol), etc. are known.

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

[0004] Various methods for producing C-aryl hydroxyglycoside derivatives have been proposed, including, for example, a method in which an aryl lithium is reacted with a D-gluconolactone derivative at an ultralow temperature of -78°C to add an aryl group (Non-Patent Documents 1 and 3), a method in which a turbo Grignard reagent such as ArMgBr·LiCl (Ar represents an aryl group) is reacted with a D-gluconolactone derivative at a low temperature of -20 to -10°C to add an aryl group (Non-Patent Document 2), and a method in which an aryl group is added to a D-gluconolactone derivative at a temperature of about -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 an organic zinc reagent is reacted with a thioester derivative in the presence of a nickel catalyst to obtain a ketone derivative (Non-Patent Documents 4 and 5).

[0005] 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 respiratory syncytial virus and coronavirus.

[0006] [ka]

[0007] Patent Document 3 discloses a method for producing remdesivir and its intermediates. Patent Document 3 describes that a hydroxynucleoside represented by the following formula (XII) can be obtained by reacting a lactone represented by the following formula (XI) with a bromopyrazole represented by the following formula (Ar″) at −78° C. in the presence of chlorotrimethylsilane (TMSCl) and n-butyllithium. This hydroxynucleoside can be used as an intermediate for synthesizing remdesivir. In addition, “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 Summary of the Invention [Problem to be solved by the invention]

[0011] There is a need for a process capable of producing compounds such as C-aryl hydroxyglycoside derivatives in high yields.

[0012] An object of the present invention is to provide a method for producing compounds such as C-aryl hydroxyglycoside derivatives in high yields. [Means for solving the problem]

[0013] The present invention includes the following inventions. [1] Formula (III): [ka] [In the formula, R 100 represents an alkyl group which may have a substituent, and Ar represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent. A method for producing a compound (III) represented by the following formula: The following formula (I): [ka] [In the formula, each R independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent, and Ar has the same meaning as defined above.] Compound (I) represented by the formula: The following formula (II): [ka] [In the formula, R 200 represents an alkyl group which may have a substituent. and a compound (II) represented by The formula: [ka] [In the formula, R 100 has the same meaning as above.] The method includes contacting in a solvent containing an alcohol represented by the formula: [2] The method according to [1], wherein the alcohol has 1 to 5 carbon atoms. [3] The method according to [2], wherein the alcohol having 1 to 5 carbon atoms is selected from methanol and ethanol. [4] Formula (IV): [ka] [In the formula, Ar represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent.] A method for producing a compound (IV) represented by A method comprising the step of producing compound (III) by the method according to claim 1 and then contacting the resulting compound (III) with a silane compound. [5] The method according to claim [4], wherein the silane compound is selected from triethylsilane and triisopropylsilane. [6] The method according to [4] or [5], wherein the contact of compound (III) with the silane compound is carried out in the presence of a Lewis acid. [7] The method according to [6], wherein the Lewis acid is selected from boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, titanium tetrachloride, aluminum trichloride, iron trichloride, tin dichloride and zinc dichloride. Effect of the Invention

[0014] According to the present invention, there is provided a method for producing compounds such as C-aryl hydroxyglycoside derivatives in high yields. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 is a diagram showing a 1H NMR spectrum of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol obtained in Example 1. [Diagram 2]FIG. 2 is a diagram showing the C NMR spectrum of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol obtained in Example 1. [Diagram 3] FIG. 3 is a diagram showing a 1H NMR spectrum of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin) obtained in Example 2. [Figure 4] FIG. 3 is a diagram showing the C NMR spectrum of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin) obtained in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention will be described below. Two or more embodiments described in this specification can be combined, and the combination of two or more embodiments is also included in the present invention.

[0017] <Terminology explanation> The terms used in this specification will be explained below. The following explanations are applied throughout this specification unless otherwise specified. The expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0018] Halogen atoms The halogen atoms are selected from fluorine, chlorine, bromine and iodine atoms.

[0019] Alkyl group The alkyl group has, for example, 1 to 20, preferably 1 to 15, and more preferably 1 to 12 (for example, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2). The alkyl group may be linear or branched. A linear alkyl group has 1 or more carbon atoms, and a branched alkyl group has 3 or more carbon atoms.

[0020] Alkenyl group The alkenyl group has, for example, 2 to 20, preferably 2 to 15, and more preferably 2 to 12 (for example, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3). The alkenyl group may be linear or branched. A linear alkenyl group has 2 or more carbon atoms, and a branched alkenyl group has 3 or more carbon atoms.

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

[0022] Heterocycloalkyl Groups The heterocycloalkyl group is a monocyclic saturated aliphatic heterocyclic group containing, as a ring-constituting atom, one or more heteroatoms independently selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms in addition to carbon atoms. The saturated aliphatic heterocyclic group is an aliphatic heterocyclic group in which the ring is constituted only by saturated bonds. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of the heterocycloalkyl group is, for example, 3 to 8, preferably 4 to 7, more preferably 5 to 7, and even more preferably 5 or 6. Examples of the heterocycloalkyl group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, those containing 1 to 4 nitrogen atoms, and those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms. The heterocycloalkyl group preferably contains an oxygen atom as a heteroatom. Examples of heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl (wherein the sulfur atom on the ring may be oxidized), azepanyl, diazepanyl, oxepanyl, azocanyl, and diazocanyl groups.

[0023] In one embodiment, the heterocycloalkyl group is selected from tetrahydrofuranyl and tetrahydropyranyl groups. The heterocycloalkyl group is preferably a tetrahydrofuranyl group.

[0024] Aryl Group The aryl group is, for example, a monocyclic or polycyclic (for example, bicyclic or tricyclic) aromatic hydrocarbon ring group having 4 to 14 carbon atoms, preferably 6 to 14, more preferably 6 to 10. The polycyclic group is preferably a condensed ring group. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group is preferably a phenyl group.

[0025] Heteroaryl Groups The heteroaryl group is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic heterocyclic group containing, as ring-constituting atoms, one or more heteroatoms independently selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms in addition to carbon atoms. The polycyclic group is preferably a condensed ring system. The number of heteroatoms is, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of the heteroaryl group is preferably 4 to 14, and more preferably 5 to 10. Examples of the heteroaryl group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, those containing 1 to 4 nitrogen atoms, and those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms. The heteroaryl group is preferably a monocyclic or bicyclic 4 to 10-membered, preferably 5 to 10-membered aromatic heterocyclic group.

[0026] Examples of the monocyclic aromatic heterocyclic group include 5- to 7-membered monocyclic aromatic heterocyclic groups such as a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group (e.g., a 1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, etc.), a thiadiazolyl group (e.g., a 1,2,4-thiadiazolyl group, a 1,3,4-thiadiazolyl group, etc.), a triazolyl group (e.g., a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, etc.), a tetrazolyl group, and a triazinyl group.

[0027] Examples of the condensed polycyclic aromatic heterocyclic group include a benzothiophenyl group, a benzofuranyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group, a benzotriazolyl group, an imidazopyridinyl group, a thienopyridinyl group, a furopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, an oxazolopyridinyl group, a thiazolopyridinyl group, an imidazopyrazinyl group, an imidazopyrimidinyl group, a thienopyrimidinyl group, a furopyrimidinyl group, a pyrrolopyrimidinyl group, a pyrazolopyrimid ...rimidinyl group, a thiazolopyridinyl group, a pyrrolopyrimidinyl group, a pyrazolopyrimidinyl group, a thiazolopyridinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl group, a pyrazolopyrimidinyl Examples of such aromatic heterocyclic groups include 8-14 membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as a pyrimidinyl group, a thiazolopyrimidinyl group, a pyrazolotriazinyl group, a naphtho[2,3-b]thienyl group, a phenoxathiinyl group, an indolyl group, an isoindolyl group, a 1H-indazolyl group, a purinyl group, an isoquinolyl group, a quinolyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, an α-carbolinyl group, a phenanthridinyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, and a phenoxazinyl group.

[0028] In one embodiment, the heteroaryl group is selected from thienyl, benzothiophenyl, furyl, pyrrolyl, imidazolyl and pyridyl groups. The heteroaryl group is preferably selected from thienyl and benzothiophenyl groups.

