Method for producing C-arylhydroxyglycoxide derivatives

Abstract

This invention provides a method for industrially producing C-arylhydroxyglycoxide derivatives inexpensively and efficiently. [Solution] A method for producing a C-arylhydroxyglycoxide derivative represented by the following formula (I), comprising the steps of obtaining compound (IV) and the hydroxyl protecting group R in compound (IV). 5 The process includes removing to obtain compound (I). TIFF2026153008000097.tif46150

Description

[Technical Field]

[0001] The present invention relates to a method for producing C-arylhydroxyglycoxide derivatives, and more particularly to a method for producing C-arylhydroxyglycoxide derivatives that are useful as intermediates for SGLT-2 inhibitors. [Background technology]

[0002] Currently, various medications are commercially available for the treatment of diabetes, including sulfonylurea drugs, glinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, and glucose-like peptide 1 (GLP-1) agonists. In recent years, sodium-glucose cotransporter-2 (SGLT-2) inhibitors have also been developed and are attracting attention as a new type of diabetes treatment with a novel mechanism of action.

[0003] An example of an SGLT-2 inhibitor is canagliflozin (1-(β-D-glacopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), and a method for producing these compounds has been proposed, which involves deprotecting the oxygen protecting group of the 1-(β-D-glacopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor to synthesize canagliflozin (Patent Document 1). This 1-(β-D-glacopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor is also called a C-arylhydroxyglycoxide derivative and is attracting attention as an intermediate for producing SGLT-2 inhibitors (see Non-Patent Documents 1, 2, 3, 1 and 2).

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

[0005] Incidentally, it has been reported that coupling occurs when a thioester derivative is reacted with an organozinc reagent in the presence of a nickel catalyst, yielding a ketone derivative (Non-Patent Document 4, Non-Patent Document 5). [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] WO2010 / 043682 publication [Patent Document 2] WO2015 / 012110 publication [Non-patent literature]

[0007] [Non-Patent Document 1] J.Med.Chem. 2008, 51, 1145-1149 [Non-Patent Document 2] Org.Lett.2014,16,4090-4093 [Non-Patent Document 3] J.Org.Chem. 1989, 54, 610-612 [Non-Patent Document 4] Tetrahedron Letters 2002,43, 1039-1042 [Non-Patent Document 5] Chem.Eur.J.2018,24,8774-8778 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] Previous methods used to produce C-arylhydroxyglycoxide derivatives all required the use of expensive reagents under severe low-temperature conditions, resulting in extremely high equipment and running costs, making it difficult to mass-produce the final active pharmaceutical ingredient at a low cost.

[0009] Therefore, one objective of the present invention is to provide a method for industrially producing C-arylhydroxyglycoxide derivatives inexpensively and efficiently. [Means for solving the problem]

[0010] The present inventors have now discovered that by carrying out a cross-coupling reaction with specific raw materials in the presence of a nickel catalyst or a palladium catalyst, and then performing a cyclization reaction, it is possible to produce a C-arylhydroxyglycoxide derivative (hereinafter also referred to as compound (I) represented by the following formula (I)) industrially, inexpensively, and efficiently, thus completing the present invention.

[0011] The present invention provides the following: [1] Formula (I): [ka] [In the formula, R 1 and R 2 Each of these independently represents a hydroxyl protecting group. R 3 and R 4each independently represent a hydroxyl-protecting group or a hydrogen atom; Ar represents an organic group comprising an aromatic hydrocarbon ring group or an aromatic heterocyclic group as a functional group that bonds to the oxane ring in the formula, wherein the aromatic hydrocarbon ring group and the aromatic heterocyclic group each may have one or more substituents.]] A method for producing compound (I) represented by the formula, the following formula (II):

Chemical Formula

Chemical Formula

Chemical Formula

[10] The organic group represented by Ar is an organic group that includes an aromatic hydrocarbon ring group having 6 to 14 carbon atoms or an aromatic heterocyclic group having 3 to 12 carbon atoms as a functional group bonded to the oxane ring in the formula, wherein the aromatic hydrocarbon ring group having 6 to 14 carbon atoms and the aromatic heterocyclic group having 3 to 12 carbon atoms each have one or more substituents, the method according to any one of [1] to [9].

[11] The organic group represented by Ar is given by formula (V): [ka] [In the formula, R aEach of these independently represents a functional group selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an arylalkyloxy group, an arylalkenyloxy group, and an arylalkynyloxy group, and each of the alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl group, arylalkenyloxy group, aryl group, alkyloxy group, arylalkynyloxy group, and arylalkynyloxy group may have one or more substituents. n is an integer between 0 and 4. Ar' represents an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, or an aromatic heterocyclic group, and each of the aromatic hydrocarbon ring group, aliphatic heterocyclic group, and aromatic heterocyclic group may have one or more substituents. A method represented by any of [1] to

[10] .

[12] R a The functional group represented by is independently selected from alkyl groups and halogen atoms, and the alkyl group may have one or more substituents, according to the method in

[11] .

[13] The organic group represented by Ar is given by the following formula (Va): [ka] [In the formula, R a This is synonymous with the above, Ar' is given by the following equations (Va-I), (Va-II), and (Va-III): [ka] [In the formula, R bEach of these independently represents a functional group selected from the group consisting of an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group, and each of the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may have one or more substituents, and p represents an integer from 0 to 5. This represents a functional group selected from the group consisting of [the specified elements]. The method described in

[11] or

[12] , represented by

[11] .

[14] R b The functional group represented by is independently selected from the group consisting of C1-C20 alkyl groups, C2-C20 alkenyl groups, C2-C20 alkynyl groups, C6-C14 aromatic hydrocarbon ring groups, C2-C12 aliphatic heterocyclic groups, and C3-C12 aromatic heterocyclic groups, and each of the alkyl groups, alkenyl groups, alkynyl groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups may have one or more substituents. The method according to

[13] .

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

[14] , wherein the one or more substituents that the aromatic hydrocarbon ring group or aromatic heterocyclic group contained in the organic group represented by Ar may have are each independently selected from the group consisting of a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected sulfonyl group, an alkyl group, an alkenyl group, and an alkynyl group.

[16] Formula (VI): [ka] [In the formula, R 1 ~R 4 This is synonymous with the above. Compound (VI) represented by, The following equation (VII): [ka] [In the formula, Q is equivalent to the above.] The compound (VII) represented by the following formula (VIII) is reacted with the compound (VII) to produce the following: [ka] [In the formula, R 1 ~R 4 This is synonymous with the above. A step to obtain a compound (VIII) represented by, and The hydroxyl group in the above compound (VIII) is R 5 The process of protecting with to obtain compound (II) A method according to any of [1] to

[15] , further comprising the above.

[17] The method according to

[16] , wherein the reaction between compound (VI) and compound (VII) is carried out at -30 to 40°C.

[18] The reaction between compound (VI) and compound (VII) is given by the following formula (IX): [ka] [In the formula, R c and R d Each of these independently represents a functional group selected from the group consisting of a halogen atom, an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group, and each of the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may have one or more substituents. q represents an integer between 0 and 3. r represents an integer between 0 and 3, where q + r = 3. The method according to

[16] or

[17] , carried out in the presence of a compound represented by (IX).

[19] R c and R d The method according to

[18] , wherein each of the functional groups represented is independently selected from the group consisting of alkyl groups, aryl groups, and arylalkyl groups, and each of the alkyl groups, aryl groups, and arylalkyl groups may have one or more substituents.

[20] Formula (II) below: [ka] [In the formula, R 1 ~R 5 And Q are synonymous with the above. The compound (II) represented by the following formula (XI): [ka] [In the formula, Ar is equivalent to the above, and R 1 '~R 4 Each of these independently represents either a hydrogen atom or a hydroxyl protecting group. A reagent for producing compound (XI) represented by [formula].

[21] Compounds of the following formula (XI): [ka] [In the formula, Ar and R 1 '~R 4 ' is synonymous with the above.' As a manufacturing intermediate for compound (XI) represented by, Formula (II) below: [ka] [In the formula, R 1 ~R 5 And Q are synonymous with the above. The use of compound (II) represented by . [Effects of the Invention]

[0012] According to the present invention, compound (I) can be manufactured industrially at low cost and efficiently. The present invention is advantageous for industrial production because it can significantly reduce equipment costs and running costs. [Modes for carrying out the invention]

[0013] The present invention will now be described. If two or more embodiments described herein can be combined, the present invention also encompasses such combinations.

[0014] <Definition> The following definitions of terms and expressions used herein are explained below. Unless otherwise specified, the following definitions apply throughout this specification. For example, the definition of “alkyl group” also applies to “alkyl group” or functional groups containing an “alkyl group” (e.g., alkylaryl group, arylalkyl group, etc.).

[0015] An "organic group" refers to a functional group containing one or more carbon atoms. An organic group may contain one or more heteroatoms. A "heteroatom" refers to an atom other than a hydrogen atom and a carbon atom. Examples of heteroatoms include nitrogen, oxygen, sulfur, halogen, and silicon atoms. A "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom. The bonds of an organic group are preferably formed by the bonds of carbon atoms contained within the organic group.

[0016] In one embodiment, the organic group is an aliphatic hydrocarbon group which may have one or more substituents, or includes an aliphatic hydrocarbon group which may have one or more substituents. In this embodiment, it is preferable that the bond of the organic group is formed by the bond of the aliphatic hydrocarbon group.

[0017] In another embodiment, the organic group is an aromatic hydrocarbon ring group which may have one or more substituents, or includes an aromatic hydrocarbon ring group which may have one or more substituents. In this embodiment, the bond of the organic group is preferably formed by the bond of the aromatic hydrocarbon ring group.

[0018] In another embodiment, the organic group is an aliphatic heterocyclic group which may have one or more substituents, or includes an aliphatic heterocyclic group which may have one or more substituents. In this embodiment, the bond of the organic group is preferably formed by the bond of the aliphatic heterocyclic group.

[0019] In another embodiment, the organic group is an aromatic heterocyclic group which may have one or more substituents, or includes an aromatic heterocyclic group which may have one or more substituents. In this embodiment, the bond of the organic group is preferably formed by the bond of the aromatic heterocyclic group.

[0020] In another embodiment, the organic group includes a functional group formed by combining two or more selected from an aliphatic hydrocarbon group which may have one or more substituents, an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, and an aromatic heterocyclic group which may have one or more substituents. In this embodiment, the bond of the organic group is preferably formed by a bond of an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, or an aromatic heterocyclic group.

[0021] An "aliphatic hydrocarbon group" refers to a functional group (a hydrocarbon group that does not possess aromaticity) produced by removing a hydrogen atom from an aliphatic hydrocarbon. Depending on the context, an "aliphatic hydrocarbon group" may refer to a monovalent or divalent functional group. Aliphatic hydrocarbon groups may be linear, cyclic, or a combination thereof. Linear groups may be linear or branched. Aliphatic hydrocarbon groups are preferably linear or branched. Aliphatic hydrocarbon groups may be saturated or unsaturated. Unsaturated bonds may be carbon-carbon double bonds or carbon-carbon triple bonds.

[0022] Examples of monovalent aliphatic hydrocarbon groups include alkyl groups, alkenyl groups, and alkynyl groups. Examples of divalent aliphatic hydrocarbon groups include alkylene groups, alkenylene groups, and alkynylene groups.

[0023] "Alkyl group" refers to a monovalent functional group produced by removing one hydrogen atom from an alkane. Alkyl groups may be linear, cyclic, or a combination thereof. Note that cyclic alkyl groups are synonymous with "cycloalkyl groups". Linear groups may be linear or branched. Alkyl groups are preferably linear or branched. Linear alkyl groups typically have 1 to 20 carbon atoms, preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, and even more preferably 1 to 3. Branched alkyl groups typically have 3 to 20 carbon atoms, preferably 3 to 10, more preferably 3 to 8, even more preferably 3 to 6, and even more preferably 3 to 4. Cyclic alkyl groups typically have 3 to 20 carbon atoms, preferably 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6. The number of carbon atoms in an alkyl group having a linear or branched portion and a cyclic portion is usually 4 to 20, preferably 4 to 10, more preferably 4 to 8, and even more preferably 4 to 6.

[0024] Examples of alkyl groups include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, and decyl groups; cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups; and alkyl groups having linear or branched portions and cyclic portions, such as cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, and cyclohexylethyl groups.

[0025] An "alkenyl group" refers to a monovalent functional group produced by removing one hydrogen atom from an alkene. An alkenyl group has at least one carbon-carbon double bond. An alkenyl group may be linear, cyclic, or a combination thereof. Note that a cyclic alkenyl group is synonymous with a "cycloalkenyl group". The linear structure may be straight or branched. Alkenyl groups are preferably linear or branched. The number of carbon atoms in a linear alkenyl group is usually 2 to 20, preferably 2 to 10, more preferably 2 to 8, even more preferably 2 to 6, and even more preferably 2 to 4. The number of carbon atoms in a branched alkenyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, even more preferably 3 to 6, and even more preferably 3 to 4. The number of carbon atoms in a cyclic alkenyl group is typically 3 to 20, preferably 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6. The number of carbon atoms in an alkenyl group having a linear or branched portion and a cyclic portion is typically 4 to 20, preferably 4 to 10, more preferably 4 to 8, and even more preferably 4 to 6. The number of double bonds in an alkenyl group is typically 1 to 9, preferably 1 to 7, more preferably 1 to 4, and even more preferably 1 to 3.

[0026] Examples of alkenyl groups include linear or branched alkenyl groups such as vinyl group, 2-propenyl group, 3-butenyl group, 4-pentenyl group, 3-pentenyl group, 2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 3-octenyl group, 3-nonenyl group, and 4-decenyl group; cyclic alkenyl groups such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, and cyclooctenyl group; and alkenyl groups having a linear or branched portion and a cyclic portion, such as cyclopentenylmethyl group, cyclopentenylethyl group, cyclopentenylpropyl group, cyclohexenylmethyl group, and cyclohexenylethyl group.

[0027] An "alkynyl group" refers to a monovalent functional group produced by removing one hydrogen atom from an alkyne. An alkynyl group has at least one carbon-carbon triple bond. An alkynyl group may be linear, cyclic, or a combination thereof. Note that a cyclic alkynyl group is synonymous with a "cycloalkynyl group". The linear structure may be straight or branched. Alkynyl groups are preferably linear or branched. A linear alkynyl group typically has 2 to 20 carbon atoms, preferably 2 to 10, more preferably 2 to 8, even more preferably 2 to 6, and even more preferably 2 to 4. A branched alkynyl group typically has 4 to 20 carbon atoms, preferably 4 to 10, more preferably 4 to 8, and even more preferably 3 to 6. A cyclic alkynyl group typically has 4 to 20 carbon atoms, preferably 4 to 10, more preferably 4 to 8, and even more preferably 4 to 6. The number of carbon atoms in an alkynyl group having a linear or branched portion and a cyclic portion is usually 5 to 20, preferably 5 to 10, more preferably 5 to 8, and even more preferably 5 to 6. The number of triple bonds in the alkynyl group is usually 1 to 9, preferably 1 to 7, more preferably 1 to 4, and even more preferably 1 to 3.

[0028] Examples of alkynyl groups include linear or branched alkynyl groups such as 2-propynyl group, 3-butynyl group, 4-pentynyl group, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octinyl group, 3-noninyl group, and 4-decynyl group; cyclic alkynyl groups such as cyclobutynyl group, cyclopentynyl group, cycloheptynyl group, and cyclooctinyl group; and alkynyl groups having a linear or branched portion and a cyclic portion, such as cyclopentynylmethyl group, cyclopentenylethyl group, cyclopentinylpropyl group, cyclopentinylmethyl group, and cyclopentinylethyl group.

[0029] An "alkylene group" refers to a divalent functional group produced by removing one hydrogen atom from an alkyl group. The explanation of alkyl groups is the same as above.

[0030] An "alkenylene group" refers to a divalent functional group created by removing one hydrogen atom from an alkenyl group. The explanation of the alkenyl group is the same as above.

[0031] An "alkynylene group" refers to a divalent functional group created by removing one hydrogen atom from an alkynyl group. The explanation of the alkynyl group is the same as above.

[0032] An "aromatic hydrocarbon ring group" refers to a functional group produced by removing a hydrogen atom from an aromatic hydrocarbon ring. Depending on the context, an "aromatic hydrocarbon ring group" can refer to a monovalent or divalent functional group.

[0033] Examples of monovalent aromatic hydrocarbon ring groups include aryl groups. Examples of divalent aromatic hydrocarbon ring groups include arylene groups.

[0034] The term "aryl group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic carbon-hydrogen ring group. Aryl groups are typically 1-4 cyclic, preferably 1-3 cyclic, and more preferably 1 or 2 cyclic aromatic carbon-hydrogen ring groups. The number of ring-constituting carbon atoms in an aryl group is typically 6-18, preferably 6-14, and more preferably 6-10.

[0035] An example of a monocyclic aromatic carbon-hydrogen ring group is the phenyl group.

[0036] The aryl group includes fused polycyclic aromatic hydrocarbon ring groups and partially saturated fused polycyclic aromatic hydrocarbon ring groups. Partially saturated fused polycyclic aromatic hydrocarbon ring groups are fused polycyclic aromatic hydrocarbon ring groups in which some of the bonds constituting the ring are hydrogenated. Examples of fused polycyclic aromatic hydrocarbon ring groups include 2- to 4-cyclic aromatic carbon-hydrogen ring groups such as naphthyl, anthryl, phenantrenyl, tetracenyl, and pyrenyl groups, as well as fluorenyl, indenyl, and acenaphthirenyl groups. Examples of partially saturated fused polycyclic aromatic hydrocarbon ring groups include dihydronaphthyl, indanyl, and acenaphthenyl groups.

[0037] An "arylene group" is a divalent functional group produced by removing one hydrogen atom bonded to a ring-constituting carbon atom from an aryl group. The explanation of the aryl group is the same as above. Examples of arylene groups include 1,3-phenylene and 1,4-phenylene groups.

[0038] An "aliphatic heterocyclic group" refers to a functional group produced by removing a hydrogen atom from a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aliphatic heterocycle (non-aromatic heterocycle) that contains, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen atoms. Depending on the context, an "aliphatic heterocyclic group" may refer to a monovalent or divalent functional group. In functional groups containing an "aliphatic heterocycle" (e.g., aliphatic heterocyclic thio group, aliphatic heterocyclic oxy group, etc.), "aliphatic heterocycle" refers to an aliphatic heterocyclic group.

[0039] The number of heteroatoms in the aliphatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members in the aliphatic heterocyclic group is usually 3 to 16, preferably 4 to 10, more preferably 5 to 8, even more preferably 5 to 7, and even more preferably 5 or 6. The aliphatic heterocyclic group is, for example, monocyclic, bicyclic, or tricyclic, and is preferably monocyclic or bicyclic. The number of ring-constituting carbon atoms in the aliphatic heterocyclic group is appropriately selected according to the number of heteroatoms and the number of members in the aliphatic heterocyclic group. The number of ring-constituting carbon atoms in the aliphatic heterocyclic group is usually 2 to 12, preferably 2 to 8, and more preferably 2 to 5.

[0040] A monocyclic aliphatic heterocyclic group is, for example, a monocyclic saturated aliphatic heterocyclic group. A monocyclic saturated aliphatic heterocyclic group is a monocyclic aliphatic heterocyclic group in which the ring is formed solely by saturated bonds. In one embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 2 oxygen atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 2 sulfur atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 4 nitrogen atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms. In a monocyclic saturated aliphatic heterocyclic group, the two carbon atoms constituting the ring may be bridged by an alkylene group. In a monocyclic saturated aliphatic heterocyclic group, two adjacent carbon atoms constituting the ring may form a double bond. In a monocyclic saturated aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. The number of oxo groups that a monocyclic saturated aliphatic heterocyclic group may have is preferably one or two. If the heteroatom contained in the monocyclic saturated aliphatic heterocyclic group is a sulfur atom, the monocyclic saturated aliphatic heterocyclic group may be a dioxide.

