WO2020129899A1

WO2020129899A1 - Method for producing c-aryl hydroxy glycoxide derivatives

Info

Publication number: WO2020129899A1
Application number: PCT/JP2019/049174
Authority: WO
Inventors: 雅彦関; 真島　和志; 隼人劒; ジャリンダバウサヘブタルデ
Original assignee: 株式会社トクヤマ
Priority date: 2018-12-17
Filing date: 2019-12-16
Publication date: 2020-06-25
Also published as: TW202039428A

Abstract

In order to provide a method for the economical and efficient industrial production of C-aryl hydroxy glycoxide derivatives, the present invention provides a method for producing a C-aryl hydroxy glycoxide derivative represented by formula (I), the method comprising: a step for reacting a compound (II), which is represented by formula (II), with an organic zinc compound in the presence of a nickel catalyst or a palladium catalyst in order to obtain a reaction product; and a step for removing R⁵ from the reaction product to obtain the C-aryl hydroxy glycoxide derivative.

Description

Process for producing C-aryl hydroxyglycoxide derivative

Reference to related applications

This patent application is accompanied by a priority claim based on Japanese Patent Application 2018-235903 filed on December 17, 2018 and Japanese Patent Application 2019-34357 filed on February 27, 2019. The entire disclosure of the above patent application is incorporated herein by reference.

The present invention relates to a method for producing a C-arylhydroxyglycoxide derivative, and more particularly to a method for producing a C-arylhydroxyglycoxide derivative useful as an intermediate for an SGLT-2 inhibitor.

Currently, various therapeutic agents are marketed as antidiabetic agents, including sulfonylurea drugs, glinide drugs, biguanide drugs, thiazolidine drugs, α-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucose-like peptides. 1 (GLP-1) passive agonists are known. Further, in recent years, a sodium-glucose cotransporter-2 (hereinafter, also referred to as SGLT-2) inhibitor has been developed and attracted attention as a novel therapeutic drug for diabetes.

Examples of SGLT-2 inhibitors include canagliflozin (1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene) and the like. As a method for producing these compounds, the oxygen protecting group of the 1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor is deprotected. It has been proposed to synthesize canagliflozin (Patent Document 1). This 1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor is also referred to as a C-aryl hydroxyglycoxide derivative, and SGLT-2 It has been drawing attention as an intermediate for producing an inhibitor (see Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Patent Document 1 and Patent Document 2).

Various proposals have been made as a method for producing the above-mentioned C-arylhydroxyglycoxide derivative, for example, a method in which aryllithium is allowed to act on a D-gluconolactone derivative at an ultralow temperature of −78° C. to cause an addition reaction of an aryl group. (Non-Patent Documents 1 and 3), an aryl group is added to a D-gluconolactone derivative at a low temperature of −20 to −10° C. by using a turbo-Grignard reagent such as ArMgBr·LiCl (Ar is an aryl group). A reaction method (Non-Patent Document 2), and further, using a magnesium ate complex obtained from lithium tri-n-butylmagnesate (nBu ₃ MgLi), D-gluconolactone under a temperature environment of about −15° C. A method of adding an aryl group to a derivative (Patent Document 2) and the like are known.

By the way, it has been reported that a ketone derivative can be obtained by reacting an organic zinc reagent with a thioester derivative in the presence of a nickel catalyst to obtain a ketone derivative (Non-Patent Documents 4 and 5).

WO2010/043682 WO2015/012110

All of the methods used before in the production of C-aryl hydroxyglycoxide derivatives require the use of expensive reagents under severe low temperature conditions, resulting in extremely high equipment costs and running costs, and the final drug substance. It was difficult to mass-produce them at low cost.

Therefore, one object of the present invention is to provide a method for industrially inexpensively and efficiently producing a C-aryl hydroxyglycoxide derivative.

The present inventors have recently conducted a cross-coupling reaction with a specific raw material in the presence of a nickel catalyst or a palladium catalyst, and further carried out a cyclization reaction, so that the C-aryl hydroxyglycoxide derivative is industrially inexpensive and efficient. It has been found that a compound (I) represented by the following formula (I) can be produced, and the present invention has been completed.

According to the present invention, the following inventions are provided.
[1] The following formula (I):

[In the formula,
R ¹ and R ² each independently represent a hydroxyl-protecting group,
R ³ and R ⁴ each independently represent a hydroxyl group-protecting group or a hydrogen atom, and Ar contains an aromatic hydrocarbon ring group or an aromatic heterocyclic group as a functional group that bonds to the oxane ring in the formula. It represents an organic group, and the aromatic hydrocarbon ring group and the aromatic heterocyclic group each may have one or more substituents. ]
A method for producing a compound (I) represented by
Formula (II) below:

[In the formula,
R ¹ to R ⁴ are as defined above,
R ⁵ represents a hydroxyl protecting group (however, the same hydroxyl protecting group as the hydroxyl protecting group represented by R ¹ and the same hydroxyl protecting group as the hydroxyl protecting group represented by R ² are excluded);
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 bonding to the sulfur atom in the formula, and the aliphatic carbon group Each of the hydrogen group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group may have one or more substituents. ]
A compound (II) represented by
The following formula (III-I):

[In the formula, Ar has the same meaning as described above, and X represents a halogen atom. ]
A compound (III-I) represented by
Formula (III-II) below:

[In the formula, Ar has the same meaning as described above. ]
Compound (III-II) represented by
At least one organozinc compound selected from the group consisting of:
In the presence of one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or a supported catalyst having the one or more transition metal catalysts and a carrier carrying the one or more transition metal catalysts. After reaction, the following formula (IV):

[In the formula, R ¹ to R ⁵ and Ar have the same meanings as described above. ]
And a step of removing the hydroxyl-protecting group represented by R ⁵ from the compound (IV) to obtain the compound (I).
[2] The method according to [1], wherein the reaction of the compound (II) with the at least one organozinc compound is performed at 0 to 60°C.
[3] The supported catalyst has 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. The method according to [1] or [2].
[4] The at least one organozinc compound contains the compound (III-I),
The compound (III-I) has the following formula:

[In the formula, Ar and X are as defined above. ]
The method according to any one of [1] to [3], which is in a Schlenk equilibrium state represented by.
[5] The method according to any one of [1] to [4], wherein R ³ and R ⁴ represent a hydroxyl-protecting group.
[6] The method according to any one of [1] to [5], wherein the hydroxyl group-protecting group represented by R ⁵ is different from the hydroxyl group-protecting group represented by R ¹ to R ⁴ .
[7] The hydroxyl group-protecting groups represented by R ¹ to R ⁵ are each independently an ester-type protecting group, an arylalkyl-type protecting group, an alkyl-type protecting group, an arylalkyloxyalkyl-type protecting group, an alkyloxyalkyl-type protecting group. The method according to any one of [1] to [6], which is selected from the group consisting of a protecting group, a silyl type protecting group and an oxycarbonyl type protecting group.
[8] The organic group represented by Q contains an alkyl group, an alkenyl group, an alkynyl group or an aryl group as a functional group that bonds to a sulfur atom in the formula, and the alkyl group, the alkenyl group, the alkynyl group and The method according to any one of [1] to [7], wherein each of the aryl groups may have one or more substituents.
[9] The 1 which the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group or the aromatic heterocyclic group contained in the organic group represented by Q may have. Or more substituents, each independently, a halogen atom, a hydroxyl group which may be protected, a thiol group which may be protected, an amino group which may be protected, a formyl group which may be protected, The method according to any one of [1] to [8], which is selected from the group consisting of an optionally protected carboxyl group and an optionally protected sulfonyl group.
[10] The organic group represented by Ar contains 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 that bonds to the oxane ring in the formula. An organic group, wherein the aromatic hydrocarbon ring group having 6 to 14 carbon atoms and the aromatic heterocyclic group having 3 to 12 carbon atoms each may have one or more substituents, [1] ~ The method according to any one of [9].
[11] The organic group represented by Ar has the following formula (V):

[In the formula,
R ^a is each independently 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, or aryloxy. Group, an arylalkyloxy group, an arylalkenyloxy group and a functional group selected from the group consisting of an arylalkynyloxy group, the alkyl group, the alkenyl group, the alkynyl group, the aryl group, the arylalkyl group, the The arylalkenyl group, the arylalkynyl group, the alkyloxy group, the alkenyloxy group, the alkynyloxy group, the aryloxy group, the arylalkyloxy group, the arylalkenyloxy group and the arylalkynyloxy group are each 1 May have one or more substituents,
n is an integer of 0 to 4,
Ar′ represents an aromatic hydrocarbon ring group, an aliphatic heterocyclic group or an aromatic heterocyclic group, wherein the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group are each 1 It may have the above substituents. ]
The method according to any one of [1] to [10], which is represented by:
[12] In [11], the functional group represented by ^Ra is independently selected from an alkyl group and a halogen atom, and the alkyl group may have one or more substituents. The method described.
[13] The organic group represented by Ar has the following formula (Va):

[In the formula,
^Ra is as defined above,
Ar' is represented by the following formulas (Va-I), (Va-II) and (Va-III):

[Wherein each R ^b 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 heterocycle each may have one or more substituents, and p is an integer of 0 to 5 Represents. ]
Represents a functional group selected from the group consisting of: ]
The method according to [11] or [12], which is represented by:
[14] The functional groups represented by R ^b are each independently an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, and a carbon number of 6 to 14 An aromatic hydrocarbon ring group, an aliphatic heterocyclic group having 2 to 12 carbon atoms, and an aromatic heterocyclic group having 3 to 12 carbon atoms, the alkyl group, the alkenyl group, the alkynyl group, The method according to [13], wherein each of the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group may have one or more substituents.
[15] Each of the one or more substituents optionally contained in the aromatic hydrocarbon ring group or the aromatic heterocyclic group contained in the organic group represented by Ar is independently a halogen atom. , Optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected The method according to any one of [1] to [14], which is selected from the group consisting of a good sulfonyl group, an alkyl group, an alkenyl group and an alkynyl group.
[16] The following formula (VI):

[In the formula, R ¹ to R ⁴ have the same meanings as described above. ]
A compound (VI) represented by
The following formula (VII):

[In the formula, Q has the same meaning as described above. ]
By reacting with a compound (VII) represented by the following formula (VIII):

[In the formula, R ¹ to R ⁴ have the same meanings as described above. ]
Any of [1] to [15], further comprising a step of obtaining a compound (VIII) represented by: and a step of protecting the hydroxyl group in the compound (VIII) with R ⁵ to obtain the compound (II). The method described in crab.
[17] The method according to [16], wherein the reaction between the compound (VI) and the compound (VII) is performed at -30 to 40°C.
[18] The reaction of the compound (VI) with the compound (VII) can be carried out by the following formula (IX):

[In the formula,
R ^c and R ^d each independently represent 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. The aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group each may have one or more substituents,
q represents an integer of 0 to 3,
r represents an integer of 0 to 3, provided that q+r=3. ]
The method according to [16] or [17], which is performed in the presence of the compound (IX) represented by:
[19] The functional groups represented by R ^c and R ^d are each independently selected from the group consisting of an alkyl group, an aryl group and an arylalkyl group, and the alkyl group, the aryl group and the arylalkyl group are each The method according to [18], each of which may have one or more substituents.
[20] The following formula (II):

[In the formula, R ¹ to R ⁵ and Q have the same meanings as described above. ]
A compound represented by the following formula (XI):

[In the formula, Ar has the same meaning as described above, and R ¹ ′ to R ⁴ ′ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ]
A reagent for producing a compound (XI) represented by:
[21] The following compound (XI):

[In the formula, Ar and R ¹ ′ to R ⁴ ′ have the same meanings as described above. ]
As an intermediate for the production of compound (XI) represented by
Formula (II) below:

[In the formula, R ¹ to R ⁵ and Q have the same meanings as described above. ]
Use of the compound (II) represented by:

According to the present invention, compound (I) can be industrially manufactured at low cost and efficiently. According to the present invention, equipment costs and running costs can be significantly reduced, which is advantageous in industrial production.

The present invention will be described below. When two or more embodiments among the embodiments described in the present specification can be combined, the present invention also includes the combination.

<Definition>
Hereinafter, terms and expressions used in this specification will be described. The following definitions apply throughout the specification, unless otherwise specified. For example, the definition of "alkyl group" also applies to functional groups containing "alkyl" or "alkyl groups" (eg, alkylaryl groups, arylalkyl groups, etc.).

“Organic group” means a functional group containing one or more carbon atoms. The organic group can contain one or more heteroatoms. "Heteroatom" means atoms other than hydrogen and carbon atoms. Examples of the hetero atom include a nitrogen atom, an oxygen atom, a sulfur atom, a halogen atom, a silicon atom and the like. “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The bond of the organic group is preferably formed of a bond of a carbon atom contained in the organic group.

In one embodiment, the organic group is an aliphatic hydrocarbon group which may have one or more substituents, or an aliphatic hydrocarbon group which may have one or more substituents. Including a group. In this embodiment, the bond of the organic group is preferably formed of the bond of an aliphatic hydrocarbon group.

In another embodiment, the organic group is an aromatic hydrocarbon ring group which may have one or more substituents, or an aromatic hydrocarbon ring which may have one or more substituents. Contains a hydrocarbon ring group. In this embodiment, the bond of the organic group is preferably formed of the bond of the aromatic hydrocarbon ring group.

In another embodiment, the organic group is an aliphatic heterocyclic group which may have one or more substituents, or an aliphatic heterocyclic group which may have one or more substituents. Including a ring group. In this embodiment, the bond of the organic group is preferably formed of the bond of the aliphatic heterocyclic group.

In another embodiment, the organic group is an aromatic heterocyclic group optionally having one or more substituents, or an aromatic heterocyclic group optionally having one or more substituents. Including a ring group. In this embodiment, the bond of the organic group is preferably formed of the bond of the aromatic heterocyclic group.

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

“Aliphatic hydrocarbon group” means a functional group (hydrocarbon group having no aromaticity) produced by removing a hydrogen atom from an aliphatic hydrocarbon. "Aliphatic hydrocarbon group" may mean a monovalent or divalent functional group depending on the context. Hereinafter, the monovalent aliphatic hydrocarbon group may be referred to as "-aliphatic hydrocarbon group" and the divalent aliphatic hydrocarbon group may be referred to as "-aliphatic hydrocarbon group-". The aliphatic hydrocarbon group may be linear, cyclic or a combination thereof. The chain may be a straight chain or a branched chain. The aliphatic hydrocarbon group is preferably linear or branched. The aliphatic hydrocarbon group may be saturated or unsaturated. The unsaturated bond may be a carbon-carbon double bond or a carbon-carbon triple bond.

Examples of the monovalent aliphatic hydrocarbon group include an alkyl group, an alkenyl group and an alkynyl group. Examples of the divalent aliphatic hydrocarbon group include an alkylene group, an alkenylene group, an alkynylene group and the like.

“Alkyl group” means a monovalent functional group generated by removing one hydrogen atom from an alkane. The alkyl group may be linear, cyclic or a combination thereof. The cyclic alkyl group has the same meaning as the "cycloalkyl group". The chain may be a straight chain or a branched chain. The alkyl group is preferably linear or branched. The carbon number of the linear alkyl group is usually 1 to 20, preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, and even more preferably 1 to 4, More preferably, it is 1 to 3. The number of carbon atoms of the branched alkyl 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. is there. The carbon number of the cyclic alkyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6. The number of carbon atoms of the 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. Is.

Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, isohexyl group, heptyl group, 4 , 4-Dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group, nonyl group, decyl group and other linear or branched alkyl groups; cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group , A cycloalkyl group such as a cycloheptyl group and a cyclooctyl group; having a linear or branched chain portion such as a cyclopentylmethyl group, a cyclopentylethyl group, a cyclopentylpropyl group, a cyclohexylmethyl group, and a cyclohexylethyl group, and a cyclic portion An alkyl group etc. are mentioned.

“Alkenyl group” means a monovalent functional group formed by removing one hydrogen atom from an alkene. An alkenyl group has at least one carbon-carbon double bond. The alkenyl group may be linear, cyclic or a combination thereof. The cyclic alkenyl group has the same meaning as "cycloalkenyl group". The chain may be a straight chain or a branched chain. The alkenyl group is preferably linear or branched. The number of carbon atoms of the 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. is there. The number of carbon atoms of the 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. is there. The carbon number of the cyclic alkenyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6. The number of carbon atoms of the alkenyl 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. Is. The number of double bonds in the alkenyl group is usually 1 to 9, preferably 1 to 7, more preferably 1 to 4, and even more preferably 1 to 3.

Examples of the alkenyl group include a vinyl group, 2-propenyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group, 2-hexenyl group, 3-hexenyl group, 2-heptenyl group, Linear or branched alkenyl groups such as 3-heptenyl group, 4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group; cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group Cyclic alkenyl groups such as groups, cycloheptenyl groups, cyclooctenyl groups; linear or branched moieties such as cyclopentenylmethyl groups, cyclopentenylethyl groups, cyclopentenylpropyl groups, cyclohexenylmethyl groups, cyclohexenylethyl groups and cyclic groups And an alkenyl group having a moiety.

“Alkynyl group” means a monovalent functional group generated by removing one hydrogen atom from an alkyne. An alkynyl group has at least one carbon-carbon triple bond. The alkynyl group may be linear, cyclic or a combination thereof. The cyclic alkynyl group has the same meaning as the "cycloalkynyl group". The chain may be a straight chain or a branched chain. The alkynyl group is preferably linear or branched. The number of carbon atoms of the linear alkynyl 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. is there. The branched alkynyl group has usually 4 to 20 carbon atoms, preferably 4 to 10 carbon atoms, more preferably 4 to 8 carbon atoms, and still more preferably 4 to 6 carbon atoms. The carbon number of the cyclic alkynyl group is usually 4 to 20, preferably 4 to 10, more preferably 4 to 8, and even more preferably 4 to 6. The number of carbon atoms of the 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. Is. 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.