[0029] Haloalkyl, haloaryl and haloheteroaryl groups The haloalkyl group, haloaryl group and haloheteroaryl group are respectively an alkyl group, an aryl group and a heteroaryl group having one or more halogen atoms, and the explanations regarding the alkyl group, the aryl group and the heteroaryl group are as above. The number of halogen atoms in the haloalkyl group, the haloaryl group or the haloheteroaryl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0030] Alkylene, arylene and heteroarylene groups An alkylene group, an arylene group, and a heteroarylene group are divalent functional groups generated by removing one hydrogen atom from an alkyl group, an aryl group, and a heteroaryl group, respectively, and the explanations for the alkyl group, the aryl group, and the heteroaryl group are as described above.

[0031] Haloalkylene groups, haloarylene groups and haloheteroarylene groups A haloalkylene group, a haloarylene group, and a haloheteroarylene group are divalent functional groups generated by removing one hydrogen atom from a haloalkyl group, a haloaryl group, and a haloheteroaryl group, respectively, and the explanations for the haloalkyl group, the haloaryl group, and the haloheteroaryl group are as described above.

[0032] Arylalkyl group The arylalkyl group is an alkyl group having one or more aryl groups, and the explanation of the alkyl group and the aryl group is as above. The number of aryl groups in the arylalkyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0033] Arylalkenyl Group The arylalkenyl group is an alkenyl group having one or more aryl groups, and the explanation regarding the alkenyl group and the aryl group is as described above. The number of aryl groups contained in the arylalkenyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

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

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

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

[0037] Alkyloxycarbonyl group The alkyloxycarbonyl group is a group represented by the formula: -CO-O-alkyl group, and the explanation of the alkyl group is as above. The number of carbon atoms of the alkyl group contained in the alkyloxycarbonyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2.

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

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

[0040] Dialkylamino group A dialkylamino group has the formula: -N(-Q 2 )(-Q 3 )[where, Q 2 and Q 3 Each of Q independently represents an alkyl group. Q is a group represented by the formula: 2 Or Q 3 The alkyl group represented by the following formula (1) preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, and more preferably 1 or 2 carbon atoms.

[0041] Alicyclic amino group The alicyclic amino group is, for example, a 5- or 6-membered alicyclic amino group, and examples of the 5- or 6-membered alicyclic amino group include a morpholino group, a thiomorpholino group, a pyrrolidin-1-yl group, a pyrazolidin-1-yl group, an imidazolidin-1-yl group, and a piperidin-1-yl group. The alicyclic amino group may contain, in addition to the nitrogen atom having the bond of the alicyclic amino group, a heteroatom (for example, one heteroatom) independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. The alicyclic amino group is preferably a morpholino group.

[0042] Aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group and alicyclic aminocarbonyl group The aminocarbonyl group, the monoalkylaminocarbonyl group, the dialkylaminocarbonyl group and the alicyclic aminocarbonyl group are groups represented by the formula: -CO-amino group, the formula: -CO-monoalkylamino group, the formula: -CO-dialkylamino group and the formula: -CO-alicyclic amino group, respectively, and the explanations regarding the monoalkylamino group, the dialkylamino group and the alicyclic amino group are as described above.

[0043] One or more substituents One or more substituents preferably means 1 to 3 substituents, more preferably 1 or 2 substituents.

[0044] Substituent group α The substituent group α is composed of the following substituents. (α-1) halogen atom (α-2) Nitrile group (α-3) Nitro group (α-4) Amino group (α-5) alkyl group (α-6) Haloalkyl group (α-7) Monoalkylamino group (α-8) Dialkylamino group (α-9) Alicyclic amino group (α-10) Alkyloxycarbonyl group (α-11) Aminocarbonyl group (α-12) Monoalkylaminocarbonyl group (α-13) Dialkylaminocarbonyl group (α-14) Alicyclic aminocarbonyl group (α-15) Hydroxy group optionally protected by a protecting group (α-16) A thiol group which may be protected by a protecting group

[0045] Substituent group β The substituent group β is composed of the following substituents. (β-1) Substituent represented by formula (i) (β-2) Substituent represented by formula (ii)

[0046] The substituent groups α and β will be described below.

[0047] In (α-5), the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2 carbon atoms.

[0048] In (α-6), the number of carbon atoms in the haloalkyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2. The number of halogen atoms in the haloalkyl group is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0049] (α-15) Hydroxy group optionally protected by a protecting group The hydroxyl group-protecting group is preferably one that can protect the hydroxyl group during the intended reaction and can be detached from the hydroxyl group after the intended reaction is completed. Examples of the hydroxyl group-protecting group include an alkylcarbonyl type protecting group, an arylcarbonyl type protecting group, an arylalkyl type protecting group, an alkyl type protecting group, an arylalkyloxyalkyl type protecting group, an alkyloxyalkyl type protecting group, a silyl type protecting group, an oxycarbonyl type protecting group, an acetal type protecting group, and an aryl type protecting group. These protecting groups may have one or more halogen atoms.

[0050] Examples of the alkylcarbonyl-type protecting group include an alkylcarbonyl group having 2 to 10 carbon atoms which may have one or more substituents. The substituent may be selected from, for example, a halogen atom, a nitro group, a cyano group, a phenyl group, an alkyl group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms), an alkyloxy group having 1 to 10 carbon atoms (preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms), an alkyloxycarbonyl group having 2 to 11 carbon atoms (preferably 2 to 9 carbon atoms, more preferably 2 to 7 carbon atoms, more preferably 2 to 5 carbon atoms), and the like. Examples of the alkylcarbonyl group having 2 to 10 carbon atoms which may have one or more substituents include an acetyl group, a propanoyl group, a butanoyl group, an isopropanoyl group, a pivaloyl group, and the like. The alkylcarbonyl-type protecting group is preferably an alkylcarbonyl group having 2 to 5 carbon atoms, more preferably an acetyl group or a pivaloyl group, and even more preferably an acetyl group.

[0051] Examples of the arylcarbonyl-type protecting group include an arylcarbonyl group having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. Examples of the arylcarbonyl group having 7 to 11 carbon atoms which may have one or more substituents include a benzoyl group, a 4-nitrobenzoyl group, a 4-methyloxybenzoyl group, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, a 4-fluorobenzoyl group, a 4-chlorobenzoyl group, a 4-bromobenzoyl group, a 4-phenylbenzoyl group, and a 4-methyloxycarbonylbenzoyl group.

[0052] Examples of the arylalkyl type protecting group include arylalkyl groups having 7 to 11 carbon atoms which may have one or more substituents. Specific examples of the substituents are the same as those of the alkylcarbonyl type protecting group. Examples of the arylalkyl group 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 type protecting group is preferably a benzyl group.

[0053] Examples of the alkyl-type protecting group include an alkyl group having 1 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The alkyl-type protecting group is preferably an alkyl group having 1 to 5 carbon atoms which may have one or more substituents, more preferably a methyl group, an ethyl group, or a tert-butyl group, and even more preferably a methyl group.

[0054] Examples of the arylalkyloxyalkyl type protecting group include arylalkyloxyalkyl groups such as an arylalkyloxymethyl group having 8 to 12 carbon atoms which may have one or more substituents, an arylalkyloxyethyl group having 9 to 13 carbon atoms which may have one or more substituents, and an arylalkyloxypropyl group having 10 to 14 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl type protecting group. Examples of the arylalkyloxyalkyl type protecting group include a benzyloxymethyl group which may have one or more substituents, preferably a benzyloxymethyl group which may be substituted with a halogen atom, a nitro group, a cyano group, a methyl group, or a methyloxy group, more preferably a benzyloxymethyl group.

[0055] Examples of the alkyloxyalkyl type protecting group include alkyloxyalkyl groups such as an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, an alkyloxyethyl group having 3 to 10 carbon atoms which may have one or more substituents, and an alkyloxypropyl group having 4 to 10 carbon atoms which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl type protecting group. The alkyloxyalkyl type protecting group is preferably an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, more preferably an alkyloxymethyl group having 2 to 6 carbon atoms which may have a halogen atom, a nitro group, a cyano group, a methyloxy group, or an ethyloxy group, and even more preferably a methyloxymethyl group.