[0041] Examples of monocyclic aliphatic heterocyclic groups include azilidinyl group, oxyranyl group, thyranyl group, azetidinyl group, oxetanyl group, thietanyl group, tetrahydrothienyl group, tetrahydrofuranyl group, pyrrolinyl group, pyrrolidinyl group, imidazolinyl group, imidazolidinyl group, oxazolinyl group, oxazolidinyl group, pyrazolinyl group, pyrazolidinyl group, thiazolinyl group, thiazolidinyl group, tetrahydroisothiazolyl group, tetrahydrooxazolyl group, and tetrahydroisoxazolyl group. Examples include 3- to 8-membered monocyclic aliphatic heterocyclic groups such as piperidinyl group, piperazinyl group, tetrahydropyridinyl group, dihydropyridinyl group, dihydrothiopyranyl group, tetrahydropyrimidinyl group, tetrahydropyridazinyl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group (the sulfur atom on the ring may be oxidized), azepanyl group, diazepanyl group, azepinyl group, oxepanyl group, azokanyl group, and diazokanyl group.

[0042] Monocyclic aliphatic heterocyclic groups also include partially saturated monocyclic aromatic heterocyclic groups. Partially saturated monocyclic aromatic heterocyclic groups are monocyclic aromatic heterocyclic groups in which some of the bonds constituting the ring are hydrogenated. Examples of partially saturated monocyclic aromatic heterocyclic groups include 4,5-dihydro-1H-imidazolyl group, 1,2,3,6-tetrahydropyridyl group, 4H-1,3-oxazinyl group, and 5,6-dihydro-4H-1,3-oxazinyl group. In a partially saturated monocyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. The number of oxo groups that a partially saturated monocyclic aromatic heterocyclic group may have is preferably one or two.

[0043] A polycyclic aliphatic heterocyclic group is, for example, a fused polycyclic aliphatic heterocyclic group. A fused polycyclic aliphatic heterocyclic group is, for example, a fused polycyclic saturated aliphatic heterocycle. A fused polycyclic saturated aliphatic heterocycle is a fused polycyclic aliphatic heterocyclic group in which the ring is formed solely by saturated bonds. In one embodiment, a fused polycyclic saturated aliphatic heterocyclic group contains 1 to 3 oxygen atoms. In another embodiment, a fused polycyclic saturated aliphatic heterocyclic group contains 1 to 3 sulfur atoms. In another embodiment, a fused polycyclic saturated aliphatic heterocyclic group contains 1 to 3 oxygen atoms and 1 to 3 sulfur atoms. In another embodiment, a fused polycyclic saturated aliphatic heterocyclic group contains 1 to 5 nitrogen atoms. In another embodiment, a fused polycyclic saturated aliphatic heterocyclic group contains 1 to 4 nitrogen atoms, 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms. In a fused polycyclic saturated aliphatic heterocyclic group, two carbon atoms constituting the ring may be bridged by an alkylene group. In a fused polycyclic saturated aliphatic heterocyclic group, two adjacent carbon atoms constituting the ring may form a double bond. In a fused polycyclic saturated aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted by an oxo group. The number of oxo groups that a fused polycyclic aliphatic heterocyclic group may have is preferably 1, 2, or 3. If the heteroatom included in the fused polycyclic saturated aliphatic heterocyclic group is a sulfur atom, the fused polycyclic saturated aliphatic heterocyclic group may be a dioxide.

[0044] Examples of condensed polycyclic aliphatic heterocyclic groups include the octahydro-1H-isoindolyl group, decahydroquinolyl group, decahydroisoquinolyl group, hexahydro-2H-[1,4]dioxyno[2,3-c]pyrrolyl group, and 3-azabicyclo[3.1.0]hexa-3-yl group.

[0045] Aliphatic heterocyclic groups also include spirocyclic heterocyclic groups. A spirocyclic heterocyclic group is a heterocyclic group formed by two rings sharing one spirocarbon atom. Examples of combinations of two rings include a combination of a monocyclic aliphatic heterocyclic group and a monocyclic aliphatic hydrocarbon ring group (e.g., a cycloalkyl group, a cycloalkenyl group, etc.), or a combination of two monocyclic aliphatic heterocyclic groups. In a spirocyclic heterocyclic group, two adjacent carbon atoms among the carbon atoms constituting the ring may form a double bond. In a spirocyclic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. The number of oxo groups that a spirocyclic heterocyclic group may have is preferably one, two, or three. If the heteroatom included in the spirocyclic heterocyclic group is a sulfur atom, the spirocyclic heterocyclic group may be a dioxide.

[0046] Examples of spirocyclic heterocyclic groups include 2-oxa-6-azaspiro[3.3]heptanyl group, 1-oxa-6-azaspiro[3.3]heptanyl group, 6-oxa-1-azaspiro[3.3]heptanyl group, 1-oxo-2,8-diazaspiro[4.5]decanyl group, 1,4-dioxa-8-azaspiro[4.5]decanyl group, 2-azaspiro[3.3]heptyl group, 7-oxa-2-azaspiro[3.5]nonyl group, 5,8-oxa-2-azaspiro[3.4]octyl group, 1,4-dioxa-8-azaspiro[4.5]decanyl group, and 1-oxaspiro[4.5]decanyl group.

[0047] An "aromatic heterocyclic group" refers to a functional group produced by removing a hydrogen atom from a monocyclic or polycyclic aromatic heterocyclic ring that, in addition to carbon atoms, contains one or more heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen atoms. Depending on the context, an "aromatic heterocyclic group" may refer to a monovalent or divalent functional group.

[0048] Examples of monovalent aromatic heterocyclic groups include heteroaryl groups. Examples of divalent aromatic heterocyclic groups include heteroarylene groups.

[0049] A "heteroaryl group" refers to a monocyclic or polycyclic aromatic heterocyclic group. A heteroaryl group is usually a 1- to 4-cyclic, preferably 1- to 3-cyclic, and more preferably 1- or 2-cyclic aromatic heterocyclic group. The number of heteroatoms in a heteroaryl group is usually 1-4, preferably 1-3, and even more preferably 1 or 2. The number of members in a heteroaryl group is preferably 5- to 14, more preferably 5- to 10. The number of ring-constituting carbon atoms in a heteroaryl group is appropriately determined according to the number of heteroatoms and the number of members. The number of ring-constituting carbon atoms in an aromatic heterocyclic group is usually 3- to 12, preferably 3-8, and even more preferably 3-5. In a heteroaryl group, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. In one embodiment, the heteroaryl group is a 5- to 7-membered monocyclic aromatic heterocyclic group. In another embodiment, the heteroaryl group is an 8- to 14-membered bicyclic or tricyclic aromatic heterocyclic group.

[0050] A heteroaryl group is, for example, a monocyclic aromatic heterocyclic group. In one embodiment, the monocyclic aromatic heterocyclic group contains 1 to 2 oxygen atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 2 sulfur atoms. In yet another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. In yet another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 4 nitrogen atoms. In yet another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms.

[0051] Examples of monocyclic aromatic heterocyclic groups include 5-7 member monocyclic aromatic heterocyclic groups such as pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, and triazinyl groups. In monocyclic aromatic heterocyclic groups, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. The number of oxo groups that a monocyclic aromatic heterocyclic group may have is preferably one or two.

[0052] A heteroaryl group is, for example, a polycyclic aromatic heterocyclic group. A polycyclic aromatic heterocyclic group is, for example, a fused polycyclic aromatic heterocyclic group. In one embodiment, the fused polycyclic aromatic heterocyclic group contains 1 to 3 oxygen atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1 to 3 sulfur atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1 to 3 oxygen atoms and 1 to 3 sulfur atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1 to 5 nitrogen atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1 to 4 nitrogen atoms, 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms.

[0053] Examples of condensed polycyclic aromatic heterocyclic groups include benzothiophenyl group, benzofuranyl group, benzimidazolyl group, benzoxazolyl group, benzoisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group, benzotriazolyl group, imidazopyridinyl group, thienopyridinyl group, phlopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyridinyl group, imidazopyridinyl group, thienopyridinyl group, phlopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolo Examples include 8-14 member fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as pyrimidinyl group, thiazolopyrimidinyl group, pyrazolotriazinyl group, naphtho[2,3-b]thienyl group, phenoxathiinyl group, indolyl group, isoindolyl group, 1H-indazolyl group, prinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthylidinyl group, quinoxalinyl group, quinazolinyl group, synnolinyl group, carbazolyl group, β-carbolinyl group, phenantridinyl group, acridinyl group, phenazinyl group, phenothiazinyl group, and phenoxazinyl group. In the polycyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. The number of oxo groups that a polycyclic aromatic heterocyclic group may have is preferably 1, 2, or 3.

[0054] Heteroaryl groups also include fused polycyclic aromatic heterocyclic groups (e.g., cyclic groups in which an aliphatic heterocyclic ring is fused to an aromatic ring) that have a partially saturated monocyclic ring (e.g., a monocyclic aromatic hydrocarbon ring group, a monocyclic aromatic heterocyclic group, etc.). A fused polycyclic aromatic heterocyclic group with a partially saturated monocyclic ring is a fused polycyclic aromatic heterocyclic group having a monocyclic ring in which some of the bonds constituting the ring are hydrogenated. Examples of partially saturated monocyclic condensed polycyclic aromatic heterocyclic groups include dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzoazepinyl, and tetrahydroquinoxalinyl groups. Examples include 9-14 member fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as tetrahydrophenanthridinyl group, hexahydrophenothiazinyl group, hexahydrophenoxazinyl group, tetrahydrophthalazinyl group, tetrahydronaphthilidinyl group, tetrahydroquinazolinyl group, tetrahydrocinnolinyl group, tetrahydrocarbazolyl group, tetrahydro-β-carbolinyl group, tetrahydroacridinyl group, tetrahydrophenazinyl group, tetrahydrothioxanthenyl group, and octahydroisoquinolyl group. In a fused polycyclic aromatic heterocyclic group having a partially saturated monocycle, two hydrogen atoms bonded to the same carbon atom may be substituted with oxo groups. The number of oxo groups that a fused polycyclic aromatic heterocyclic group having a partially saturated monocycle may have is preferably 1, 2, or 3.

[0055] The heteroaryl group also includes partially saturated fused polycyclic aromatic heterocyclic groups. Partially saturated fused polycyclic aromatic heterocyclic groups are fused polycyclic aromatic heterocyclic groups that have a monocyclic ring in which some of the bonds constituting the ring are hydrogenated. Examples of partially saturated condensed polycyclic aromatic heterocyclic groups include 1,3-dihydrobenzimidazole-2-onyl group, 2-benzoxazolinonyl group, octahydroisoindolyl group, 2H-pyrido[3,2-b]-1,4-oxazine-3(4H)-onyl group, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-yl group, [1,3]dioxolo[4,5-b]pyridyl group, 2,3-dihydrobenzo[b]thienyl group, 2,3-dihydro-1-benzofuran-5-yl group, 2,3-dihydro-1-benzofuran-6-yl group, 1,3-dihydro-2-benzofuran-5-yl group, and 2,3 Examples include the -dihydro-1H-indole-5-yl group, 1,3-benzodioxol-5-yl group, 2,3-dihydro-1,4-benzodioxin-2-yl group, 2,3-dihydro-1,4-benzodioxin-6-yl group, 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl group, 1,4-benzodioxanyl group, 2H-benzo[b][1,4]oxazine-3(4H)-on-yl group, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl group, indolinyl group, 2H-isoindolinyl group, chromanyl group, chromonyl group, isochromanyl group, and 1,2,3,4-tetrahydroisoquinolyl group.

[0056] A "heteroarylene group" refers to a divalent functional group produced by removing one hydrogen atom from a heteroaryl group. The explanation of heteroaryl groups is the same as above.

[0057] Examples of functional groups formed by combining two or more groups selected from aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups include functional groups formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, functional groups formed by combining an aliphatic hydrocarbon group and an aliphatic heterocyclic group, and functional groups formed by combining an aliphatic hydrocarbon group and an aromatic heterocyclic group.

[0058] Functional groups formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group are represented by the formula:(*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group, or the formula:(*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group. (*) represents the bond of an organic group containing a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. Each of the aliphatic hydrocarbon group and the aromatic hydrocarbon ring group in the formula may have one or more substituents. The aliphatic hydrocarbon group in the formula may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aliphatic hydrocarbon group selected as a substituent may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. Each of the aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups selected as substituents may have one or more substituents selected from, for example, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups.

[0059] Examples of functional groups represented by the formula (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group include alkylaryl groups, alkenylaryl groups, and alkynylaryl groups. The explanations of alkyl groups, alkenyl groups, alkynyl groups, and aryl groups in "alkylaryl group," "alkenylaryl group," and "alkynylaryl group" are the same as above.

[0060] The number of alkyl groups in an alkylaryl group, the number of alkenyl groups in an alkenylaryl group, and the number of alkynyl groups in an alkynylaryl group are usually 1 to 4, preferably 1 to 3, and more preferably 1 to 2. Examples of alkylaryl groups include o-tolyl, m-tolyl, p-tolyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, o-ethylphenyl, m-ethylphenyl, and p-ethylphenyl. Examples of alkenylaryl groups include o-styryl, m-styryl, and p-styryl. Examples of alkynylaryl groups include 2-ethynyl-2-phenyl.

[0061] Examples of functional groups represented by the formula (*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group include arylalkyl groups, arylalkenyl groups, and arylalkynyl groups. The explanations of alkyl groups, alkenyl groups, alkynyl groups, and aryl groups in "arylalkyl group," "arylalkenyl group," and "arylalkynyl group" are the same as above.

[0062] The number of carbon atoms in an arylalkyl group is usually 7 to 15, preferably 7 to 11. Examples of arylalkyl groups include benzyl and 2-phenethyl groups. The number of carbon atoms in an arylalkenyl group is usually 8 to 16, preferably 8 to 12. Examples of aralkenyl groups include 2-phenethenyl and 2-nephthylethenyl groups. The number of carbon atoms in an arylalkynyl group is usually 8 to 16, preferably 8 to 12. Examples of aralquinyl groups include phenylethynyl groups.

[0063] Functional groups formed by combining an aliphatic hydrocarbon group and an aliphatic heterocyclic group are represented by the formula:(*)-aliphatic hydrocarbon group-aliphatic heterocyclic group, or the formula:(*)-aliphatic heterocyclic group-aliphatic hydrocarbon group. (*) represents the bond of an organic group containing a functional group formed by combining an aliphatic hydrocarbon group and an aliphatic heterocyclic group. Each of the aliphatic hydrocarbon group and the aliphatic heterocyclic group in the formula may have one or more substituents. The aliphatic hydrocarbon group in the formula may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aliphatic hydrocarbon group selected as a substituent may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. Each of the aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups selected as substituents may have one or more substituents selected from, for example, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups.

[0064] Examples of functional groups represented by the formula (*)-aliphatic hydrocarbon group-aliphatic heterocyclic group include alkyl aliphatic heterocyclic groups, alkenyl aliphatic heterocyclic groups, and alkynyl aliphatic heterocyclic groups. The explanations regarding alkyl groups, alkenyl groups, alkynyl groups, and aliphatic heterocyclic groups in "alkyl aliphatic heterocyclic groups," "alkenyl aliphatic heterocyclic groups," and "alkynyl aliphatic heterocyclic groups" are the same as above.

[0065] Examples of functional groups represented by the formula (*)-aliphatic heterocyclic group-aliphatic hydrocarbon group include aliphatic heterocyclic alkyl groups, aliphatic heterocyclic alkenyl groups, and aliphatic heterocyclic alkynyl groups. The explanations of alkyl groups, alkenyl groups, alkynyl groups, and aliphatic heterocyclic groups in "aliphatic heterocyclic alkyl groups," "aliphatic heterocyclic alkenyl groups," and "aliphatic heterocyclic alkynyl groups" are the same as above.

[0066] Functional groups formed by combining an aliphatic hydrocarbon group and an aromatic heterocyclic group are represented by the formula:(*)-aliphatic hydrocarbon group-aromatic heterocyclic group, or the formula:(*)-aromatic heterocyclic group-aliphatic hydrocarbon group. (*) represents the bond of an organic group containing a functional group formed by combining an aliphatic hydrocarbon group and an aromatic heterocyclic group. The aliphatic hydrocarbon group and the aromatic heterocyclic group in the formula may each have one or more substituents. The aliphatic hydrocarbon group in the formula may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aromatic heterocyclic group in the formula may have one or more substituents selected from, for example, an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aliphatic hydrocarbon group selected as a substituent may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. Each of the aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups selected as substituents may have one or more substituents selected from, for example, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups.

[0067] Examples of functional groups represented by the formula (*)-aliphatic hydrocarbon group-aromatic heterocyclic group include alkyl heteroaryl groups, alkenyl heteroaryl groups, and alkynyl heteroaryl groups. The explanations regarding alkyl groups, alkenyl groups, alkynyl groups, and heteroaryl groups in "alkyl heteroaryl group," "alkenyl heteroaryl group," and "alkynyl heteroaryl group" are the same as above.

[0068] The number of alkyl groups in an alkyl heteroaryl group, the number of alkenyl groups in an alkenyl heteroaryl group, and the number of alkynyl groups in an alkynyl heteroaryl group are usually 1 to 4, preferably 1 to 3, and more preferably 1 to 2.

[0069] Examples of functional groups represented by the formula (*)-aromatic heterocyclic group-aliphatic hydrocarbon group include heteroarylalkyl groups, heteroarylalkenyl groups, and heteroarylalkynyl groups. The explanations of alkyl groups, alkenyl groups, alkynyl groups, and heteroaryl groups in "heteroarylalkyl groups," "heteroarylalkenyl groups," and "heteroarylalkynyl groups" are the same as above.

[0070] The number of carbon atoms in a heteroarylalkyl group is usually 8 to 14, preferably 8 to 10. Examples of heteroarylalkyl groups include furylethyl group, thienylmethyl group, and bensothiophenylmethyl group. The number of carbon atoms in a heteroarylalkenyl group is usually 7 to 15, preferably 7 to 11. Examples of heteroaralkenyl groups include pyridylethenyl group, thienylethenyl group, and bensothiophenylethenyl group. The number of carbon atoms in a heteroarylalkynyl group is usually 7 to 15, preferably 7 to 11. Examples of heteroaralquinyl groups include imidazoylethynyl group, thienylethynyl group, and bensothiophenylethynyl group.

[0071] The expression "may have one or more substituents" with respect to a functional group means that one or more hydrogen atoms of that functional group may be independently replaced by other atoms or groups of atoms. The expression "may be substituted" is synonymous with the expression "may have one or more substituents."

[0072] The number of substituents that an aliphatic hydrocarbon group may have can be appropriately determined depending on the number of carbon atoms in the aliphatic hydrocarbon group. An aliphatic hydrocarbon group may have, for example, 1 to 6 substituents, preferably 1 to 3, and more preferably 1 or 2 substituents at the substituted positions. When a hydrocarbon group has two or more substituents, the two or more substituents may be the same or different.

[0073] When the alkyl group has 1 to 4 carbon atoms, the number of substituents it may have is usually 1 to 3, preferably 1 or 2, and more preferably 1. When the alkyl group has 5 to 9 carbon atoms, the number of substituents it may have is usually 1 to 6, preferably 1 to 5, more preferably 1 to 4, and even more preferably 1 or 2. When the alkyl group has 10 or more carbon atoms, the number of substituents it may have is usually 1 to 9, preferably 1 to 5, even more preferably 1 to 4, and even more preferably 1 or 2.

[0074] When the alkenyl group has 2 to 4 carbon atoms, the number of substituents it may have is usually 1 to 3, preferably 1 or 2, and more preferably 1. When the alkenyl group has 5 to 9 carbon atoms, the number of substituents it may have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. When the alkenyl group has 10 or more carbon atoms, the number of substituents it may have is usually 1 to 8, preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2.

[0075] When the alkynyl group has 2 to 4 carbon atoms, the number of substituents that the alkynyl group may have is usually 1 to 3, preferably 1 or 2, and more preferably 1. When the alkynyl group has 5 to 9 carbon atoms, the number of substituents that the alkynyl group may have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. When the alkynyl group has 10 or more carbon atoms, the number of substituents that the alkynyl group may have is usually 1 to 8, preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 or 2.

[0076] The number of substituents that an aromatic hydrocarbon ring group may have can be appropriately determined according to the number of carbon atoms, the number of members, etc., of the aromatic hydrocarbon ring group. An aromatic hydrocarbon ring group may have, for example, 1 to 5 substituents, preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2 substituents at the substituted positions. If an aromatic hydrocarbon ring group has two or more substituents, the two or more substituents may be the same or different.