Examples of the alkynyl group include 2-propynyl group, 3-butynyl group, 2-butynyl group, 4-pentynyl group, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group. Group, linear or branched alkynyl group such as 4-heptynyl group, 3-octynyl group, 3-nonynyl group and 4-decynyl group; cyclic such as cyclobutynyl group, cyclopentynyl group, cycloheptynyl group and cyclooctynyl group An alkynyl group having a linear or branched portion such as a cyclopentynylmethyl group, a cyclopentenylethyl group, a cyclopentynylpropyl group, a cyclopentynylmethyl group, a cyclopentynylethyl group and a cyclic portion. Etc.

“Alkylene group” means a divalent functional group formed by removing one hydrogen atom from an alkyl group. The description on the alkyl group is the same as above.

“Alkenylene group” means a divalent functional group formed by removing one hydrogen atom from an alkenyl group. The description on the alkenyl group is the same as above.

“Alkynylene group” means a divalent functional group formed by removing one hydrogen atom from an alkynyl group. The description on the alkynyl group is the same as above.

“Aromatic hydrocarbon ring group” means a functional group formed by removing a hydrogen atom from an aromatic hydrocarbon ring. “Aromatic hydrocarbon ring group” may mean a monovalent or divalent functional group, depending on the context. Hereinafter, the monovalent aromatic hydrocarbon ring group may be referred to as "-aromatic hydrocarbon ring group" and the divalent aromatic hydrocarbon ring group may be referred to as "-aromatic hydrocarbon ring group-". The monovalent aromatic hydrocarbon ring group has the same meaning as the "aryl group", and the divalent aromatic hydrocarbon ring group has the same meaning as the "arylene group".

The aromatic hydrocarbon ring group includes, for example, a monocyclic or polycyclic (eg, bicyclic or tricyclic) aromatic carbohydrogen ring group. The aromatic hydrocarbon ring group is usually 1 to 4 ring type, preferably 1 to 3 ring type, and more preferably 1 or 2 ring type. The number of ring-constituting carbon atoms in the aromatic hydrocarbon ring group is usually 6 to 18, preferably 6 to 14, and more preferably 6 to 10.

Examples of the monocyclic aromatic carbon-hydrogen ring group include a phenyl group.

The aromatic hydrocarbon ring group also includes a condensed polycyclic aromatic hydrocarbon ring group and a partially saturated condensed polycyclic aromatic hydrocarbon ring group. The partially saturated fused polycyclic aromatic hydrocarbon ring group is a fused polycyclic aromatic hydrocarbon ring group in which some of the bonds constituting the ring are hydrogenated. Examples of the condensed polycyclic aromatic hydrocarbon ring group include, for example, naphthenyl group, anthryl group, phenanthrenyl group, tetracenyl group, pyrenyl group, and other 2- to 4-cyclic aromatic carbon-hydrogen ring groups, and fluorenyl group. , Indenyl group, acenaphthylenyl and the like. Examples of the partially saturated fused polycyclic aromatic hydrocarbon ring group include a dihydronaphthyl group, an indanyl group, an acenaphthenyl group and the like.

The divalent aromatic hydrocarbon ring group is a divalent functional group produced by removing one hydrogen atom from the monovalent aromatic hydrocarbon ring group. The description on the monovalent aromatic hydrocarbon ring group is the same as above. Examples of the divalent aromatic hydrocarbon ring group include a 1,3-phenylene group and a 1,4-phenylene group.

“Aliphatic heterocyclic group” means, as a ring-constituting atom, a monocyclic group containing, in addition to a carbon atom, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or It means a functional group formed by removing a hydrogen atom from a polycyclic (eg, bicyclic or tricyclic) aliphatic heterocycle (non-aromatic heterocycle). The “aliphatic heterocyclic group” may mean a monovalent or divalent functional group depending on the context. Hereinafter, the monovalent aliphatic heterocyclic group may be referred to as "-aliphatic heterocyclic group", and the divalent aliphatic heterocyclic group may be referred to as "-aliphatic heterocycle-". The “aliphatic heterocycle” in the functional group containing “aliphatic heterocycle” (eg, aliphatic heterocyclic thio group, aliphatic heterocyclic oxy group, etc.) means an aliphatic heterocyclic group.

The number of heteroatoms contained in the aliphatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of the aliphatic heterocyclic group is usually 3 to 16 members, preferably 4 to 10 members, more preferably 5 to 8 members, still more preferably 5 to 7 members, still more preferably 5 or 6 members. The aliphatic heterocyclic group is, for example, monocyclic, bicyclic or tricyclic, 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 of 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.

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

Examples of the monocyclic aliphatic heterocyclic group include an aziridinyl group, an oxiranyl group, a thiylanyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a tetrahydrothienyl group, a tetrahydrofuranyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolinyl group, and an imidazolidinyl group. Group, oxazolinyl group, oxazolidinyl group, pyrazolinyl group, pyrazolidinyl group, thiazolinyl group, thiazolidinyl group, tetrahydroisothiazolyl group, tetrahydrooxazolyl group, tetrahydroisoxazolyl group, piperidinyl group, piperazinyl group, tetrahydropyridinyl group , Dihydropyridinyl group, dihydrothiopyranyl group, tetrahydropyrimidinyl group, tetrahydropyridazinyl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group (sulfur on the ring Atom may be oxidized), a azepanyl group, a diazepanyl group, an azepinyl group, an oxepanyl group, an azocanyl group, a diazocanyl group and the like, and a 3- to 8-membered monocyclic aliphatic heterocyclic group.

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

The polycyclic aliphatic heterocyclic group is, for example, a condensed polycyclic aliphatic heterocyclic group. The condensed polycyclic aliphatic heterocyclic group is, for example, a condensed polycyclic saturated aliphatic heterocyclic ring. The condensed polycyclic saturated aliphatic heterocyclic ring is a condensed polycyclic aliphatic heterocyclic group in which the ring is composed of only saturated bonds. In one embodiment, the fused polycyclic saturated aliphatic heterocyclic group contains 1-3 oxygen atoms. In another embodiment, the fused polycyclic saturated aliphatic heterocyclic group contains 1-3 sulfur atoms. In another embodiment, the fused polycyclic saturated aliphatic heterocyclic group contains 1-3 oxygen atoms and 1-3 sulfur atoms. In another embodiment, the fused polycyclic saturated aliphatic heterocyclic group contains 1-5 nitrogen atoms. In another embodiment, the fused polycyclic saturated aliphatic heterocyclic group contains 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms. In the fused polycyclic saturated aliphatic heterocyclic group, two carbon atoms constituting the ring may be bridged with an alkylene group. In the fused polycyclic saturated aliphatic heterocyclic group, two adjacent carbon atoms among the carbon atoms constituting the ring may form a double bond. In the fused polycyclic saturated aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group. The number of oxo groups that the fused polycyclic aliphatic heterocyclic group may have is preferably 1, 2 or 3. When the heteroatom contained in the condensed polycyclic saturated aliphatic heterocyclic group is a sulfur atom, the condensed polycyclic saturated aliphatic heterocyclic group may be a dioxide.

Examples of the condensed polycyclic aliphatic heterocyclic group include octahydro-1H-isoindolyl group, decahydroquinolyl group, decahydroisoquinolyl group, hexahydro-2H-[1,4]dioxino[2,3-c ] Pyrrolyl group, 3-azabicyclo[3.1.0]hex-3-yl group and the like.

The aliphatic heterocyclic group also includes a spiro cyclic heterocyclic group. A spirocyclic heterocyclic group is a heterocyclic group formed by two rings sharing one spiro carbon atom. Examples of the combination of two rings include a combination of a monocyclic aliphatic heterocyclic group and a monocyclic aliphatic hydrocarbon ring group (eg, cycloalkyl group, cycloalkenyl group, etc.), monocyclic And the like, and a combination of the aliphatic heterocyclic group and the monocyclic aliphatic heterocyclic group. In the spiro cyclic heterocyclic group, two adjacent carbon atoms of the ring-constituting carbon atoms may form a double bond. In the spiro cyclic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group. The number of oxo groups that the spirocyclic heterocyclic group may have is preferably 1, 2 or 3. When the heteroatom contained in the spiro cyclic heterocyclic group is a sulfur atom, the spiro cyclic heterocyclic group may be in a dioxide form.

Examples of the spiro cyclic heterocyclic group include, for example, 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, Examples thereof include a 1-oxaspiro[4.5]decanyl group.

The "aromatic heterocyclic group" is, as a ring-constituting atom, a monocyclic group containing, in addition to a carbon atom, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or It means a functional group formed by removing a hydrogen atom from a polycyclic aromatic heterocycle. The "aromatic heterocyclic group" may mean a monovalent or divalent functional group depending on the context. Hereinafter, the monovalent aromatic heterocyclic group may be referred to as "-aromatic heterocyclic group" and the divalent aromatic heterocyclic group may be referred to as "-aromatic heterocyclic group-". The monovalent aromatic heterocyclic group has the same meaning as the “heteroaryl group”, and the divalent aromatic heterocyclic group has the same meaning as the “heteroarylene group”.

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

The aromatic heterocyclic group is, for example, a monocyclic aromatic heterocyclic group. In one embodiment, the monocyclic aromatic heterocyclic group contains 1-2 oxygen atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1-2 sulfur atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1-2 oxygen atoms and 1-2 sulfur atoms. In another embodiment, a monocyclic aromatic heterocyclic group contains 1 to 4 nitrogen atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1-3 nitrogen atoms, 1-2 sulfur atoms and/or 1-2 oxygen atoms.

Examples of the monocyclic aromatic heterocyclic group include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, Isoxazolyl group, oxadiazolyl group (eg, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, etc.), thiadiazolyl group (eg, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group) Etc.), a triazolyl group (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.), a tetrazolyl group, a triazinyl group, and other 5- to 7-membered monocyclic aromatic heterocyclic groups Can be mentioned. In the monocyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group. The number of oxo groups which the monocyclic aromatic heterocyclic group may have is preferably 1 or 2.

The aromatic heterocyclic group is, for example, a polycyclic aromatic heterocyclic group. The polycyclic aromatic heterocyclic group is, for example, a condensed polycyclic aromatic heterocyclic group. In one embodiment, the fused polycyclic aromatic heterocyclic group contains 1-3 oxygen atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1-3 sulfur atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1-3 oxygen atoms and 1-3 sulfur atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1-5 nitrogen atoms. In another embodiment, the fused polycyclic aromatic heterocyclic group contains 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms.

Examples of the condensed polycyclic aromatic heterocyclic group include a benzothiophenyl group, a benzofuranyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzoisothiazolyl group, and benzotria. Zolyl group, imidazopyridinyl group, thienopyridinyl group, furopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyrazinyl group, imidazopyrimidinyl group, Thienopyrimidinyl group, furopyrimidinyl group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, oxazolopyrimidinyl group, thiazolopyrimidinyl group, pyrazolotriazinyl group, naphtho[2,3-b]thienyl group, phenoxathiynyl group , Indolyl group, isoindolyl group, 1H-indazolyl group, purinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, carbazolyl group, β-carbolinyl group, phenanthridinyl group, Examples thereof include an 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group such as an acridinyl group, a phenazinyl group, a phenothiazinyl group and a phenoxazinyl group. In the polycyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group. The number of oxo groups which the polycyclic aromatic heterocyclic group may have is preferably 1, 2 or 3.

The aromatic heterocyclic group is a fused polycyclic aromatic group having a partially saturated monocycle (eg, a monocyclic aromatic hydrocarbon ring group, a monocyclic aromatic heterocyclic group, etc.) A heterocyclic group (for example, a cyclic group in which an aliphatic heterocycle is condensed with an aromatic ring) is also included. A fused polycyclic aromatic heterocyclic group having a partially saturated monocycle is a fused polycyclic aromatic heterocyclic group having a monocycle in which some of the bonds constituting the ring are hydrogenated. is there. Examples of the fused polycyclic aromatic heterocyclic group having a partially saturated monocycle include dihydrobenzofuranyl group, dihydrobenzimidazolyl group, dihydrobenzoxazolyl group, dihydrobenzothiazolyl group, dihydro Benzisothiazolyl group, dihydronaphtho[2,3-b]thienyl group, tetrahydroisoquinolyl group, tetrahydroquinolyl group, 4H-quinolizinyl group, indolinyl group, isoindolinyl group, tetrahydrothieno[2,3-c]pyridinyl group Group, tetrahydrobenzazepinyl group, tetrahydroquinoxalinyl group, tetrahydrophenanthridinyl group, hexahydrophenothiazinyl group, hexahydrophenoxazinyl group, tetrahydrophthalazinyl group, tetrahydronaphthyridinyl group, tetrahydroquina 9 such as zolinyl group, tetrahydrocinnolinyl group, tetrahydrocarbazolyl group, tetrahydro-β-carbolinyl group, tetrahydroacridinyl group, tetrahydrophenazinyl group, tetrahydrothioxanthenyl group, octahydroisoquinolyl group Examples thereof include condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups having 14 to 14 members. 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 an oxo group. The number of oxo groups that the fused polycyclic aromatic heterocyclic group having a partially saturated monocycle may have is 1, 2 or 3.

The aromatic heterocyclic group also includes a partially saturated fused polycyclic aromatic heterocyclic group. The partially saturated fused polycyclic aromatic heterocyclic group is a fused polycyclic aromatic heterocyclic group having a monocycle in which some of the bonds constituting the ring are hydrogenated. Examples of the partially saturated fused polycyclic aromatic heterocyclic group include, for example, 1,3-dihydrobenzimidazole-2-onyl group, 2-benzoxazolinonyl group, octahydroisoindolyl group, 2H -Pyrido[3,2-b]-1,4-oxazin-3(4H)-on-yl group, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4 ] Oxazin-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, 2,3-dihydro-1H-indol-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-benzoxazin-6-yl group, 1,4-benzodioxanyl group, 2H-benzo[b][1,4]oxazin-3(4H)-one- Group, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl group, indolinyl group, 2H-isoindolinyl group, chromanyl group, chromonyl group, isochromanyl group, 1,2,3,4-tetrahydroiso Examples thereof include a quinolyl group.

The divalent aromatic heterocyclic group means a divalent functional group produced by removing one hydrogen atom from the monovalent aromatic heterocyclic group. The description regarding the monovalent aromatic heterocyclic group is the same as above.

Examples of the functional group formed by combining two or more kinds selected from an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group include, for example, an aliphatic hydrocarbon group and Functional group formed by combining an aromatic hydrocarbon ring group, functional group formed by combining an aliphatic hydrocarbon group and an aliphatic heterocyclic group, formed by combining an aliphatic hydrocarbon group and an aromatic heterocyclic group And functional groups to be mentioned.

The functional group formed by combining the aliphatic hydrocarbon group and the aromatic hydrocarbon ring group is represented by the formula: (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group, or the formula: (*)-aromatic It is represented by an aromatic hydrocarbon ring group-aliphatic hydrocarbon group. (*) represents a 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, for example, one or more substituents selected from an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group. The aromatic hydrocarbon ring group in the formula has, for example, one or more substituents selected from an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group. May be The aliphatic hydrocarbon group selected as a substituent may have, for example, one or more substituents selected from an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group. .. The aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group selected as the substituent are, for example, an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic group, respectively. It may have one or more substituents selected from a heterocyclic group.

Examples of the functional group represented by the formula: (*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group include an alkylaryl group, an alkenylaryl group, an alkynylaryl group, and the like. The description of the alkyl group, alkenyl group, alkynyl group and aryl group in the “alkylaryl group”, “alkenylaryl group” and “alkynylaryl group” is the same as above.

The number of alkyl groups in the alkylaryl group, the number of alkenyl groups in the alkenylaryl group, and the number of alkynyl groups in the alkynylaryl group are usually 1 to 4, preferably 1 to 3, and more preferably 1 to 2. .. The number of carbon atoms of the alkylaryl group is usually 7 to 30, preferably 7 to 20, more preferably 7 to 18, even more preferably 7 to 15, and even more preferably 7 to 11. The number of carbon atoms of the alkenylaryl group and the number of carbon atoms of the alkynylaryl group are generally 8 to 30, preferably 8 to 20, more preferably 8 to 18, even more preferably 8 to 16, and even more preferably 8. It is up to 12. Examples of the alkylaryl group include o-toluyl, m-toluyl, p-toluyl, 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, p-ethylphenyl and the like can be mentioned. Examples of the alkenylaryl group include alkenylaryl groups such as o-styryl, m-styryl, p-styryl and the like. Examples of the alkynylaryl group include alkynylaryl groups such as 2-ethynyl-2-phenyl.

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group include arylalkyl groups, arylalkenyl groups, arylalkynyl groups, and the like. The description of the alkyl group, alkenyl group, alkynyl group and aryl group in the “arylalkyl group”, “arylalkenyl group” and “arylalkynyl group” is the same as above.