[0056] Examples of the silyl-type protecting group include a silyl group having a functional group selected from an alkyl group having 1 to 10 carbon atoms, which may have one or more substituents, an arylalkyl group having 7 to 11 carbon atoms, which may have one or more substituents, and an aryl group having 6 to 10 carbon atoms, which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The silyl-type protecting group is preferably a silyl group having a functional group selected from an alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 10 carbon atoms, more preferably a silyl group having a functional group selected from an alkyl group having 1 to 5 carbon atoms and a phenyl group, and even more preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.

[0057] Examples of the oxycarbonyl-type protecting group include an alkyloxycarbonyl group having 2 to 10 carbon atoms, which may have one or more substituents, an alkenyloxycarbonyl group having 3 to 10 carbon atoms, which may have one or more substituents, and an arylalkyloxycarbonyl group having 8 to 12 carbon atoms, which may have one or more substituents. Specific examples of the substituent are the same as those of the alkylcarbonyl-type protecting group. The oxycarbonyl-type protecting group is preferably an alkyloxycarbonyl group having 2 to 6 carbon atoms, an alkenyloxycarbonyl group having 3 to 6 carbon atoms, or a benzyloxycarbonyl group, and more preferably a methyloxymethyl group, an allyloxycarbonyl group, or a benzyloxycarbonyl group.

[0058] Examples of the acetal type protecting group include a tetrahydrofuranyl group, a tetrahydropyranyl group, and the like.

[0059] The aryl-type protecting group includes, for example, an aryl group such as a phenyl group.

[0060] The hydroxy group protected by a 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.

[0061] (α-16) A thiol group which may be protected by a protecting group The thiol group protecting group is preferably one that can protect the thiol group during the target reaction and can be detached from the thiol group after the target reaction is completed. Examples of the thiol group protecting group include an alkylcarbonyl type protecting group, an arylcarbonyl type protecting group, an arylalkyl type protecting group, an alkyl type protecting group, an arylalkyloxyalkyl type protecting group, an alkyloxyalkyl type protecting group, a silyl type protecting group, an oxycarbonyl type protecting group, an acetal type protecting group, and an aryl type protecting group. These protecting groups may have one or more halogen atoms. The explanation of these protecting groups is as above.

[0062] The thiol group protected by a protecting group is preferably a group represented by the formula: -SQ, where Q is as described above.

[0063] (β-1) Substituent represented by formula (i) [ka]

[0064] In formula (i), R 11 , R 12 and R 13each independently represents an alkyl group, a haloalkyl group, an aryl group, a haloaryl group, or a hydroxy group which may be protected by a protecting group. The hydroxy group which may be protected by a protecting group is preferably a group represented by the above formula: -OQ. a is 0 or more and 3 or less.

[0065] (β-2) Substituent represented by formula (ii) [ka]

[0066] In formula (ii), V 10 represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond, or a carbonyl group. The number of carbon atoms in the alkylene group and the haloalkylene group is preferably 1 to 10, and more preferably 1 to 8. The number of carbon atoms in the arylene group and the haloarylene group is preferably 4 to 14, and more preferably 6 to 14. The number of carbon atoms in the heteroarylene group and the haloheteroarylene group is preferably 4 to 14. V 10 is preferably an alkylene group, more preferably a methylene group or an ethylene group.

[0067] In formula (ii), b represents 0 or 1. It is preferable that b is 1.

[0068] In formula (ii), W 10 represents an alkylene group, a haloalkylene group, an arylene group, a haloarylene group, a heteroarylene group, a haloheteroarylene group, an ester bond, an ether bond, or a carbonyl group. 10 is preferably a heteroarylene group, more preferably a 5-membered heteroarylene group containing a sulfur atom as a heteroatom, and even more preferably thienylene.

[0069] In formula (ii), c represents 0 or 1. It is preferable that c is 1.

[0070] In formula (ii), X 10 represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. The alkyl group, the aryl group, and the heteroaryl group may each have one or more substituents. The one or more substituents may each be independently selected from the substituent group α. The one or more substituents are preferably independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group, more preferably selected from a halogen atom, an alkyloxy group and a heterocycloalkyloxy group having 1 to 3 carbon atoms, and more preferably selected from a fluorine atom, an ethyloxy group, and a tetrahydrofuranyloxy group. The heterocycloalkyloxy group preferably contains an oxygen atom as a heteroatom. The number of substituents which each of the alkyl group, the aryl group, and the heteroaryl group may have is preferably 1 to 3, more preferably 1 or 2.

[0071] X 10 is preferably an aryl group which may have a substituent or a heteroaryl group which may have a substituent, more preferably an aryl group having a halogen atom, an alkyloxy group or a heterocycloalkyloxy group having 1 to 3 carbon atoms, 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. The heterocycloalkyloxy group preferably contains an oxygen atom as a heteroatom.

[0072] ≪Compound (I)≫ Compound (I) is represented by the following formula (I).

[0073] [ka]

[0074] In formula (I), R each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. The alkyl group and the aryl group are as described above. The alkyl group may be linear or branched, but is preferably linear. The number of carbon atoms 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. The aryl group is preferably a phenyl group. The alkyl group and the aryl group may each have one or more substituents. The number of substituents that the alkyl group and the aryl group may each have is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β. The one or more substituents are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, and a haloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a haloalkyloxy group having 1 to 3 carbon atoms, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0075] In formula (I), the five R's may be different from each other, but are preferably the same from the viewpoint of efficient introduction and removal of the hydroxy-protecting group represented by the formula: -CO-R. In one embodiment, all of the five R's are methyl groups. In another embodiment, all of the five R's are phenyl groups.

[0076] In formula (I), Ar 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 optionally substituted aryl group, (6) an optionally substituted heteroaryl group, (7) an arylalkyl group which may have a substituent, or (8) An arylalkenyl group which may have a substituent Represents.

[0077] The functional groups (1) to (8) will be described below.

[0078] (1) An alkyl group which may have a substituent The alkyl group is as described above. The alkyl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0079] (2) an alkenyl group which may have a substituent The alkenyl group is as described above. The alkenyl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0080] (3) an optionally substituted cycloalkyl group The cycloalkyl group is as described above. The cycloalkyl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0081] (4) Optionally substituted heterocycloalkyl group The heterocycloalkyl group is as described above. The heterocycloalkyl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0082] (5) An aryl group which may have a substituent The aryl group is as described above. The aryl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0083] (6) Optionally substituted heteroaryl group The heteroaryl group is as described above. The heteroaryl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0084] (7) Arylalkyl group optionally having a substituent The arylalkyl group is as described above. The arylalkyl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0085] (8) An arylalkenyl group which may have a substituent The arylalkenyl group is as described above. The arylalkenyl group may have one or more substituents. The number of the substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β.

[0086] In the functional group (5) (i.e., an aryl group which may have a substituent), it is preferable that the carbon atoms located on both sides of the carbon atom having a bond of the aryl group (i.e., the carbon atom bonded to -CO-) do not have a substituent. The remaining carbon atoms may have a substituent.

[0087] In the functional group (6) (i.e., a heteroaryl group which may have a substituent), it is preferable that the carbon atoms or heteroatoms located on both sides of the carbon atom having a bond of the heteroaryl group (i.e., the carbon atom bonded to -CO-) do not have a substituent. The remaining carbon atoms or heteroatoms may have a substituent.

[0088] In one embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is functional group (1).

[0089] In another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is functional group (2).

[0090] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is functional group (3).

[0091] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is functional group (4).

[0092] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is the functional group (5).

[0093] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is functional group (6).

[0094] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups) and Ar is functional group (7).

[0095] In yet another embodiment, the five R are the same (e.g., all five R are methyl or phenyl groups) and Ar is a functional group (8).

[0096] It is preferable that Ar is a functional group represented by the following formula (iv): In one embodiment, the five R are the same (for example, all five R are methyl groups or phenyl groups), and Ar is a functional group represented by the following formula (iv).

[0097] [ka]

[0098] In formula (iv), Y 10represents an alkylene group which may have a substituent, an arylene group which may have a substituent, or a heteroarylene group which may have a substituent. The number of carbon atoms in the alkylene group is preferably 1 to 10, and more preferably 1 to 8. The number of carbon atoms in the arylene group is preferably 4 to 14, and more preferably 6 to 14. The number of carbon atoms in the heteroarylene group is preferably 4 to 14. The alkylene group, the arylene group, and the heteroarylene group may each have one or more substituents. The one or more substituents may 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 selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms. The number of substituents that the alkylene group, the arylene group, and the heteroarylene group may each have is preferably 1 to 3, and more preferably 1 or 2.