[0077] The number of substituents that an aliphatic heterocyclic group may have can be appropriately determined depending on the number of carbon atoms, the number of carbon atoms, etc. An aliphatic heterocyclic group may have, for example, 1 to 4 substituents, preferably 1 to 3, and more preferably 1 or 2 substituents at the substituted positions. If an aliphatic heterocyclic group has two or more substituents, the two or more substituents may be the same or different.

[0078] The number of substituents that an aromatic heterocyclic group may have can be appropriately determined depending on the number of carbon atoms, the number of members, etc. An aromatic heterocyclic group may have, for example, 1 to 4 substituents, preferably 1 to 3, and more preferably 1 or 2 substituents at the substituted positions. If an aromatic heterocyclic group has two or more substituents, the two or more substituents may be the same or different.

[0079] When the arylalkyl group or alkylaryl group has 7 to 11 carbon atoms, the number of substituents that the arylalkyl group or alkylaryl group may have is usually 1 to 5, preferably 1 to 4, and more preferably 1 to 2. When the arylalkyl group or alkylaryl group has 12 to 15 carbon atoms, the number of substituents that the arylalkyl group or alkylaryl group may have is usually 1 to 6, preferably 1 to 4, and more preferably 1 to 2. When the arylalkyl group or alkylaryl group has 16 or more carbon atoms, the number of substituents that the arylalkyl group or alkylaryl group may have is usually 1 to 8, preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 to 2.

[0080] When the arylalkenyl group or alkenylaryl group has 8 to 11 carbon atoms, the number of substituents that the arylalkenyl group or alkenylaryl group may have is usually 1 to 5, preferably 1 to 4, and more preferably 1 to 2. When the arylalkenyl group or alkenylaryl group has 12 to 15 carbon atoms, the number of substituents that the arylalkenyl group or alkenylaryl group may have is usually 1 to 6, preferably 1 to 4, and more preferably 1 to 2. When the arylalkenyl group or alkenylaryl group has 16 or more carbon atoms, the number of substituents that the arylalkenyl group or alkenylaryl group may have is usually 1 to 8, preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 to 2.

[0081] When the arylalkynyl group or alkynylaryl group has 8 to 11 carbon atoms, the number of substituents that the arylalkynyl group or alkynylaryl group may have is usually 1 to 5, preferably 1 to 4, and more preferably 1 to 2. When the arylalkynyl group or alkynylaryl group has 12 to 15 carbon atoms, the number of substituents that the arylalkynyl group or alkynylaryl group may have is usually 1 to 6, preferably 1 to 4, and more preferably 1 to 2. When the arylalkynyl group or alkynylaryl group has 16 or more carbon atoms, the number of substituents that the arylalkynyl group or alkynylaryl group may have is usually 1 to 8, preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 to 2.

[0082] The one or more substituents that an aliphatic hydrocarbon group (including monovalent and divalent) contained in an organic group may have, the one or more substituents that an aromatic hydrocarbon ring group (including monovalent and divalent) contained in an organic group may have, the one or more substituents that an aliphatic heterocyclic group (including monovalent and divalent) contained in an organic group may have, and the one or more substituents that an aromatic heterocyclic group (including monovalent and divalent) contained in an organic group may have can each be independently selected from the following substituent groups A to M.

[0083] [Substituent group A] (A-1) Halogen atom (A-2) Nitro group (A-3) Cyano group (A-4) Oxo group (A-5) Hydroxyl groups that may be protected (A-6) Protected thiol groups (A-7) Protected amino groups (A-8) Protected formyl group (A-9) Carboxyl groups that do not need to be protected (A-10) Carbamoyl groups that may be protected (A-11) Protected sulfonyl group

[0084] [Substituent group B] (B-1) alkyl group (B-2) Alkylthio group (B-3) Alkyloxy group (B-4) Alkylcarbonyloxy group (B-5) Alkylcarbamoyloxy group (B-6) Alkyl sulfonyl oxy group (B-7) Alkyloxycarbonyloxy group (B-8) alkylcarbonyl group (B-9) Alkyloxycarbonyl group (B-10) Alkylaminocarbonyl group (B-11) Alkylcarbamoyl group (B-12) Alkyl sulfonyl group (B-13) Alkyl sulfinyl group (B-14) Mono- or di-alkylamino group (B-15) Alkylcarbonylamino group (B-16) Alkyl sulfonyl amino group (B-17) Alkyloxycarbonylamino group (B-18) Alkyloxyalkyloxy group

[0085] [Substituent group C] (C-1) alkenyl group (C-2) Alkenylthio group (C-3) Alkenyloxy group (C-4) Alkenylcarbonyloxy group (C-5) Alkenylcarbamoyloxy group (C-6) Alkenylsulfonyl oxy group (C-7) Alkenyloxycarbonyloxy group (C-8) Alkenylcarbonyl group (C-9) Alkenyloxycarbonyl group (C-10) Alkenylaminocarbonyl group (C-11) Alkenylcarbamoyl group (C-12) Alkenylsulfonyl group (C-13) Alkenyl sulfinyl group (C-14) Mono- or di-alkenylamino group (C-15) Alkenylcarbonylamino group (C-16) Alkenylsulfonylamino group (C-17) Alkenyloxycarbonylamino group (C-18) Alkenyloxyalkyl group

[0086] [Substituent group D] (D-1) Alkynyl group (D-2) Alkinylthio group (D-3) Alkynyloxy group (D-4) Alkynylcarbonyloxy group (D-5) Alkynylcarbamoyloxy group (D-6) Alkynylsulfonyl oxy group (D-7) Alkynyloxycarbonyloxy group (D-8) Alkynylcarbonyl group (D-9) Alkynyloxycarbonyl group (D-10) Alkynylaminocarbonyl group (D-11) Alkinylcarbamoyl group (D-12) Alkynylsulfonyl group (D-13) Alkynylsulfinyl group (D-14) Mono- or di-alkynylamino group (D-15) Alkynylcarbonylamino group (D-16) Alkynylsulfonylamino group (D-17) Alkynyloxycarbonylamino group (D-18) Alkynyloxyalkyl group

[0087] [Substituent group E] (E-1) Aryl group (E-2) Arylthio group (E-3) Aryloxy group (E-4) Arylcarbonyloxy group (E-5) Arylcarbamoyloxy group (E-6) Arylsulfonyl oxy group (E-7) Aryloxycarbonyloxy group (E-8) Arylcarbonyl group (E-9) Aryloxycarbonyl group (E-10) Arylaminocarbonyl group (E-11) Arylcarbamoyl group (E-12) Arylsulfonyl group (E-13) Aryl sulfinyl group (E-14) Mono- or diarylamino group (E-15) Arylcarbonylamino group (E-16) Arylsulfonylamino group (E-17) Aryloxycarbonylamino group (E-18) Aryloxyalkyl group

[0088] [Substituent group F] (F-1) heteroaryl group (F-2) heteroarylthio group (F-3) Heteroaryloxy group (F-4) Heteroarylcarbonyloxy group (F-5) Heteroarylcarbamoyloxy group (F-6) Heteroarylsulfonyloxy group (F-7) Heteroaryloxycarbonyloxy group (F-8) Heteroarylcarbonyl group (F-9) Heteroaryloxycarbonyl group (F-10) Heteroarylaminocarbonyl group (F-11) Heteroarylcarbamoyl group (F-12) Heteroarylsulfonyl group (F-13) Heteroarylsulfinyl group (F-14) Mono- or di-heteroarylamino group (F-15) Heteroarylcarbonylamino group (F-16) Heteroarylsulfonylamino group (F-17) Heteroaryloxycarbonylamino group (F-18) Heteroaryloxyalkyl group

[0089] [Substituent group G] (G-1) Aliphatic heterocyclic group (G-2) Aliphatic heterocyclic thio group (G-3) Aliphatic heterocyclic oxy group (G-4) Aliphatic heterocyclic carbonyloxy group (G-5) Aliphatic heterocyclic carbamoyloxy group (G-6) Aliphatic heterocyclic sulfonyloxy group (G-7) Aliphatic heterocyclic oxycarbonyloxy group (G-8) Aliphatic heterocyclic carbonyl group (G-9) Aliphatic heterocyclic oxycarbonyl group (G-10) Aliphatic heterocyclic aminocarbonyl group (G-11) Aliphatic heterocyclic carbamoyl group (G-12) Aliphatic heterocyclic sulfonyl group (G-13) Aliphatic heterocyclic sulfinyl group (G-14) Mono- or di-aliphatic heterocyclic amino group (G-15) Aliphatic heterocyclic carbonylamino group (G-16) Aliphatic heterocyclic sulfonylamino group (G-17) Aliphatic heterocyclic oxycarbonylamino group (G-18) Aliphatic heterocyclic alkyloxyalkyloxy group

[0090] [Substituent group H] (H-1) arylalkyl groups (H-2) Arylalkylthio group (H-3) arylalkyloxy group (H-4) Arylalkylcarbonyloxy group (H-5) Arylalkylcarbamoyloxy group (H-6) Arylalkylsulfonyl oxy group (H-7) Arylalkyloxycarbonyloxy group (H-8) arylalkylcarbonyl group (H-9) Arylalkyloxycarbonyl group (H-10) Arylalkylaminocarbonyl group (H-11) Arylalkylcarbamoyl group (H-12) Arylalkylsulfonyl group (H-13) Arylalkylsulfinyl group (H-14) Mono- or di-arylalkylamino group (H-15) Arylalkylcarbonylamino group (H-16) Arylalkylsulfonylamino group (H-17) Arylalkyloxycarbonylamino group (H-18) Arylalkyloxyalkyloxy group

[0091] [Substituent group I] (I-1) Aryl alkenyl group (I-2) Aryl alkenylthio group (I-3) Aryl alkenyl oxy group (I-4) Aryl alkenyl carbonyl oxy group (I-5) Aryl alkenyl carbamoyl oxy group (I-6) Aryl alkenyl sulfonyl oxy group (I-7) Aryl alkenyl oxycarbonyl oxy group (I-8) Aryl alkenyl carbonyl group (I-9) Aryl alkenyl oxycarbonyl group (I-10) Aryl alkenylaminocarbonyl group (I-11) Aryl alkenyl carbamoyl group (I-12) Aryl alkenyl sulfonyl group (I-13) Aryl alkenyl sulfinyl group (I-14) Mono- or di-arylalkenylamino group (I-15) Aryl alkenylcarbonylamino group (I-16) Aryl alkenyl sulfonyl amino group (I-17) Aryl alkenyloxycarbonylamino group (I-18) Aryl alkenyl oxyalkyl group

[0092] [Substituent group J] (J-1) Arylalkynyl group (J-2) Arylalkynylthio group (J-3) Arylalkynyloxy group (J-4) Arylalkynylcarbonyloxy group (J-5) Arylalkynylcarbamoyloxy group (J-6) Arylalkynylsulfonyloxy group (J-7) Arylalkynyloxycarbonyloxy group (J-8) Arylalkynylcarbonyl group (J-9) Arylalkynyloxycarbonyl group (J-10) Arylalkynylaminocarbonyl group (J-11) Arylalkynylcarbamoyl group (J-12) Arylalkynylsulfonyl group (J-13) Arylalkynylsulfinyl group (J-14) Mono- or di-arylalkynylamino group (J-15) Arylalkynylcarbonylamino group (J-16) Arylalkynylsulfonylamino group (J-17) Arylalkynyloxycarbonylamino group (J-18) Arylalkynyloxyalkyl group

[0093] [Substituent group K] (K-1) heteroarylalkyl groups (K-2) heteroarylalkylthio group (K-3) Heteroarylalkyl oxy group (K-4) Heteroarylalkylcarbonyloxy group (K-5) Heteroarylalkylcarbamoyloxy group (K-6) Heteroarylalkylsulfonyloxy group (K-7) Heteroarylalkyloxycarbonyloxy group (K-8) heteroarylalkylcarbonyl group (K-9) Heteroarylalkyloxycarbonyl group (K-10) Heteroarylalkylaminocarbonyl group (K-11) Heteroarylalkylcarbamoyl group (K-12) Heteroarylalkylsulfonyl group (K-13) Heteroarylalkylsulfinyl group (K-14) Mono- or di-heteroarylalkylamino group (K-15) Heteroarylalkylcarbonylamino group (K-16) Heteroarylalkylsulfonylamino group (K-17) Heteroarylalkyloxycarbonylamino group (K-18) Heteroarylalkynyloxyalkyl group

[0094] [Substituent group L] (L-1) heteroaryl alkenyl group (L-2) heteroarylalkenylthio group (L-3) heteroarylalkenyloxy group (L-4) Heteroarylalkenylcarbonyloxy group (L-5) Heteroarylalkenylcarbamoyloxy group (L-6) Heteroarylalkenylsulfonyloxy group (L-7) Heteroarylalkenyloxycarbonyloxy group (L-8) heteroarylalkenylcarbonyl group (L-9) heteroarylalkenyloxycarbonyl group (L-10) Heteroaryl alkenylaminocarbonyl group (L-11) heteroarylalkenylcarbamoyl group (L-12) heteroaryl alkenyl sulfonyl group (L-13) Heteroarylalkenylsulfinyl group (L-14) Mono- or di-heteroarylalkenylamino group (L-15) Heteroaryl alkenylcarbonylamino group (L-16) Heteroarylalkenylsulfonylamino group (L-17) Heteroaryl alkenyloxycarbonylamino group (L-18) Heteroarylalkenyloxyalkyl group

[0095] [Substituent group M] (M-1) Heteroarylalkynyl group (M-2) heteroarylalkynylthio group (M-3) Heteroarylalkynyloxy group (M-4) Heteroarylalkynylcarbonyloxy group (M-5) Heteroarylalkynylcarbamoyloxy group (M-6) Heteroarylalkynylsulfonyloxy group (M-7) Heteroarylalkynyloxycarbonyloxy group (M-8) Heteroarylalkynylcarbonyl group (M-9) Heteroarylalkynyloxycarbonyl group (M-10) Heteroarylalkynylaminocarbonyl group (M-11) Heteroarylalkynylcarbamoyl group (M-12) Heteroarylalkynylsulfonyl group (M-13) Heteroarylalkynylsulfinyl group (M-14) Mono- or di-heteroarylalkynylamino group (M-15) Heteroarylalkynylcarbonylamino group (M-16) Heteroarylalkynylsulfonylamino group (M-17) Heteroarylalkynyloxycarbonylamino group (M-18) Heteroarylalkynyloxyalkyl group

[0096] The one or more substituents that an aliphatic hydrocarbon group (including monovalent and divalent) contained in an organic group may have are, independently of each other, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an aryl group, an aliphatic heterocyclic group, a heteroaryl group, an alkylaryl group, an alkyl aliphatic heterocyclic group, an alkyl heteroaryl group, an aryl alkyl group, an aliphatic heterocyclic alkyl group, a heteroaryl alkyl group, an alkyl thio group, an aryl thio group, an aliphatic heterocyclic thio You can choose from the following: o group, heteroarylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkylaliphatic heterocyclic carbonyl group, alkylheteroarylcarbonyl group, arylalkylcarbonyl group, aliphatic heterocyclic alkylcarbonyl group, heteroarylalkylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aliphatic heterocyclic oxycarbonyl group, heteroaryloxycarbonyl group, alkylaryloxycarbonyl group, alkylaliphatic heterocyclic oxycarbonyl group, alkylheteroaryloxycarbonyl group, arylalkyloxycarbonyl group, aliphatic heterocyclic alkyloxycarbonyl group, and heteroarylalkyloxycarbonyl group. Furthermore, if the aliphatic hydrocarbon group (including monovalent and divalent groups) is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group may have a cyclic aliphatic hydrocarbon group (e.g., a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

[0097] One or more substituents that an aromatic hydrocarbon ring group (including monovalent and divalent) contained in an organic group may have, one or more substituents that an aliphatic heterocyclic group (including monovalent and divalent) contained in an organic group may have, and one or more substituents that an aromatic heterocyclic group (including monovalent and divalent) contained in an organic group may have, each independently may be, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, Protected carbamoyl group, protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic group, heteroaryl group, alkylaryl group, alkylaliphatic heterocyclic group, alkylheteroaryl group, arylalkyl group, aliphatic heterocyclic alkyl group, heteroarylalkyl group, alkyloxy group, aryloxy group, aliphatic heterocyclic oxy group, heteroaryloxy group, alkylaryloxy group, alkylaliphatic heterocyclic oxy group, alkylheteroaryloxy group, arylalkyloxy group, aliphatic heterocyclic alkyloxy group, heteroarylalkyloxy group, alkylthio group, arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkylaliphatic heterocyclic carbonyl group, alkylheteroarylcarbonyl group, You can choose from a reel alkylcarbonyl group, an aliphatic heterocyclic alkylcarbonyl group, a heteroarylalkylcarbonyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an aliphatic heterocyclic oxycarbonyl group, a heteroaryloxycarbonyl group, an alkylaryloxycarbonyl group, an alkylaliphatic heterocyclic oxycarbonyl group, an alkylheteroaryloxycarbonyl group, an arylalkyloxycarbonyl group, an aliphatic heterocyclic alkyloxycarbonyl group, and a heteroarylalkyloxycarbonyl group.

[0098] With respect to a functional group, "may be protected" means that the functional group is either unsubstituted or protected by a commonly used protecting group.

[0099] A "protecting group" is not particularly limited as long as it can convert a target functional group into an inert functional group in the target reaction and can be removed from the target functional group after the reaction is complete. It can be appropriately selected depending on the target functional group, the target reaction, etc.

[0100] A "hydroxyl group that may be protected" is a hydroxyl group or a hydroxyl group protected by a hydroxyl protecting group, which can be represented, for example, by the formula: -OP1 (wherein P1 represents a hydrogen atom or a hydroxyl protecting group). Examples of hydroxyl protecting groups include ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, and oxycarbonyl-type protecting groups.

[0101] Examples of ester-type protecting groups include C1-C10 alkylcarbonyl groups which may have one or more substituents, and C6-C10 arylcarbonyl groups which may have one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that an alkylcarbonyl group may have are the same as those for aliphatic hydrocarbon groups. The substituents that an arylcarbonyl group may have are the same as those for aromatic hydrocarbon ring groups. Examples of alkylcarbonyl groups which may have one or more substituents include acetyl, propanoyl, butanoyl, isopropanoyl, and pivaloyl groups. Examples of arylcarbonyl groups that may have one or more substituents include benzoyl group, 4-nitrobenzoyl group, 4-methyloxybenzoyl group, 4-methylbenzoyl group, 4-tert-butylbenzoyl group, 4-fluorobenzoyl group, 4-chlorobenzoyl group, 4-bromobenzoyl group, 4-phenylbenzoyl group, and 4-methyloxycarbonylbenzoyl group. The ester-type protecting group is preferably an alkylcarbonyl group having 1 to 10 carbon atoms, more preferably an alkylcarbonyl group having 1 to 5 carbon atoms, and even more preferably an acetyl group or a pivaloyl group.

[0102] Examples of arylalkyl protecting groups include arylalkyl groups having 7 to 11 carbon atoms, which may have one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that "alkyl" in arylalkyl groups may have are the same as those for aliphatic hydrocarbon groups. The substituents that "aryl" in arylalkyl groups may have are the same as those for aromatic hydrocarbon ring groups. The one or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups, methyloxy groups, phenyl groups, and naphthyl groups. Examples of arylalkyl groups having 7 to 11 carbon atoms, which may have one or more substituents, include benzyl groups, 1-phenylethyl groups, diphenylmethyl groups, 1,1-diphenylethyl groups, and naphthylmethyl groups.

[0103] Examples of alkyl-type protecting groups include C1-C10 alkyl groups which may have one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that alkyl groups may have are the same as those for aliphatic hydrocarbon groups. The one or more substituents are preferably selected from halogen atoms, nitro groups, and cyano groups. The alkyl-type protecting group is preferably a C1-C5 alkyl group which may be substituted with one or more substituents, and more preferably a methyl group, an ethyl group, a tert-butyl group, etc.

[0104] Examples of arylalkyloxyalkyl type protecting groups include arylalkyloxyalkyl groups such as arylalkyloxymethyl groups having 7 to 11 carbon atoms that may have one or more substituents, arylalkyloxyethyl groups having 7 to 11 carbon atoms that may have one or more substituents, and arylalkyloxypropyl groups having 7 to 11 carbon atoms that may have one or more substituents. The one or more substituents can be selected, for example, from substituent groups A to M. The substituents that "alkyl" in arylalkyloxyalkyl groups may have are the same as those for aliphatic hydrocarbon groups. The substituents that "aryl" in arylalkyloxyalkyl groups may have are the same as those for aromatic hydrocarbon ring groups. The one or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups, and methyloxy groups. Examples of arylalkyloxyalkyl type protecting groups include benzyloxymethyl groups having one or more substituents, preferably benzyloxymethyl groups that may be substituted with halogen atoms, nitro groups, cyano groups, methyl groups, or methyloxy groups, and more preferably benzyloxymethyl groups.