The carbon number of the arylalkyl group is usually 7 to 30, preferably 7 to 20, more preferably 7 to 18, even more preferably 7 to 15, and even more preferably 7 to 11. Examples of the arylalkyl group include a benzyl group and a 2-phenethyl group. The carbon number of the arylalkenyl group is usually 8 to 30, preferably 8 to 20, more preferably 8 to 18, even more preferably 8 to 16, and even more preferably 8 to 12. Examples of the arylalkenyl group include a 2-phenethenyl group and a 2-nephtylethenyl group. The carbon number of the arylalkynyl group is usually 8 to 30, preferably 8 to 20, more preferably 8 to 18, even more preferably 8 to 16, and even more preferably 8 to 12. Examples of the arylalkynyl group include a phenylethynyl group and the like.

The functional group formed by combining the aliphatic hydrocarbon group and the aliphatic heterocyclic group is represented by the formula: (*)-aliphatic hydrocarbon group-aliphatic heterocyclic group, or the formula: (*)-aliphatic heterocyclic group. It is represented by a ring group-aliphatic hydrocarbon group. (*) represents a 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, for example, one or more substituents selected from an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group. The aliphatic heterocyclic group in the formula has, for example, one or more substituents selected from an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group. May be. The aliphatic hydrocarbon group selected as a substituent may have, for example, one or more substituents selected from an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic heterocyclic group. .. The aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group selected as the substituent are, for example, an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group and an aromatic group, respectively. It may have one or more substituents selected from a heterocyclic group.

Examples of the functional group represented by the formula: (*)-aliphatic heterocyclic group-aliphatic hydrocarbon group include alkylaliphatic heterocyclic groups, alkenylaliphatic heterocyclic groups, alkynylaliphatic heterocyclic groups and the like. Can be mentioned. The description of the alkyl group, alkenyl group, alkynyl group and aliphatic heterocyclic group in the “alkyl aliphatic heterocyclic group”, “alkenyl aliphatic heterocyclic group” and “alkynyl aliphatic heterocyclic group” is the same as above. ..

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aliphatic heterocyclic group include an aliphatic heterocyclic alkyl group, an aliphatic heterocyclic alkenyl group, an aliphatic heterocyclic alkynyl group and the like. Can be mentioned. The description of the alkyl group, alkenyl group, alkynyl group and aliphatic heterocyclic group in the "aliphatic heterocyclic alkyl group", "aliphatic heterocyclic alkenyl group" and "aliphatic heterocyclic alkynyl group" is the same as above. ..

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

Examples of the functional group represented by the formula: (*)-aromatic heterocyclic group-aliphatic hydrocarbon group include an alkylheteroaryl group, an alkenylheteroaryl group, an alkynylheteroaryl group, and the like. The description of the alkyl group, alkenyl group, alkynyl group and heteroaryl group in the “alkylheteroaryl group”, “alkenylheteroaryl group” and “alkynylheteroaryl group” is the same as above.

The number of alkyl groups in the alkylheteroaryl group, the number of alkenyl groups in the alkenylheteroaryl group, and the number of alkynyl groups in the alkynylheteroaryl group are usually 1 to 4, preferably 1 to 3, and more preferably 1 to 2. It is an individual. The number of carbon atoms of the alkylheteroaryl group is usually 3 to 30, preferably 3 to 20, more preferably 3 to 18, even more preferably 3 to 15, and even more preferably 3 to 11. The number of carbon atoms of the alkenylheteroaryl group and the number of carbon atoms of the alkynylheteroaryl group are usually 4 to 30, preferably 4 to 20, more preferably 4 to 18, even more preferably 4 to 15, and even more preferably Is 4 to 11.

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aromatic heterocyclic group include a heteroarylalkyl group, a heteroarylalkenyl group, a heteroarylalkynyl group and the like. The description of the alkyl group, alkenyl group, alkynyl group and heteroaryl group in the “heteroarylalkyl group”, “heteroarylalkenyl group” and “heteroarylalkynyl group” is the same as above.

The carbon number of the heteroarylalkyl group is usually 3 to 30, preferably 3 to 20, more preferably 3 to 18, even more preferably 3 to 15, and even more preferably 3 to 11. Examples of the heteroarylalkyl group include a furylethyl group, a thienylmethyl group, a benzothiophenylmethyl group and the like. The carbon number of the heteroarylalkenyl group is usually 4 to 30, preferably 4 to 20, more preferably 4 to 18, even more preferably 4 to 15, and even more preferably 4 to 11. Examples of the heteroarylalkenyl group include a pyridylethenyl group, a thienylethenyl group, a benzothiophenylethenyl group and the like. The carbon number of the heteroarylalkynyl group is usually 4 to 30, preferably 4 to 20, more preferably 4 to 18, even more preferably 4 to 15, and even more preferably 4 to 11. Examples of the heteroarylalkynyl group include an imidazoylethynyl group, a thienylethynyl group, a benzothiophenylethynyl group and the like.

The expression “which may have one or more substituents” with respect to a functional group means that one or more hydrogen atoms of the functional group are independently replaced with other atoms or atomic groups. Means that you may. The expression "which may be substituted" is synonymous with the expression "which may have one or more substituents".

The number of substituents that the aliphatic hydrocarbon group can have can be appropriately determined according to the number of carbon atoms in the aliphatic hydrocarbon group. The aliphatic hydrocarbon group can have, for example, 1 to 6, preferably 1 to 3, more preferably 1 or 2 substituents at substitutable positions. When the hydrocarbon group has two or more substituents, the two or more substituents may be the same or different.

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

When the alkenyl group has 2 to 4 carbon atoms, the number of substituents that the alkenyl group 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 that the alkenyl group can have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, It is more preferably 1 or 2. When the alkenyl group has 10 or more carbon atoms, the number of substituents that the alkenyl group can have is usually 1 to 8, preferably 1 to 4, and more preferably 1 to 3 It is more preferably 1 or 2.

When the alkynyl group has 2 to 4 carbon atoms, the number of substituents that the alkynyl group can 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. It is 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, more preferably 1 to 3, and even more preferably Is 1 or 2.

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

The number of substituents that the aliphatic heterocyclic group can have can be appropriately determined according to the number of carbon atoms and the number of members of the aliphatic heterocyclic group. The aliphatic heterocyclic group can have, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2 substituents at substitutable positions. When the aliphatic heterocyclic group has two or more substituents, the two or more substituents may be the same or different.

The number of substituents that the aromatic heterocyclic group can have can be appropriately determined according to the number of carbon atoms and the number of members of the aromatic heterocyclic group. The aromatic heterocyclic group can have, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2 substituents at substitutable positions. When the aromatic heterocyclic group has two or more substituents, the two or more substituents may be the same or different.

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

When the arylalkenyl group or the alkenylaryl group has 8 to 11 carbon atoms, the number of substituents that the arylalkenyl group or the alkenylaryl group can have is usually 1 to 5, preferably 1 to 4 It is 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 It is 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 can have is usually 1 to 8, preferably 1 to 6 and more preferably Is 1 to 4, and more preferably 1 to 2.

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 It is 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 It is 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 can have is usually 1 to 8, preferably 1 to 6 and more preferably Is 1 to 4, and more preferably 1 to 2.

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

[Substituent Group A]
(A-1) Halogen atom (A-2) Nitro group (A-3) Cyano group (A-4) Oxo group (A-5) May be protected Hydroxyl group (A-6) May be protected Good thiol group (A-7) optionally protected amino group (A-8) optionally protected formyl group (A-9) optionally protected carboxyl group (A-10) protected Optionally carbamoyl group (A-11) optionally protected sulfonyl group

[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) Alkylsulfonyloxy group ( B-7) Alkyloxycarbonyloxy group (B-8) Alkylcarbonyl group (B-9) Alkyloxycarbonyl group (B-10) Alkylaminocarbonyl group (B-11) Alkylcarbamoyl group (B-12) Alkylsulfonyl Group (B-13) alkylsulfinyl group (B-14) mono- or di-alkylamino group (B-15) alkylcarbonylamino group (B-16) alkylsulfonylamino group (B-17) alkyloxycarbonylamino group (B-18) alkyloxyalkyloxy group

[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) alkenylsulfonyloxy group (C-7) alkenyloxycarbonyloxy group (C-8) alkenylcarbonyl group (C-9) alkenyloxycarbonyl group (C-10) alkenylaminocarbonyl group (C-11) alkenylcarbamoyl group (C-12) alkenyl Sulfonyl group (C-13) alkenylsulfinyl group (C-14) mono- or di-alkenylamino group (C-15) alkenylcarbonylamino group (C-16) alkenylsulfonylamino group (C-17) alkenyloxycarbonylamino Group (C-18) alkenyloxyalkyloxy group

[Substituent Group D]
(D-1) alkynyl group (D-2) alkynylthio group (D-3) alkynyloxy group (D-4) alkynylcarbonyloxy group (D-5) alkynylcarbamoyloxy group (D-6) alkynylsulfonyloxy group (D-7) alkynyloxycarbonyloxy group (D-8) alkynylcarbonyl group (D-9) alkynyloxycarbonyl group (D-10) alkynylaminocarbonyl group (D-11) alkynylcarbamoyl group (D-12) alkynyl Sulfonyl 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) alkynyloxyalkyloxy group

[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) Arylsulfonyloxy 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) Arylsulfinyl group (E-14) Mono- or di-arylamino group (E-15) Arylcarbonylamino group (E-16) Arylsulfonylamino group (E-17) Aryloxycarbonylamino group (E-18) Aryloxyalkyloxy group

[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) Heteroaryloxyalkyloxy group

[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) Fat Group 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 Ring 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 oxycarbonyl Amino group (G-18) Aliphatic heterocyclic alkyloxyalkyloxy group

[Substituent Group H]
(H-1) Arylalkyl group (H-2) Arylalkylthio group (H-3) Arylalkyloxy group (H-4) Arylalkylcarbonyloxy group (H-5) Arylalkylcarbamoyloxy group (H-6) Arylalkylsulfonyloxy 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

[Substituent Group I]
(I-1) Arylalkenyl group (I-2) Arylalkenylthio group (I-3) Arylalkenyloxy group (I-4) Arylalkenylcarbonyloxy group (I-5) Arylalkenylcarbamoyloxy group (I-6 ) Arylalkenylsulfonyloxy group (I-7) Arylalkenyloxycarbonyloxy group (I-8) Arylalkenylcarbonyl group (I-9) Arylalkenyloxycarbonyl group (I-10) Arylalkenylaminocarbonyl group (I-11 ) Arylalkenylcarbamoyl group (I-12) Arylalkenylsulfonyl group (I-13) Arylalkenylsulfinyl group (I-14) Mono- or di-arylalkenylamino group (I-15) Arylalkenylcarbonylamino group (I- 16) Arylalkenylsulfonylamino group (I-17) Arylalkenyloxycarbonylamino group (I-18) Arylalkenyloxyalkyloxy group

[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) Arylalkynyloxyalkyloxy group

[Substituent group K]
(K-1) Heteroarylalkyl group (K-2) Heteroarylalkylthio group (K-3) Heteroarylalkyloxy 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) Hetero Arylalkylaminocarbonyl 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) Heteroarylalkynyloxyalkyloxy group

[Substituent group L]
(L-1) Heteroarylalkenyl 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) Heteroarylalkenylaminocarbonyl group (L-11) Heteroarylalkenylcarbamoyl group (L-12) Heteroarylalkenylsulfonyl group (L-13) Heteroarylalkenylsulfinyl group (L-14) Mono- or di-heteroarylalkenylamino Group (L-15) Heteroarylalkenylcarbonylamino group (L-16) Heteroarylalkenylsulfonylamino group (L-17) Heteroarylalkenyloxycarbonylamino group (L-18) Heteroarylalkenyloxyalkyloxy group

[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) Heteroarylalkynyloxyalkyloxy group

The one or more substituents which the aliphatic hydrocarbon group (including monovalent and divalent) contained in the organic group may have, are each independently, for example, a halogen atom, a nitro group, a cyano group, an oxo group, Optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected Carbamoyl group, optionally protected sulfonyl 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 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 , An alkylheteroarylcarbonyl group, an arylalkylcarbonyl group, an aliphatic heterocyclic alkylcarbonyl group, a heteroarylalkylcarbonyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an aliphatic heterocyclic oxycarbonyl group, a heteroaryloxycarbonyl group, It can be selected from an alkylaryloxycarbonyl group, an alkylaliphatic heterocyclic oxycarbonyl group, an alkylheteroaryloxycarbonyl group, an arylalkyloxycarbonyl group, an aliphatic heterocyclic alkyloxycarbonyl group and a heteroarylalkyloxycarbonyl group. When the aliphatic hydrocarbon group (including monovalent and divalent) is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group is cyclic. May have an aliphatic hydrocarbon group (for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.)

One or more substituents that an aromatic hydrocarbon ring group (including monovalent and divalent) contained in the organic group may have, and an aliphatic heterocyclic group (including monovalent and divalent) contained in the organic group And one or more substituents that the aromatic heterocyclic group (including monovalent and divalent) contained in the organic group can have, each independently, for example, , Halogen atom, nitro group, cyano group, oxo group, optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally protected formyl group, protected Optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic group, heteroaryl group, alkylaryl group, alkylaliphatic heterocycle Group, alkylheteroaryl group, arylalkyl group, aliphatic heterocyclic alkyl group, heteroarylalkyl group, alkyloxy group, aryloxy group, aliphatic heterocyclic oxy group, heteroaryloxy group, alkylaryloxy group, alkyl fat Group heterocyclic oxy group, alkylheteroaryloxy group, arylalkyloxy group, aliphatic heterocyclic alkyloxy group, heteroarylalkyloxy group, alkylthio group, arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkyl Arylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocyclic carbonyl group, hetero Arylcarbonyl 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 alkyloxy group It can be selected from carbonyl groups and heteroarylalkyloxycarbonyl groups.

The term “may be protected” with respect to a certain functional group means that the functional group is unsubstituted or the functional group is protected by a commonly used protecting group.

The “protecting group” means that a target functional group can be converted into a functional group that is inactive in a target reaction, and as long as it can be removed from the target functional group after completion of the target reaction. It is not particularly limited and can be appropriately selected depending on the intended functional group, the intended reaction and the like.

The “optionally protected hydroxyl group” is a hydroxyl group or a hydroxyl group protected by a hydroxyl protecting group, for example, formula: —OP ₁ (wherein, P ₁ represents a hydrogen atom or a hydroxyl protecting group). Can be represented. Examples of the hydroxyl group protecting group include ester type protecting group, arylalkyl type protecting group, alkyl type protecting group, arylalkyloxyalkyl type protecting group, alkyloxyalkyl type protecting group, silyl type protecting group, oxycarbonyl type protecting group, etc. Is mentioned.

Examples of the ester type protecting group include an alkylcarbonyl group having 2 to 10 carbon atoms which may have one or more substituents, and 7 to carbon atoms which may have one or more substituents. Examples include 10 arylcarbonyl groups. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent that the alkylcarbonyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The substituent that the arylcarbonyl group may have is the same as the substituent for the aromatic hydrocarbon ring group. Examples of the alkylcarbonyl group which may have one or more substituents include, for example, an acetyl group, a propanoyl group, a butanoyl group, an isopropanoyl group and a pivaloyl group. Examples of the arylcarbonyl group which may have one or more substituents include, for example, 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 and the like. The ester type protecting group is preferably an alkylcarbonyl group having 2 to 10 carbon atoms, more preferably an alkylcarbonyl group having 2 to 5 carbon atoms, still more preferably an acetyl group or a pivaloyl group.

Examples of the arylalkyl type protecting group include an arylalkyl group having 7 to 11 carbon atoms which may have one or more substituents. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent that “alkyl” in the arylalkyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The substituent which "aryl" in the arylalkyl group may have is the same as the substituent for the aromatic hydrocarbon ring group. 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 the arylalkyl group having 7 to 11 carbon atoms which may have one or more substituents include, for example, benzyl group, 1-phenylethyl group, diphenylmethyl group, 1,1-diphenylethyl group and naphthyl. Examples thereof include a methyl group.

Examples of the alkyl type protecting group include an alkyl group having 1 to 10 carbon atoms which may have one or more substituents. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent that the alkyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The one or more substituents are preferably selected from halogen atoms, nitro groups and cyano groups. The alkyl type protecting group is preferably an alkyl group having 1 to 5 carbon atoms which may be substituted with one or more substituents, more preferably a methyl group, an ethyl group, a tert-butyl group or the like. ..

Examples of the arylalkyloxyalkyl type protecting group include an arylalkyloxymethyl group having 8 to 11 carbon atoms which may have one or more substituents, and one or more substituents. Examples thereof include arylalkyloxyethyl groups having 9 to 11 carbon atoms and arylalkyloxyalkyl groups having 10 to 11 carbon atoms which may have one or more substituents. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent which "alkyl" in the arylalkyloxyalkyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The substituent that “aryl” in the arylalkyloxyalkyl group may have is the same as the substituent for the aromatic hydrocarbon ring group. The one or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups and methyloxy groups. The arylalkyloxyalkyl-type protecting group is, for example, substituted with a benzyloxymethyl group which may have one or more substituents, preferably a halogen atom, a nitro group, a cyano group, a methyl group or a methyloxy group. Optionally a benzyloxymethyl group, more preferably a benzyloxymethyl group.

Examples of the alkyloxyalkyl-type protecting group include an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, and a carbon which may have one or more substituents. Examples thereof include an alkyloxyethyl group having a number of 3 to 10 and an alkyloxyalkyl group such as an alkyloxypropyl group having a carbon number of 4 to 10 which may have one or more substituents. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent that “alkyl” in the alkyloxyalkyl group may have is the same as the substituent for the aliphatic hydrocarbon group. 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 an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, more preferably a halogen atom, a nitro group, a cyano group or methyl. An alkyloxymethyl group having 2 to 5 carbon atoms which may have an oxy group or an ethyloxy group, and more preferably a methyloxymethyl group.