[0099] 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 more preferably a phenylene group having a fluorine atom, a chlorine atom, or a methyl group.

[0100] Y 10 is preferably an arylene group in which the carbon atoms on both sides of the carbon atom bonded to -CO- have no substituents and the remaining carbon atoms may have a substituent, or a heteroarylene group in which the carbon atoms or hetero atoms on both sides of the carbon atom bonded to -CO- have no substituents and the remaining carbon atoms or hetero atoms may have a substituent. 10 is more preferably a phenylene group which has no substituent at the ortho position relative to the carbon atom bonded to --CO-- and which may have substituents at the meta and / or para positions.

[0101] In formula (iv), V 10 , W10 , X 10 , b and c are defined as in formula (ii).

[0102] Alternatively, Ar is preferably a functional group represented by the following formula (vi): In one embodiment, the five R are the same (for example, all five R are methyl groups or phenyl groups), and Ar is a functional group represented by the following formula (vi).

[0103] [ka]

[0104] In formula (vi), R 41 and R 42 Each of R independently represents a hydrogen atom or a protecting group for an amino group. As the protecting group for an amino group, any protecting group such as a carbamate, acyl, amide, sulfonamide, or phthaloyl group may be used. As the protecting group for a carbamate group, for example, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, or an allyloxycarbonyl group may be mentioned. As the protecting group for an acyl group, for example, an acetyl group, a pivaloyl group, or a benzoyl group may be mentioned. As the protecting group for an amide group, for example, a trifluoroacetyl group may be mentioned. As the protecting group for a sulfonamide group, for example, a p-toluenesulfonyl group or a 2-nitrobenzenesulfonyl group may be mentioned. The protecting group for an amino group is preferably an acyl or amide protecting group. The protecting group for an amino group is more preferably a pivaloyl or trifluoroacetyl group. R 41 and R 42 may be bonded to each other to form a protecting group for an amino group such as a phthaloyl group. When Ar has the structure of formula (vi), it can be suitably used as an intermediate for remdesivir.

[0105] From the viewpoint of using compound (I) as a raw material for producing an SGLT-2 inhibitor or a derivative thereof, Ar in formula (I) is preferably the same as a functional group possessed by an SGLT-2 inhibitor or a functional group derived from a functional group possessed by an SGLT-2 inhibitor.

[0106] 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-[(1 SGLT-2 inhibitors, including {4-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-triol), have a functional group represented by the following formula (A).

[0107] Therefore, Ar in formula (I) is preferably a functional group represented by the following formula (A): In one embodiment, the five R are the same (for example, all five R are methyl groups or phenyl groups), and Ar is a functional group represented by the following formula (A).

[0108] [ka]

[0109] In formula (A), d represents an integer of 0 to 4. d is preferably 1 to 3, more preferably 1 or 2, and more preferably 1. When d is 2 or more, d R a may be the same or different.

[0110] In formula (A), d R amay each be independently selected from the substituent group α. 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.

[0111] In formula (A), Ar′ is a functional group represented by the following formula (v).

[0112] [ka]

[0113] In formula (v), W 10 , X 10 and c each have the same meaning as in formula (ii).

[0114] In formula (A), Ar' is preferably a functional group represented by the following formula (Ar'-1), (Ar'-2) or (Ar'-3).

[0115] [ka]

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

[0117] In the formulae (Ar'-1), (Ar'-2) and (Ar'-3), p R b are each independently selected from the group consisting of substituent group α, an aryl group which may have one or more substituents selected from the group consisting of substituent group α, and a heteroaryl group which may have one or more substituents selected from the group consisting of substituent group α. bare preferably each independently selected from the group α of substituents and an aryl group which may have one or more substituents selected from the group α of substituents. The one or more substituents selected from the group α of substituents are preferably each independently selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, a haloalkylthio group, a heterocycloalkyloxy group, and a heterocycloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a heterocycloalkyloxy group, and more preferably selected from a fluorine atom, an ethyloxy group, and a tetrahydrofuranyloxy group. The number of substituents which each of the aryl group and the heteroaryl group may have is preferably 1 to 3, more preferably 1 or 2.

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

[0119] In formula (Ar'-1), p is preferably 1, and R b is preferably a phenyl group which may have a substituent, more preferably a phenyl group having a halogen atom, and more preferably a phenyl group having a fluorine atom. The position to which the unsubstituted or substituted phenyl group is bonded is preferably the 2-position of the thiophene ring. In the phenyl group having a halogen atom, the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.

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

[0121] In formula (Ar'-3), p is preferably 1, and R bis preferably an alkyloxy group which may have a substituent or a heterocycloalkyloxy group which may have a substituent. The alkyloxy group which may have a substituent is preferably an alkyloxy group having 1 to 3 carbon atoms, more preferably a methoxy group or an ethoxy group. The heterocycloalkyloxy group which may have a substituent is preferably a tetrahydrofuranyloxy group. The position to which the alkyloxy group which may have a substituent or the heterocycloalkyloxy group which may have a substituent is bonded is preferably the 4-position of the benzene ring.

[0122] When d=1, the functional group represented by formula (A) is preferably a functional group represented by the following formula (B).

[0123] [ka]

[0124] In formula (B), R a and Ar' have the same meaning as in formula (A).

[0125] The functional group represented by formula (A) or (B) is preferably a functional group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4), where "Et" represents an ethyl group (the same applies throughout this specification).

[0126] [ka]

[0127] In one embodiment, the five R's are the same (eg, all five R's are methyl or phenyl groups), and Ar is a functional group represented by formula (Ar-1).

[0128] In another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups), and Ar is a functional group represented by formula (Ar-2).

[0129] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups), and Ar is a functional group represented by formula (Ar-3).

[0130] In yet another embodiment, the five R are the same (eg, all five R are methyl or phenyl groups), and Ar is a functional group represented by formula (Ar-4).

[0131] <Compound (II)> Compound (II) is represented by the following formula (II): Compound (II) includes alkylsulfonic acids.

[0132] [ka]

[0133] In formula (II), R 200 represents an alkyl group which may have a substituent. The alkyl group is as described above. The alkyl group may be linear or branched, but is preferably linear. 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. The alkyl group may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β. The one or more substituents are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, and a haloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a haloalkyloxy group having 1 to 3 carbon atoms, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0134] Compound (II) is preferably methanesulfonic acid.

[0135] ≪Compound (III)≫ Compound (III) is represented by the following formula (III).

[0136] [ka]

[0137] In formula (III), Ar has the same meaning as in formula (I). Therefore, the explanation for Ar in formula (I) also applies to Ar in formula (III).

[0138] In formula (III), R 100 represents an alkyl group which may have a substituent. The alkyl group is as described above. The alkyl group may be linear or branched, but is preferably linear. 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. The alkyl group may have one or more substituents. The number of substituents is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β. The one or more substituents are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, and a haloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a haloalkyloxy group having 1 to 3 carbon atoms, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0139] ≪Compound (IV)≫ Compound (IV) is represented by the following formula (IV).

[0140] [ka]

[0141] In formula (IV), Ar has the same meaning as in formula (I). Therefore, the explanation for Ar in formula (I) also applies to Ar in formula (IV).

[0142] <<Method 1>> The first method relates to a method for producing compound (III).

[0143] The first method is to react compound (I) with compound (II) in a reaction system represented by the following formula: [ka] [In the formula, R 100 has the same meaning as formula (III). According to the first method, compound (III) can be obtained from compound (I) in a high yield with fewer steps. The yield of compound (III) is, for example, 50% or more, preferably 60% or more, and more preferably 70% or more.

[0144] Hereinafter, compound (I) and compound (II) are referred to as compounds represented by the formula: R 100 The mechanism by which compound (III) is produced by contacting the compound with the alcohol represented by the formula -OH in a solvent containing the alcohol is described below with reference to the following reaction scheme. In the following reaction scheme, R is a methyl group (i.e., the group represented by the formula -CO-R is an acetyl group), Ar is a group represented by the formula (Ar-4), and R 100 is a methyl group (i.e., the formula: R 100 The alcohol represented by -OH is methanol, and R 200 is a methyl group (i.e., compound (II) is methanesulfonic acid). In the following reaction formula, "Ac" represents an acetyl group and "Me" represents a methyl group.