[0105] Examples of alkyloxyalkyl-type protecting groups include alkyloxyalkyl groups such as a C1-C10 alkyloxymethyl group which may have one or more substituents, a C1-C10 alkyloxyethyl group which may have one or more substituents, and a C1-C10 alkyloxypropyl group which may have one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that "alkyl" in an alkyloxyalkyl group may have are the same as those for aliphatic hydrocarbon groups. The one or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups, and methyloxy groups. The alkyloxyalkyl-type protecting group is preferably a C1-C10 alkyloxymethyl group which may have one or more substituents, more preferably a C1-C5 alkyloxymethyl group 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.

[0106] Examples of silyl-type protecting groups include silyl groups having a functional group selected from C1-C10 alkyl groups which may have one or more substituents, C7-C10 arylalkyl groups which may have one or more substituents, and C6-C10 aryl groups which may have one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that "alkyl" in alkyl groups and arylalkyl groups may have are the same as those for aliphatic hydrocarbon groups. The substituents that "aryl" in aryl groups and arylalkyl groups may have are the same as those for aromatic hydrocarbon ring groups. The silyl-type protecting group is preferably a silyl group having a functional group selected from C1-C10 alkyl groups and C6-C10 aryl groups, more preferably a silyl group having a functional group selected from C1-C5 alkyl groups and phenyl groups, and even more preferably a trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, or tert-butyldiphenylsilyl group.

[0107] Examples of oxycarbonyl-type protecting groups include an alkyloxycarbonyl group having 1 to 10 carbon atoms which may have one or more substituents, an alkenyloxycarbonyl group having 2 to 10 carbon atoms which may have one or more substituents, and an arylalkyloxycarbonyl group having 7 to 11 carbon atoms which may have one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that may be possessed by "alkyl" in an alkyloxycarbonyl group, "alkenyl" in an alkenyloxycarbonyl group, and "alkyl" in an arylalkyloxycarbonyl group are the same as the substituents for an aliphatic hydrocarbon group. The substituents that may be possessed by "aryl" in an arylalkyloxycarbonyl group are the same as the substituents for an aromatic hydrocarbon ring group. The oxycarbonyl-type protecting group is preferably an alkyloxycarbonyl group having 1 to 5 carbon atoms, an alkenyloxycarbonyl group having 2 to 5 carbon atoms, or a benzyloxycarbonyl group, and more preferably a methyloxymethyl group, an allyloxycarbonyl group, or a benzyloxycarbonyl group.

[0108] The "optionally protected thiol group" is a thiol group or a thiol group protected with a thiol-protecting group, and can be represented, for example, by the formula: -SP2 (wherein P2 represents a hydrogen atom or a thiol-protecting group). Examples of thiol-protecting groups include ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, and oxycarbonyl-type protecting groups. The explanation for these protecting groups is the same as that described above.

[0109] The "optionally protected amino group" is an amino group or an amino group protected with an amino-protecting group, and can be represented, for example, by formula -NH-P3, formula -N(-P3)(-P4), or formula =N(-P3) (wherein P3 and P4 each independently represent an amino-protecting group). Examples of the amino-protecting group include alkyloxycarbonyl groups having 1 to 10 carbon atoms (e.g., methyloxycarbonyl group, tert-butyloxycarbonyl group, etc.), arylalkyloxycarbonyl groups having 7 to 11 carbon atoms (e.g., benzyloxycarbonyl group, etc.), 9-fluorenylmethyloxycarbonyl group, benzhydryl group, trityl group, 2,2,2-trichloroethyloxycarbonyl group, allyloxycarbonyl group, and the like. Note that amino groups also include alicyclic amino groups and heterocyclic amino groups.

[0110] The "optionally protected carboxyl group" is a carboxyl group or a carboxyl group protected with a carboxyl-protecting group, and can be represented, for example, by formula -C(=O)(-OP5) (wherein P5 represents a hydrogen atom or a carboxyl-protecting group). Examples of the carboxyl-protecting group include alkyl groups having 1 to 10 carbon atoms (e.g., methyl group, ethyl group, propyl group, etc.), arylalkyl groups having 7 to 11 carbon atoms (e.g., benzyl group, etc.), and the like.

[0111] The "optionally protected formyl group" is a formyl group or a formyl group protected with a formyl-protecting group, and can be represented, for example, by formula -C(Y a P6)(Y a P7) (wherein Y a represents a heteroatom, P6 and P7 each independently represent a hydroxyl-protecting group, or P6 and P7 may together form an alkylene group). The heteroatom is preferably an oxygen atom or a sulfur atom. Examples of the hydroxyl-protecting group include alkyl groups having 1 to 5 carbon atoms, preferably methyl group, ethyl group, propyl group, butyl group, and the like. Further, the number of carbon atoms in the alkylene formed together by P6 and P7 is preferably 2 to 10, more preferably 2 to 5, and still more preferably 2 or 3.

[0112] The "carbamoyl group which may be protected" is preferably represented by the formula -OC(=O)-NH(-P8) (wherein P8 represents an amino group protecting group). Examples of amino group protecting groups include alkyloxycarbonyl groups having 1 to 10 carbon atoms (e.g., methyloxycarbonyl group, tert-butyloxycarbonyl group, etc.), arylalkyloxycarbonyl groups having 7 to 11 carbon atoms (e.g., benzyloxycarbonyl group, etc.), 9-fluorenylmethyloxycarbonyl group, benzhydryl group, trityl group, 2,2,2-trichloroethyloxycarbonyl group, allyloxycarbonyl group, etc.

[0113] The "optionally protected sulfonyl group" is a sulfonyl group or a sulfonyl group protected by a sulfonyl protecting group, such as an alkylsulfonyl group which may be substituted with one or more substituents, or an arylsulfonyl group which may be substituted with one or more substituents. The one or more substituents can be selected from substituent groups A to M, for example. The substituents that "alkyl" in an alkylsulfonyl group may have are the same as those for aliphatic hydrocarbon groups. The substituents that "aryl" in an arylsulfonyl group may have are the same as those for aromatic hydrocarbon ring groups. The number of carbon atoms in the alkyl group in an alkylsulfonyl group is usually 1 to 10, preferably 1 to 5, and more preferably 1 to 3. The alkylsulfonyl group which may be substituted with one or more substituents is, for example, an alkylsulfonyl group which may be substituted with a halogen atom (e.g., methylsulfonyl group, trifluoromethylsulfonyl group, etc.). The number of carbon atoms in the aryl group in an arylsulfonyl group is usually 6 to 14, preferably 6 to 10. An arylsulfonyl group which may be substituted with one or more substituents is, for example, an alkylsulfonyl group which may be substituted with a halogen atom (e.g., a phenylsulfonyl group, a p-toluenesulfonyl group, etc.).

[0114] The substituents in substituent groups A to M, namely "alkyl," "alkenyl," "alkynyl," "aryl," "heteroaryl," and "aliphatic heterocycle," may each be substituted with one or more substituents selected from substituent group A. The one or more substituents selected from substituent group A to further substitute the substituents, namely "alkyl," "alkenyl," "alkynyl," "aryl," "heteroaryl," or "aliphatic heterocycle," are each independently preferably selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, and an optionally substituted sulfonyl group; more preferably selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected formyl group, and an optionally protected carboxyl group; and even more preferably, a halogen atom.

[0115] <Compound (I)> Compound (I) of the present invention is of the following formula (I): [ka] It is represented as follows. Compound (I), as mentioned above, is also called a C-arylhydroxyglycoxide derivative and is suitably used as an intermediate for SGLT-2 inhibitors.

[0116] In equation (I), R 1 and R 2 Each of these independently represents a hydroxyl protecting group, R 3 and R 4 Each of these independently represents either a hydroxyl protecting group or a hydrogen atom.

[0117] R 1 and R 2 The hydroxyl protecting groups represented by may be the same or different, but it is preferable that they be the same, considering the efficient introduction and removal of the hydroxyl protecting groups.

[0118] R1 and R 2 The hydroxyl protecting group represented by is not particularly limited, but examples include ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, and oxycarbonyl-type protecting groups. These protecting groups are synonymous with those described above.

[0119] R 1 and R 2 The hydroxyl protecting group represented by is preferably methyloxymethyl group, benzyloxymethyl group, acetyl group, propanoyl group, butanoyl group, isopropanoyl group, pivaloyl group, benzoyl group, 4-nitrobenzoyl group, 4-methyloxybenzoyl group, 4-methylbenzoyl group, 4-tert-butylbenzoyl group, 4-fluorobenzoyl group, 4-chlorobenzoyl group, 4-bromobenzoyl group, 4-phenylbenzoyl group, 4-methyloxycarbonylbenzoyl group, benzyl group, 1-F The group is phenylethyl, diphenylmethyl, 1,1-diphenylethyl, naphthylmethyl, methyl, tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butyloxycarbonyloxy, or benzyloxycarbonyl, more preferably benzyl, acetyl, pivaloyl, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0120] In equation (I), R 3 and R 4 The functional group represented by may be a hydrogen atom. However, from the viewpoint of efficiently forming the 6-membered ring of formula (I), R 3 and R 4 The functional group represented is preferably a hydroxyl protecting group.

[0121] R 3 and R 4 The hydroxyl protecting group represented by R 1 A hydroxyl protecting group or R represented by 2The hydroxyl protecting group represented by may be the same as or different from the hydroxyl protecting group represented by R, but from the viewpoint of efficient introduction and removal of protecting groups, 1 and R 2 It is preferable that it is the same as the hydroxyl protecting group represented by .

[0122] The organic group represented by Ar is not particularly limited in that it includes an aromatic hydrocarbon ring group or an aromatic heterocyclic group, which may have one or more substituents, as a functional group bonded to the oxane ring in formula (I).

[0123] In one embodiment, the organic group represented by Ar is an aromatic hydrocarbon ring group which may have one or more substituents, or an aromatic hydrocarbon ring group which may have one or more substituents is included as a functional group bonded to the carbon atom of the oxane ring in formula (I).

[0124] In another embodiment, the organic group represented by Ar is an aromatic heterocyclic group which may have one or more substituents, or an aromatic hydrocarbon ring group which may have one or more substituents, is included as a functional group bonded to the carbon atom of the oxane ring in formula (I).

[0125] An organic group containing an aromatic hydrocarbon ring group, which may have one or more substituents, as a functional group bonded to a carbon atom of the oxane ring in formula (I) can be represented, for example, by the following formula. [ka]

[0126] In the above formula, J1 represents an aromatic hydrocarbon ring group which may have one or more substituents, J2 represents an aliphatic hydrocarbon group which may have one or more substituents, J3 represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents, and (*) represents a bond that is bonded to the carbon atom of the oxane ring in formula (I).

[0127] In one embodiment, J1 is an unsubstituted aromatic hydrocarbon ring group, and J2 is an unsubstituted aliphatic hydrocarbon group.

[0128] In another embodiment, J1 is an unsubstituted aromatic hydrocarbon ring group, and J2 is an aliphatic hydrocarbon group having one or more substituents.

[0129] In another embodiment, J1 is an aromatic hydrocarbon ring group having one or more substituents, and J2 is an unsubstituted aliphatic hydrocarbon group.

[0130] In another embodiment, J1 is an aromatic hydrocarbon ring group having one or more substituents, and J2 is an aliphatic hydrocarbon group having one or more substituents.

[0131] In one embodiment, J3 is an unsubstituted aromatic hydrocarbon ring group. This embodiment can be combined with the above-described embodiments relating to J1 and J2.

[0132] In another embodiment, J3 is an aromatic hydrocarbon ring group having one or more substituents. This embodiment can be combined with the above-described embodiments relating to J1 and J2.

[0133] In another embodiment, J3 is an unsubstituted aliphatic heterocyclic group. This embodiment can be combined with the above-described embodiments relating to J1 and J2.

[0134] In another embodiment, J3 is an aliphatic heterocyclic group having one or more substituents. This embodiment can be combined with the above-described embodiments relating to J1 and J2.

[0135] In another embodiment, J3 is an unsubstituted aromatic heterocyclic group. This embodiment can be combined with the above-described embodiments relating to J1 and J2.

[0136] In another embodiment, J3 is an aromatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiment relating to J1 and J2.

[0137] In embodiments in which the aliphatic hydrocarbon group represented by J2 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M. One or more substituents on the aliphatic hydrocarbon group represented by J2 can be independently, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an aryl group, an aliphatic heterocyclic group, a heteroaryl group, an alkylaryl group, an alkyl aliphatic heterocyclic group, an alkyl heteroaryl group, an aryl alkyl group, an aliphatic heterocyclic alkyl group, a heteroaryl alkyl group, an alkyl thio group, an aryl thio group, an aliphatic heterocyclic thio group, a heteroaryl group You can choose from a reelthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkylaliphatic heterocyclic carbonyl group, alkylheteroarylcarbonyl group, arylalkylcarbonyl group, aliphatic heterocyclic alkylcarbonyl group, heteroarylalkylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aliphatic heterocyclic oxycarbonyl group, heteroaryloxycarbonyl group, alkylaryloxycarbonyl group, alkylaliphatic heterocyclic oxycarbonyl group, alkylheteroaryloxycarbonyl group, arylalkyloxycarbonyl group, aliphatic heterocyclic alkyloxycarbonyl group, and heteroarylalkyloxycarbonyl group.Preferably, one or more substituents are independently selected from a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyloxy group, an alkylthio group, an alkylcarbonyl group, and an alkyloxycarbonyl group. Furthermore, if the aliphatic hydrocarbon group represented by J2 is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group may have cyclic aliphatic hydrocarbon groups (e.g., cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, etc.) as substituents.

[0138] In embodiments in which an aromatic hydrocarbon ring group represented by J1 and / or an aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by J3 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M.The aromatic hydrocarbon ring group represented by J1 and / or the aromatic hydrocarbon ring group, aliphatic heterocyclic group, or one or more substituents on the aromatic heterocyclic group represented by J3 can, independently, be, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an aryl group, an aliphatic heterocyclic group, a heteroaryl group, an alkylaryl group, an alkyl aliphatic heterocyclic group, an alkyl heteroaryl group, an aryl alkyl group, an aliphatic heterocyclic alkyl group, a heteroaryl alkyl group, an alkyl thio You can choose from the following groups: arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkylaliphatic heterocyclic carbonyl group, alkylheteroarylcarbonyl group, arylalkylcarbonyl group, aliphatic heterocyclic alkylcarbonyl group, heteroarylalkylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aliphatic heterocyclic oxycarbonyl group, heteroaryloxycarbonyl group, alkylaryloxycarbonyl group, alkylaliphatic heterocyclic oxycarbonyl group, alkylheteroaryloxycarbonyl group, arylalkyloxycarbonyl group, aliphatic heterocyclic alkyloxycarbonyl group, and heteroarylalkyloxycarbonyl group.

[0139] An organic group containing an aromatic heterocyclic group, which may have one or more substituents, as a functional group bonded to a carbon atom of the oxane ring in formula (I) can be represented, for example, by the following formula. [ka]

[0140] In the above formula, K1 represents an aromatic heterocyclic group which may have one or more substituents, K2 represents an aliphatic hydrocarbon group which may have one or more substituents, K3 represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents, and (*) represents a bond that is bonded to the carbon atom of the carbonyl group in formula (I).

[0141] In one embodiment, K1 is an unsubstituted aromatic heterocyclic group, and K2 is an unsubstituted aliphatic hydrocarbon group.

[0142] In another embodiment, K1 is an unsubstituted aromatic heterocyclic group, and K2 is an aliphatic hydrocarbon group having one or more substituents.

[0143] In another embodiment, K1 is an aromatic heterocyclic group having one or more substituents, and K2 is an unsubstituted aliphatic hydrocarbon group.

[0144] In another embodiment, K1 is an aromatic heterocyclic group having one or more substituents, and K2 is an aliphatic hydrocarbon group having one or more substituents.

[0145] In one embodiment, K3 is an unsubstituted aromatic hydrocarbon ring group. This embodiment can be combined with the above embodiments relating to K1 and K2.

[0146] In another embodiment, K3 is an aromatic hydrocarbon ring group having one or more substituents. This embodiment can be combined with the above embodiments relating to K1 and K2.

[0147] In another embodiment, K3 is an unsubstituted aliphatic heterocyclic group. This embodiment can be combined with the above embodiment relating to K1 and K2.

[0148] In another embodiment, K3 is an aliphatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiments relating to K1 and K2.

[0149] In another embodiment, K3 is an unsubstituted aromatic heterocyclic group. This embodiment can be combined with the above embodiment relating to K1 and K2.

[0150] In another embodiment, K3 is an aromatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiment relating to K1 and K2.

[0151] In embodiments in which the aliphatic hydrocarbon group represented by K2 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M. One or more substituents on the aliphatic hydrocarbon group represented by K2 can be independently, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an aryl group, an aliphatic heterocyclic group, a heteroaryl group, an alkylaryl group, an alkyl aliphatic heterocyclic group, an alkyl heteroaryl group, an aryl alkyl group, an aliphatic heterocyclic alkyl group, a heteroaryl alkyl group, an alkyl thio group, an aryl thio group, an aliphatic heterocyclic thio group, a heteroaryl group You can choose from a reelthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkylaliphatic heterocyclic carbonyl group, alkylheteroarylcarbonyl group, arylalkylcarbonyl group, aliphatic heterocyclic alkylcarbonyl group, heteroarylalkylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aliphatic heterocyclic oxycarbonyl group, heteroaryloxycarbonyl group, alkylaryloxycarbonyl group, alkylaliphatic heterocyclic oxycarbonyl group, alkylheteroaryloxycarbonyl group, arylalkyloxycarbonyl group, aliphatic heterocyclic alkyloxycarbonyl group, and heteroarylalkyloxycarbonyl group.Preferably, one or more substituents are independently selected from a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyloxy group, an alkylthio group, an alkylcarbonyl group, and an alkyloxycarbonyl group. Furthermore, if the aliphatic hydrocarbon group represented by K2 is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group may have cyclic aliphatic hydrocarbon groups (e.g., cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, etc.) as substituents.

[0152] In embodiments in which an aromatic heterocyclic group represented by K1 and / or an aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by K3 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M.The aromatic heterocyclic group represented by K1 and / or the aromatic hydrocarbon ring group, aliphatic heterocyclic group, or one or more substituents on the aromatic heterocyclic group represented by K3 may independently be, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an aryl group, an aliphatic heterocyclic group, a heteroaryl group, an alkylaryl group, an alkyl aliphatic heterocyclic group, an alkyl heteroaryl group, an aryl alkyl group, an aliphatic heterocyclic alkyl group, a heteroaryl alkyl group, an alkyl thio group The following can be selected: arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkylarylthio group, alkyl aliphatic heterocyclic thio group, alkyl heteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkyl aliphatic heterocyclic carbonyl group, alkyl heteroarylcarbonyl group, arylalkylcarbonyl group, aliphatic heterocyclic alkylcarbonyl group, heteroarylalkylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aliphatic heterocyclic oxycarbonyl group, heteroaryloxycarbonyl group, alkylaryloxycarbonyl group, alkyl aliphatic heterocyclic oxycarbonyl group, alkyl heteroaryloxycarbonyl group, arylalkyloxycarbonyl group, aliphatic heterocyclic alkyloxycarbonyl group, and heteroarylalkyloxycarbonyl group.

[0153] The aromatic hydrocarbon ring group or aromatic heterocyclic group bonded to the oxane ring in formula (I) within the organic group represented by Ar is preferably an aromatic hydrocarbon ring group having 6 to 14 carbon atoms or an aromatic heterocyclic group having 3 to 12 carbon atoms, more preferably an aromatic hydrocarbon ring group having 6 to 10 carbon atoms or an aromatic heterocyclic group having 3 to 8 carbon atoms, even more preferably a phenyl group, a thienyl group, a benzothiophenyl group, a furyl group, a pyrrolyl group, an imidazolyl group, or a pyridyl group, even more preferably a phenyl group, a thienyl group, or a benzothiophenyl group, and even more preferably a phenyl group.