Examples of the silyl-type protecting group include an alkyl group having 1 to 10 carbon atoms which may have one or more substituents, and 7 to 10 carbon atoms which may have one or more substituents. Silyl groups having a functional group selected from aryl groups having 6 to 10 carbon atoms and optionally having 1 or more substituents. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent that “alkyl” in the alkyl group and arylalkyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The substituent that “aryl” in the aryl group and arylalkyl group may have is the same as the substituent for the aromatic hydrocarbon ring group. The silyl type protecting group is preferably a silyl group having a functional group selected from an alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms. A silyl group having a functional group selected from an alkyl group and a phenyl group, and more preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group.

Examples of the oxycarbonyl-type protecting group include an alkyloxycarbonyl group having 2 to 10 carbon atoms which may have one or more substituents, and a carbon number which may have one or more substituents. Examples thereof include an alkenyloxycarbonyl group having 3 to 10 carbon atoms and an arylalkyloxycarbonyl group having 8 to 11 carbon atoms which may have one or more substituents. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent which "alkyl" in the alkyloxycarbonyl group, "alkenyl" in the alkenyloxycarbonyl group and "alkyl" in the arylalkyloxycarbonyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The substituent that “aryl” in the arylalkyloxycarbonyl group may have is the same as the substituent for the aromatic hydrocarbon ring group. The oxycarbonyl-type protecting group is preferably an alkyloxycarbonyl group having 2 to 5 carbon atoms, an alkenyloxycarbonyl group having 3 to 5 carbon atoms or a benzyloxycarbonyl group, more preferably a methyloxymethyl group, allyloxy. A carbonyl group or a benzyloxycarbonyl group.

The “optionally protected thiol group” is a thiol group or a thiol group protected with a thiol group-protecting group, and has, for example, the formula: —SP ₂ (wherein P ₂ is a hydrogen atom or a thiol group-protecting group). Can be represented by.). Examples of the thiol group-protecting group 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, oxycarbonyl-type protecting groups. Etc. The description of these protecting groups is the same as above.

The “optionally protected amino group” is an amino group or an amino group protected by an amino group-protecting group, and is represented by, for example, the formula —NH—P ₃ , the formula —N(—P ₃ )(—P ₄ ). Or the formula =N(-P ₃ ) (in the formula, P ₃ and P ₄ each independently represents an amino group-protecting group). Examples of the amino group-protecting group include an alkyloxycarbonyl group having 2 to 10 carbon atoms (eg, methyloxycarbonyl group, tert-butyloxycarbonyl group, etc.), an arylalkyloxycarbonyl group having 8 to 11 carbon atoms (eg, Benzyloxycarbonyl group), 9-fluorenylmethyloxycarbonyl group, benzhydryl group, trityl group, 2,2,2-trichloroethyloxycarbonyl group, allyloxycarbonyl group and the like. The amino group also includes an alicyclic amino group and a heterocyclic amino group.

The “optionally protected carboxyl group” is a carboxyl group or a carboxyl group protected with a carboxyl group-protecting group, and is represented by, for example, the formula —C(═O)(—OP ₅ ), where P ₅ is A hydrogen atom or a carboxyl group-protecting group). Examples of the carboxyl-protecting group include an alkyl group having 1 to 10 carbon atoms (eg, methyl group, ethyl group, propyl group, etc.), an arylalkyl group having 7 to 11 carbon atoms (eg, benzyl group), etc. To be

The “optionally protected formyl group” is a formyl group or a formyl group protected by a formyl group-protecting group, and has, for example, the formula —C(Y _a P ₆ )(Y _a P ₇ ), in which Y _a represents _a hetero atom, P ₆ and P ₇ each independently represent a hydroxyl group-protecting group, or P ₆ and P ₇ may together form an alkylene). it can. The heteroatoms are preferably oxygen or sulfur atoms. Examples of the hydroxyl-protecting group include an alkyl group having 1 to 5 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group and the like. Further, P ₆ and P ₇ together form an alkylene having preferably 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and more preferably 2 or 3 carbon atoms.

The “optionally protected carbamoyl group” is preferably represented by the formula —O—C(═O)—NH(—P ₈ ), where P ₈ represents an amino group-protecting group. .. Examples of the amino group-protecting group include an alkyloxycarbonyl group having 2 to 10 carbon atoms (eg, methyloxycarbonyl group, tert-butyloxycarbonyl group, etc.), an arylalkyloxycarbonyl group having 8 to 11 carbon atoms (eg, Benzyloxycarbonyl group), 9-fluorenylmethyloxycarbonyl group, benzhydryl group, trityl group, 2,2,2-trichloroethyloxycarbonyl group, allyloxycarbonyl group and the like.

The “sulfonyl group which may be protected” is a sulfonyl group or a sulfonyl group which is protected by a sulfonyl group protecting group, for example, an alkylsulfonyl group which may be substituted with one or more substituents, one or more. And an arylsulfonyl group which may be substituted with the substituent. The one or more substituents can be selected, for example, from the substituent groups AM. The substituent which "alkyl" in the alkylsulfonyl group may have is the same as the substituent for the aliphatic hydrocarbon group. The substituent that “aryl” in the arylsulfonyl group may have is the same as the substituent related to the aromatic hydrocarbon ring group. The number of carbon atoms of the alkyl group in the 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 (eg, methylsulfonyl group, trifluoromethylsulfonyl group, etc.). The aryl group in the arylsulfonyl group has usually 6 to 14, preferably 6 to 10 carbon atoms. The 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 (eg, phenylsulfonyl group, p-toluenesulfonyl group, etc.).

The “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “heteroaryl” and “aliphatic heterocycle” contained in the substituents in the substituent groups A to M are each selected from the substituent group A. It may be substituted with one or more substituents. One or more substituents selected from Substituent group A for further substituting "alkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl" or "aliphatic heterocycle" included in the substituent Substituents are each independently preferably a halogen atom, a hydroxyl group which may be protected, a thiol group which may be protected, an amino group which may be protected, a formyl group which may be protected, It is more preferably selected from an optionally protected carboxyl group, an optionally protected carbamoyl group and an optionally substituted sulfonyl group, and is more preferably a halogen atom, an optionally protected hydroxyl group, or an optionally protected group. It is selected from an amino group, an optionally protected formyl group and an optionally protected carboxyl group, and even more preferably a halogen atom.

<Compound (I)>
The compound (I) of the present invention has the following formula (I):

It is represented by. As mentioned above, the compound (I) is also referred to as a C-aryl hydroxyglycoxide derivative and is preferably used as an intermediate of an SGLT-2 inhibitor.

In formula (I), R ¹ and R ² each independently represent a hydroxyl group-protecting group, and R ³ and R ⁴ each independently represent a hydroxyl group-protecting group or a hydrogen atom.

The hydroxyl-protecting groups represented by R ¹ and R ² may be the same or different, but are preferably the same in consideration of efficient introduction and removal of the hydroxyl-protecting group.

The hydroxyl-protecting group represented by R ¹ and R ² is not particularly limited, and examples thereof include ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, arylalkyloxyalkyl-type protecting groups, alkyloxyalkyl-type protecting groups. Group, a silyl type protecting group, an oxycarbonyl type protecting group and the like. These protecting groups are as defined above.

The hydroxyl-protecting group represented by R ¹ and R ² is preferably methyloxymethyl group, benzyloxymethyl group, acetyl group, propanoyl group, butanoyl group, isopropanoyl group, pivaloyl group, benzoyl group, 4-nitro. Benzoyl 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-phenylethyl group, diphenylmethyl group, 1,1-diphenylethyl group, naphthylmethyl group, methyl group, tert-butyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethyl group Silyl group, tert-butyldiphenylsilyl group, tert-butyloxycarbonyloxy group or benzyloxycarbonyl group, more preferably benzyl group, acetyl group, pivaloyl group, trimethylsilyl group, tert-butyldimethylsilyl group or tert-butyldiphenylsilyl It is a base.

In the formula (I), the functional groups represented by R ³ and R ⁴ may be hydrogen atoms. However, from the viewpoint of efficiently forming the 6-membered ring of the formula (I), the functional groups represented by R ³ and R ⁴ are preferably hydroxyl group-protecting groups.

The hydroxyl protecting group represented by R ³ and R ⁴ may be the same as or different from the hydroxyl protecting group represented by R ¹ or the hydroxyl protecting group represented by R ² , but is an effective protective group. From the viewpoint of introducing and removing a group, it is preferably the same as the hydroxyl protecting group represented by R ¹ and R ² .

The organic group represented by Ar is an aromatic hydrocarbon ring group which may have one or more substituents or an aromatic heterocyclic group which may have one or more substituents. There is no particular limitation as long as it is contained as a functional group that bonds to the oxane ring in (I).

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

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

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

In the above formula, J ₁ represents an aromatic hydrocarbon ring group which may have one or more substituents, and J ₂ represents an aliphatic hydrocarbon group which may have one or more substituents. Represents a hydrogen group, J ₃ is an aromatic hydrocarbon ring group optionally having one or more substituents, an aliphatic heterocyclic group optionally having one or more substituents, or one The aromatic heterocyclic group which may have the above substituents is represented, and (*) represents a bond which is bonded to the carbon atom of the oxane ring in the formula (I).

In one embodiment, J ₁ is an unsubstituted aromatic hydrocarbon ring group and J ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, J ₁ is an unsubstituted aromatic hydrocarbon ring group and J ₂ is an aliphatic hydrocarbon group having one or more substituents.

In another embodiment, J ₁ is an aromatic hydrocarbon ring group having one or more substituents and J ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, J ₁ is an aromatic hydrocarbon ring group having one or more substituents and J ₂ is an aliphatic hydrocarbon group having one or more substituents.

In one embodiment, J ₃ is an unsubstituted aromatic hydrocarbon ring group. This embodiment can be combined with the above embodiments for J ₁ and J ₂ .

In another embodiment, J ₃ is an aromatic hydrocarbon ring group having one or more substituents. This embodiment can be combined with the above embodiments for J ₁ and J ₂ .

In another embodiment, J ₃ is an unsubstituted aliphatic heterocyclic group. This embodiment can be combined with the above embodiments for J ₁ and J ₂ .

In another embodiment, J ₃ is an aliphatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiments for J ₁ and J ₂ .

In another embodiment, J ₃ is an unsubstituted aromatic heterocyclic group. This embodiment can be combined with the above embodiments for J ₁ and J ₂ .

In another embodiment, J ₃ is an aromatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiments for J ₁ and J ₂ .

In the embodiment where the aliphatic hydrocarbon group represented by J ₂ has one or more substituents, the one or more substituents may be independently selected from, for example, the substituent groups A to M. it can. The one or more substituents contained in the aliphatic hydrocarbon group represented by J ₂ are each independently, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, or a protected group. Optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected sulfonyl 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, hetero Arylalkyloxy group, alkylthio group, arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocycle 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 heterocycle It can be selected from a ring oxycarbonyl group, an alkylheteroaryloxycarbonyl group, an arylalkyloxycarbonyl group, an aliphatic heterocyclic alkyloxycarbonyl group and a heteroarylalkyloxycarbonyl group. The one or more substituents are each independently a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, or 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 alkyloxy group. It is preferably selected from carbonyl groups. In addition, when the aliphatic hydrocarbon group represented by J ₂ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group is a cyclic aliphatic group. It may have a hydrocarbon group (for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

An embodiment in which the aromatic hydrocarbon ring group represented by J ₁ and/or the aromatic hydrocarbon ring group represented by J ₃ , the aliphatic heterocyclic group or the aromatic heterocyclic group has one or more substituents. In, the one or more substituents can be independently selected, for example, from the substituent groups A to M. The aromatic hydrocarbon ring group represented by J ₁ and/or the aromatic hydrocarbon ring group represented by J ₃ , the aliphatic heterocyclic group or the aromatic heterocyclic group has one or more substituents, respectively, 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, or an optionally protected Formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic group, heteroaryl group, alkylaryl group, Alkyl aliphatic heterocyclic group, alkylheteroaryl group, arylalkyl group, aliphatic heterocyclic alkyl group, heteroarylalkyl group, alkyloxy group, aryloxy group, aliphatic heterocyclic oxy group, heteroaryloxy group, alkylaryl Oxy group, alkylaliphatic heterocyclic oxy group, alkylheteroaryloxy group, arylalkyloxy group, aliphatic heterocyclic alkyloxy group, heteroarylalkyloxy group, alkylthio group, arylthio group, aliphatic heterocyclic thio group, hetero Arylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocycle Ring 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, fat It can be selected from group heterocyclic alkyloxycarbonyl groups and heteroarylalkyloxycarbonyl groups.

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

In the above formula, K ₁ represents an aromatic heterocyclic group which may have one or more substituents, and K ₂ represents an aliphatic hydrocarbon which may have one or more substituents. Represents a group, K ₃ is an aromatic hydrocarbon ring group optionally having one or more substituents, an aliphatic heterocyclic group optionally having one or more substituents, or one or more Represents an optionally substituted aromatic heterocyclic group, and (*) represents a bond that bonds to the carbon atom of the carbonyl group in formula (I).

In one embodiment, K ₁ is an unsubstituted aromatic heterocyclic group and K ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, K ₁ is an unsubstituted aromatic heterocyclic group and K ₂ is an aliphatic hydrocarbon group having one or more substituents.

In another embodiment, K ₁ is an aromatic heterocyclic group having one or more substituents and K ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, K ₁ is an aromatic heterocyclic group having one or more substituents and K ₂ is an aliphatic hydrocarbon group having one or more substituents.

In one embodiment, K ₃ is an unsubstituted aromatic hydrocarbon ring group. This embodiment can be combined with the above embodiments for K ₁ and K ₂ .

In another embodiment, K ₃ is an aromatic hydrocarbon ring group having one or more substituents. This embodiment can be combined with the above embodiments for K ₁ and K ₂ .

In another embodiment, K ₃ is an unsubstituted aliphatic heterocyclic group. This embodiment can be combined with the above embodiments for K ₁ and K ₂ .

In another embodiment, K ₃ is an aliphatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiments for K ₁ and K ₂ .

In another embodiment, K ₃ is an unsubstituted aromatic heterocyclic group. This embodiment can be combined with the above embodiments for K ₁ and K ₂ .

In another embodiment, K ₃ is an aromatic heterocyclic group having one or more substituents. This embodiment can be combined with the above embodiments for K ₁ and K ₂ .

In the embodiment where the aliphatic hydrocarbon group represented by K ₂ has one or more substituents, the one or more substituents may be independently selected from, for example, the substituent groups A to M. it can. The one or more substituents contained in the aliphatic hydrocarbon group represented by K ₂ are each independently, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, or a protected group. Optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected sulfonyl 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, hetero Arylalkyloxy group, alkylthio group, arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocycle 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 heterocycle It can be selected from a ring oxycarbonyl group, an alkylheteroaryloxycarbonyl group, an arylalkyloxycarbonyl group, an aliphatic heterocyclic alkyloxycarbonyl group and a heteroarylalkyloxycarbonyl group. The one or more substituents are each independently a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, an optionally protected thiol group, or 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 alkyloxy group. It is preferably selected from carbonyl groups. In addition, when the aliphatic hydrocarbon group represented by K ₂ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group is a cyclic aliphatic hydrocarbon group. It may have a hydrocarbon group (for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

In an embodiment in which the aromatic heterocyclic group represented by K ₁ and/or the aromatic hydrocarbon cyclic group represented by K ₃ , the aliphatic heterocyclic group or the aromatic heterocyclic group has one or more substituents. The one or more substituents can each be independently selected, for example, from the substituent groups A to M. The aromatic heterocyclic group represented by K ₁ and/or the aromatic hydrocarbon ring group represented by K ₃ , the aliphatic heterocyclic group, or the one or more substituents possessed by the aromatic heterocyclic group are each independently Then, 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, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic group, heteroaryl group, alkylaryl group, alkyl Aliphatic 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, heteroaryl Ruthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocyclic alkylthio group, heteroarylalkylthio group, alkylcarbonyl group, arylcarbonyl group, aliphatic heterocycle 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 It can be selected from heterocyclic alkyloxycarbonyl groups and heteroarylalkyloxycarbonyl groups.

The aromatic hydrocarbon ring group or aromatic heterocyclic group bonded to the oxane ring in the formula (I) contained in the organic group represented by Ar is preferably an aromatic hydrocarbon ring having 6 to 14 carbon atoms. Group 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, and still more preferably Is a phenyl group, a thienyl group, a benzothiophenyl group, a furyl group, a pyrrolyl group, an imidazolyl group or a pyridyl group, more preferably a phenyl group, a thienyl group or a benzothiophenyl group, and even more preferably a phenyl group. It is a base.

From the viewpoint of producing an SGLT-2 inhibitor or a derivative thereof, the organic group represented by Ar is the same as the aromatic hydrocarbon ring group or aromatic heterocyclic group contained in the SGLT-2 inhibitor, or It is preferably a group derived from an aromatic hydrocarbon ring group or an aromatic heterocyclic group.

Here, canagliflozin (1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene), empagliflozin ((1S)-1 ,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol), ipragliflozin ( (1S)-1,5-Anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carvone Acid) and dapagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3, 4,5-thiol) and other SGLT-2 inhibitors have an aromatic hydrocarbon ring group or aromatic heterocyclic group represented by the following formula (V) or formula (Va).