[0145] [ka]

[0146] Compound (I) and compound (II) are reacted with a compound of the formula: R 100 When the compound (I) is contacted with the alcohol represented by -OH in a solvent, a group represented by the formula: -CO-R (in this example, an acetyl group) is eliminated from the compound (I), and the cyclization of the cyclized compound (I) produces a compound (Va). The compound (Va) is then dehydrated to produce an oxonium salt (Vb). The oxonium salt (Vb) is then reacted with a group represented by the formula: R 100 The addition of an alcohol represented by -OH (methanol in this example) produces compound (III).

[0147] Compound (I) and compound (II) are reacted with a compound of the formula: R 100 Compound (III) can be obtained by contacting them in a solvent containing an alcohol represented by -OH at a temperature of, for example, -70 to 50°C, preferably -30 to 45°C, more preferably -20 to 35°C for, for example, 0.5 to 48 hours, preferably 1 to 36 hours, more preferably 2 to 20 hours. Compound (I) and compound (II) can be contacted in an inert atmosphere (for example, under an argon atmosphere or nitrogen atmosphere).

[0148] Compound (I) and compound (II) may be commercially available products or may be produced according to a conventional method.

[0149] The contact of compound (I) with compound (II) is carried out by reacting a compound represented by the formula: R 100 The reaction is carried out in a solvent containing an alcohol represented by the formula: R 100 Compound (I) and compound (II) are mixed in a solvent containing an alcohol represented by the formula: R 100 The contact can be carried out in a solvent containing an alcohol represented by --OH.

[0150] The amount of compound (II) used is, for example, 1 to 30 mol, preferably 2 to 20 mol, and more preferably 3 to 10 mol, relative to 1 mol of compound (I).

[0151] Compound (II) may be added to the reaction system in several portions (e.g., two portions). For example, a portion of the above amount of compound (II) may be added to the reaction system, and then the remainder may be added to the reaction system.

[0152] The solvent used to contact compound (I) with compound (II) has the formula: 100 or may contain one alcohol represented by the formula: R 100 It may contain two or more kinds of alcohols represented by --OH.

[0153] Formula:R 100The alcohol represented by -OH is a monohydric chain aliphatic alcohol. The monohydric chain aliphatic alcohol may be linear or branched. The number of carbon atoms in the monohydric chain aliphatic alcohol is, for example, 1 to 10. From the viewpoint of increasing the yield of compound (III), the number of carbon atoms in the monohydric chain aliphatic alcohol is preferably 1 to 5, more preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. Examples of the monohydric chain aliphatic alcohol include monohydric alcohols having 1 to 10 carbon atoms. Examples of the monohydric chain aliphatic alcohol include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, 2-butyl alcohol, isobutyl alcohol, 2-methyl-2-propyl alcohol, n-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butyl alcohol, 2-methyl-2-butyl alcohol, 3-methyl-1-butyl alcohol, 3-methyl-2-butyl alcohol, neopentyl alcohol, n-hexanol, 2-hexanol, Examples of the alcohol include 3-hexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 4-methyl-1-pentanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 2-methyl-3-pentanol, 3-methyl-3-pentanol, 2,2-dimethyl-1-butanol, 2,3-dimethyl-1-butanol, 3,3-dimethyl-1-butanol, 2,3-dimethyl-2-butanol, 3,3-dimethyl-2-butanol, and 2-ethyl-1-butanol. From the viewpoint of increasing the yield of compound (III), the monovalent chain aliphatic alcohol is preferably selected from methanol and ethanol.

[0154] The solvent used to contact compound (I) with compound (II) has the formula: 100 It may contain alcohols other than the alcohol represented by --OH (hereinafter referred to as "other alcohols").

[0155] The other alcohol may be a monohydric alcohol or a polyhydric alcohol.

[0156] Examples of the monohydric alcohol include monohydric cyclic aliphatic alcohols and monohydric aromatic alcohols.

[0157] Examples of the monohydric cyclic aliphatic alcohol include cyclic aliphatic alcohols having 4 to 6 carbon atoms, such as cyclobutanol, cyclopentanol, and cyclohexanol.

[0158] Examples of the monohydric aromatic alcohol include benzyl alcohol and phenylethyl alcohol.

[0159] Examples of the polyhydric alcohol include dihydric to decahydric alcohols, preferably dihydric to hexahydric alcohols. The polyhydric alcohol may be linear or branched. Examples of the polyhydric alcohol include dihydric alcohols such as ethylene glycol, diethylene glycol, polyethylene glycol (e.g., 3- to 15-mer of ethylene glycol), propylene glycol, dipropylene glycol, polypropylene glycol (e.g., 3- to 15-mer of propylene glycol), 1,3-propanediol, 1,2-propanediol, 1,3-butanediol, 1,4-butanediol, 2-methyl-1,2-propanediol, 2-methyl-1,3-propanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, and neopentyl glycol. alcohols; and polyhydric alcohols such as glycerin, polyglycerin (for example, dimer to octamer of glycerin, specifically, diglycerin, triglycerin, tetraglycerin, etc.), trimethylolalkanes (for example, trimethylolethane, trimethylolpropane, trimethylolbutane, etc.) and dimer to octamer thereof, pentaerythritol and dimer to tetramer thereof, 1,2,4-butanetriol, 1,3,5-pentanetriol, 1,2,6-hexanetriol, 1,2,3,4-butanetetrol, sorbitol, sorbitan, sorbitol-glycerin condensates, adonitol, arabitol, xylitol, and mannitol.

[0160] Formula:R100 The amount of the alcohol represented by -OH used is, for example, 0.1 to 100 mL, preferably 1 to 50 mL, and more preferably 5 to 20 mL, per 1 g of compound (I). 100 The amount of alcohol used, represented by -OH, is determined by the formula: R 100 When one type of alcohol represented by the formula: R is used, the amount of the one type of alcohol used is indicated. 100 When two or more kinds of alcohols represented by --OH are used, the amount means the total amount of the two or more alcohols used.

[0161] The solvent used for contacting compound (I) with compound (II) may contain one or more organic solvents other than alcohol. Examples of organic solvents other than alcohol include polyhydric alcohol derivatives such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol dimethyl ether, and propylene glycol diethyl ether; ether-based solvents such as tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, cyclopentyl methyl ether, dibutyl ether, 1,4-dioxane, methyl tert-butyl ether (MTBE), diisopropyl ether, dimethoxyethane, and diglyme; ketone-based solvents such as acetone, methyl ethyl ketone, and diethyl ketone; ester-based solvents such as methyl acetate and ethyl acetate; halogenated hydrocarbon-based solvents such as dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbon-based solvents such as toluene and xylene; and aliphatic hydrocarbon-based solvents such as hexane and heptane. The organic solvent other than the alcohol may be selected from, for example, ethylene glycol, ethylene glycol monomethyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, xylene, methylene chloride, chloroform, hexane, methyl acetate, and ethyl acetate. From the viewpoint of increasing the yield of compound (III), the organic solvent other than the alcohol is preferably an ether solvent, more preferably tetrahydrofuran.

[0162] In order to increase the yield of compound (III), the solvent used in contacting compound (I) with compound (II) is represented by the formula: 100 A mixed solvent of an alcohol represented by the formula: R and an ether solvent is preferable, and a mixed solvent of methanol and tetrahydrofuran is more preferable. 100In the mixed solvent of an alcohol represented by -OH and an ether solvent, the volume of the alcohol is preferably equal to or larger than the volume of the ether solvent, and the mixed solvent represented by the formula: R 100 The ratio of the volume of the alcohol represented by -OH to the volume of the ether solvent (equation: R 100 The ratio (volume of the alcohol represented by -OH / volume of the ether solvent) is, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 3. 100 The volume of the alcohol represented by -OH is given by the formula: R 100 When one type of alcohol represented by the formula: R 100 When two or more types of alcohols represented by -OH are used, the volume means the total volume of the two or more types of alcohols. When one type of ether solvent is used, the volume means the one type of ether solvent, and when two or more types of ether solvents are used, the volume means the total volume of the two or more ether solvents.