[0154] From the viewpoint of producing SGLT-2 inhibitors or their derivatives, the organic group represented by Ar is preferably identical to the aromatic hydrocarbon ring group or aromatic heterocyclic group possessed by the SGLT-2 inhibitor, or is a group derived from said aromatic hydrocarbon ring group or aromatic heterocyclic group.

[0155] Here, canagliflozin, empagiflozin (also called "(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxyphenyl)methyl]phenyl}-D-glucitol"), ipragliflozin ("(1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol-( SGLT-2 inhibitors, including "(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-thiol", have an aromatic hydrocarbon ring group or an aromatic heterocyclic group represented by the following formula (V) or formula (Va).

[0156] Therefore, according to one embodiment, the organic group represented by Ar is given by the following formula (V): [ka] It is represented as follows.

[0157] In equation (V), R a Each of these independently represents a functional group selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an arylalkyloxy group, an arylalkenyloxy group, and an arylalkynyloxy group, and each of the alkyl groups, alkenyl groups, alkynyl groups, an aryl group, an arylalkyl group, an arylalkenyloxy group, an arylalkynyloxy group, an alkyloxy group, an arylalkynyloxy group, and an arylalkynyloxy group may have one or more substituents.

[0158] In equation (V), R a Each of the functional groups represented is independently preferably selected from a hydrogen atom, a halogen atom, a C1-C20 alkyl group, a C6-C14 aryl group, a C7-C15 arylalkyl group, a C1-C20 alkyloxy group, and a C7-C15 arylalkyloxy group, and more preferably selected from a halogen atom and a C1-C10 alkyl group.

[0159] In equation (V), n represents an integer between 0 and 4. The integer represented by n is preferably between 1 and 3, and more preferably 1 or 2.

[0160] In formula (V), Ar' represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents. Preferably, Ar' represents an aromatic hydrocarbon ring group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents.

[0161] The functional group represented by Ar' is preferably an aromatic hydrocarbon ring group having 6 to 14 carbon atoms or an aromatic heterocycle having 3 to 12 carbon atoms, more preferably an aromatic hydrocarbon ring group having 6 to 14 carbon atoms or an aromatic heterocycle having 3 to 12 carbon atoms, even more preferably a phenyl group, a thienyl group, a benzothiophenyl group, a furyl group, a pyrrolyl group, an imidazolyl group, or a pyridyl group, and even more preferably a phenyl group, a thienyl group, or a benzothiophenyl group.

[0162] The one or more substituents on the functional group represented by Ar' are preferably a phenyl group which may be substituted with a halogen atom, an alkyloxy group having 1 to 5 carbon atoms, or an aliphatic heterocyclic oxy group (for example, a tetrahydrofuranyloxy group).

[0163] In a more preferred embodiment, the organic group represented by Ar in formula (I) is the following: [ka] [In the formula, R a The functional group represented by the above is synonymous with the above, Ar' is given by the following equations (Va-I), (Va-II), and (Va-III): [ka] It is represented as follows.

[0164] R b Each of these independently represents a functional group selected from the group consisting of aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups, and each of the aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups included in the group may have one or more substituents.

[0165] R bThe functional groups represented by are preferably independently selected from C1-C20 alkyl groups, C2-C20 alkenyl groups, C2-C20 alkynyl groups, C6-C14 aromatic hydrocarbon ring groups, C2-C12 aliphatic heterocyclic groups, and C3-C12 aromatic heterocyclic groups; more preferably selected from C1-C10 alkyl groups, C2-C10 alkenyl groups, C2-C10 alkynyl groups, C6-C10 aromatic hydrocarbon ring groups, and C2-C5 aliphatic heterocyclic groups; and even more preferably be phenyl groups or tetrahydrofuranyl groups.

[0166] R b The one or more substituents on the functional group represented by can each be independently selected, for example, from substituent groups A to M. bThe functional group represented by each of the following substituents may independently be, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an aryl group, an aliphatic heterocyclic group, a heteroaryl group, an alkylaryl group, an alkyl aliphatic heterocyclic group, an alkyl heteroaryl group, an aryl alkyl group, an aliphatic heterocyclic alkyl group, a heteroaryl alkyl group, an alkyl thio group, an aryl thio group, an aliphatic heterocyclic thio group, a heteroaryl group You can choose from a reelthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, heteroarylcarbonyl group, alkylarylcarbonyl group, alkylaliphatic heterocyclic carbonyl group, alkylheteroarylcarbonyl group, arylalkylcarbonyl group, aliphatic heterocyclic alkylcarbonyl group, heteroarylalkylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, aliphatic heterocyclic oxycarbonyl group, heteroaryloxycarbonyl group, alkylaryloxycarbonyl group, alkylaliphatic heterocyclic oxycarbonyl group, alkylheteroaryloxycarbonyl group, arylalkyloxycarbonyl group, aliphatic heterocyclic alkyloxycarbonyl group, and heteroarylalkyloxycarbonyl group.It is preferable that one or more substituents are independently selected from a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an alkyloxy group, an alkylthio group, an alkylcarbonyl group, and an alkyloxycarbonyl group. It is more preferable that one or more substituents are independently selected from a halogen atom, a nitro group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected formyl group, an optionally protected amino group, an optionally protected carboxyl group, an optionally protected sulfonyl group, and a C1-C10 alkyloxycarbonyl group, and even more preferable that they are selected from a halogen atom, an amino group, a nitro group, a C1-C10 alkyloxy group, and a C1-C10 alkyloxycarbonyl group.

[0167] In formula (Va-I), p represents an integer between 0 and 5. The integer represented by p is preferably between 0 and 3, more preferably between 0 and 2, and even more preferably between 0 and 1. In formulas (Va-II) and (Va-III), the integer represented by p is preferably between 0 and 5, more preferably between 0 and 3, and even more preferably between 0 and 2.

[0168] In a more preferred embodiment, in formula (I), the organic group represented by Ar is (VII), (V-II-I), (V-III-I), or (V-III-II): [ka] It is represented as follows.

[0169] <Method for producing compound (I)> The method for producing compound (I) of the present invention is characterized by comprising the following steps (a) and (b). Process (a): Formula (II) below: [ka] Compound (II) represented by, The following equation (III-I): [ka] Compound (III-I) represented by the following formula (III-II): [ka] Compound (III-II) represented by At least one organozinc compound selected from the group consisting of the following, The reaction is carried out in the presence of one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or in the presence of a supported catalyst having one or more transition metal catalysts and a carrier supporting the one or more transition metal catalysts, resulting in the following formula (IV): [ka] A step to obtain compound (IV) represented by; Step (b): R in compound (IV) 5 A step of removing the hydroxyl protecting group represented by to obtain compound (I).

[0170] The following describes steps (a) and (b) in order. <Process (a)> [ka]

[0171] <Compound (II)> In process (a), the following formula (II): [ka] Prepare compound (II), represented by [formula]. Details of the preparation process for compound (II) will be described later as step (a-1).

[0172] R 5The hydroxyl protecting group represented by is, from the viewpoint of efficiently forming a 6-membered ring of formula (I), R 1 A hydroxyl protecting group or R represented by 2 R excludes those identical to the hydroxyl protecting group represented by . 5 When the hydroxyl protecting group represented by is removed, a hydroxyl group is generated, which can react with a carbonyl group within the same molecule to form the ring of formula (I). Therefore, R 1 R 2 While retaining the hydroxyl protecting group represented by R 5 R 5 It is preferable to select the type of hydroxyl protecting group represented by .

[0173] R 5 The hydroxyl protecting group represented by is not particularly limited, but examples include ester protecting groups, arylalkyl protecting groups, alkyl protecting groups, aralkyloxyalkyl protecting groups, arylalkylalkyloxyalkyl protecting groups, silyl protecting groups, and oxycarbonyl protecting groups, and more preferably ester protecting groups, aralkyloxyalkyl protecting groups, alkyloxyalkyl protecting groups, silyl protecting groups, and oxycarbonyl protecting groups. More specifically, R 5The hydroxyl-protecting group represented by is preferably a methyloxymethyl group, a benzyloxymethyl group, an acetyl group, a propanoyl group, a butanoyl group, an isopropanoyl group, a pivaloyl group, 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, a 4-methyloxycarbonylbenzoyl group, a benzyl group, a 1-phenylethyl group, a diphenylmethyl group, a 1,1-diphenylethyl group, a naphthylmethyl group, a methyl group, a tert-butyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a tert-butyloxycarbonyloxy group, or a benzyloxycarbonyl group; more preferably a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.

[0174] Further, according to a preferred embodiment, R 5 the hydroxyl-protecting group represented by is an ester-type protecting group, and R 1 the hydroxyl-protecting group represented by and R 2 the hydroxyl-protecting group represented by are each independently selected from the group consisting of arylalkyl-type protecting groups, alkyl-type protecting groups, aralkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups and arylalkyl. Further, according to a more preferred embodiment, R 5 the hydroxyl-protecting group represented by is an acetyl group or a pivaloyl group, and R 1 the hydroxyl-protecting group represented by and R 2 the hydroxyl-protecting group represented by are each independently a methyl group, a benzyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.

[0175] Further, according to another preferred embodiment of the present invention, R 5 the hydroxyl-protecting group represented by is a silyl-type protecting group, and R 1the hydroxyl-protecting group represented by and R 2 the hydroxyl-protecting group represented by is each independently selected from the group consisting of ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, aralkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, oxycarbonyl-type protecting groups, and arylalkyl. According to another more preferred embodiment, R 5 the hydroxyl-protecting group represented by is a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, and R 1 the hydroxyl-protecting group represented by and R 2 the hydroxyl-protecting group represented by is each independently a methyl group, a benzyl group, an acetyl group, or a pivaloyl group.

[0176] Further, from the viewpoint of more efficient 6-membered ring formation of formula (I), R 5 the hydroxyl-protecting group represented by is R 1 , R 2 , R 3 and R 4 is preferably different from the hydroxyl-protecting group represented by.

[0177] According to one embodiment, R 5 the hydroxyl-protecting group represented by is an ester-type protecting group, and R 1 , R 2 , R 3 and R 4 the hydroxyl-protecting group represented by is each independently selected from the group consisting of arylalkyl-type protecting groups, alkyl-type protecting groups, aralkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups, silyl-type protecting groups, and oxycarbonyl-type protecting groups. According to a more preferred embodiment, R 5 the hydroxyl-protecting group represented by is an acetyl group or a pivaloyl group, and R 1 , R 2 , R 3 and R 4 the hydroxyl-protecting group represented by is each independently selected from the group consisting of a methyl group, a benzyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.

[0178] Furthermore, according to another preferred embodiment of the present invention, R 5 The hydroxyl protecting group represented by R is a silyl protecting group, 1 , R 2 , R 3 and R 4 The hydroxyl protecting groups represented by are each independently selected from the group consisting of aralkyloxyalkyl protecting groups, alkyloxyalkyl protecting groups, and arylalkyl oxycarbonyl protecting groups. In another more preferred embodiment, R 5 The hydroxyl protecting group represented by is a trimethylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, R 1 , R 2 , R 3 and R 4 The hydroxyl protecting groups represented by are each independently selected from the group consisting of methyl, benzyl, acetyl, and pivaloyl groups.

[0179] In formula (II), Q represents an organic group that contains an aliphatic hydrocarbon group which may have one or more substituents, an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents, as a functional group that is bonded to the sulfur atom in formula (II).

[0180] In one embodiment, the organic group represented by Q is an aliphatic hydrocarbon group which may have one or more substituents, or it includes an aliphatic hydrocarbon group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II).

[0181] In another embodiment, the organic group represented by Q is an aromatic hydrocarbon ring group which may have one or more substituents, or it includes an aromatic hydrocarbon ring group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II).

[0182] In another embodiment, the organic group represented by Q is an aliphatic heterocyclic group which may have one or more substituents, or it includes an aliphatic heterocyclic group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II).

[0183] In another embodiment, the organic group represented by Q is an aromatic heterocyclic group which may have one or more substituents, or includes an aromatic heterocyclic group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II).

[0184] An organic group containing an aliphatic hydrocarbon group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) is, for example, the following: [ka] [In the formula, L1 represents an aliphatic hydrocarbon group which may have one or more substituents, L2 represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents, and (*) represents a bond that connects to the sulfur atom in formula (II).] It can be expressed as follows.

[0185] Furthermore, an organic group containing an aliphatic hydrocarbon group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) is, for example, the following formula: [ka] [In the formula, L1 and L2 are as defined above, L3 represents an aliphatic hydrocarbon group which may have one or more substituents, and (*) represents a bond that connects to the sulfur atom in formula (II).] It can be expressed as follows.

[0186] Furthermore, an organic group containing an aliphatic hydrocarbon group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) is, for example, the following formula: [ka] [In the formula, L1, L2, and L3 are as defined above, L4 represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents, and (*) represents a bond that connects to the sulfur atom in formula (II).] It can be expressed as follows.

[0187] The one or more substituents that the aliphatic hydrocarbon group represented by L1 or L3 may have can each be independently selected from, for example, substituent groups A to M, preferably substituent group A. The one or more substituents that the aliphatic hydrocarbon group represented by L1 or L3 may have can each preferably be independently selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, and an optionally protected sulfonyl group. The aliphatic hydrocarbon group represented by L1 or L3 may be unsubstituted. Furthermore, if the aliphatic hydrocarbon group represented by L1 and / or L3 is a linear or branched aliphatic hydrocarbon group, it may have a cyclic aliphatic hydrocarbon group (e.g., a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

[0188] The one or more substituents that an aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by L2 or L4 may have can be selected from substituent groups A to M, preferably substituent groups A to D and G, and more preferably substituent groups A, B and G. The one or more substituents that an aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by L2 or L4 may have can each be independently selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an alkyloxy group, an aryloxy group, an arylalkyloxy group, an alkylarylalkyloxy group, a heteroaryloxy group, a heteroarylalkyloxy group, an alkylheteroarylalkyloxy group, an aliphatic heterocyclic oxy group, an aliphatic heterocyclic alkyloxy group, and an alkylaliphatic heterocyclic alkyloxy group. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by L2 or L4 may be unsubstituted.

[0189] An organic group containing an aromatic hydrocarbon ring group having one or more substituents, an aliphatic heterocyclic group having one or more substituents, or an aromatic heterocyclic group having one or more substituents as a functional group bonded to the sulfur atom in formula (II) is, for example, the following formula: [ka] [In the formula, M1 represents an aromatic hydrocarbon ring group having one or more substituents, an aliphatic heterocyclic group having one or more substituents, or an aromatic heterocyclic group having one or more substituents; M2 represents an aliphatic hydrocarbon group having one or more substituents; and (*) represents a bond that connects to the sulfur atom in formula (II).] It can be expressed as follows.

[0190] Furthermore, an organic group containing an aromatic hydrocarbon ring group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) is, for example, the following formula: [ka] [In the formula, M1 and M2 are as defined above, M3 represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents, and (*) represents a bond that connects to the sulfur atom in formula (II).] It can be expressed as follows.

[0191] Furthermore, an organic group containing an aromatic hydrocarbon ring group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) is, for example, the following formula: [ka] [In the formula, M1, M2, and M3 are as defined above, M4 represents an aliphatic hydrocarbon group which may have one or more substituents, and (*) represents a bond that connects to the sulfur atom in formula (II).] It can be expressed as follows.

[0192] In embodiments in which the aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by M1 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M. Preferably, each of the one or more substituents on the aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by M1 can be independently selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an alkenyl group, and an alkynyl group. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by M1 may be unsubstituted.

[0193] In embodiments in which the aliphatic hydrocarbon group represented by M2 and / or M4 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M. Preferably, each of the one or more substituents on the aliphatic hydrocarbon group represented by M2 and / or M4 can be independently selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, and an optionally protected sulfonyl group. The aliphatic hydrocarbon group represented by M2 or M4 may be unsubstituted. When the aliphatic hydrocarbon group represented by M2 and / or M4 is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group may have a cyclic aliphatic hydrocarbon group (e.g., a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

[0194] In embodiments in which the aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by M3 has one or more substituents, each of the one or more substituents can be independently selected, for example, from substituent groups A to M. Preferably, each of the one or more substituents on the aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by M3 can be independently selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected carbamoyl group, an optionally protected sulfonyl group, an alkyl group, an alkyloxy group, an aryloxy group, an arylalkyloxy group, an alkylarylalkyloxy group, a heteroaryloxy group, a heteroarylalkyloxy group, an alkylheteroarylalkyloxy group, an aliphatic heterocyclic oxy group, an aliphatic heterocyclic alkyloxy group, and an alkylaliphatic heterocyclic alkyloxy group. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by M3 may be unsubstituted.

[0195] The organic group represented by Q preferably includes an alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroaryl group, heteroarylalkyl group, heteroarylalkenyl group, or heteroarylalkynyl group as a functional group that bonds to the sulfur atom in formula (II), and more preferably includes an alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl group, arylalkenyl group, or arylalkynyl group as a functional group that bonds to the sulfur atom in formula (II). The number of carbon atoms in the alkyl group is, for example, 1 to 20, preferably 1 to 10; the number of carbon atoms in the arylalkyl group is, for example, 7 to 20, preferably 7 to 15; the number of carbon atoms in the aryl group is, for example, 6 to 20, preferably 6 to 10; and the number of carbon atoms in the heteroaryl group is, for example, 5 to 20, preferably 5 to 9.

[0196] <Reactions using organozinc compounds> In step (a), compound (II) and the following formula (III-I): [ka] Compounds represented by (III-I), and The following equation (III-II): [ka] Compound (III-II) represented by At least one organozinc compound selected from the group consisting of the following is reacted in the presence of one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or a supported catalyst having one or more transition metal catalysts and a carrier supporting one or more transition metal catalysts, to produce the following formula (IV): [ka] We obtain compound (IV) represented by [formula].

[0197] In step (a), the organozinc compound is used as a reagent to introduce an Ar group into compound (II). Either compound (III-I) or compound (III-II) may be used individually, but in step (a), compound (III-I) and compound (III-II) are combined in the reaction system according to the following formula: [ka] Since it is possible to suitably achieve the equilibrium state represented by , it is preferable to use both compound (III-I) and compound (III-II). In a preferred embodiment, at least one organozinc compound contains compound (III-I), and compound (III-I) is in the above equilibrium state.

[0198] The halogen atom represented by X is not particularly limited, but is preferably a chlorine atom, a bromine atom, or an iodine atom.

[0199] The organozinc compounds of compound (III-I) and compound (III-II) may be commercially available products or may be manufactured according to known methods as described in Non-Patent Document 5, etc.

[0200] According to one embodiment, the organozinc compound (III-I) is produced by reacting the Grignard reagent ArMgX with zinc halide ZnX2 in an organic solvent.

[0201] In the preparation of compound (III-I), the amount of zinc halide used is usually about 0.9 to 1.5 equivalents, preferably about 1 to 1.2 equivalents, and more preferably about 1 to 1.1 equivalents, per equivalent of Grignard reagent.

[0202] From the viewpoint of stable production, the organic solvent used in the production of compound (III-I) is preferably an ether-based solvent, more preferably 2-methyltetrahydrofuran, tetrahydrofuran, and even more preferably tetrahydrofuran.

[0203] The reaction temperature in the production of compound (III-I) is typically -50 to 50°C, preferably 0 to 30°C.

[0204] Compound (III-I) may also be used as a complex with a lithium salt (wherein Y is a halogen atom). The lithium salt complex of compound (III-I) is given by the following formula (III-Ia): [ka] [In the formula, X and Y each independently represent a halogen atom.] It is represented as follows. The lithium salt complex (III-Ia) can be preferably obtained by producing compound (III-I) in the presence of a lithium salt. The lithium salt complex (III-Ia) may also be a lithium salt complex of compound (III-I).

[0205] In step (a), the use of a lithium salt complex (III-Ia) is preferable for improving the reaction rate of the organozinc compound.

[0206] Examples of lithium salts include lithium chloride, lithium bromide, and lithium iodide, but lithium chloride is preferred. Therefore, in the lithium salt complex (III-Ia) of organozinc compounds, X and Y are preferably chlorine, bromine, or iodine, and more preferably chlorine or bromine.

[0207] The lithium salt complex (III-Ia) of the organozinc compound may be a commercially available product or may be prepared by known methods. A preferred method of preparation involves reacting the turbogrignard reagent ArMgXa·LiY [wherein Ar is as defined above, and Xa is a halogen atom] with zinc halide ZnX2 [wherein X is a halogen atom, which may be the same as or different from Y] in an organic solvent.