Therefore, according to one embodiment, the organic group represented by Ar has the following formula (V):

It is represented by.

In formula (V), R ^a is each independently 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, It represents a functional group selected from the group consisting of an alkynyloxy group, an aryloxy group, an arylalkyloxy group, an arylalkenyloxy group and an arylalkynyloxy group, and is an alkyl group, an alkenyl group, an alkynyl group or an aryl group included in the 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, each of which is 1 or more. It may have a substituent.

In the formula (V), the functional groups represented by R ^a are preferably each independently a halogen atom, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 14 carbon atoms, or 7 to 15 carbon atoms. Is selected from the group consisting of an arylalkyl group having 1 to 20 carbon atoms, an alkyloxy group having 1 to 20 carbon atoms and an arylalkyloxy group having 7 to 15 carbon atoms, and more preferably a halogen atom and an alkyl group having 1 to 10 carbon atoms.

In the formula (V), n represents an integer of 0-4. The integer represented by n is preferably 1 to 3, and more preferably 1 or 2. When n is 2 or more, n R ^{a s} may be the same or different.

In the 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 1 Represents an aromatic heterocyclic group which may have one or more substituents. Ar' preferably 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.

The functional group represented by Ar′ preferably has an aromatic hydrocarbon ring group having 6 to 14 carbon atoms which may have one or more substituents, or one or more substituents. Is an aromatic heterocycle having 3 to 12 carbon atoms, more preferably an aromatic hydrocarbon ring group having 6 to 14 carbon atoms which may have one or more substituents, or one or more substituents. An aromatic heterocycle having 3 to 12 carbon atoms which may have a group, more preferably a phenyl group which may have one or more substituents, and one or more substituents. Optionally a thienyl group, an optionally substituted benzothiophenyl group, an optionally substituted furyl group, an optionally substituted one or more substituents A pyrrolyl group which may have one or more, an imidazolyl group which may have one or more substituents, or a pyridyl group which may have one or more substituents, and more preferably one or more A phenyl group which may have a substituent, a thienyl group which may have one or more substituents, or a benzothiophenyl group which may have one or more substituents.

The one or more substituents contained in 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, an aliphatic heterocyclic oxy group ( For example, a tetrahydrofuranyloxy group etc.) and the like.

According to a more preferred embodiment, in formula (I), the organic group represented by Ar is represented by the following formula (Va).

The functional group represented by ^Ra is as defined above.

In the formulas (V) and (Va), Ar′ is preferably a functional group represented by the following formulas (Va-I), (Va-II) and (Va-III).

It is represented by.

In formulas (IVa-I), (IVa-II) and (IVa-III), R ^b is each independently an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group or an aromatic group. Represents a functional group selected from the group consisting of heterocyclic groups, wherein the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocycle included in the group are each one or more. It may have a substituent.

The functional groups represented by R ^b are each independently an alkyl group having 1 to 20 carbon atoms, which may have one or more substituents, and one or more substituents. An alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms which may have one or more substituents, and an alkynyl group having 6 to 14 carbon atoms which may have one or more substituents Aromatic hydrocarbon ring group, aliphatic heterocyclic group having 2 to 12 carbon atoms which may have one or more substituents, and 3 to 12 carbon atoms which may have one or more substituents Preferably, it is selected from the aromatic heterocyclic groups of, and an alkyl group having 1 to 10 carbon atoms which may have one or more substituents, and a carbon which may have one or more substituents. Alkenyl group having 2 to 10 carbon atoms, alkynyl group having 2 to 10 carbon atoms that may have one or more substituents, and fragrance having 6 to 10 carbon atoms that may have one or more substituents More preferably selected from an aromatic hydrocarbon ring group and an aliphatic heterocyclic group having 2 to 5 carbon atoms, which may have one or more substituents, and has one or more substituents. Is more preferably a phenyl group or a tetrahydrofuranyl group which may have one or more substituents.

The one or more substituents contained in the functional group represented by R ^b can be independently selected from, for example, the substituent groups A to M. The one or more substituents contained in the functional group represented by R ^b are each independently, for example, a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxyl group, or an optionally protected group. Good thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally 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, hetero Arylalkyloxy group, alkylthio group, arylthio group, aliphatic heterocyclic thio group, heteroarylthio group, alkylarylthio group, alkylaliphatic heterocyclic thio group, alkylheteroarylthio group, arylalkylthio group, aliphatic heterocycle 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 heterocycle It can be selected from a ring oxycarbonyl group, an alkylheteroaryloxycarbonyl group, an arylalkyloxycarbonyl group, an aliphatic heterocyclic alkyloxycarbonyl group and a heteroarylalkyloxycarbonyl group. The one or more substituents are each independently 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. , Optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected sulfonyl group, alkyl group, alkyloxy group, alkylthio group, alkylcarbonyl group And alkyloxycarbonyl groups are preferred. The one or more substituents are each independently a halogen atom, a nitro group, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected formyl group, or an optionally protected formyl group. More preferably selected from a good amino group, an optionally protected carboxyl group, an optionally protected sulfonyl group and an alkyloxycarbonyl group having 1 to 10 carbon atoms, a halogen atom, an amino group, a nitro group, Even more preferably, it is selected from an alkyloxy group having 1 to 10 carbon atoms and an alkyloxycarbonyl group having 1 to 10 carbon atoms.

In the formula (Va-I), p represents an integer of 0-5. The integer represented by p is preferably 0 to 3, more preferably 0 to 2, and even more preferably 0 or 1. In formulas (Va-II) and (Va-III), the integer represented by p is preferably 0 to 5, more preferably 0 to 3, and even more preferably 0 to 2. When p is 2 or more, p R ^{b s} may be the same or different.

In formula (Va-I), p is preferably 1, R ^b is preferably a phenyl group optionally having one or more substituents, and more preferably has a halogen atom. It is a phenyl group, and more preferably a phenyl group having a fluorine atom. The position to which the phenyl group, which may have one or more substituents, is bonded is preferably the 2-position of the thiophene ring. In the phenyl group having a halogen atom, the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.

In the formula (Va-II), p is preferably 0.

In formula (Va-III), p is preferably 1 and R ^b is preferably an alkyl group optionally having one or more substituents or one or more substituents. It may be an aliphatic heterocyclic group. The alkyl group which may have one or more substituents is preferably an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group or an ethyl group. The aliphatic heterocyclic group which may have one or more substituents is preferably a tetrahydrofuranyl group. The position at which the alkyl group which may have one or more substituents or the aliphatic heterocyclic group which may have one or more substituents is bonded is preferably the 4-position of the benzene ring. Is.

According to another more preferred embodiment, in the formula (I), the organic group represented by Ar is the following (VI-I), (V-II-I), (V-III-I) or (V-III-I) V-III-II).

<Method for producing compound (I)>
The method for producing the compound (I) of the present invention is characterized by comprising the following step (a) and step (b).
Step (a): The following formula (II):

A compound (II) represented by
The following formula (III-I):

And a compound (III-I) represented by the following formula (III-II):

Compound (III-II) represented by
At least one organozinc compound selected from the group consisting of:
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 the one or more transition metal catalysts. After reaction, the following formula (IV):

A step of obtaining a compound (IV) represented by:
Step (b): a step of removing the hydroxyl-protecting group represented by R ⁵ in the compound (IV) to obtain the compound (I).

Hereinafter, the step (a) and the step (b) will be described in order.
<Step (a)>

<Compound (II)>
In the step (a), the following formula (II):

A compound (II) represented by is prepared. Details of the preparation step of compound (II) will be described later as step (a-1).

The hydroxyl protecting group represented by R ⁵ is the same as the hydroxyl protecting group represented by R ¹ or R ² from the viewpoint of efficiently forming the 6-membered ring of formula (I). Excluding items. When the hydroxyl-protecting group represented by R ⁵ is removed, a hydroxyl group is generated and can react with a carbonyl group in the same molecule to form a ring of formula (I). Thus, it is possible to select the type of hydroxyl-protecting group represented by R ⁵ to allow selective removal of the hydroxyl-protecting group represented by R ⁵ while maintaining the hydroxyl-protecting group represented by R ¹ R ² preferable.

The hydroxyl group-protecting group represented by R ⁵ is not particularly limited, and examples thereof include ester type protecting groups, arylalkyl type protecting groups, alkyl type protecting groups, arylalkyloxyalkyl type protecting groups, arylalkylalkyloxyalkyl type protecting groups, There are silyl type protecting groups and oxycarbonyl type protecting groups, and more preferred are ester type protecting groups, arylalkyloxyalkyl type protecting groups, alkyloxyalkyl type protecting groups, silyl type protecting groups, and oxycarbonyl type protecting groups. More specifically, the hydroxyl-protecting group represented by R ⁵ 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, 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-phenylethyl group, diphenylmethyl group, 1,1-diphenylethyl group, naphthylmethyl group, methyl group, tert-butyl group, trimethylsilyl group, triethylsilyl group, tert- Butyldimethylsilyl group, tert-butyldiphenylsilyl group, tert-butyloxycarbonyloxy group, benzyloxycarbonyl group, more preferably methyl group, benzyl group, acetyl group, pivaloyl group, trimethylsilyl group or tert-butyldimethylsilyl group. A tert-butyldiphenylsilyl group.

Further, according to a preferred embodiment, the hydroxyl protecting group represented by R ⁵ is an ester protecting group, and the hydroxyl protecting group represented by R ¹ and the hydroxyl protecting group represented by R ² are each independently , 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 arylalkyl. Further, according to a more preferred embodiment, the hydroxyl group protecting group represented by R ⁵ is an acetyl group or a pivaloyl group, and the hydroxyl group protecting group represented by R ¹ and the hydroxyl group protecting group represented by R ² are each independently And a methyl group, a benzyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.

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

From the viewpoint of forming a 6-membered ring of formula (I) more efficiently, the hydroxyl-protecting group represented by R ⁵ is a hydroxyl-protecting group represented by R ¹ , R ² , R ³ and R ^4. Is preferred.

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

Further, according to another preferred embodiment of the present invention, the hydroxyl protecting group represented by R ⁵ is a silyl type protecting group, and the hydroxyl protecting group represented by R ¹ , R ² , R ³ and R ⁴ is Each of them is independently selected from the group consisting of an arylalkyloxyalkyl type protecting group, an alkyloxyalkyl type protecting group and an oxycarbonyl type protecting group arylalkyl. Further, according to another more preferable embodiment, the hydroxyl-protecting group represented by R ⁵ is a trimethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, and R ¹ , R ² , R ³ and R ³ ^The hydroxyl protecting group represented by ⁴ is independently selected from the group consisting of a methyl group, a benzyl group, an acetyl group and a pivaloyl group.

In the formula (II), Q is an aliphatic hydrocarbon group optionally having one or more substituents, an aromatic hydrocarbon ring group optionally having one or more substituents, one A functional group for bonding the above-mentioned aliphatic heterocyclic group optionally having substituents or aromatic heterocyclic group optionally having one or more substituents to the sulfur atom in the formula (II). Represents an organic group contained as.

In one embodiment, the organic group represented by Q is an aliphatic hydrocarbon group which may have one or more substituents, or has one or more substituents. It contains a good aliphatic hydrocarbon group as a functional group bonded to the sulfur atom in the formula (II).

In another embodiment, the organic group represented by Q is an aromatic hydrocarbon ring group which may have one or more substituents, or has one or more substituents. And optionally contains an aromatic hydrocarbon ring group as a functional group bonded to the sulfur atom in the formula (II).

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

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

Examples of the organic group containing an aliphatic hydrocarbon group which may have one or more substituents as a functional group bonding to the sulfur atom in the formula (II) include compounds represented by the following formula:

[In the formula, L ₁ represents an aliphatic hydrocarbon group which may have one or more substituents, and L ₂ represents an aromatic hydrocarbon group which may have one or more substituents. Represents a cyclic group, 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 the formula (II ) Represents a bond to be bonded to the sulfur atom. ]
Can be expressed as

Further, an organic group containing an aliphatic hydrocarbon group which may have one or more substituents as a functional group bonding to the sulfur atom in the formula (II) is, for example, the following formula:

[In the formula, L ₁ and L ₂ have the same meanings as described above, L ₃ represents an aliphatic hydrocarbon group which may have one or more substituents, and (*) represents formula (II). Represents a bond that bonds to the sulfur atom in. ]
Can be expressed as

[In the formula, L ₁ , L ₂ and L ₃ have the same meanings as described above, and L ₄ is an aromatic hydrocarbon ring group which may have one or more substituents, and one or more substituents. Represents an aliphatic heterocyclic group which may have or an aromatic heterocyclic group which may have one or more substituents, and (*) is a bond which is bonded to the sulfur atom in the formula (II). Represents a hand. ]
Can be expressed as

The _one or more substituents which the aliphatic hydrocarbon group represented by L ₁ or L ₃ may have may be independently selected from, for example, the substituent groups A to M, preferably the substituent group A. it can. The _one or more substituents that the aliphatic hydrocarbon group represented by L ₁ or L ₃ may have are each independently a halogen atom, an optionally protected hydroxyl group, or an optionally protected thiol group. Selected from 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. Is preferred. The aliphatic hydrocarbon group represented by L ₁ or L ₃ may be unsubstituted. When the aliphatic hydrocarbon group represented by L ₁ and/or L ₃ is a linear or branched aliphatic hydrocarbon group, a linear or branched aliphatic hydrocarbon group is It may have a cyclic aliphatic hydrocarbon group (for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

The one or more substituents which the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by L ₂ or L ₄ may have are, for example, Substituent groups A to M, preferably substituted It can be selected from the groups A to D and G, more preferably the groups A, B and G of substituents. One or more substituents that the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by L ₂ or L ₄ may have are independently a halogen atom or a protected group. Optionally hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, Optionally protected sulfonyl group, alkyl group, alkyloxy group, aryloxy group, arylalkyloxy group, alkylarylalkyloxy group, heteroaryloxy group, heteroarylalkyloxy group, alkylheteroarylalkyloxy group, fat It is preferably selected from a group 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 L ₂ or L ₄ may be unsubstituted.

Having an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or one or more substituents Examples of the organic group containing an optionally substituted aromatic heterocyclic group as a functional group bonding to the sulfur atom in the formula (II) include compounds represented by the following formula:

[Wherein, M ₁ is an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or 1 Represents an aromatic heterocyclic group which may have one or more substituents, M ₂ represents an aliphatic hydrocarbon group which may have one or more substituents, and (*) is a formula It represents a bond that bonds to the sulfur atom in (II). ]
Can be expressed as

Further, an organic group containing an aromatic hydrocarbon ring group which may have one or more substituents as a functional group bonding to the sulfur atom in the formula (II) is, for example, the following formula:

[Wherein, M ₁ and M ₂ have the same meanings as described above, and M ₃ has an aromatic hydrocarbon ring group which may have one or more substituents, and one or more substituents. Represents an optionally substituted aliphatic heterocyclic group or an aromatic heterocyclic group which may have one or more substituents, and (*) represents a bond which bonds to the sulfur atom in the formula (II). Represent ]
Can be expressed as

[Wherein M ₁ , M ₂ and M ₃ have the same meanings as defined above, M ₄ represents an aliphatic hydrocarbon group which may have one or more substituents, and (*) represents It represents a bond that bonds to the sulfur atom in (II). ]
Can be expressed as

In the embodiment where the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₁ has one or more substituents, one or more substituents are each independently For example, it can be selected from the substituent groups A to M. The one or more substituents contained in the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₁ are each independently a halogen atom, an optionally protected hydroxyl group, Optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected It is preferably selected from good sulfonyl groups, alkyl groups, alkenyl groups and alkynyl groups. The aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₁ may be unsubstituted.

In the embodiment where the aliphatic hydrocarbon group represented by M ₂ and/or M ₄ has one or more substituents, each of the one or more substituents independently represents, for example, the substituent group A to M. You can choose from. The one or more substituents contained in the aliphatic hydrocarbon group represented by M ₂ and/or M ₄ are each independently a halogen atom, an optionally protected hydroxyl group, or an optionally protected thiol group. Selected from 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. Is preferred. The aliphatic hydrocarbon group represented by M ₂ or M ₄ may be unsubstituted. When the aliphatic hydrocarbon group represented by M ₂ and/or M ₄ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group is It may have a cyclic aliphatic hydrocarbon group (for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, etc.) as a substituent.

In the embodiment where the aromatic hydrocarbon ring group, the aliphatic heterocyclic group or the aromatic heterocyclic group represented by M ₃ has one or more substituents, one or more substituents are each independently, For example, it can be selected from the substituent groups A to M. One or more substituents contained in the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₃ are each independently a halogen atom, an optionally protected hydroxyl group, Optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected carbamoyl group, optionally protected Good sulfonyl group, alkyl group, alkyloxy group, aryloxy group, arylalkyloxy group, alkylarylalkyloxy group, heteroaryloxy group, heteroarylalkyloxy group, alkylheteroarylalkyloxy group, aliphatic heterocyclic oxy group It is preferably selected from 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 M ₃ may be unsubstituted.

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

<Reaction using organic zinc compound>
In step (a), compound (II) and the following formula (III-I):

A compound (III-I) represented by
Formula (III-II) below:

Compound (III-II) represented by
At least one organozinc compound selected from the group consisting of: a nickel catalyst and a palladium catalyst; one or more transition metal catalysts; or one or more transition metal catalysts The reaction is carried out in the presence of a supported catalyst having a carrier supporting a metal catalyst to give the following formula (IV):

A compound (IV) represented by

In step (a), the organozinc compound is used as a reagent for introducing an Ar group into compound (II). As the organozinc compound, either the compound (III-I) or the compound (III-II) may be used alone, but the compound (III-I) and the compound (III-II) can be used in the step (a) In the reaction system, the following formula:

It is preferable to use both the compound (III-I) and the compound (III-II) because the equilibrium state represented by According to a preferred embodiment, at least one organozinc compound comprises said compound (III-I), compound (III-I) being in said equilibrium state.