[0163] Alternatively, in order to increase the yield of compound (III), the solvent used for contacting compound (I) with compound (II) is represented by the formula: 100 Preferably, the alcohol is one or more alcohols represented by the formula: 100 It is more preferred that it is composed of one type of alcohol represented by -OH, and even more preferred that it is composed of methanol.

[0164] The amount of the solvent used for contacting compound (I) with compound (II) is, for example, 1 to 100 mL per 1 g of compound (I).

[0165] The solvent used to contact compound (I) with compound (II) is represented by the formula: 100 In the case of a mixed solvent of an alcohol represented by -OH and an ether solvent, the amount of the solvent used for contacting compound (I) with compound (II) is preferably 5 to 50 mL, more preferably 10 to 20 mL, per 1 g of compound (I).

[0166] The solvent used to contact compound (I) with compound (II) is represented by the formula: 100 One or more alcohols represented by —OH (preferably represented by the formula: R 100 When the solvent is composed of one kind of alcohol represented by —OH), the amount of the solvent used for contacting compound (I) with compound (II) is preferably 3 to 50 mL, more preferably 5 to 15 mL, per 1 g of compound (I).

[0167] The solvent used to contact compound (I) with compound (II) is represented by the formula: 100 One or more alcohols represented by —OH (preferably represented by the formula: R 100 When the solvent used for contacting compound (I) with compound (II) is a carboxylic acid represented by the formula: R 100 One or more alcohols represented by —OH (preferably represented by the formula: R 100 When the alcohol is composed of one kind of alcohol represented by the formula (II) -OH, it is possible to realize a reduction in the amount of compound (II) used and an improvement in the yield of compound (III).

[0168] Compound (III) can be isolated from the reaction mixture according to conventional methods.

[0169] For example, compound (I) and compound (II) can be reacted with a compound represented by the formula: R 100 After carrying out the step of contacting in a solvent containing an alcohol represented by -OH, compound (III) is extracted from the reaction mixture obtained in the step to obtain an extract (crude product) containing compound (III), and the obtained extract is subjected to purification treatment such as solidification treatment and silica gel column chromatography treatment, thereby compound (III) can be isolated.

[0170] Compound (I) and compound (II) are reacted with a compound of the formula: R 100By the step of contacting in a solvent containing an alcohol represented by -OH, a high-purity compound (III) can be obtained, and compound (III) is easily solidified. Therefore, by combining this step with a solidification treatment, compound (III) can be obtained as a solid, and compound (III) can also be obtained as a crystal.

[0171] When extracting compound (III) from the reaction mixture, it is preferable to use an organic solvent as the extraction solvent. One type of organic solvent may be used alone, or two or more types of organic solvents may be used in combination. The organic solvent used to extract compound (III) from the reaction mixture is preferably different from the organic solvent used to contact compound (I) with compound (II). The organic solvent used to extract compound (III) from the reaction mixture is preferably ethyl acetate, methyl acetate, methylene chloride, chloroform, methyl tert-butyl ether, hexane, toluene, xylene, 1,4-dioxane, ether, dibutyl ether, cyclopentyl methyl ether, or a mixture thereof.

[0172] Compound (III) can be extracted from the reaction mixture, for example, by the following method.

[0173] First, a quenching liquid (e.g., water, an aqueous HCl solution, an aqueous NaHCO3 solution, etc.) and an organic solvent, if necessary, are added to the reaction mixture to stop the reaction. The reaction mixture to which the quenching liquid and an organic solvent, if necessary, have been added, is stirred to separate into an aqueous layer and an organic layer (hereinafter referred to as "organic layer (A)"). After the organic layer (A) is removed, an organic solvent is added to the aqueous layer to separate it again into an aqueous layer and an organic layer (hereinafter referred to as "organic layer (B)"). The organic layer (B) may be removed and combined with the previously removed organic layer (A) to obtain a total organic layer. Next, a residue containing compound (III) is obtained from the organic layer (A) or the total organic layer. For example, the organic layer (A) or the total organic layer is washed with a washing liquid (e.g., water, an aqueous HCl solution, an aqueous NaHCO3 solution, a brine solution, etc.) if necessary, dried using sodium sulfate, etc., and then filtered, dried under reduced pressure, etc., to obtain a residue containing compound (III). The residue containing compound (III) thus obtained is an example of an extract (crude product) containing compound (III).

[0174] The organic solvent added to the reaction mixture or the aqueous layer may be one type of organic solvent alone or two or more types of organic solvents in combination. The organic solvent added to the reaction mixture or the aqueous layer is preferably different from the organic solvent used for contacting compound (I) with compound (II). The organic solvent added to the reaction mixture or the aqueous layer is preferably ethyl acetate, methyl acetate, methylene chloride, chloroform, methyl tert-butyl ether, hexane, toluene, xylene, 1,4-dioxane, ether, dibutyl ether, cyclopentyl methyl ether, or a mixture thereof.

[0175] The solidification treatment of the extract is preferably carried out using two kinds of solvents. The two kinds of solvents are selected to be mutually soluble (i.e., compatible). Of the two kinds of solvents, one solvent is a solvent having a high dissolving ability for compound (III) (hereinafter referred to as "first solvent"), and the other solvent is a solvent having a low dissolving ability for compound (III) (hereinafter referred to as "second solvent").

[0176] Examples of the first solvent include methyl acetate, ethyl acetate, methylene chloride, chloroform, methyl tert-butyl ether, etc. The first solvent is preferably methyl tert-butyl ether.

[0177] The second solvent may be, for example, pentane, hexane, heptane, etc. The second solvent is preferably heptane. The heptane is preferably n-heptane.

[0178] The combination of two solvents is preferably methyl tert-butyl ether / pentane.

[0179] The solidification treatment of the extract may be carried out by adding the first solvent to the extract, then adding the second solvent, stirring, and then allowing to stand, or by adding a mixture of the first solvent and the second solvent to the extract, stirring, and then allowing to stand. The volume ratio of the amount of the first solvent to the amount of the second solvent used (amount of the first solvent used / amount of the second solvent used) is, for example, 1 / 1 to 1 / 10, preferably 1 / 1 to 1 / 5, and more preferably 1 / 1 to 1 / 3. The stirring time is, for example, 1 to 360 minutes, preferably 1 to 240 minutes, and more preferably 1 to 120 minutes. The solidification treatment may be carried out, for example, at room temperature. The room temperature is, for example, a temperature of 15 to 35°C (particularly 25°C).

[0180] The solid of compound (III) produced by the solidification treatment can be isolated by solid-liquid separation, such as filtration or decantation.

[0181] The isolated solid of compound (III) may be washed with a washing solution. As the washing solution, an organic solvent is preferably used. One type of organic solvent may be used alone, or two or more types of organic solvents may be used in combination. Examples of the washing solution include pentane, hexane, heptane, diisopropyl ether, and methyl tert-butyl ether, and among these, pentane is preferred.

[0182] The structure of compound (III) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy.

[0183] <<Second Method>> The second method relates to a method for producing compound (IV).

[0184] The second method includes a step of producing compound (III) by the first method, and then contacting the compound (III) with a silane compound. The yield of compound (IV) is, for example, 50% or more, preferably 60% or more, and more preferably 70% or more.

[0185] The description of the first method is given above.

[0186] Compound (IV) can be obtained by contacting compound (III) with a silane compound for, for example, 10 to 240 minutes, preferably 20 to 120 minutes, more preferably 30 to 120 minutes at a temperature of, for example, −50 to 25° C., preferably −40 to 10° C., more preferably −30 to 5° C. Compound (III) can be contacted with a silane compound in an inert atmosphere (for example, in an argon atmosphere or nitrogen atmosphere).

[0187] The silane compound acts as a reducing agent, and therefore, when the compound (III) is brought into contact with the silane compound, the reduction reaction of the compound (III) proceeds to produce the compound (IV).