[0208] Turbogrignard reagents can be obtained by reacting magnesium with a halogen organic compound ArXa [wherein Ar and Xa are as defined above] in an organic solvent in the presence of a lithium salt in a reaction vessel substituted with an inactivating gas (nitrogen, argon, etc.).

[0209] From the viewpoint of improving reactivity, magnesium is preferably used as a pulverized or shaving-like material. Furthermore, from the viewpoint of improving its reactivity, a reducing agent such as diisobutylaluminum hydride (DIBAL-H) ​​in a catalytic amount of about 0.05 to 0.2 equivalents per equivalent of magnesium may be added to the magnesium in an organic solvent.

[0210] In the preparation of turbogrignard reagents, the amount of lithium salt used is typically about 0.5 to 5.0 equivalents, preferably about 0.5 to 3.0 equivalents, and more preferably about 0.5 to 2.0 equivalents, per 1 equivalent of magnesium.

[0211] In the preparation of the turbogrignard reagent, the amount of the halogen organic compound ArXa used is usually about 0.5 to 3.0 equivalents, preferably about 0.5 to 2.0 equivalents, and more preferably about 0.5 to 1.5 equivalents, per equivalent of magnesium.

[0212] From the viewpoint of stable production, the organic solvent used in the manufacture of the Turbogrignard reagent is preferably an ether-based solvent, more preferably diethyl ether, tetrahydrofuran, etc., and even more preferably tetrahydrofuran. The amount of solvent used is usually 1 to 1000 times the volume of the halogen organic compound ArXa, preferably 1 to 100 times the volume.

[0213] The reaction temperature in the preparation of turbogrignard reagents is typically -50 to 50°C, preferably -20 to 20°C. Furthermore, the reaction time is usually 0.5 to 5 hours, preferably 1 to 3 hours.

[0214] Furthermore, the turbogrignard reagent ArMgXa·LiY is prepared according to the known method described in Angew Chem.Int.Ed2006,45,2958, etc., using the following formula: [ka] As shown, it may also be produced by reacting the Noschel-Hauser base TMPMgXa·LiY (where TMP is 2,2,6,6-tetramethylpiperidine) with the compound Ar-H, and this embodiment is also included in the present invention.

[0215] Lithium salt complexes of organozinc compounds can be prepared by mixing a turbogrignard reagent with zinc halide in a solvent. The reaction between the turbogrignard reagent and zinc halide is preferably carried out in an ether-based solvent (such as tetrahydrofuran), similar to the preparation of the turbogrignard reagent.

[0216] The reaction between the turbogrignard reagent and zinc halide can usually be carried out at a temperature of around -30 to 30°C. Furthermore, the reaction time is typically 0.1 to 1 hour.

[0217] In step (a), the amount of organozinc compound or its lithium salt complex used can be appropriately set according to the amount of compound (II). The amount of organozinc compound used can usually be 1 to 5 equivalents, preferably 1 to 3 equivalents, per equivalent of compound (II).

[0218] The organozinc compound or its lithium salt composite may be added to the reaction system after mixing it with the transition catalyst and compound (II), or it may be mixed with the transition catalyst and compound (II) simultaneously, but it is preferable to mix the transition catalyst and compound (II) before adding it to the reaction system.

[0219] In step (a), zinc halide ZnX2 may be added to the reaction system of step (a) together with the organozinc compound or its lithium salt complex, from the viewpoint of activating the organozinc compound and improving the yield. The amount of zinc halide added to the reaction system together with the organozinc compound or its lithium salt complex is usually about 0.05 to 1.0 equivalents, preferably about 0.05 to 0.3 equivalents, and more preferably about 0.05 to 0.2 equivalents, per equivalent of the organozinc compound or its lithium salt complex. Zinc halide may be added to the reaction system of step (a) separately from the organozinc compound or its lithium salt complex, or added simultaneously with the organozinc compound or its lithium salt complex, but it is preferable to add the zinc halide and the organozinc compound or its lithium salt complex to the reaction system of step (a) in a pre-mixed state.

[0220] The reaction atmosphere is preferably an inert gas atmosphere such as argon or nitrogen, taking into consideration the activity of the transition catalyst. It may also be carried out under pressure, atmospheric pressure, or reduced pressure.

[0221] In one embodiment, the nickel catalyst is a nickel salt or solvate. The valence of the nickel atoms in the nickel salt is usually divalent. Examples of nickel salts include nickel(II) dichloride, nickel(II) dibromide, nickel(II) difluoride, nickel(II) iodide (NiI2), nickel(II) sulfate, nickel(II) carbonate, nickel(II) dimethylglyoxime, nickel(II) hydroxide, nickel(II) hydroxyacetate, nickel(II) oxalate, nickel(II) 2-ethylhexanoate, nickel(II) acetate, nickel(II) trifluoroacetate, nickel(II) triflate, and nickel(II) acetylacetonate (Ni(acac)2).

[0222] In another embodiment, the nickel catalyst is a nickel complex catalyst. The nickel complex catalyst comprises nickel atoms and ligands that chelate the nickel atoms. The nickel complex catalyst can be advantageously used from the viewpoint of improving the reaction yield or reducing by-products. The valence of the nickel atoms in the nickel complex catalyst is preferably 0 or 2, more preferably 2. The nickel atoms contained in the nickel complex catalyst originate, for example, from a nickel salt or solvate added to the reaction system. In embodiments where the nickel catalyst is a nickel complex catalyst, a pre-formed nickel complex catalyst may be added to the reaction system, or a nickel salt or solvate and ligands may be added to the reaction system to form the nickel complex catalyst in the reaction system. When forming the nickel complex catalyst in the reaction system, the amount of ligand may be, for example, usually about 1 to 3 equivalents, preferably about 1 to 2 equivalents, per 1 equivalent of nickel salt.

[0223] The ligands in a nickel complex catalyst are molecules or ions bonded to nickel atoms by coordinate bonds. The ligands may be monodentate or polydentate. A monodentate ligand is a single-dentate ligand. A polydentate ligand is a ligand with two or more dentates. A bidentate ligand has two coordinating atoms, a tridentate ligand has three coordinating atoms, and a tetradentate ligand has four coordinating atoms. Coordinating atoms are atoms directly involved in the coordinate bond. In a nickel complex catalyst, the ratio of ligands to nickel atoms is not particularly limited, but when the ligand is monodentate, the number of ligands per nickel atom is usually 2 to 4, preferably 2. When the ligand is polydentate, it is preferable that one or more nickel atoms coordinate to each ligand. The number of nickel atoms per ligand is, for example, 1 to 3. Preferred ligands are phosphine ligands or nitrogen ligands.

[0224] A phosphine ligand is a ligand that contains a phosphorus atom as a coordinating atom. A phosphine ligand may be a monodentate ligand or a polydentate ligand, but a polydentate phosphine ligand is preferred.

[0225] Examples of phosphine ligands include trimethylphosphine and tri-n-butylphosphine (P n Monodentate phosphines such as Bu3, tricyclopentylphosphine, tricyclohexylphosphine (PCy3), trioctylphosphine (P(Oct)3), triphenylphosphine (PPh3); 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,2-bis(diphenylphosphino)ethane (dppe), 1,2-bis(diphenylphosphino)butane (dppb), 1,2-bis(dicyclohexylphosph Bidentate polydentate phosphines such as fino)ethane (dcype), 1,2-bis(dimethylphosphino)ethane (dmpe), 3,4-bis(dicyclohexylphosphino)thiophene (dcypt), 1,3-bis(diphenylphosphino)propane (dppp), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP); bis(2-diphenylphosphinoethyl)phenylphosphine, 1,1,1-tris( Examples include tridentate polydentate phosphines such as diphenylphosphinomethyl)ethane and 1,1,1-tris(bis(3,5-dimethylphenyl)phosphinomethyl)ethane; and tetradentate polydentate phosphines such as tris(2-diphenylphosphinoethyl)phosphine. Preferably, the phosphine is monodentate or bidentate, such as tricyclohexylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(dicyclohexylphosphino)ethane, 1,2-bis(dimethylphosphino)ethane, or 3,4-bis(dicyclohexylphosphino)thiophene. More preferably, the phosphine is bidentate, such as triphenylphosphine, 1,2-bis(dicyclohexylphosphino)ethane, or 3,4-bis(dicyclohexylphosphino)thiophene, and even more preferably, 3,4-bis(dicyclohexylphosphino)thiophene.

[0226] The term "phosphine ligand" also includes derivatives of the above-mentioned phosphine ligands. Examples of derivatization of phosphine ligands include the introduction of one or more substituents. Examples of one or more substituents that can be introduced to a phosphine ligand include alkyl groups, aryl groups, arylalkyl groups, alkylaryl groups, alkyloxy groups, alkyloxyalkyl groups, aryloxy groups, aryloxyalkyl groups, halogen atoms, dialkyl groups, nitro groups, oxycarbonyl groups, and the like.

[0227] A nitrogen ligand is a ligand that contains a nitrogen atom as a coordinating atom. Nitrogen ligands are usually basic. Examples of nitrogen ligands include amine-type or imine-type polydentate ligands.

[0228] Examples of nitrogen ligands include 2,2-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (bmbpy), 4,4'-di-tert-butyl-2,2'-bipyridine (BBBPY), 4,4'-di-(5-nonyl)-2,2'-bipyridine, 1,10-phenanthroline, N-(n-propyl)pyridylmethanymine, N-(n-octyl)pyridylmethanymine, and N,N,N',N'-tetramethylethylenediamine (TMDT). A) Bidentate polydentate amines such as; N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA), N-propyl-N,N-di(2-pyridylmethyl)amine, and other tridentate polydentate amines; hexamethyltris(2-aminoethyl)amine, N,N-bis(2-dimethylaminoethyl)-N,N'-dimethylethylenediamine, 2,5,9,12-tetramethyl-2,5,9,12-tetraazatetradecane, 2,6,9,13-tetramethyl Tetramethyl-2,6,9,13-tetraazatetradecane, 4,11-dimethyl-1,4,8,11-tetraazabicyclohexadecane, N',N''-dimethyl-N',N''-bis((pyridin-2-yl)methyl)ethane-1,2-diamine, tris[(2-pyridyl)methyl]amine, 2,5,8,12-tetramethyl-2,5,8,12-tetraazatetradecane, and other tetradentate polydentate amines; N,N,N',N'',N''',N'''' Examples include pentadent polydentate amines such as N''''-heptamethyltetraethylenetetramine; hexadent polydentate amines such as N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; and polydentate amines such as polyamines and polyethyleneimines. Preferably, the polydentate amines are bidentate polydentate amines having a bipyridine group, such as 2,2-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 4,4'-di-tert-butyl-2,2'-bipyridine.

[0229] The nitrogen ligands also include derivatives of the above-mentioned nitrogen ligands. Examples of derivatization of nitrogen ligands include the introduction of one or more substituents. Examples of one or more substituents that can be introduced to a nitrogen ligand include alkyl groups, aryl groups, arylalkyl groups, alkylaryl groups, alkyloxy groups, alkyloxyalkyl groups, aryloxy groups, aryloxyalkyl groups, halogen atoms, dialkyl groups, nitro groups, oxycarbonyl groups, and the like.

[0230] Other ligands included in nickel complex catalysts include cyclooctadiene (COD), tetrahydrofuran (thf), and dimethoxyethane (dme).

[0231] Examples of nickel catalysts used in the present invention include nickel(0) cycloocdadiene complex (Ni(COD)2), nickel(II) acetylacetonate, nickel(II) dichloride or its dimethoxyethane adduct, nickel(II) dibromide, nickel(II) dichloride bistriphenylphosphine complex, nickel(II) dibromide bistriphenylphosphine complex, nickel(II) dichloride tri-n-butylphosphine complex, nickel(II) dichloride 1,2-diphenylphosphine complex, nickel(II) dichloride 1,3-diphenylphosphine propane complex, and bis(tetrahydrofuran)nickel(II). Examples of divalent nickel catalysts include dichloride complexes (NiCl2(thf)2), but preferably nickel(II) dichloride or its dimethoxyethane adduct, nickel(II) dichloride 1,2-diphenylphosphinoethane complex, nickel(II) acetylacetonate, or bis(tetrahydrofuran)nickel(II) dichloride complex, more preferably nickel(II) dichloride 1,2-diphenylphosphinoethane complex, nickel(II) acetylacetonate, or bis(tetrahydrofuran)nickel(II) dichloride complex, and even more preferably bis(tetrahydrofuran)nickel(II) dichloride complex. These may be used individually or in combination of two or more. Using a nickel catalyst in step (a) is particularly advantageous for rapidly advancing the reaction.

[0232] Examples of palladium catalysts used in the present invention include palladium(II) dichloride, palladium(II) dibromide, palladium(II) dichloride bistriphenylphosphine complex, palladium(O) tetrakistriphenylphosphine complex, palladium(II) acetate, palladium(II) oxide, palladium(O), palladium(II) dichloride, palladium(II) dibromide, palladium(II) dichloride bistriphenylphosphine complex, palladium(O) tetrakistriphenylphosphine complex, palladium(II) acetate, palladium(II) oxide, and other 0-valent or 2-valent palladium catalysts, but palladium(O) tetrakistriphenylphosphine complex and palladium(O) are preferred. Using a palladium catalyst is advantageous in reducing the amount of by-products generated by coupling reactions between Ar groups, etc.

[0233] The transition catalyst used in the present invention may be a homogeneous catalyst or a heterogeneous catalyst.

[0234] When the transition metal catalyst used in the present invention is a homogeneous catalyst, the transition metal catalyst is preferably a zero-valent or divalent nickel complex or a zero-valent or divalent palladium complex. The nickel complex is preferably nickel(II) acetylacetonate, a dimethoxyethane adduct of nickel(II) dichloride, or a bis(tetrahydrofuran)nickel(II) dichloride complex. The palladium complex is preferably a palladium(O) tetrakistriphenylphosphine complex or a bis(tetrahydrofuran)nickel(II) dichloride complex.

[0235] In the present invention, if the transition metal catalyst used is a heterogeneous catalyst, it is preferable that the transition metal catalyst is a supported catalyst comprising one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, and a carrier supporting the one or more transition metal catalysts. A supported catalyst is advantageous for easily separating the transition metal catalyst from the reaction mixture.

[0236] Examples of the support for the supported catalyst include activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite, hydrotalcite, aluminum oxide, titanium dioxide, zirconium dioxide, silicon dioxide, clay, silicates, zeolites, and polymer matrices. The polymer matrix may be, for example, styrene-divinylbenzene resin or phenol-formaldehyde resin, and the resin may have chelate ligands (phosphine, 1,10-phenanthroline, or 2,2′-bipyridine, etc.) bound to it. The ligands bound to the resin form complexes with palladium catalysts or nickel catalysts, immobilizing these transition catalysts and creating heterogeneous catalysts.

[0237] The transition metal catalyst in the supported catalyst is preferably a 0-valent or 2-valent palladium catalyst, and more preferably palladium(0). Furthermore, when the transition metal catalyst in the supported catalyst is a palladium catalyst, the support in the supported catalyst is preferably activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite and hydrotalcite, aluminum oxide, titanium dioxide, or zirconium dioxide, and more preferably activated carbon. In a particularly preferred embodiment, the supported catalyst is palladium black or palladium carbon (Pd / C).

[0238] The amount of transition metal catalyst in the supported catalyst is, for example, 0.05 to 10% by weight, preferably 0.1 to 7% by weight, and more preferably 4 to 7% by weight, relative to the total weight of the supported catalyst.

[0239] The amount of transition metal catalyst used is typically about 0.001 to 2 moles, preferably about 0.01 to 1 mole, per mole of organozinc compound.

[0240] The solvent used in step (a) is preferably an organic solvent, such as polar aprotic solvents like N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, cyclopentyl methyl ether (CPME), tert-butyl methyl ether, diisopropyl ether, N,N-dimethylacetamide (DMA), diglyme, methyl-tetrahydrofuran, and 1,4-dioxane; or nonpolar solvents like toluene, methylene chloride, hexane, heptane, xylene, 1,4-dioxane, dibutyl ether, mesitylene, and p-cymene, or combinations thereof. Preferably, the solvent is THF, 2-methyl-THF, dibutyl ether, toluene, DMF, or a mixture thereof, and more preferably THF.

[0241] The amount of solvent used in step (a) is not particularly limited, but for example, it can be 1 to 100 times the volume of compound (II).

[0242] According to one embodiment, in step (a), the reaction temperature may be around 0 to 100°C, but is usually 0 to 60°C, preferably 0 to 50°C, and more preferably 10 to 50°C. Obtaining compound (a) under such mild temperature conditions is preferable for carrying out industrial production while suppressing equipment costs related to temperature control.

[0243] Furthermore, when the transition metal catalyst is a nickel catalyst, the reaction temperature in step (a) is preferably 0 to 50°C, more preferably 10 to 50°C, more preferably 20 to 30°C, and even more preferably around 25°C. Furthermore, when the transition metal catalyst is a palladium catalyst, the reaction temperature in step (a) is preferably 45 to 90°C, more preferably 45 to 80°C, more preferably 50 to 70°C, and even more preferably around 60°C.

[0244] In step (a), the reaction time may be appropriately determined depending on the amount of substrate used, the amount of catalyst, the reaction temperature, etc., and is usually 0.5 to 48 hours, preferably 1 to 24 hours.

[0245] <Process (b)> [ka] In step (b), the R of compound (IV) obtained in step (a) 5 Compound (I) is obtained by removing the hydroxyl protecting group represented by .

[0246] R 5 The removal method depends on the type of hydroxyl protecting group and can be performed by known methods described in Peter GM Wuts' "Protective Group in Organic Synthesis, 5th Edition" (published by John Wiley & Sons). A typical method involves reacting compound (II) with an acidic or basic reagent in an inert solvent to remove R 5 One method for removing it is to remove it.

[0247] Examples of acidic reagents include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and hydrogen bromide, and organic acids such as trifluoroacetic acid, trichloroacetic acid, p-toluenesulfonic acid, formic acid, and phthalic acid. Examples of basic reagents, though not particularly limited, include fluorides such as tetra-n-butylammonium fluoride, ammonium fluoride, ammonium bifluoride, and hydrofluoric acid, as well as potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methyl oxide, sodium ethyl oxide, and aqueous ammonia.

[0248] The amount of acidic reagent used is typically 0.1 to 1000 equivalents, preferably 1 to 5 equivalents, per equivalent of compound (II). The amount of basic reagent used is typically 0.001 to 10 equivalents, preferably 0.01 to 2 equivalents, per equivalent of compound (II).

[0249] The solvent used in step (b) is preferably an organic solvent, such as polar protic solvents like methanol, ethanol, isopropanol, and butanol; polar aprotic solvents like acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diglyme, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, and butyl acetate; and nonpolar solvents like methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane, or combinations thereof, but preferably methanol, ethanol, isopropanol, or a mixture thereof.

[0250] The amount of solvent used in step (b) is typically 1 to 1000 times the volume of compound (II), preferably 1 to 100 times the volume.

[0251] In step (b), the reaction temperature is typically -30 to 100°C, preferably 0 to 100°C, more preferably 0 to 40°C, and even more preferably 0 to 50°C. Employing such mild temperature conditions to obtain compound (I) is preferable for implementing industrial production while suppressing equipment costs related to temperature control.

[0252] <Process (a-1): Manufacturing of compound (II)> [ka] In the method for producing compound (I), compound (II) used as a starting material may be purchased or manufactured, but it is preferable to manufacture it according to step (a-1).

[0253] Process (a-1) can be carried out by dividing it into the following processes (a-1-1) and (a-1-2). Process (a-1-1): Equation (VI): [ka] Compound (VI) represented by, The following equation (VII): [ka] Compound (VII) represented by The reaction is performed as follows (VIII): [ka] A step to obtain a compound (VIII) represented by, and Step (a-1-2): The hydroxyl group in compound (VIII) is R 5 A step to obtain compound (II) by protecting with a hydroxyl protecting group represented by .

[0254] <Process (a-1-1): Manufacturing of compound (VIII)> [ka] In step (a-1-1), compound (VI) is reacted with compound (VII) to obtain compound (VIII).

[0255] Compound (VI) used as a starting material in step (a-1-1) is not particularly limited and may be produced by known methods described in Non-Patent Document 1, Non-Patent Document 2, etc., or by the method described in Example 1 below, or a commercially available product may be used.