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

As the organozinc compounds of the compound (III-I) and the compound (III-II), commercially available products may be used, or they may be produced according to a known method as described in Non-Patent Document 5 and the like.

In one embodiment, the organozinc compound of compound (III-I) is prepared by reacting a Grignard reagent ArMgX with a zinc halide ZnX ₂ in an organic solvent.

In the production of the 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, more preferably 1 to 1 equivalent of the Grignard reagent. It is about 1.1 equivalents.

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

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

The compound (III-I) may be used as a complex with a lithium salt (wherein Y is a halogen atom). The lithium salt complex of the compound (III-I) has the following formula (III-Ia):

[In the formula, X and Y each independently represent a halogen atom. ]
It is represented by. The lithium salt complex (III-Ia) can be suitably obtained by carrying out the production of the compound (III-I) in the presence of a lithium salt. The lithium salt complex (III-Ia) may be a lithium salt complex of the compound (III-I).

In the step (a), it is preferable to use the lithium salt complex (III-Ia) in order to improve the reaction rate of the organozinc compound.

Examples of the lithium salt include lithium chloride, lithium bromide, lithium iodide, and the like, with lithium chloride being preferred. Therefore, in the lithium salt complex (III-Ia) of the organozinc compound, X and Y are preferably chlorine, bromine or iodine, and more preferably chlorine or bromine.

As the lithium salt complex (III-Ia) of the organozinc compound, a commercially available product may be used, or a known method may be used. As a preferable production method, a turbo-Grignard reagent ArMgXa.LiY [wherein, Ar has the same meaning as described above, and Xa is a halogen atom. ], and zinc halide ZnX ₂ [In formula, X is a halogen atom and may be the same as or different from Y. ] With the reaction in an organic solvent.

The turbo-Grignard reagent is magnesium and a halogen organic compound ArXa in the presence of a lithium salt in a reaction vessel in which an inert gas (nitrogen, argon, etc.) is substituted [wherein Ar and Xa are as defined above]. ] Can be obtained by reacting with an organic solvent.

Magnesium is preferably used as a pulverized product or shavings from the viewpoint of improving reactivity. From the viewpoint of improving the reactivity of magnesium, a reducing agent such as diisobutylaluminum hydride (DIBAL-H) in a catalytic amount of about 0.05 to 0.2 equivalents relative to 1 equivalent of magnesium is used as an organic solvent. It may be added in.

In the production of the turbo-Grignard reagent, the amount of the lithium salt used is usually about 0.5 to 5.0 equivalents, preferably about 0.5 to 3.0 equivalents, and more preferably 0, relative to 1 equivalent of magnesium. It may be about 0.5 to 2.0 equivalents.

In the production of the turbo Grignard 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 0, relative to 1 equivalent of magnesium. It may be about 0.5 to 1.5 equivalents.

From the viewpoint of stable production, the organic solvent used for producing the turbo-Grignard reagent is preferably an ether solvent, more preferably diethyl ether, tetrahydrofuran, etc., and even more preferably tetrahydrofuran. The amount of the solvent used is usually 1 to 1000 times, preferably 1 to 100 times the volume of the halogen organic compound ArXa.

The reaction temperature in the production of the turbo-Grignard reagent is usually -50 to 50°C, preferably -20 to 20°C.
The reaction time is usually 0.5 to 5 hours, preferably 1 to 3 hours.

The turbo-Grignard reagent ArMgXa.LiY was prepared as described in Angew Chem. Int. According to the known method described in Ed 2006, 45, 2958, etc., the following formula:

As shown in, the compound may be produced by reacting Noschel-Hauser base TMPMgXa.LiY (TMP is 2,2,6,6-tetramethylpiperidine) with a compound Ar—H. Is also included.

A lithium salt complex of an organozinc compound can be produced by mixing a turbo Grignard reagent and zinc halide in a solvent. The reaction between the turbo-Grignard reagent and zinc halide is preferably carried out in an ether solvent (tetrahydrofuran or the like) as in the production of the turbo-Grignard reagent.

The reaction between the turbo-Grignard reagent and zinc halide can be usually performed at a temperature of about -30 to 30°C.
The reaction time is usually 0.1 to 1 hour.

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

The organozinc compound or its lithium salt complex may be added to the reaction system after mixing the transition catalyst and the compound (II), or may be mixed with the transition catalyst and the compound (II) at the same time. It is preferable that the transition catalyst and the compound (II) are mixed and then added to the reaction system.

In the step (a), zinc halide ZnX ₂ is added to the reaction system of the step (a) together with the organozinc compound or its lithium salt complex from the viewpoint of activating the organozinc compound and improving the yield. May be. 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 equivalent with respect to 1 equivalent of the organozinc compound or its lithium salt complex. , Preferably about 0.05 to 0.3 equivalents, more preferably about 0.05 to 0.2 equivalents. The zinc halide may be added to the reaction system of step (a) separately from the organozinc compound or the lithium salt complex thereof, or may be added simultaneously with the organozinc compound or the lithium salt complex thereof. It is preferable to add zinc oxide and an organozinc compound or a lithium salt complex thereof in a state of being premixed to the reaction system of step (a).

The reaction atmosphere is preferably an atmosphere of an inert gas such as argon or nitrogen in consideration of the activity of the transition catalyst. Further, it may be under pressure, normal pressure, or reduced pressure.

In one embodiment, the nickel catalyst is a nickel salt or solvate. The valence of the nickel atom contained in the nickel salt is usually divalent. Examples of the nickel salt include nickel (II) dichloride, nickel (II) dibromide, nickel (II) difluoride, nickel (II) iodide (NiI ₂ ), nickel (II) sulfate, nickel (II) carbonate, nickel (II) dimethyl. Glyoxime, nickel (II) hydroxide, nickel (II) hydroxyacetate, nickel (II) oxalate, nickel (II) 2-ethylhexanoate, nickel (II) acetate, nickel (II) trifluoroacetate, nickel Examples thereof include (II) triflate and nickel(II) acetylacetonate (Ni(acac) ₂ ).

In another embodiment, the nickel catalyst is a nickel complex catalyst. The nickel complex catalyst comprises a nickel atom and a ligand chelating to the nickel atom. The nickel complex catalyst can be advantageously used from the viewpoint of improving the reaction yield or reducing the by-products. The valence of the nickel atom in the nickel complex catalyst is preferably 0 or divalent, and more preferably divalent. The nickel atom contained in the nickel complex catalyst is derived from, for example, a nickel salt or a solvate added to the reaction system. In an embodiment in which the nickel catalyst is a nickel complex catalyst, a preformed nickel complex catalyst may be added to the reaction system, or a nickel salt or solvate and a ligand may be added to the reaction system. A nickel complex catalyst may be formed therein. When the nickel complex catalyst is formed in the reaction system, the amount of the ligand may be, for example, usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the nickel salt.

The ligand contained in the nickel complex catalyst is a molecule or ion bonded to the nickel atom by a coordinate bond. The ligand may be a monodentate ligand or a polydentate ligand. A monodentate ligand is a monodentate ligand. The polydentate ligand is a bidentate or higher-dentate ligand. The bidentate ligand is a ligand having two coordination atoms, the tridentate ligand is a ligand having three coordination atoms, and the tetradentate ligand is a coordination ligand. It is a ligand having four atoms. A coordinating atom is an atom that is directly involved in the coordination bond. In the nickel complex catalyst, the ratio of the ligand to the nickel atom is not particularly limited, but when the ligand is a monodentate ligand, the number of ligands per nickel atom is usually 2 to 4 And preferably two. Further, when the ligand is a polydentate ligand, it is preferable that one or more nickel atoms coordinate with each ligand. The number of nickel atoms per ligand is, for example, 1 to 3. Preferred ligands are phosphine ligands or nitrogen ligands.

Phosphine ligand is a ligand containing a phosphorus atom as a coordinating atom. The phosphine ligand may be a monodentate ligand or a polydentate ligand, but is preferably a polydentate phosphine ligand.

Examples of the phosphine ligand include trimethylphosphine, tri-n-butylphosphine (P ⁿ Bu ₃ ), tricyclopentylphosphine, tricyclohexylphosphine (PCy ₃ ), trioctylphosphine (P(Oct) ₃ ), triphenyl Monodentate coordination phosphines such as phosphine (PPh ₃ ); 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,2-bis(diphenylphosphino)ethane (dppe), 1,2-bis( Diphenylphosphino)butane (dppb), 1,2-bis(dicyclohexylphosphino)ethane (dcype), 1,2-bis(dimethylphosphino)ethane (dmpe), 3,4-bis(dicyclohexylphosphino)thiophene (Dcypt), 1,3-bis(diphenylphosphino)propane (dpppp), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), etc. Bis(2-diphenylphosphinoethyl)phenylphosphine, 1,1,1-tris(diphenylphosphinomethyl)ethane, 1,1,1-tris(bis(3,5-dimethylphenyl)phosphinomethyl)ethane And tridentate phosphine such as tris(2-diphenylphosphinoethyl)phosphine, and tridentate phosphine such as tris(2-diphenylphosphinoethyl)phosphine. Monodentate or bidentate of (diphenylphosphino)ethane, 1,2-bis(dicyclohexylphosphino)ethane, 1,2-bis(dimethylphosphino)ethane or 3,4-bis(dicyclohexylphosphino)thiophene Coordination phosphine, more preferably tridentate phosphine, 1,2-bis(dicyclohexylphosphino)ethane, or 3,4-bis(dicyclohexylphosphino)thiophene, or other bidentate phosphine. Preferred is 3,4-bis(dicyclohexylphosphino)thiophene.

The phosphine ligand also includes derivatives of the above phosphine ligand. Examples of derivatization of the phosphine ligand include introduction of one or more substituents. Examples of the one or more substituents introduced into the phosphine ligand include an alkyl group, an aryl group, an arylalkyl group, an alkylaryl group, an alkyloxy group, an alkyloxyalkyl group, an aryloxy group, an aryloxyalkyl group. , Halogen atoms, dialkyl groups, nitro groups, oxycarbonyl groups and the like.

A nitrogen ligand is a ligand containing a nitrogen atom as a coordinating atom. Nitrogen ligands are usually basic. The nitrogen ligand is, for example, an amine-based or imine-based polydentate ligand.

Examples of the nitrogen ligand 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)pyridylmethanimine, N-(n-octyl) Bidentate polydentate amines such as pyridylmethanimine, N,N,N′,N′-tetramethylethylenediamine (TMDTA); N,N,N′,N″,N″-pentamethyldiethylenetriamine( PMDTA), tridentate polydentate amines such as N-propyl-N,N-di(2-pyridylmethyl)amine; hexamethyltris(2-aminoethyl)amine, N,N-bis(2-dimethyl) Aminoethyl)-N,N'-dimethylethylenediamine, 2,5,9,12-tetramethyl-2,5,9,12-tetraazatetradecane, 2,6,9,13-tetramethyl-2,6 9,13-Tetraazatetradecane, 4,11-Dimethyl-1,4,8,11-tetraazabicyclohexadecane, N',N"-dimethyl-N',N"-bis((pyridine-2- Tetradentate coordination such as (yl)methyl)ethane-1,2-diamine, tris[(2-pyridyl)methyl]amine, 2,5,8,12-tetramethyl-2,5,8,12-tetraazatetradecane Polydentate amine; N,N,N′,N″,N′″,N″″,N″″-pentacoordinate tetradentate amine such as heptamethyltetraethylenetetramine; N , N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine and other hexadentate polydentate amines; polyamines, polyethylenimine and other polydentate amines, but preferably 2,2-bipyridine, It is a bidentate polydentate amine having a bipyridine group such as 4,4′-dimethyl-2,2′-bipyridine and 4,4′-di-tert-butyl-2,2′-bipyridine.

The nitrogen ligand also includes derivatives of the above nitrogen ligand. Examples of derivatization of the nitrogen ligand include introduction of one or more substituents. The one or more substituents introduced into the nitrogen ligand include, for example, an alkyl group, an aryl group, an arylalkyl group, an alkylaryl group, an alkyloxy group, an alkyloxyalkyl group, an aryloxy group, an aryloxyalkyl group. , Halogen atoms, dialkyl groups, nitro groups, oxycarbonyl groups and the like.

Other ligands contained in the nickel complex catalyst include cyclooctadiene (COD), tetrahydrofuran (thf), dimethoxyethane (dme) and the like.

Examples of the nickel catalyst used in the present invention include nickel (0) cyclooctadiene 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 Examples of the divalent nickel catalyst include a complex, nickel(II) dichloride 1,3-diphenylphosphinopropane complex, and bis(tetrahydrofuran) nickel(II) dichloride complex (NiCl ₂ (thf) ₂ ), but nickel is preferable. (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 more preferably bis(tetrahydrofuran) nickel(II) dichloride complex. Is. These may be used alone or in combination of two or more. The use of a nickel catalyst in step (a) is particularly advantageous in that the reaction proceeds rapidly.

Examples of the palladium catalyst used in the present invention include palladium(II) dichloride, palladium(II) dibromide, palladium(II) dichloride bistriphenylphosphine complex, palladium(0) tetrakistriphenylphosphine complex, and palladium(II) acetate. , Palladium(II) oxide, palladium(0), palladium(II) dichloride, palladium(II) dibromide, palladium(II) dichloride bistriphenylphosphine complex, palladium(0) tetrakistriphenylphosphine complex, palladium(II) acetate, Examples of the catalyst include zero-valent or divalent palladium catalysts such as palladium(II) oxide, and palladium(0) tetrakistriphenylphosphine complex and palladium(0) are preferable. The use of a palladium catalyst is advantageous in reducing the amount of by-products generated by the coupling reaction between Ar groups and the like.

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

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 palladium(0) tetrakistriphenylphosphine complex or bis(tetrahydrofuran) nickel(II) dichloride complex.

When the transition metal catalyst used in the present invention is a heterogeneous catalyst, the transition metal catalyst carries one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, and one or more transition metal catalysts. A supported catalyst having a carrier for Supported catalysts are advantageous because they facilitate the separation of the transition metal catalyst from the reaction mixture.

Examples of the carrier that the supported catalyst has include activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite, hydrotalcite, aluminum oxide, titanium dioxide, zirconium dioxide, silicon dioxide, clay, silicates, zeolites, polymer matrices, and the like. Are listed. The polymeric matrix may be, for example, a styrene-divinylbenzene resin or a phenol-formaldehyde resin, said resin having a chelating ligand (phosphine, 1,10-phenanthroline or 2,2'-bipyridine) attached thereto. May be The ligand bound to the resin forms a complex with a palladium catalyst or a nickel catalyst, and these transition catalysts can be immobilized to give a heterogeneous catalyst.

The transition metal catalyst in the supported catalyst is preferably a zero-valent or divalent palladium catalyst, more preferably palladium (0). When the transition metal catalyst of the supported catalyst is a palladium catalyst, the carrier in the supported catalyst is preferably activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyapatite and hydrotalcite, aluminum oxide, titanium dioxide, zirconium dioxide. Yes, and more preferably activated carbon. According to a particularly preferred embodiment, the supported catalyst is palladium black, palladium carbon (Pd/C).

The amount of the transition metal catalyst in the supported catalyst is, for example, 0.05 to 10% by weight, preferably 0.1 to 7% by weight, more preferably 4 to 7% by weight, based on the total weight of the supported catalyst.

The amount of the transition metal catalyst used is usually about 0.001 to 2 mol, preferably about 0.01 to 1 mol, based on 1 mol of the organozinc compound.

The solvent used in step (a) is preferably an organic solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane, tetrahydrofuran (THF), 2 A polar aprotic solvent such as -methyl-tetrahydrofuran, cyclopentyl methyl ether (CPME), tert-butyl methyl ether, diisopropyl ether, N,N-dimethylacetamide (DMA), diglyme, methyl-tetrahydrofuran, 1,4-dioxane; Nonpolar solvents such as toluene, methylene chloride, hexane, heptane, xylene, 1,4-dioxane, dibutyl ether, mesitylene, p-cymene, and the like, or a combination thereof can be mentioned, with preference given to THF, 2-methyl-THF and diethylene. Butyl ether, toluene, DMF or a mixed solvent thereof, and more preferably THF.

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

According to one embodiment, in step (a), the reaction temperature may be carried out at about 0 to 100°C, but is usually 0 to 60°C, preferably 0 to 50°C, more preferably 10 to 50°C. Is. Obtaining the compound (a) by adopting such a mild temperature condition is preferable from the viewpoint of suppressing the facility cost related to temperature control and implementing industrial production.

When the transition metal catalyst is a nickel catalyst, in step (a), the reaction temperature is preferably 0 to 50° C., more preferably 10 to 50° C., more preferably 20 to 30° C., and even more preferably Is about 25°C. 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 Is about 60°C.

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

In the step (b), the hydroxyl protecting group represented by R ⁵ in the compound (IV) obtained in the step (a) is removed to obtain the compound (I).

The method for removing R ⁵ is described in Peter G. M. It can be removed by a known method described in Wuts, "Protective Group in Organic Synthesis, 5th Edition" (published by JOHN WILEY & SONS) and the like. A typical method is a method of reacting compound (II) with an acidic reagent or a basic reagent in an inert solvent to remove R ⁵ .