[0188] The silane compound is, for example, H-Si-R 1 (-R 2 )(-R 3 R 1 , R 2 and R 3each independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent. The alkyl group and the aryl group are as described above. The alkyl group may be linear or branched, but is preferably linear. The number of carbon atoms 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. The aryl group is preferably a phenyl group. The alkyl group and the aryl group may each have one or more substituents. The number of substituents that the alkyl group and the aryl group may each have is preferably 1 to 3, more preferably 1 or 2. The one or more substituents may each be independently selected from the substituent groups α and β. One or more substituents may be selected from the substituent group α, and one or more substituents may be selected from the substituent group β. The one or more substituents are each independently preferably selected from a halogen atom, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkylthio group, and a haloalkylthio group, more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, and a haloalkyloxy group having 1 to 3 carbon atoms, and even more preferably selected from a halogen atom, an alkyl group having 1 to 3 carbon atoms, and an alkyloxy group having 1 to 3 carbon atoms.

[0189] In one embodiment, R 1 , R 2 and R 3 In another embodiment, one of R is an optionally substituted alkyl group, and the remaining two are optionally substituted aryl groups. 1 , R 2 and R 3 In yet another embodiment, two of R are optionally substituted alkyl groups and the remaining one is optionally substituted aryl group. 1 , R 2 and R 3 In yet another embodiment, R 1 , R2 and R 3 All of R are optionally substituted aryl groups. 1 , R 2 and R 3 Preferably, one or more of these are alkyl groups which may have a substituent, more preferably, two or more of these are alkyl groups which may have a substituent, and even more preferably, all three of these are alkyl groups which may have a substituent.

[0190] Examples of the silane compound include triethylsilane, triisopropylsilane, etc. From the viewpoint of increasing the yield of compound (IV), the silane compound is preferably triethylsilane.

[0191] From the viewpoint of increasing the yield of compound (IV), the amount of the silane compound used is, for example, 1 to 5 moles, more preferably 1 to 4 moles, and more preferably 1 to 3 moles, relative to 1 mole of compound (III). The amount of the silane compound used means the amount of one silane compound used when one type of silane compound is used, and means the total amount of the two or more silane compounds used when two or more types of silane compounds are used.

[0192] The contact of compound (III) with the silane compound is preferably carried out in the presence of a Lewis acid.

[0193] Examples of Lewis acids include boron trifluoride diethyl ether complex (BF3·Et2O), boron trifluoride tetrahydrofuran complex (BF3·THF), titanium tetrachloride (TiCl4), aluminum trichloride (AlCl3), iron trichloride (FeCl3), tin dichloride (SnCl2), and zinc dichloride (ZnCl2). One type of Lewis acid may be used alone, or two or more types of Lewis acids may be used in combination. From the viewpoint of increasing the yield of compound (IV), the Lewis acid is preferably selected from boron trifluoride diethyl ether complex and boron trifluoride tetrahydrofuran, and more preferably is boron trifluoride diethyl ether complex.

[0194] The amount of Lewis acid used is, for example, 0.1 to 5 mol, preferably 0.2 to 4 mol, more preferably 0.5 to 3 mol, relative to 1 mol of compound (III). When one type of Lewis acid is used, the amount of Lewis acid used means the amount of the one type of Lewis acid used, and when two or more types of Lewis acids are used, the amount of the two or more types of Lewis acids used means the total amount of the two or more types of Lewis acids used.

[0195] The contact between the compound (III) and the silane compound is preferably carried out in a solvent. The solvent is preferably an organic solvent. Examples of the organic solvent include nitriles such as acetonitrile and propionitrile; ethers such as tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, t-butyl methyl ether, diisopropyl ether, dimethoxyethane, and diglyme; ketones such as acetone, methyl ethyl ketone, and diethyl ketone; esters such as methyl acetate, ethyl acetate, and butyl acetate; halogenated hydrocarbons such as dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbons such as toluene and xylene; and aliphatic hydrocarbons such as hexane and heptane. One type of solvent may be used alone, or two or more types of solvents may be used in combination. The organic solvent is preferably acetonitrile, dichloromethane, or a mixture thereof. These are aprotic polar solvents and are preferable in that they are not easily subjected to silane reduction.

[0196] The amount of the solvent used is, for example, 3 to 100 mL, preferably 4 to 50 mL, and more preferably 5 to 30 mL, relative to 1 g of compound (III).

[0197] Compound (IV) can be isolated from the reaction mixture according to conventional methods.

[0198] Compound (IV) can be isolated, for example, by the following method.

[0199] First, a quenching liquid (e.g., water, an aqueous HCl solution, an aqueous NaHCO3 solution, etc.) and an organic solvent, if necessary, are added to the reaction mixture to terminate the reaction. The reaction mixture to which the quenching liquid and an organic solvent, if necessary, have been added, is stirred to separate into an aqueous layer and an organic layer (hereinafter referred to as "organic layer (C)"). After removing the organic layer (C), an organic solvent is added to the aqueous layer to separate it again into an aqueous layer and an organic layer (hereinafter referred to as "organic layer (D)"). The organic layer (D) may be removed and combined with the organic layer (C) previously removed to obtain a total organic layer. Next, a residue containing compound (IV) is obtained from the organic layer (C) or the total organic layer. For example, the organic layer (C) or the total organic layer is washed with a washing liquid (e.g., water, an aqueous HCl solution, an aqueous NaHCO3 solution, a brine solution, etc.) if necessary, dried using sodium sulfate, etc., and then filtered, dried under reduced pressure, etc., to obtain a residue containing compound (IV).

[0200] Specific examples of the organic solvent added to the reaction mixture or the aqueous layer are the same as those of the organic solvent used in contacting the compound (III) with the silane compound. One type of organic solvent may be used alone, or two or more types of organic solvents may be used in combination.

[0201] Compound (IV) can be isolated by subjecting the residue containing compound (IV) to purification treatment such as silica gel column chromatography, preparative TLC, solidification treatment, etc. The solidification treatment can be carried out in the same manner as described above.

[0202] The structure of compound (IV) can be confirmed, for example, by nuclear magnetic resonance (NMR) spectroscopy. EXAMPLES

[0203] <Example 1> Compound IIIa ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol) was produced from compound Ia ((2R,3R,4S,5R)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate) according to the following reaction scheme. In the formula, "Ac" represents an acetyl group.

[0204] [ka]

[0205] To a solution of compound Ia (300 mg, 0.472 mmol) in tetrahydrofuran (THF) (1.5 mL), a solution of methanesulfonic acid (MSA) (153 μL, 2.360 mmol, 5 equiv.) in methanol (MeOH) (3 mL) was added dropwise at a temperature of -70°C and stirred at -70°C for 2 hours. The mixture was then slowly warmed to room temperature and stirred at room temperature for 12 hours. Methanesulfonic acid (61 μL, 0.944 mmol, 2 equiv.) was added to the reaction mixture at room temperature and stirred for another 12 hours. Complete consumption of the starting material and formation of the reaction product were confirmed by TLC. The reaction mixture was diluted with ethyl acetate (EtOAc) (10 mL) and aqueous sodium bicarbonate (NaHCO3) solution (10 mL) was added. The organic layer was then separated, dried over sodium sulfate (Na2SO4), and concentrated by vacuum to give a sticky off-white solid. The solid was then dissolved in methyl tert-butyl ether (MTBE) (2 mL). n-Pentane (5 mL) was added and the solvent was removed by decantation. The resulting solid was then added with n-heptane, stirred, filtered and dried to give compound IIIa (160 mg, 77%) as a white solid.

[0206] The analytical results of the obtained compound IIIa are shown below. 1H NMR(500MHz, CDCl3, 25℃):δ 7.36(s,1H),7.24(s,2H),7.01(d,J=8.5Hz,2H),6.72(d,J=8.5Hz,2H),4.84(d,J=5. 7Hz,1H),4.65(d,J=5.3Hz,1H),4.49(d,J=7.4Hz,1H),4.40-4.27(m,1H),4.00-3.93( m,2H),3.89(dd,J=13.8,6.8Hz,3H),3.80(dd,J=17.3,11.9Hz,3H),3.57(d,J=3.5Hz, 1H),3.47(d,J=9.9Hz,2H),3.18(t,J=8.1Hz,1H),2.86(s,3H),1.35(t,J=6.9Hz,3H); 13 C NMR(126MHz, CDCl3, 25℃):δ 157.35,138.60,136.71,134.40,131.52,130.18,129.71,129.67,129.33,126.86,114.4 7,101.11,76.88,74.63,72.64,69.88,63.46,61.74,49.24,38.55,29.13,27.06,14.92.