[0256] Compound (VII) may also be prepared by known methods, or a commercially available organic thiol compound may be used.

[0257] The amount of compound (VII) used is not particularly limited, but for example, it is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, per equivalent of compound (VI).

[0258] The reaction conditions between compound (VI) and compound (VII) are not particularly limited as long as compound (VIII) can be obtained, but the following formula (IX): [ka] It is preferable to carry out the procedure in the presence of compound (IX) represented by . The method for obtaining compound (IX) is not particularly limited and may be produced by known methods or a commercially available aluminum catalyst may be used.

[0259] R c and R d Each of these independently represents a functional group selected from the group consisting of halogen atoms, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups, and each of the aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups included in the group may have one or more substituents.

[0260] R c and R d Each of the functional groups represented is preferably an alkyl group, an aryl group, or an arylalkyl group, more preferably an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, or an arylalkyl group having 7 to 20 carbon atoms, even more preferably an alkyl group having 1 to 10 carbon atoms, and even more preferably a methyl group, an ethyl group, or a propyl group.

[0261] In equation (IX), R c Functional groups represented by and R d The functional groups represented by may be the same or different from each other, but it is preferable that they be the same. In a preferred embodiment, either q or r represents 0, and the other represents 3.

[0262] In step (a-1-1), the amount of compound (IX) used is usually 1 to 5 equivalents, preferably 3 to 5 equivalents, per equivalent of compound (VI).

[0263] The solvent used in step (a-1-1) is preferably an organic solvent, such as polar aprotic solvents like acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diglyme, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, and butyl acetate; or nonpolar solvents like methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane, or combinations thereof. Preferably, it is methylene chloride, toluene, hexane, or a mixture thereof, and more preferably, methylene chloride.

[0264] The amount of solvent used in step (a-1-1) is not particularly limited, but is usually 1 to 1000 times the volume of compound (VI), preferably 1 to 100 times the volume.

[0265] In step (a-1-1), the reaction temperature is not particularly limited, but is usually -30 to 80°C, preferably -10 to 40°C, and more preferably 0 to 40°C. Adopting relatively mild temperature conditions in this step is preferable from the viewpoint of suppressing equipment costs related to temperature control.

[0266] In step (a-1-1), the aluminum catalyst reaction can be terminated using water, an aqueous HCl solution, an aqueous ammonium chloride solution, etc., and the catalyst can be easily removed.

[0267] Therefore, in step (a-1), after obtaining compound (VIII), it is preferable to carry out the next manufacturing step (a-1-2) as quickly as possible, and it is even more preferable to carry out steps (a-1-1) and (a-1-2) in the same reaction system. Moving quickly from step (a-1-1) to step (a-1-2) is advantageous in preventing the regeneration of compound (VI) by the ring-closing reaction of compound (VIII).

[0268] <Process (a-1-2): Manufacturing process for compound (II)> [ka]

[0269] In process (a-1-2), the following formula (VIII): [ka] The hydroxyl group in compound (VIII) represented by R 5 Compound (II) is obtained by protecting the compound with a hydroxyl protecting group represented by .

[0270] R for the hydroxyl group in compound (VIII) 5 The introduction of the base is not particularly limited, R 5 Depending on the type of hydroxyl protecting group represented by , the process can be carried out by known methods described in Peter GM Wuts, "Protective Group in Organic Synthesis, 5th Edition" (published by JOHN WILEY & SONS), etc. A typical method involves reacting compound (VIII) with a protecting group introduction reagent in an inert solvent in the presence of an acid or basic reagent to form R 5 One possible method is to implement it.

[0271] The protecting group introduction reagent is R 5The type of protecting group can be appropriately determined depending on the type, but examples include ester-type protecting group introducers such as acetic anhydride, pivalic acid anhydride, acetyl chloride, and pivaloyl chloride; aryl alkyl ether-type protecting group introducers such as benzyl bromide; alkyl ether-type protecting group introducers such as iodomethane; silyl-type protecting group introducers such as trimethylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilyl chloride; and oxycarbonyl-type protecting groups such as bis(tert-butyloxycarbonyloxy)oxide. Preferably, the protecting group introducer is an ester-type protecting group introducer such as acetic anhydride, pivalic acid anhydride, acetyl chloride, or pivaloyl chloride, and more preferably acetic anhydride.

[0272] Examples of acidic reagents include inorganic acids such as acetic acid and hydrogen bromide, and organic acids such as p-toluenesulfonic acid and phthalic acid. Basic reagents are not particularly limited, but examples include organic amines such as triethylamine, 4-dimethylaminopyridine (DMAP), diazabicycloundecene (DBU), and diethylaniline, but triethylamine, 4-dimethylaminopyridine (DMAP), or mixtures thereof are preferred.

[0273] The amount of acidic reagent used is not particularly limited, but is usually 0.1 to 1000 equivalents, preferably 1 to 5 equivalents, per equivalent of compound (VIII). Similarly, the amount of basic reagent used is not particularly limited, but is usually 0.001 to 10 equivalents, preferably 0.01 to 2 equivalents, per equivalent of compound (VIII).

[0274] The solvent used in step (a-1-2) is preferably an organic solvent, such as polar aprotic solvents like acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diglyme, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, and butyl acetate; or nonpolar solvents like methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane, or combinations thereof, but preferably methylene chloride, toluene, or a mixture thereof.

[0275] The amount of solvent used in step (a-1-2) is not particularly limited, but is usually 1 to 1000 times the volume of compound (VIII), preferably 1 to 100 times the volume.

[0276] In step (a-1-2), the reaction temperature is not particularly limited, but is usually -30 to 100°C, preferably -30 to 40°C, more preferably -10 to 40°C, and even more preferably 0 to 30°C. Adopting relatively mild temperature conditions in this step is advantageous in suppressing the reversal reaction from compound (VIII) to compound (VI). Furthermore, adopting relatively mild temperature conditions in this step is preferable for implementing industrial production by reducing equipment costs related to temperature control.

[0277] <Manufacturing process for β-C-arylglycoside derivative (compound (XI))> [ka]

[0278] Compound (I) in this invention is defined by the following formula (XI): [ka] Compound (XI), represented by , can be advantageously used as a raw material for the production of β-C-arylglycoside derivatives.

[0279] The reaction from compound (I) to compound (XI) can be carried out using known reduction reactions. Specifically, reduction methods include reducing compound (I) with triethylsilane in the presence of boron trifluoride diethyl ether complex (BF3·OEt2), or reacting compound (I) with a Lewis acid such as BF3·OEt2, boron trifluoride tetrahydrofuran (BF3·THF), or aluminum chloride in the presence of a silane compound such as triethylsilane, triisopropylsilane, or tetramethyldisiloxane.

[0280] The resulting compound (XI) can be used as is, or R 1 ', R 2 ', R 3 'or R 4 If ' is a hydroxyl protecting group, it can be deprotected by known methods as desired, as described in Peter GM Wuts, "Protective Group in Organic Synthesis, 5th Edition" (published by JOHN WILEY & SONS), and used as a β-C-aryl glycoside derivative.

[0281] <Uses of Compound (II) / Manufacturing Intermediate> According to the present invention, as described above, compound (II) can be used as a manufacturing intermediate to produce compound (I), which can then be converted into compound (XI), which is either the SGLT2 inhibitor itself or a synthetic intermediate thereof. In other words, according to the present invention, compound (II) can be suitably applied as a reagent or intermediate for the production of compound (XI).

[0282] Therefore, according to a preferred embodiment of the present invention, the following formula (II): [ka] The compound (II) represented by the following formula (XI): [ka] A reagent for producing the compound (XI) represented by is provided. In addition, according to a preferred embodiment of the present invention, in the reagent, Ar in formula (XI) is represented by formula (V) or (Va).

[0283] Furthermore, according to another aspect of the present invention, the following compound (XI): [ka] As a manufacturing intermediate for the compound (XI) represented by the above, Formula (II) below: [ka] The use of compound (II), represented by , is provided. Furthermore, according to a preferred embodiment of the present invention, in the above use, Ar in formula (XI) is represented by formula (V) or (Va). [Examples]

[0284] The following describes embodiments of the present invention, but the present invention is not limited to these embodiments.

[0285] Example 1: Preparation of compound (2) ((3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one) [ka]

[0286] A solution containing compound (1) (2,3,4,6-tetra-O-benzyl-D-glucopyranose; 5.0 g, 9.24 mmol) in dimethyl sulfoxide (25 mL) was stirred under an argon atmosphere at 20-25°C for 30 minutes. To this reaction mixture, acetic anhydride (15 mL) was added over 5 minutes at 25°C. After the addition was complete, the resulting reaction mixture was stirred at 20-25°C for 20 hours while monitoring by thin-layer chromatography (TLC). Next, the reaction mixture was diluted with toluene (100 mL), and 120 mL of 1 N HCl aqueous solution was added to the resulting dilute solution to quench the excess acetic anhydride. The resulting reaction mixture was stirred at 20-25°C for 20 minutes, and then phase separation was performed. The resulting organic phase was washed with 1 M NaHCO3 aqueous solution (3 × 50 mL). The organic phase was further washed with water (15 mL) and saline solution (15 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 2 / 20 to 3 / 20) to obtain compound (2) ((3R, 4S, 5R, 6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one; 4.8 g, yield 96%) as a colorless oil.

[0287] Compound (2) IR(KBr):νmax=3030,2868,1754,1496,1363,1164,1097,737,698cm -1 1 H NMR(400MHz,CDCl3)δ:7.39-7.16(m,20H),4.97(d,J=11.4Hz,1H),4.73-4.44(m,8H),4.12(d,J=6.3Hz,1H),3.96-3.89(m,2H),3.73-3.64(m,2H) 13C NMR(101MHz,CDCl3)δ:169.38,137.71,137.64,137.63,137.06,128.57,128.53,128.48,128.19 ,128.09,128.07,128.02,127.91,81.06,78.26,77.51,76.20,73.98,73.80,73.78,73.66,68.40 HRMS[M+H] + C 34 H 35 O6 calculated value: 539.2428; measured value: 539.2420 Mass spectrometry [M+H] + :539

[0288] Example 2: Preparation of compound (3) ((2R,3S,4R,5R)-S-decyl 2,3,4,6-tetrakis(benzoyloxy)-5-hydroxyhexanethioate) [ka]

[0289] To a solution containing decanethiol (0.72 g, 4.1 mmol) in anhydrous CH2Cl2 (10 mL) cooled to 0°C, trimethylaluminum (1 M toluene solution; 4.1 mL, 4.1 mmol) was added dropwise over 10 minutes, and the mixture was stirred for 20 minutes. Next, to the resulting reaction mixture, a solution containing compound (2) (2 g, 3.71 mmol) in anhydrous CH2Cl2 (12 mL) was slowly added over 10 minutes, and the mixture was stirred for 1 hour. The resulting reaction mixture was diluted with CH2Cl2 (20 mL) and added to a 250 mL beaker containing ice-cold water (20 mL). Then, 10 mL of 1 N HCl aqueous solution was slowly poured into the beaker while stirring, and phase separation was performed. The resulting aqueous phase was extracted with cold CH2Cl2 (3 × 30 mL). The organic phase, consisting of organic extracts, was washed with water and saline solution, dried over Na2SO4, and filtered through a flash silica column using CH2Cl2 as the eluent to obtain the crude product of compound (3) ((2R,3S,4R,5R)-S-decyl 2,3,4,6-tetrakis(benzoyloxy)-5-hydroxyhexanethioate). The crude product of compound (3) obtained thereafter was used in the next step without purification.

[0290] Example 3: Preparation of compound (4) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-(decylthio)-6-oxohexane-2-ylacetate) [ka]

[0291] To a solution containing the crude product of compound (3) (2.8 g, 3.71 mmol) in anhydrous CH2Cl2 cooled to 0°C under an argon atmosphere, acetic anhydride (Ac2O; 0.88 mL, 9.5 mmol) was added, followed by DMAP (9 mg, 2 mol%). After 5 minutes, triethylamine (1.32 mL, 9.5 mmol) was added to the resulting mixture, and the mixture was stirred under an argon atmosphere for 4 hours. The resulting reaction mixture was quenched with water (30 mL), and the organic phase was extracted with CH2Cl2 (3 × 30 mL). The organic phase, including the organic extracts, was washed with water (30 mL) and saline solution (30 mL), dried over anhydrous Na2SO4, and concentrated. The crude product obtained was purified by silica chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (4) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-(decylthio)-6-oxohexane-2-ylacetate; 2.6 g, yield 92% relative to compound (2)) as a colorless liquid.

[0292] Compound (4) IR (KBr):νmax=3063,3031,2926,2860,1745,1676,1452,1375,1244,1093,1069,745,696cm -1 1H-NMR(400MHz, CDCl3)δ:7.40(d,J=6.5Hz,2H),7.36-7.15(m,18H),5.15(q,J=4.3Hz,1H) ,4.79(d,J=10.8Hz,1H),4.71(d,J=11.4Hz,1H),4.65-4.39(m,6H),4.25(d,J=4.3Hz,1H) ,4.01-3.95(m,2H),3.82(dd,J=10.6,4.1Hz,1H),3.65(dd,J=10.6,5.7Hz,1H),2.84(t,J =7.4Hz,2H),1.96(s,3H),1.55(p,J=7.3Hz,2H),1.41-1.18(m,15H),0.88(t,J=6.7Hz,3H) 13 C-NMR(101MHz, CDCl3)δ:201.90,170.02,138.51,138.08,137.98,137.08,12 8.65,128.43,128.39,128.36,128.25,128.17,128.04,127.97,127.80,127. 71,127.59,127.53,85.28,80.31,78.45,75.71,74.67,74.53,73.23,72.91,68.06,31.95,29.61,29.55,29.36,29.20,29.05,28.39,22.74,21.11,14.18 HRMS [M+H] + C 46 H 59 O7S calculated value: 755.3981; measured value: 755.3976 Quality Analysis [M+H] + 755

[0293] Example 4: Nickel(II) acetylacetonate (Ni(acac) 2 Preparation of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate) using ))

change

[0294] In a Schlenk tube dried in a hot oven, compound (4) (0.25 mmol, 190 mg) was added under an argon atmosphere, followed by Ni(acac)2 (0.0125 mmol, 3.2 mg) and THF (2 mL). The resulting mixture was stirred for 5 minutes, and then a THF solution (0.125 M) of the organozinc compound and lithium chloride complex PhZnCl·LiCl (0.375 mmol, 3 mL) was added by syringe. The resulting reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then quenched with water and extracted with ethyl acetate (3 × 30 mL). The organic extract was washed with saline solution, dried over anhydrous Na2SO4, and concentrated. The crude product obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate; 105 mg, 0.16 mmol, yield 64%). In addition to compound (5), unreacted compound (4) (49 mg, 0.065 mmol, yield 26%) and the by-product biphenyl Ph-Ph (10 mg, 0.064 mmol, yield 35%) were also obtained.

[0295] Compound (5) IR (KBr):νmax=3027,2870,1735,1724,1449,1369,1236,1090,1027,738,696cm -1 1 H-NMR(400MHz,CDCl3)δ:7.92(d,J=7.8Hz,2H),7.47(t,J=7.4Hz,1H),7.37-7.22(m,15H), 7.21-7.11(m,5H),7.06-7.00(m,2H),5.27(q,J=5.2Hz,1H),4.89(d,J=4.2Hz,1H),4.73-4. 55(m,4H),4.53-4.46(m,3H),4.31(d,J=10.8Hz,1H),4.21(dd,J=6.8,4.3Hz,1H),4.07(dd ,J=6.8,3.4Hz,1H),3.87(dd,J=10.2,5.4Hz,1H),3.63(dd,J=10.2,5.5Hz,1H),1.98(s,3H) 13 C-NMR(101MHz, CDCl3)δ:198.88,169.94,138.43,137.88,137.77,137.10,136.05,133.06,128.96,128.76,128.45,128.35,128.31,128.2 6,128.19,128.05,127.92,127.80,127.73,127.70,127.49,127.45, 82.68,80.39,79.62,75.29,74.62,73.22,73.05,72.59,67.87,21.08 HRMS[M+H] + :C 42 H 43 O7 calculated value: 659.3009; measured value: 659.3004 Quality Analysis [M+H] + :659

[0296] Example 5: Nickel(II) dichloride (NiCl 2 Preparation of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate) using )

change

[0297] In a Schlenk tube dried in a hot oven, compound (4) (0.25 mmol, 190 mg) was added under an argon atmosphere, followed by NiCl2 (0.0125 mmol, 3.2 mg) and THF (2 mL). The resulting mixture was stirred for 5 minutes, and then a THF solution (0.125 M) of the Ph organozinc compound and lithium chloride complex ZnCl·LiCl (0.375 mmol, 3 mL) was added by syringe. The resulting reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then quenched with water and extracted with ethyl acetate (3 × 30 mL). The organic extract was washed with saline solution, dried over anhydrous Na2SO4, and concentrated. The crude product obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate; 96 mg, 0.145 mmol, yield 58%). In addition to compound (5), unreacted compound (4) (60 mg, 0.08 mmol, yield 32%) and the by-product biphenyl Ph-Ph (11.6 mg, 0.075 mmol, yield 40%) were also obtained.

[0298] Example 6: Nickel(II) dichloride (dimethoxyethane adduct) (NiCl 2 Preparation of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate) using (dme) [ka]

[0299] In a Schlenk tube dried in a hot oven, compound (4) (0.25 mmol, 190 mg) was added under an argon atmosphere, followed by NiCl2 (dme) (0.0125 mmol, 3 mg) and THF (2 mL). The resulting mixture was stirred for 5 minutes, and then a THF solution (0.125 M) of the organozinc compound and lithium chloride complex PhZnCl·LiCl (0.375 mmol, 3 mL) was added by syringe. The resulting reaction mixture was stirred at 25°C (room temperature) for 1 hour. The reaction mixture was then quenched with water and extracted with ethyl acetate (3 × 30 mL). The organic extract was washed with saline solution, dried over anhydrous Na2SO4, and concentrated. The crude product obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate; 99 mg, 0.15 mmol, yield 60%). In addition to compound (5), unreacted compound (4) (9 mg, 0.058 mmol, yield 31%) and the by-product biphenyl Ph-Ph (65 mg, 0.085 mmol, yield 34%) were also obtained.

[0300] Example 7: Study on nickel catalysts [ka]

[0301] Compound (5) was synthesized in THF (3 mL) using the same procedure as in Example 6, except that PhZnCl·LiCl was replaced with PhZnBr and NiCl2(dme) was replaced with the nickel catalyst (Ni cat.) or a combination of nickel catalyst and ligand shown in Table 1.

[0302] The results are shown in Table 1. The yield of compound (5) in test number 6, using the combination of nickel catalyst NiCl2(thf)2 and ligand PPh3, was higher than the yields in tests 1-5 and 7. [Table 1]

[0303] Furthermore, the yield of the by-product biphenyl Ph-Ph in test number 6 was 20%, which was lower than the yield of the by-product biphenyl Ph-Ph in tests 1-5 and 7.

[0304] Example 8: Study on ligands in nickel catalysts In tests 7-11 shown in Table 2, compound (5) was synthesized using the same procedure as in test 6 of Example 7, except that the ligand was changed to the one shown in Table 2. Furthermore, in test 12, compound (5) was synthesized using the same procedure as in test 11, except that the nickel catalyst NiCl2(thf)2 was changed to Ni(COD)2.

[0305] The results are shown in Table 2. The yield of compound (5) in tests 10, 11, and 12 using a bidentate phosphine ligand was higher than the yield in test 6.

[0306] [Table 2]

[0307] Furthermore, the yields of the by-product biphenyl Ph-Ph in tests 8, 9, 10, 11, and 12 using a bidentate phosphine ligand were 18%, 10%, 16%, 9%, and 14%, respectively, which were lower than the 20% yield in test 6 using a monodentate phosphine ligand.

[0308] Example 9: Investigation of reaction temperature in reaction systems using nickel catalysts In tests 13 and 14 shown in Table 3, compound (5) was synthesized using the same procedure as in test 11 of Example 8, except that the reaction temperature was changed to that shown in Table 3. Similarly, in tests 15 and 16, compound (5) was synthesized using the same procedure as in tests 11 and 14, except that the ligand dcype was changed to dcypt, respectively. The results are shown in Table 3.