Examples of the acidic reagent include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid and hydrogen bromide, and organic acids such as trifluoroacetic acid, trichloroacetic acid, p-toluenesulfonic acid, formic acid and phthalic acid. The basic reagent is not particularly limited, but tetra-n-butylammonium fluoride, ammonium fluoride, ammonium bifluoride, fluorides such as hydrofluoric acid, potassium carbonate, lithium hydroxide, sodium hydroxide. , Potassium hydroxide, sodium methyl oxide, sodium ethyl oxide, aqueous ammonia and the like.

The amount of the acidic reagent used is usually 0.1 to 1000 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (II). The amount of the basic reagent used is usually 0.001 to 10 equivalents, preferably 0.01 to 2 equivalents, relative to 1 equivalent of the compound (II).

The solvent used in step (b) is preferably an organic solvent, and examples thereof include polar protic solvents such as methanol, ethanol, isopropanol, butanol; 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, butyl acetate and other polar aprotic solvents: methylene chloride, chloroform, tetrachloride Examples thereof include nonpolar solvents such as carbon, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, heptane, and combinations thereof, with preference given to methanol, ethanol, isopropanol or a mixed solvent thereof.

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

In the step (b), the reaction temperature is usually −30 to 100° C., preferably 0 to 100° C., more preferably 0 to 40° C., and even more preferably 0 to 50° C. Obtaining the compound (I) by adopting such a mild temperature condition is preferable in order to suppress the facility cost related to temperature control and to carry out industrial production.

In the method for producing compound (I), compound (II) used as a starting material may be purchased or produced, but it is preferably produced according to step (a-1).

The step (a-1) can be carried out separately in the following step (a-1-1) and step (a-1-2).
Step (a-1-1): The following formula (VI):

A compound (VI) represented by
The following formula (VII):

And a compound (VII) represented by
After reaction, the following formula (VIII):

A step of obtaining a compound (VIII) represented by: and a step (a-1-2): protecting the hydroxyl group in the compound (VIII) with a hydroxyl-protecting group represented by R ⁵ to obtain the compound (II) Process.

In step (a-1-1), the step of reacting compound (VI) with compound (VII) to give compound (VIII) is carried out.

The compound (VI) used as a starting material in the step (a-1-1) is not particularly limited, and examples thereof include known methods described in Non-Patent Document 1 and Non-Patent Document 2 and Example 1 described later. It may be produced by the method described or a commercially available product may be used.

The compound (VII) may also be produced by a known method, or a commercially available organic thiol compound may be used.

The amount of the compound (VII) to be used is not particularly limited, but is, for example, usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (VI).

The reaction conditions of the compound (VI) and the compound (VII) are not particularly limited as long as the compound (VIII) can be obtained, but the following formula (IX):

It is preferable to carry out in the presence of a compound (IX) represented by The method for obtaining the compound (IX) is not particularly limited, and the compound (IX) may be produced by a known method, or a commercially available aluminum catalyst may be used.

R ^c and R ^d each independently represent 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. The aliphatic hydrocarbon group, aromatic hydrocarbon ring group, aliphatic heterocyclic group and aromatic heterocyclic group included in the above group may each have one or more substituents.

The functional groups represented by R ^c and R ^d are each independently preferably an alkyl group, an aryl group or an arylalkyl group, more preferably an alkyl group having 1 to 20 carbon atoms or a carbon atom having 6 to 20 carbon atoms. An aryl group and an arylalkyl group having 7 to 20 carbon atoms, more preferably an alkyl group having 1 to 10 carbon atoms, and even more preferably a methyl group, an ethyl group and a propyl group.

In the formula (IX), the functional group represented by R ^c and the functional group represented by R ^d may be the same or different, but are preferably the same.
Moreover, according to a preferable aspect, one of q and r represents 0, and the other represents 3.

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

The solvent used in step (a-1-1) is preferably an organic solvent, for example, 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, butyl acetate and other polar aprotic solvents; methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Non-polar solvents such as toluene, xylene, hexane, heptane and combinations thereof can be mentioned, but methylene chloride, toluene, hexane or a mixed solvent thereof is preferable, and methylene chloride is more preferable.

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

In step (a-1-1), the reaction temperature is not particularly limited, but is usually −30 to 80° C., preferably −10 to 40° C., more preferably 0 to 40° C. It is preferable to adopt a relatively mild temperature condition in this step from the viewpoint of suppressing the equipment cost related to temperature management.

In the step (a-1-1), water, HCl aqueous solution, ammonium chloride aqueous solution or the like can be used to terminate the reaction of the aluminum catalyst and the catalyst can be easily removed.

Therefore, in this step (a-1), after the compound (VIII) is obtained, the production step of the next step (a-1-2) is preferably carried out as quickly as possible. ) And step (a-1-2) are more preferably carried out in the same reaction system. Promptly shifting from step (a-1-1) to step (a-1-2) is advantageous in preventing compound (VI) from being regenerated due to the ring closure reaction of compound (VIII). ..

In the step (a-1-2), the following formula (VIII):

The hydroxyl group in the compound (VIII) represented by is protected by a hydroxyl protecting group represented by R ⁵ to obtain the compound (II).

Introduction of the R ⁵ group to the hydroxyl group in the compound (VIII) is not particularly limited, and depending on the kind of the hydroxyl group-protecting group represented by R ⁵ , Peter G. M. It can be carried out by a known method described in Wuts, "Protective Group in Organic Synthesis, 5th Edition" (published by JOHN WILEY & SONS) and the like. As a typical method, a method of introducing R ⁵ by reacting compound (VIII) with a protecting group introducing reagent in the presence of an acid or a basic reagent in an inert solvent can be mentioned.

The protective group-introducing reagent can be appropriately determined according to the type of R ⁵ , and examples thereof include ester-type protective group-introducing agents such as acetic anhydride, pivalic anhydride, acetyl chloride, pivaloyl chloride; benzyl bromide and the like. Arylalkyl ether type protecting group introducing agent; alkyl ether type protecting group introducing agent such as iodomethane; silyl type protecting group introducing agent such as trimethylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride Examples thereof include oxycarbonyl-type protecting groups such as bis(tert-butyloxycarbonyloxy)oxide, etc., preferably acetic anhydride, pivalic anhydride, acetyl chloride, pivaloyl chloride and other ester-type protecting group introducing agents, More preferably, it is acetic anhydride.

Examples of acidic reagents include inorganic acids such as acetic acid and hydrogen bromide, and organic acids such as p-toluenesulfonic acid and phthalic acid. Examples of the basic reagent include, but are not limited to, triethylamine, 4-dimethylaminopyridine (DMAP), diazabicycloundecene (DBU), organic amines such as diethylaniline, and the like, with preference given to triethylamine and 4-dimethyl. Aminopyridine (DMAP) or a mixture thereof.

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

The solvent used in step (a-1-2) is preferably an organic solvent, for example, 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, butyl acetate and other polar aprotic solvents; methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Nonpolar solvents such as toluene, xylene, hexane, heptane and the like can be mentioned, but methylene chloride, toluene or a mixed solvent thereof is preferable.

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

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., further preferably 0 to 30. ℃. It is advantageous to employ a relatively mild temperature condition also in this step, in order to suppress the reaction of the return of the compound (VIII) to the compound (VI). Further, it is preferable to adopt a relatively mild temperature condition also in this step, in order to suppress the facility cost related to temperature management and to carry out industrial production.

The compound (I) in the present invention has the following formula (XI):

It can be advantageously used as a starting material for the production of the compound (XI) represented by, that is, a β-C-arylglycoside derivative.

A known reduction reaction can be used for the reaction from compound (I) to compound (XI). Specifically, as the reduction method, a method of reducing the compound (I) using triethylsilane in the presence of a boron trifluoride diethyl ether complex (BF ₃ ·OEt ₂ ), triethylsilane, triisopropylsilane, Examples include a method of reacting a compound (I) with a Lewis acid such as BF ₃ ·OEt ₂ , boron trifluoride tetrahydrofuran (BF ₃ ·THF), and aluminum chloride in the presence of a silane compound such as tetramethyldisiloxane. ..

The obtained compound (XI) was used as it is, or when R ¹ ′, R ² ′, R ³ ′ or R ⁴ ′ was a hydroxyl-protecting group, if desired, Peter G. M. Deprotection by a known method described in Wuts, "Protective Group in Organic Synthesis, 5th Edition" (published by JOHN WILEY & SONS) and the like, and β-C-arylglycoside. It can be used as a derivative.

<Use of compound (II)/manufacturing intermediate>
According to the present invention, as described above, compound (II) can be used as a production intermediate to produce compound (I), which can be further converted to compound (XI) which is the SGLT2 inhibitor itself or a synthetic intermediate thereof. it can. That is, according to the present invention, compound (II) can be preferably applied as a reagent or an intermediate for the production of compound (XI).

Therefore, according to a preferred embodiment of the present invention, the following formula (II):

A compound represented by the following formula (XI):

A reagent for producing the compound (XI) represented by Further, according to a preferred aspect of the present invention, in the reagent, Ar in the formula (XI) is represented by the formula (V) or (Va).

According to another aspect of the present invention, a compound of the following formula (XI):

As an intermediate for the production of the compound (XI) represented by
Formula (II) below:

The use of the compound (II) represented by Further, according to a preferred embodiment of the present invention, in the use, Ar in formula (XI) is represented by formula (V) or (Va).

Examples of the present invention will be described below, but the present invention is not limited to these examples.

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

A solution containing the compound (1) (2,3,4,6-tetra-O-benzyl-D-glucopyranose; 5.0 g, 9.24 mmol) in dimethyl sulfoxide (25 mL) was added under argon atmosphere at 20- The mixture was stirred at 25°C for 30 minutes. Acetic anhydride (15 mL) was added to this reaction mixture at 25° C. over 5 minutes. After the addition was complete, the resulting reaction mixture was stirred at 20-25° C. for 20 hours while being monitored by thin layer chromatography (TLC) analysis. Then, the reaction mixture was diluted with toluene (100 mL), and 1N HCl aqueous solution (120 mL) was added to the obtained diluted solution to quench excess acetic anhydride. The resulting reaction mixture was stirred at 20-25°C for 20 minutes and then phase separated. The resulting organic phase was washed with 1M aqueous NaHCO ₃ solution (3 x 50 mL). The organic phase was further washed with water (15 mL) and brine (15 mL), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/hexane=2/20 to 3/20) to give compound (2) as a colorless oil ((3R, 4S, 5R, 6R)-3, 4,5-Tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one; 4.8 g, yield 96%) was obtained.

Compound (2)
IR(KBr): νmax=3030, 2868, 1754, 1496, 1363, 1164, 1097, 737, 698 cm ^-1
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.39-7.16 (m, 20H), 4.97 (d, J=11.4 Hz, 1H), 4.73-4.44 (m, 8H) ), 4.12 (d, J=6.3 Hz, 1H), 3.96-3.89 (m, 2H), 3.73-3.64 (m, 2H)
¹³ C NMR (101 MHz, CDCl ₃ ) 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 O 6 Calculated 539.2428; Found: 539.2420
Mass spectrum [M+H] ⁺ : 539

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

To a solution containing decanethiol (0.72 g, 4.1 mmol) in anhydrous CH ₂ Cl ₂ (10 mL) cooled to 0° C. was added trimethylaluminum (1M toluene solution; 4.1 mL, 4.1 mmol) for 10 minutes. It dripped over, and stirred for 20 minutes. Then, to the obtained reaction mixture, a solution containing compound (2) (2 g, 3.71 mmol) in anhydrous CH ₂ Cl ₂ (12 mL) was slowly added over 10 minutes, and the mixture was stirred for 1 hour. did. The obtained reaction mixture was diluted with CH ₂ Cl ₂ (20 mL) and added to a 250 mL beaker containing ice-cold water (20 mL), and 1N HCl aqueous solution (10 mL) was slowly poured into the beaker while stirring to perform phase separation. It was The resulting aqueous phase was extracted with cold _{_{CH 2 Cl 2 (3 × 30mL}} ). The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ and filtered through a flash silica column using CH ₂ Cl ₂ as eluent to give compound (3)((2R , 3S,4R,5R)-S-decyl 2,3,4,6-tetrakis(benzoyloxy)-5-hydroxyhexanethioate) was obtained. Thereafter, the obtained crude product of compound (3) was used in the next step without purification.

Example 3: Preparation of compound (4) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-(decylthio)-6-oxohexan-2-ylacetate)

For a solution of the crude product of compound (3) (2.8 g, 3.71 mmol) in anhydrous CH ₂ Cl ₂ cooled to 0° C. under argon atmosphere, acetic anhydride (Ac ₂ O; 88 mL, 9.5 mmol) was added, and further DMAP (9 mg, 2 mol%) was added. After 5 minutes, triethylamine (1.32 mL, 9.5 mmol) was added to the obtained mixed solution, 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 CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases of the organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained crude product was purified by silica chromatography (ethyl acetate/hexane=1/20 to 2/20) to obtain compound (4) ((2R,3R,4S,5R)-1,3, as a colorless liquid. 2.6 g of 4,5-tetrakis(benzoyloxy)-6-(decylthio)-6-oxohexan-2-yl acetate were obtained, and the yield was 92% based on the compound (2).

Compound (4)
IR (KBr): νmax=3063, 3031, 2926, 2860, 1745, 1676, 1452, 1375, 1244, 1093, 1069, 745, 696 cm ^-1
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.40 (d, J=6.5 Hz, 2 H), 7.36-7.15 (m, 18 H), 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=4.3 Hz, 1H), 4.01-3.95 (m, 2H), 3.82 (dd, J=10.6, 4.1 Hz, 1H), 3.65 (dd , J=10.6, 5.7 Hz, 1H), 2.84 (t, J=7.4 Hz, 2H), 1.96 (s, 3H), 1.55 (p, J=7.3 Hz, 2H), 1.41-1.18 (m, 15H), 0.88 (t, J=6.7Hz, 3H)
¹³ C-NMR (101 MHz, CDCl ₃ ) δ: 201.90, 170.02, 138.51, 138.08, 137.98, 137.08, 128.65, 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 O 7 S Calculated 755.3981; Found: 755.3976
Mass spectrometry [M+H] ⁺ : 755

Example 4: Nickel (II) acetylacetonate (Ni(acac) _２Two Compound) (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-yl acetate)

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

Compound (5)
IR (KBr): νmax=3027,2870,1735,1724,1449,1369,1236,1090,1027,738,696 cm ⁻¹
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.92 (d, J=7.8 Hz, 2 H), 7.47 (t, J=7.4 Hz, 1 H), 7.37-7.22 ( m, 15H), 7.21 to 7.11 (m, 5H), 7.06 to 7.00 (m, 2H), 5.27 (q, J=5.2Hz, 1H), 4.89 ( d, J=4.2 Hz, 1H), 4.73-4.55 (m, 4H), 4.53-4.46 (m, 3H), 4.31 (d, J=10.8 Hz, 1H) ), 4.21 (dd, J=6.8, 4.3 Hz, 1H), 4.07 (dd, J=6.8, 3.4 Hz, 1H), 3.87 (dd, J=10. 2,5.4 Hz, 1H), 3.63 (dd, J=10.2, 5.5 Hz, 1H), 1.98 (s, 3H)
¹³ C-NMR (101 MHz, CDCl ₃ ) δ: 198.88, 169.94, 138.43, 137.88, 137.77, 137.10, 136.05, 133.06, 128.96, 128. 76,128.45,128.35,128.31,128.26,128.19,128.05,127.92,127.80,127.73,127.70,127.49,127.45, 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 O 7 Calculated 659.3009; Found: 659.3004
Mass spectrum [M+H] ⁺ : 659

Example 5: Nickel (II) dichloride (NiCl _２Two Of compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-ylacetate)

A Schlenk tube dried in a hot oven was charged with Compound (4) (0.25 mmol, 190 mg) under an argon atmosphere, followed by NiCl ₂ (0.0125 mmol, 3.2 mg) and THF (2 mL). The resulting mixture was stirred for 5 minutes, and then a THF solution (0.125M) of a complex ZnCl.LiCl (0.375 mmol, 3 mL) of Ph organozinc compound and lithium chloride was added with a syringe. The resulting reaction mixture was stirred at 25°C for 1 hour. Then the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 30 mL). The organic extract was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/hexane=1/20 to 2/20) to give compound (5) ((2R,3R,4S,5R)-1,3,4,4). 5-Tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-yl acetate; 96 mg, 0.145 mmol, yield 58%) was obtained. In addition to the compound (5), the 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 added. Obtained.

Example 6: Nickel (II) dichloride (dimethoxyethane adduct) (NiCl _２Two (Dme)) (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-ylacetate) Manufacturing of

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

Example 7: Study on nickel catalyst

Example 6 except that PhZnCl·LiCl in Example 6 was changed to PhZnBr and NiCl ₂ (dme) was changed to the nickel catalyst (Ni cat.) or the combination of nickel catalyst and ligand shown in Table 1. Compound (5) was synthesized in THF (3 mL) by the same operation.

The results are shown in Table 1. The yield of the compound (5) in the test number 6 using the combination of the nickel catalyst NiCl ₂ (thf) ₂ and the ligand PPh ₃ was higher than the yields of the test numbers 1 to 5 and 7.

The yield of the by-product biphenyl Ph-Ph in Test No. 6 was 20%, which was lower than the yields of the by-product biphenyl Ph-Ph in Test Nos. 1 to 5 and 7.