[0207] <Example 2> Compound IVa ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) (dapagliflozin) was produced from compound IIIa ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) according to the following reaction scheme. In the formula, "Me" represents a methyl group.

[0208] [ka]

[0209] To a solution of compound IIIa (70 mg, 0.159 mmol) in dichloromethane (CH2Cl2) (1.5 mL), triethylsilane (TES) (51 μL, 0.318 mmol) was added dropwise at a temperature of -15 °C, followed by slow addition of boron trifluoride diethyl ether complex (BF3·Et2O) (67 mg, 0.318 mmol) over 10 min and stirring at -10 °C for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (EtOAc) (10 mL). The reaction was then quenched by adding aqueous sodium bicarbonate (NaHCO3) solution (5 mL) to adjust the pH to 7-8. The aqueous and organic layers were separated. The organic layer was washed with water (5 mL), dried over sodium sulfate, and filtered. The organic layer was concentrated by vacuum at 40-50 °C to give a crude residue. The crude residue was purified by preparative TLC (MeOH / CHCl3:1 / 9) to give 40 mg (65% yield) of compound IVa (dapagliflozin) as a white solid.

[0210] The analytical results of the obtained compound IVa are shown below. 1 H NMR(500MHz, CDCl3, 25℃):δ 7.37(d,J=8.2Hz,1H),7.32(d,J=1.6Hz,1H),7.23(dd,J=8.2,1.6Hz,1H),7.09(d,J=8.5H z,2H),6.82(d,J=8.5Hz,2H),4.97(dd,J=4.7,3.9Hz,2H),4.85(d,J=5.8Hz,1H),4.47(t,J =5.8Hz,1H),4.03-3.92(m,5H),3.73-3.66(m,1H),3.44(dt,J=11.8,5.9Hz,1H),3.28-3. 20(m,2H),3.17(dd,J=9.0,5.2Hz,1H),3.11(td,J=9.0,6.0Hz,1H),1.29(t,J=6.9Hz,3H); 13C NMR(126MHz, CDCl3, 25℃):δ 156.93,139.72,137.86,131.96,131.25,130.85,129.62,128.72,127.41 ,114.31,81.26,80.74,78.33,74.74,70.32,62.91,61.38,37.69,14.74; HRMS: [M+Na] + C 21 H 25 O6NaCl Calculated value: 431.1232, Found value: 431.1227.

[0211] <Example 3> Compound IIIb ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol) was produced from compound Ib ((2R,3R,4S,5R)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-oxohexane-1,2,3,4,5-pentyl pentaacetate) according to the following reaction formula. In the formula, "Ac" represents an acetyl group, and "Me" represents a methyl group.

[0212] [ka]

[0213] A solution of compound Ib (300 mg, 0.44 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (1.5 mL) was added dropwise with a solution of methanesulfonic acid (MSA) (195 μL, 2.20 mmol, 5.0 equiv.) in methanol (MeOH) (3 mL) at a temperature of 15° C. and stirred at 15° C. for 2 h. The mixture was then gradually warmed to room temperature and stirred at room temperature for 12 h. As TLC showed that the reaction was not complete (unconsumed substrate remained), additional MSA (78 μL, 0.88 mmol, 2.0 equiv.) was added to the reaction mixture and stirred for another 12 h. After TLC showed the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL) and aqueous NaHCO3 (10 mL) was added. The organic layer was then extracted, dried over Na2SO4, and concentrated by vacuum. The crude compound was purified by silica gel column chromatography (SiO2 230-400, eluted with 30% ethyl acetate in hexane) to give compound IIIb (166 mg, yield 78%) as a sticky solid.

[0214] The analytical results of the obtained compound IIIb are shown below. 1 H NMR(500MHz,CDCl3):δ 7.34(s,1H),7.23-7.18(m,2H),7.01(d,J=8.0Hz,2H),6.66(d,J=8.0Hz,2H),5.21(s,1H),5.07(s,1H),4.76( s,1H),4.24(s,1H),3.99-3.76(m,9H),3.57-3.47(m,2H),3.16(d,J=8Hz,1H),2.83(s,3H),2.08-2.05(m,2H).

[0215] <Example 4> Compound IVb ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) (empagliflozin) was produced from compound IIIb ((2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) according to the following reaction scheme. In the formula, "Me" represents a methyl group.

[0216] [ka]

[0217] To a solution of compound IIIb (72 mg, 0.15 mmol, 1 equiv.) in dichloromethane (CH2Cl2) (1.5 mL), triethylsilane (TES) (51 μL, 0.318 mmol, 2 equiv.) was added dropwise at a temperature of -15 °C, followed by slow addition of boron trifluoride diethyl ether complex (BF3·Et2O) (67 mg, 0.318 mmol, 2 equiv.) over 10 min. The reaction mixture was then stirred at -10 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and quenched by adjusting the pH to 7-8 with saturated NaHCO3 (5 mL) solution. The aqueous and organic layers were separated, and the organic layer was washed with water (5 mL), dried over sodium sulfate, and filtered. The combined organic layers were concentrated by vacuum at 40-50 °C to give a crude solid. The crude solid was then crystallized using ethyl acetate (2 mL) and hexane (10 mL). The crystals were filtered, washed with hexane, and then dried to give compound IVb (59 mg, 88% yield) as a white solid.

[0218] The analytical results of the obtained compound IVb are shown below. 1H NMR(500MHz,CDCl3):δ 7.24-7.10(m,3H),7.03-6.98(m,2H),6.69-6.64(m,2H),5.15-4.95(m,2H),4.70(s,1H),4.10-2.93(m,15H),2.04-2.01(m,2H).

[0219] <Example 5> Compound IIIb was produced from compound Ib. The meanings of compound Ib and compound IIIb are the same as those in Example 3. Methanesulfonic acid (MSA) (57 mg, 0.591 mmol, 2.0 equiv.) was added dropwise to a solution of compound Ib (200 mg, 0.295 mmol, 1.0 equiv.) in methanol (MeOH) (2 mL) at 24.5° C. and stirred at 30° C. for 12 h. After confirming the completion of the reaction by HPLC, the reaction was quenched by the addition of saturated aqueous NaHCO3 solution (2 mL). The reaction mixture was diluted with ethyl acetate (2 mL), and the organic layer was then washed with brine (1 mL, 5 volumes (v / w)), dried over sodium sulfate (5 g), and filtered. The solvent was removed under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (SiO2-30 g, mobile phase-40% ethyl acetate:hexane to 70% ethyl acetate:hexane) to obtain compound IIIb (135 mg, 95% yield) as an off-white solid. The analytical results of the obtained compound IIIb were the same as those of Example 3.

Claims

1. The following formula (III): 【Chemistry 1】 [In the formula, R １００ represents an alkyl group which may have a substituent, and Ar represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent. A method for producing compound (III) represented by the following formula: The following formula (I): 【Chemistry 2】 [In the formula, each R independently represents an alkyl group which may have a substituent or an aryl group which may have a substituent, and Ar has the same meaning as defined above.] Compound (I) represented by the formula: The following formula (II): 【Chemistry 3】 [In the formula, R ２００ represents an alkyl group which may have a substituent. and a compound (II) represented by The following formula: 【Chemistry 4】 [In the formula, R １００ has the same meaning as above.] The method includes contacting in a solvent containing an alcohol represented by the formula:

2. The method according to claim 1, wherein the alcohol is an alcohol having 1 to 5 carbon atoms.

3. The method according to claim 2, wherein the alcohol having 1 to 5 carbon atoms is selected from methanol and ethanol.

4. The following formula (IV): 【Chemistry 5】 [In the formula, Ar represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent, or an arylalkenyl group which may have a substituent.] A method for producing a compound (IV) represented by A method comprising the step of producing compound (III) by the method according to claim 1 and then contacting the resulting compound (III) with a silane compound.

5. 5. The method of claim 4, wherein the silane compound is selected from triethylsilane and triisopropylsilane.

6. 6. The method according to claim 4 or 5, wherein the contact of compound (III) with the silane compound is carried out in the presence of a Lewis acid.

7. 7. The method of claim 6, wherein the Lewis acid is selected from boron trifluoride diethyl etherate, boron trifluoride tetrahydrofuran complex, titanium tetrachloride, aluminum trichloride, iron trichloride, tin dichloride and zinc dichloride.

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