[0309] The results are shown in Table 3. The yield of compound (5) in tests 11 and 15, conducted at a reaction temperature of 25°C, was higher than the yield in tests 13, 14, and 16, conducted at reaction temperatures of 0°C or 50°C.

[0310] [Table 3]

[0311] Furthermore, the yields of the by-product biphenyl Ph-Ph in tests 11 and 15, conducted at a reaction temperature of 25°C, were 9% and 16%, respectively, which were lower than the yields of the by-product biphenyl Ph-Ph in tests 13, 14, and 16, conducted at reaction temperatures of 0°C or 50°C. Example 10: Investigation of ligands in nickel catalysts In tests 17-19 shown in Table 4, compound (5) was synthesized using the same procedure as in test 11 of Example 8, except that the ligand was changed to the one shown in Table 4.

[0312] The results are shown in Table 4. The reaction was also confirmed to proceed in tests 17-19 using dipyridine-type ligands.

[0313] [Table 4]

[0314] The yields of the by-product biphenyl Ph-Ph in test numbers 17, 18, and 19 were 32%, 21%, and 18%, respectively.

[0315] Example 11: Preparation of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate) using Pd / C [ka]

[0316] In a Schlenk tube dried in a hot oven, compound (4) (0.25 mmol, 190 mg) was added under an argon atmosphere, followed by Pd / C (0.0025 mmol, 3 mg) and THF (2 mL). The resulting reaction mixture was stirred for 5 minutes, and then a THF solution (0.125 M) of the organozinc compound and lithium chloride complex PhZnCl·LiCl (0.375 mmol, 3 mL) was added by syringe. The resulting reaction mixture was stirred at 25°C (room temperature) for 24 hours. The reaction mixture was then quenched with water (1 mL), filtered through a Celite pad, and extracted with ethyl acetate (3 × 30 mL). The organic extract was washed with water and saline solution, dried over anhydrous Na₂SO₄, and concentrated. The crude product obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate; 110 mg, 0.167 mmol, yield 67%). In addition to compound (5), unreacted compound (4) (58 mg, 0.077 mmol, yield 31%) and the by-product biphenyl Ph-Ph (3 mg, 0.0187 mmol, yield 10%) were also obtained.

[0317] Example 12: Preparation of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate) using Pd / C [ka]

[0318] In a Schlenk tube dried in a hot oven, compound (4) (0.25 mmol, 190 mg) was added under an argon atmosphere, followed by Pd / C (0.05 mol, 6 mg) and THF (2 mL). The resulting reaction mixture was stirred for 5 minutes, and then a THF solution (0.125 M) of the organozinc compound and lithium chloride complex PhZnCl·LiCl (0.375 mmol, 3 mL) was added by syringe. The resulting reaction mixture was stirred at 40°C for 24 hours. The reaction mixture was then quenched with water (1 mL), filtered through a Celite pad, and extracted with ethyl acetate (3 × 30 mL). The organic extract was washed with water and saline solution, dried over anhydrous Na₂SO₄, and concentrated. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (5) (119 mg, 0.18 mmol, yield 72%). In addition, along with compound (5), unreacted compound (4) (49 mg, 0.065 mmol, yield 26%) and the by-product biphenyl Ph-Ph (5 mg, 0.032 mmol, yield 17%) were obtained.

[0319] Example 13: Examination of reaction conditions for a reaction system using Pd / C [ka]

[0320] In tests 20-25 shown in Table 5 below, compound (5) was synthesized using the same procedure as in Example 12, except that the organozinc compound, the presence or absence of additives, the reaction temperature, and the reaction time were changed as shown in Table 5. In tests 23 and 24, the additive (DMF) was added to the reaction mixture using a syringe after the PhZnCl·LiCl THF solution. In test 25, instead of the PhZnCl·LiCl THF solution, the additive (ZnBr2) was added to the reaction mixture using the THE solution containing PhZnBr and ZnBr2 as described in Example 20 below.

[0321] The results are shown in Table 5. Test number 25, which used PhZnBr as the organozinc compound and added ZnBr2, showed a higher yield of compound (5) compared to test numbers 20-24, which used PhZnCl·LiCl as the organozinc compound. [Table 5]

[0322] Example 14: Investigation of reaction conditions in a reaction system using Pd / C [ka]

[0323] In tests 20-25 in Table 6, compound (5) was synthesized using the same procedure as in Example 13, except that the organozinc compound or its amount, solvent, reaction time, and reaction temperature were changed as shown in Table 5.

[0324] The results are shown in Table 6. Tests 24 and 25, conducted at a reaction temperature of 60°C, showed a higher yield of compound (5) compared to tests 20-23, conducted at reaction temperatures of 40-50°C. Furthermore, test 25, using 2 equivalents of PhZnBr, showed a higher yield of compound (5) compared to test 24, using 1 equivalent of PhZnBr. [Table 6]

[0325] Example 15: Palladium(0) tetraxtriphenylphosphine complex (Pd(PPh 3 ) 4 Preparation of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate) using ) [ka]

[0326] In a Schlenk tube dried in a hot oven, compound (4) (0.25 mmol, 190 mg) was added under an argon atmosphere, followed by Pd(PPh3)4 (0.0125 mol, 15 mg) and THF (2 mL). The resulting reaction mixture was stirred for 5 minutes, and then a THF solution (0.125 M) of the organozinc compound and lithium chloride complex PhZnCl·LiCl (0.375 mmol, 3 mL) was added by syringe. The resulting reaction mixture was stirred at 40°C for 24 hours. The reaction mixture was then quenched with water (1 mL), filtered through a Celite pad, and extracted with ethyl acetate (3 × 30 mL). The organic extract was washed with water and saline solution, dried over anhydrous Na₂SO₄, and concentrated. The crude product obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 20 to 2 / 20) to obtain compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexane-2-ylacetate; 89 mg, 0.135 mmol, yield 54%). In addition, unreacted compound (4) (46 mg, 0.06 mmol, yield 24%) was obtained along with compound (5).

[0327] Example 16: Preparation of compound (6) (2,3,4,6-tetra-O-benzyl-1C-phenylglucose) [ka]

[0328] In a Schlenk tube dried in a hot oven, compound (5) (0.2 mmol, 132 mg) was added under an argon atmosphere, followed by sodium methoxide (0.02 mmol, 1 mg) and methanol (2 mL). The resulting reaction mixture was stirred at 25°C for 6 hours. The reaction mixture was then filtered through a silica layer and washed with methanol (3 × 20 mL). Next, the resulting solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 4 / 20 to 8 / 20) to obtain compound (6) (2,3,4,6-tetra-O-benzyl-1C-phenylglucose; 112 mg, 0.182 mmol, yield 91%) as a colorless liquid.

[0329] Compound (6) IR(KBr):νmax=3411,3027,2923,1590,1494,1452,1361,1212,1093,734,696cm -1 1 H-NMR(400MHz, CDCl3)δ:7.64(d,J=7.0Hz,2H),7.38-7.13(m,21H),6.97( d,J=6.1Hz,2H),4.95-4.81(m,3H),4.69-4.56(m,2H),4.51(d,J=12.3Hz,1 H),4.38(d,J=10.4Hz,1H),4.17(d,J=8.2Hz,1H),4.07(t,J=9.2Hz,1H),3. 84-3.79(m,3H),3.70(d,J=10.9Hz,1H),3.53(d,J=9.4Hz,1H),3.34(s,1H) 13 C-NMR(101MHz, CDCl3)δ:142.47,138.85,138.58,138.45,137.59,128.61,128.47,128.42,128.26,128.23,128.03,1 27.79,127.75,127.69,127.62,127.58,126.36,98.00,85.28,83.59,78.53,75.75,75.53,75.08,73.38,72.15,69.12 HRMS [MH] - :C 40 H 39 O6 calculated value: 615.2747; measured value: 615.2743 Quality Analysis [MH] - :615

[0330] Example 17: Preparation of compound (7) (3R,4S,5R-tribenzyloxy-6R-benzyloxymethyl-6S-phenyltetrahydropyran)

change

[0331] Triethylsilane (76 mg, 0.65 mmol) was added to a 3 mL acetonitrile solution of compound (6) (200 mg, 0.32 mmol) obtained in Example 1. The resulting solution was cooled to -40°C in a dry ice / acetone bath, and then a 1 mL methylene chloride solution of boron trifluoride ether complex (70 mg, 0.49 mmol) was added and the mixture was stirred at -40 to -30°C for 3 hours.

[0332] HPLC analysis of the reaction solution revealed that compound (6) was completely consumed, and a peak for compound (7) was observed.

[0333] Water (20 mL) was added to the reaction mixture, and the product was extracted with ethyl acetate (5 mL x 4). The organic extracts were combined and concentrated under reduced pressure. The concentrate was purified using a silica gel column (eluent: hexane / ethyl acetate = 10 / 1) to obtain compound (7) (3R,4S,5R-tribenzyloxy-6R-benzyloxymethyl-6S-phenyltetrahydropyran; 110 mg, yield 56%). The isomer ratio of compound (7) was β:α = 82 / 18.

[0334] HPLC conditions: Measurement wavelength: 210nm Flow rate: 1.0mL / min Mobile phase:acetonitrile:water = 90 / 10 → 100 / 0 (0 → 10, 20 min) Column temperature: 20℃ Filler: X Bridge, C18, 5mm, 4.8mm x 150mm) Retention time: β form 5.64min; α form 5.31min

[0335] Compound (7) 1 H-NMR(CDCl3)δ:3.50-3.55(m,1H),3.60-3.61(m,1H),3.73-3.82(m,5H),4.25(d,J=9.3Hz,1H),4 .36(d,J=10.3Hz,1H),4.55-4.68(m,3H),4.86-4.98(m,3H),6.91-6.93(m,2H),7.14-7.53(m,23H)

[0336] Example 18: Preparation of PhZnCl·LiCl, a complex of organozinc compounds and lithium chloride. [ka]

[0337] 372 mg, 15.3 mmol, 1.5 equivalents of shavings of Mg and lithium chloride (LiCl; 540 mg, 12.75 mmol, 1.25 equivalents) were placed in a 50 mL dry Schlenk tube containing a magnetic stirring bar, and the tube was placed in a glove box and dried with a hot gun. Next, argon was injected into a warm flask three times, and then 8 mL of dry THF and 0.1 mL of 1.0 M THF solution (1 mol%) were added at room temperature and stirred for 5-10 minutes. The Schlenk tube was then cooled to 0°C and 1.1 mL, 10.2 mmol, 1.0 equivalent of bromobenzene was added. The resulting reaction mixture was stirred at 0°C for 10 minutes, and then at room temperature for 2 hours to obtain a complex of Grignard reagent and lithium chloride (PhMgBr·LiCl). A complex of Grignard reagent and lithium chloride (PhMgBr·LiCl) was diluted with an appropriate amount of dry THF and titrated with LiCl and iodine to a concentration of approximately 1 M. The resulting solution containing the Grignard reagent-lithium chloride complex was added to a dry THF solution containing ZnCl2 (1 equivalent relative to the Grignard reagent) at room temperature, and the mixture was stirred for 15 minutes to obtain a 0.125 M solution containing the target complex PhZnCl·LiCl. The solution concentration was adjusted based on the titration concentration of the corresponding Grignard reagent and the dilution ratio after transmetallation.

[0338] Example 19: Production of phenyl zinc bromide (PhZnBr) [ka]

[0339] Phenylmagnesium bromide (Grignard reagent) was diluted with dry THF and titrated with LiCl and iodine to prepare a THF solution of Grignard reagent at a concentration of approximately 0.5 M. The obtained THF solution of Grignard reagent was added to a dry THF solution containing ZnBr2 (1 equivalent relative to the Grignard reagent) at 25°C and stirred for 1 hour to perform transmetrization, obtaining a THF solution containing 0.25 M PhZnBr. The solution concentration was adjusted based on the titration concentration of the corresponding Grignard reagent and the dilution ratio after transmetrization.

[0340] Example 20: Phenyl zinc bromide (PhZnBr) and zinc bromide (ZnBr) 2 Preparation of a THF solution containing ) A 0.5 M phenylmagnesium bromide (Grignard reagent) THF solution was added to a dry THF solution containing ZnBr2 at 25°C and stirred for 1 hour to perform transmetrization, obtaining a THF solution containing 0.25 M PhZnBr and ZnBr2 (0.1 equivalent excess relative to PhZnBr). The solution concentration was adjusted based on the titration concentration of the corresponding Grignard reagent and the dilution ratio after transmetrization.

Claims

1. The following formula (I): 【Chemistry 1】 [In the formula, R １ and R ２ Each of these independently represents a hydroxyl protecting group. R ３ and R ４ Each of the following independently represents a hydroxyl protecting group or a hydrogen atom, and Ar represents an organic group containing an aromatic hydrocarbon ring group or an aromatic heterocyclic group as a functional group bonded to the oxane ring in the formula, and the aromatic hydrocarbon ring group and the aromatic heterocyclic group may each have one or more substituents. A method for producing compound (I) represented by, Formula (II) below: 【Chemistry 2】 [In the formula, R １ ~R ４ This is synonymous with the above, R ５ represents a hydroxyl protecting group, provided that R １ excludes the same hydroxyl protecting group as the hydroxyl protecting group represented by and the same hydroxyl protecting group as the hydroxyl protecting group represented by R ２ .), Q represents an organic group containing an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, or an aromatic heterocyclic group as a functional group bonded to the sulfur atom in the formula, and each of the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may have one or more substituents. Compound (II) represented by, The following equation (III-I): 【Transformation 3】 [In the formula, Ar has the same meaning as above, and X represents a halogen atom.] Compounds represented by (III-I), and The following equation (III-II): 【Chemistry 4】 [In the formula, Ar has the same meaning as above.] Compound represented by (III-II) At least one organozinc compound selected from the group consisting of the following, The reaction is carried out in the presence of one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or in the presence of a supported catalyst having one or more transition metal catalysts and a carrier supporting the one or more transition metal catalysts, resulting in the following formula (IV): 【Transformation 5】 [In the formula, R １ ~R ５ And Ar are synonymous with the above. A step to obtain a compound (IV) represented by, and From the above compound (IV) to R ５ A step to remove the hydroxyl protecting group represented by to obtain compound (I). A method that includes the following:

2. The method according to claim 1, wherein the reaction between compound (II) and the at least one organozinc compound is carried out at 0 to 80°C.

3. The method according to claim 1 or 2, wherein the supported catalyst comprises at least one carrier selected from the group consisting of activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite, and hydrotalcite, and a palladium catalyst supported on the carrier.

4. The at least one organozinc compound includes the compound (III-I), The aforementioned compound (III-I) is given by the following formula: 【Transformation 6】 [In the formula, Ar and X are as defined above.] The method according to any one of claims 1 to 3, wherein the Schlenk equilibrium state is represented by the Schlenk equilibrium state.

5. R ３ and R ４ The method according to any one of claims 1 to 4, wherein represents a hydroxyl protecting group.

6. R ５ The hydroxyl protecting group represented by R １ ~R ４ The method according to any one of claims 1 to 5, which is different from the hydroxyl protecting group represented by

7. R １ ~R ５ The method according to any one of claims 1 to 6, wherein the hydroxyl protecting group represented by is independently selected from the group consisting of an ester protecting group, an arylalkyl protecting group, an alkyl protecting group, an arylalkyloxyalkyl protecting group, an alkyloxyalkyl protecting group, a silyl protecting group, and an oxycarbonyl protecting group.

8. The method according to any one of claims 1 to 7, wherein the organic group represented by Q includes an alkyl group, an alkenyl group, an alkynyl group, or an aryl group as a functional group bonded to the sulfur atom in the formula, and the alkyl group, the alkenyl group, the alkynyl group, and the aryl group may each have one or more substituents.

9. The method according to any one of claims 1 to 8, wherein the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, or the one or more substituents that the aromatic heterocyclic group may have contained in the organic group represented by Q are each independently selected from the group consisting of a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, and an optionally protected sulfonyl group.

10. The method according to any one of claims 1 to 9, wherein the organic group represented by Ar is an organic group containing an aromatic hydrocarbon ring group having 6 to 14 carbon atoms or an aromatic heterocyclic group having 3 to 12 carbon atoms as a functional group bonded to the oxane ring in the formula, and the aromatic hydrocarbon ring group having 6 to 14 carbon atoms and the aromatic heterocyclic group having 3 to 12 carbon atoms may each have one or more substituents.

11. The organic group represented by Ar is shown in the following formula (V): 【Transformation 7】 [In the formula, R ａ Each of these independently represents a functional group selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an arylalkyloxy group, an arylalkenyloxy group, and an arylalkynyloxy group, and each of the alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl group, arylalkenyloxy group, aryl group, alkyloxy group, arylalkynyloxy group, and arylalkynyloxy group may have one or more substituents. n is an integer between 0 and 4. Ar' represents an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, or an aromatic heterocyclic group, and each of the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may have one or more substituents. The method according to any one of claims 1 to 10, as represented by the following:

12. R ａ The method according to claim 11, wherein each of the functional groups represented is independently selected from alkyl groups and halogen atoms, and the alkyl group may have one or more substituents.

13. The organic group represented by Ar is given by the following formula (Va): 【Transformation 8】 [In the formula, R ａ This is synonymous with the above, Ar' is given by the following formulas (Va-I), (Va-II), and (Va-III): 【Chemistry 9】 [In the formula, R ｂ Each of these independently represents a functional group selected from the group consisting of an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic ring may each have one or more substituents, and p represents an integer from 0 to 5. This represents a functional group selected from the group consisting of [the specified elements]. The method according to claim 11 or 12, as represented by the following:

14. R ｂ The method according to claim 13, wherein each of the functional groups represented is independently selected from the group consisting of a C1-C20 alkyl group, a C2-C20 alkenyl group, a C2-C20 alkynyl group, a C6-C14 aromatic hydrocarbon ring group, a C2-C12 aliphatic heterocyclic group, and a C3-C12 aromatic heterocyclic group, and each of the alkyl group, the alkenyl group, the alkynyl group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may have one or more substituents.

15. The method according to any one of claims 1 to 14, wherein the one or more substituents that the aromatic hydrocarbon ring group or aromatic heterocyclic group contained in the organic group represented by Ar may have are each independently selected from the group consisting of a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, an optionally protected sulfonyl group, an alkyl group, an alkenyl group, and an alkynyl group.

16. The following formula (VI): 【Chemistry 10】 [In the formula, R １ ~R ４ This is synonymous with the above. Compound (VI) represented by, The following formula (VII): 【Chemistry 11】 [In the formula, Q has the same meaning as above.] The compound (VII) represented by the following formula (VIII) is reacted with the compound (VII) to produce the following: 【Chemistry 12】 [In the formula, R １ ~R ４ This is synonymous with the above. A step to obtain a compound (VIII) represented by, and The hydroxyl group in the above compound (VIII) is R ５ The step of protecting with to obtain the compound (II). The method according to any one of claims 1 to 15, further comprising:

17. The method according to claim 16, wherein the reaction between compound (VI) and compound (VII) is carried out at -30 to 40°C.

18. The reaction between compound (VI) and compound (VII) is given by the following formula (IX): 【Chemistry 13】 [In the formula, R ｃ and R ｄ Each of these independently represents a functional group selected from the group consisting of a halogen atom, an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group, and each of the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may have one or more substituents. q represents an integer between 0 and 3. r represents an integer between 0 and 3, where q + r = 3. The method according to claim 16 or 17, carried out in the presence of a compound represented by (IX).

19. R ｃ and R ｄ The method according to claim 18, wherein each of the functional groups represented is independently selected from the group consisting of alkyl groups, aryl groups, and arylalkyl groups, and each of the alkyl groups, aryl groups, and arylalkyl groups may have one or more substituents.

20. Formula (II) below: 【Chemistry 14】 [In the formula, R １ ~R ５ And Q are synonymous with the above. The compound (II) represented by the following formula (XI): 【Chemistry 15】 [In the formula, Ar is the same as above, R １ '~R ４ Each of these independently represents either a hydrogen atom or a hydroxyl protecting group. A reagent for producing compound (XI) represented by [formula].

21. Compound (XI) of the following formula: 【Chemistry 16】 [In the formula, Ar and R １ '~R ４ ' is synonymous with the above.' As a manufacturing intermediate for compound (XI) represented by, Formula (II) below: 【Chemistry 17】 [In the formula, R １ ~R ５ And Q are synonymous with the above. The use of compound (II) represented by .

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