Example 8: Examination of Ligands in Nickel Catalyst In Test Nos. 7 to 11 shown in Table 2, the same operation as Test No. 6 in Example 7 was performed except that the ligands were changed to those shown in Table 2. Then, the compound (5) was synthesized. Further, in Test No. 12, except for changing the nickel catalyst NiCl ₂ _{(thf) 2} in Ni _{(COD) 2,} was synthesized compound (5) in the same operation as test No. 11.

The results are shown in Table 2. The yield of the compound (5) in Test Nos. 10, 11 and 12 using the bidentate phosphine ligand was higher than that in Test No. 6.

The yields of the by-product biphenyl Ph-Ph in Test Nos. 8, 9, 10, 11 and 12 using the bidentate phosphine ligand were 18%, 10%, 16%, 9% and 14%, respectively. And the yield was lower than 20% in the test number 6 using the monodentate phosphine ligand.

Example 9: Examination of reaction temperature in reaction system using nickel catalyst In Test Nos. 13 and 14 shown in Table 3, the same as Test No. 11 in Example 8 except that the reaction temperature was changed to that shown in Table 3. Compound (5) was synthesized by the operation of. In Test Nos. 15 and 16, compound (5) was synthesized in the same manner as in Test Nos. 11 and 14, except that the ligand dcype was changed to dcypt. The results are shown in Table 3.

The results are shown in Table 3. The yield of the compound (5) in Test Nos. 11 and 15 performed at the reaction temperature of 25° C. was higher than that in Test Nos. 13, 14 and 16 performed at the reaction temperature of 0° C. or 50° C. ..

The yields of the by-product biphenyl Ph-Ph in Test Nos. 11 and 15 conducted at the reaction temperature of 25°C were 9% and 16%, respectively, and the test numbers conducted at the reaction temperature of 0°C or 50°C. It was low compared to the yield of the by-product biphenyl Ph-Ph in 13, 14 and 16.

Example 10: Examination of Ligands in Nickel Catalysts Test Nos. 17 to 19 shown in Table 4 were conducted in the same manner as Test No. 11 of Example 8 except that the ligands were changed to those shown in Table 4. Then, the compound (5) was synthesized.

The results are shown in Table 4. It was confirmed that the reaction also proceeded in Test Nos. 17 to 19 using the dipyridine type ligand.

The yields of the by-product biphenyl Ph-Ph in Test Nos. 17, 18 and 19 were 32%, 21% and 18%, respectively.

Example 11: Compound (5) using Pd/C ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-yl Production of acetate)

A Schlenk tube dried in a hot oven was charged with compound (4) (0.25 mmol, 190 mg) under an argon atmosphere, followed by Pd/C (0.0025 mmol, 3 mg) and THF (2 mL). The obtained reaction mixture was stirred for 5 minutes, and then a THF solution (0.125M) of a complex PhZnCl.LiCl (0.375 mmol, 3 mL) of an organozinc compound and lithium chloride was added with a 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 x 30 mL). The organic extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/hexane=1/20 to 2/20) to give compound (5) ((2R,3R,4S,5R)-1,3,4,4). 5-Tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-yl acetate; 110 mg, 0.167 mmol, yield 67%) was obtained. In addition to the compound (5), an unreacted compound (4) (58 mg, 0.077 mmol, yield 31%) and a by-product biphenyl Ph-Ph (3 mg, 0.0187 mmol, yield 10%) were obtained. ..

Example 12: Compound (5) using Pd/C ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-yl Production of acetate)

A Schlenk tube dried in a hot oven was charged with compound (4) (0.25 mmol, 190 mg) under an argon atmosphere, followed by Pd/C (0.05 mol, 6 mg) and THF (2 mL). The obtained reaction mixture was stirred for 5 minutes, and then a THF solution (0.125M) of a complex PhZnCl.LiCl (0.375 mmol, 3 mL) of an organozinc compound and lithium chloride was added with a 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 x 30 mL). The organic extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained 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 to the compound (5), an unreacted compound (4) (49 mg, 0.065 mmol, yield 26%) and a by-product biphenyl Ph-Ph (5 mg, 0.032 mmol, yield 17%) were obtained. ..

Example 13: Examination of reaction conditions of a reaction system using Pd/C

In Test Nos. 20 to 25 shown in Table 5 below, the compounds were prepared in the same manner as in Example 12 except that the organozinc compound, the presence or absence of an additive, the reaction temperature and the reaction time were changed as shown in Table 5. (5) was synthesized. In Test No. 23 and Test No. 24, an additive (DMF) was added to the reaction mixture using a THF solution of the PhZnCl.LiCl solution and then using a syringe. In Test No. 25, an additive (ZnBr ₂ ) was added to the reaction mixture using a THE solution containing PhZnBr and ZnBr ₂ described in Example 20 described later in place of the THF solution of PhZnCl·LiCl.

The results are shown in Table 5. Test number 25 in which PhZnBr was used as the organozinc compound and ZnBr ₂ was added showed a higher yield of compound (5) compared to test numbers 20 to 24 in which PhZnCl.LiCl was used as the organozinc compound.

Example 14: Examination of reaction conditions in a reaction system using Pd/C

In Test Nos. 20 to 25 in Table 6, compound (5) was synthesized by the same operation 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. went.

The results are shown in Table 6. Test Nos. 24 and 25 conducted at the reaction temperature of 60° C. showed higher yields of the compound (5) compared with Test Nos. 20 to 23 conducted at the reaction temperature of 40 to 50. Moreover, the test number 25 using 2 equivalents of PhZnBr had a higher yield of the compound (5) than the test number 24 using 1 equivalent of PhZnBr.

Example 15: Compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzoyloxy) using a palladium(0) tetrakistriphenylphosphine complex (Pd(PPh ₃ ) ₄ ). )-6-Oxo-6-phenylhexan-2-yl acetate)

A Schlenk tube dried in a hot oven was charged with compound (4) (0.25 mmol, 190 mg) under an argon atmosphere, followed by Pd(PPh ₃ ) ₄ (0.0125 mol, 15 mg) and THF (2 mL). .. The obtained reaction mixture was stirred for 5 minutes, and then a THF solution (0.125M) of a complex PhZnCl.LiCl (0.375 mmol, 3 mL) of an organozinc compound and lithium chloride was added with a 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 x 30 mL). The organic extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/hexane=1/20 to 2/20) to give compound (5) ((2R,3R,4S,5R)-1,3,4,4). 5-Tetrakis(benzoyloxy)-6-oxo-6-phenylhexan-2-yl acetate; 89 mg, 0.135 mmol, yield 54%) was obtained. An unreacted compound (4) (80 mg, 0.105 mmol, yield 42%) was obtained together with the compound (5).

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

A Schlenk tube dried in a hot oven was charged with the compound (5) (0.2 mmol, 132 mg) 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. Then the reaction mixture was filtered through a layer of silica and washed with methanol (3 x 20 mL). Next, the obtained solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane=4/20 to 8/20) to give compound (6) (2,3,4,6-tetra-O-benzyl-1C-) as a colorless liquid. Phenyl glucose; 112 mg, 0.182 mmol, yield 91%) was obtained.

Compound (6)
IR (KBr): νmax=3411, 3027, 2923, 1590, 1494, 1452, 1361, 1212, 1093, 734, 696 cm ^-1
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.64 (d, J=7.0 Hz, 2 H), 7.38-7.13 (m, 21 H), 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, 1H), 4.38( d, J=10.4 Hz, 1H), 4.17 (d, J=8.2 Hz, 1H), 4.07 (t, J=9.2 Hz, 1H), 3.84-3.79 (m , 3H), 3.70 (d, J=10.9 Hz, 1H), 3.53 (d, J=9.4 Hz, 1H), 3.34 (s, 1H).
¹³ C-NMR (101 MHz, CDCl ₃ ) δ:142.47,138.85,138.58,138.45,137.59,128.61,128.47,128.42,128.26,128. 23, 128.03, 127.79, 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 [M-H] -:}} C 40 H 39 O 6 Calculated 615.2747; Found: 615.2743
Mass spectrometry [MH] ^- : 615

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

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

When the reaction solution was analyzed by HPLC, the compound (6) was completely consumed and the peak of the compound (7) was confirmed.

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

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

Compound (7)
¹ H-NMR (CDCl ₃ ) δ: 3.50-3.55 (m, 1H), 3.60-3.61 (m, 1H), 3.73-3.82 (m, 5H), 4 0.25 (d, J=9.3 Hz, 1H), 4.36 (d, J=10.3 Hz, 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)

Example 18: Preparation of complex PhZnCl/LiCl of organozinc compound and lithium chloride

Scrap metal Mg (372 mg, 15.3 mmol, 1.5 eq) and lithium chloride (LiCl; 540 mg, 12.75 mmol, 1.25 eq) are put into a 50 mL dry Schlenk tube containing a magnetic stir bar and gloved. It was placed in a box and dried with a hot gun. Next, after injecting argon 3 times into a warm flask, dry THF (8 mL) and diisobutylaluminum hydride (DIBAL-H; 0.1 M THF solution 0.1 mL, 1 mol%) were added at room temperature, and the mixture was heated at 5-10%. Stir for minutes. The Schlenk tube was then cooled to 0° C. and bromobenzene (1.1 mL, 10.2 mmol, 1.0 eq) 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). The 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 adjust the concentration to about 1M. The resulting solution containing the complex of Grignard reagent and lithium chloride was added to a dry THF solution containing ZnCl ₂ (1 equivalent to the Grignard reagent) at room temperature and stirred for 15 minutes to give 0.125M A solution containing the target complex PhZnCl.LiCl was obtained. The solution concentration was adjusted based on the titration concentration of the corresponding Grignard reagent and the dilution rate after transmetallation.

Example 19: Preparation of phenyl zinc bromide (PhZnBr)

Phenylmagnesium bromide (Grignard reagent) was diluted with dry THF and titrated with LiCl and iodine to prepare a THF solution of Grignard reagent having a concentration of about 0.5M. The THF solution of the obtained Grignard reagent was added to a dry THF solution containing ZnBr ₂ (1 equivalent to the Grignard reagent) at 25° C. and stirred for 1 hour to carry out transmetallation to obtain a 0.25 M solution. A THF solution containing PhZnBr was obtained. The solution concentration was adjusted based on the titration concentration of the corresponding Grignard reagent and the dilution rate after transmetallation.

Example 20: A THF solution of phenyl zinc bromide (PhZnBr) and phenyl magnesium bromide prepared 0.5M concentration of THF solution containing zinc bromide (ZnBr ₂₎ (Grignard reagent), in dry THF solution containing ZnBr ₂ A THF solution containing 0.25M PhZnBr and ZnBr ₂ (0.1 equivalent excess with respect to PhZnBr) was obtained by performing transmetallation by adding at 25° C. and stirring for 1 hour. The solution concentration was adjusted based on the titration concentration of the corresponding Grignard reagent and the dilution rate after transmetallation.

Example 21: Preparation of compound (9) (aryl zinc bromide)

I-Propyl in THF (0.8 mL, 1.6 mmol, 1.06 eq) against a solution of anhydrous lithium chloride (65 mg, 1.53 mmol, 1.02 eq) in anhydrous THF (2 mL) under argon atmosphere. A 2.0 M solution of magnesium chloride was added at 0°C. Compound (8) (2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene; 612 mg, 1.5 mmol, 1 eq) in anhydrous THF (5 mL) at 0° C. with argon. The reaction mixture was allowed to come to room temperature and stirred for 1 hour. The resulting reaction solution was transmetallated by adding ZnBr ₂ (372 mg, 1.65 mmol, 1.1 eq) in dry THF (5 mL) to a solution of compound (9) to give a solution of Used in the process.

Example 22: Compound (10)((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzyloxy)-6-(3-((5-(4-fluorophenyl)thiophene-2 -Yl)methyl)-4-methylphenyl)-6-oxohexan-2-ylacetate)

The solution of compound (9) obtained in Example 21 was added dropwise to a Schlenk tube containing compound (4) (566 mg, 0.75 mmol, 0.5 eq) in THF (5 mL). The reaction was stirred for 36 hours at 25° C., then the reaction was quenched with water (1 mL), the reaction mixture was filtered through Celite™, washing with ethyl acetate (3×100 mL). The filtrate was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/hexane=1/20 to 3/20) to obtain compound (10) (492 mg, 0.57 mmol, 76%).

Compound (10)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.50 (d, J=1.3 Hz, 1 H), 7.43 (dd, J=7.8, 1.6 Hz, 1 H), 7.41- 7.14 (m, 21H), 7.07-7.04 (m, 2H), 7.00-6.93 (m, 3H), 6.60 (d, J=3.5Hz, 1H), 4.95-4.84 (m, 3H), 4.70-4.59 (m, 3H), 4.42 (d, J=10.4Hz, 1H), 4.19-4.14 (m , 2H), 4.04 (d, J=16.0 Hz, 1H), 3.91 (d, J=10.4 Hz, 1H), 3.89-3.74 (m, 4H), 3.40. (D, J=9.6 Hz, 1H), 3.16 (s, 3H), 2.34 (s, 3H)
¹³ C-NMR (101 MHz, CDCl ₃ ) δ: 198.51, 170.08, 162.2 (d, J=245.3 Hz), 142.69, 142.60, 141.79, 138.64, 138. .55, 138.06, 137.99, 137.36, 134.54, 130.84 (d, J=3.4 Hz), 130.68, 130.31, 128.76, 128.53, 128. 42, 128.38, 128.29, 128.17, 127.98, 127.91, 127.88, 127.79, 127.58, 127.55, 127.22 (d, J=8.0 Hz). , 126.24, 122.83, 115.82 (d, J=21.8 Hz), 82.94, 80.68, 79.52, 75.51, 74.64, 73.26, 73.15, 72.72, 68.12, 34.14, 21.21, 19.88
HRMS [M+Na] ⁺ C ₅₄ H ₅₁ FO ₇ SNa calcd 885.3237; found 885.3229.

Example 23: Production of compound (11)

The Schlenk tube dried in a hot oven was cooled to room temperature and the Schlenk tube was charged with compound (10) (173 mg, 0.2 mmol) in MeOH (5 mL). NaOMe (11 mg, 0.2 mmol) was added to the obtained solution under an argon atmosphere, and the reaction solution was stirred at 25° C. for 6 hours. Then, the reaction solution was neutralized with a 1N HCl (2 mL) aqueous solution. Next, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (ethyl acetate/hexane=2/20 to 8/20) to obtain compound (11) (142 mg, 0.172 mmol, 86%) as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.52 (s, 1H), 7.47-7.43 (m, 1H), 7.39-7.09 (m, 21H), 7.03. -6.89 (m, 5H), 6.61 (d, J=3.5Hz, 1H), 4.89-4.86 (m, 3H), 4.68-4.62 (m, 2H) , 4.53 (d, J=12.3 Hz, 1H), 4.38 (d, J=10.6 Hz, 1H), 4.19-4.03 (m, 4H), 3.94 (d, J=10.5Hz, 1H), 3.87-3.82(m, 2H), 3.71(d, J=11.1Hz, 1H), 3.60(d, J=9.3Hz, 1H ), 3.08 (s, 1H), 2.33 (s, 3H)
¹³ C-NMR (101 MHz, CDCl ₃ ) δ: 162.18 (d, J=246.6 Hz), 143.59, 141.58, 140.59, 138.86, 138.75, 138.50, 138. .13, 137.77, 136.95, 130.94 (d, J=3.3 Hz), 130.59, 128.52, 128.50, 128.44, 128.38, 128.28, 128. 08,127.87,127.82,127.73,127.67,127.57,127.20 (d, J=8.0 Hz), 125.94, 124.97, 122.78, 115.77. (D, J=21.6 Hz), 98.03, 85.55, 83.63, 78.53, 77.48, 77.16, 76.84, 75.84, 75.68, 75.18, 73.52, 72.39, 69.11, 34.48, 19.37
HRMS [M+Na] ⁺ : C ₅₂ H ₄₉ FO ₆ SNa calcd 843.3132, found 843.3123.

Example 24: Compound (12)((2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-((5-( Preparation of 4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran)

Under an argon atmosphere, Et ₃ SiH (88 μL, 0.55 mmol) was added to a solution of compound (11) (150 mg, 0.18 mmol) in acetonitrile/dichloromethane (3:2) (10 mL), and the reaction was then allowed to- After cooling to 40° C., BF ₃ .Et ₂ O (70 μL, 0.56 mmol) was added dropwise to the reaction solution. The reaction was then stirred for 6 hours, NaHCO ₃ aqueous solution (20 mL) was slowly added to the reaction at 0° C., and the aqueous phase was extracted with dichloromethane (3×40 mL). After phase separation, the aqueous phase was discarded and the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate/hexane=2/20 to 6/20) to obtain compound (12) (133 mg, 0.164 mmol, 90%) as a colorless gum, as it was. Used in the next step.
HRMS [M+Na] ⁺ : C ₅₂ H ₄₉ FO ₅ SNa calcd 827.33182, found 827.3176.

Example 25: Compound (13) ((2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl-4-methylphenyl)-6 -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; canagliflozin)

Iodotrimethylsilyl (0.110 ml, 0.744 mmol) was added slowly at 0° C. to a solution of compound (12) (100 mg, 0.124 mmol) in dichloromethane (5 mL) under argon atmosphere. After the addition was complete, the reaction was warmed to 25°C and stirred for 8 hours. The reaction solution was concentrated. The obtained crude product was purified by silica gel column chromatography (MeOH/DCM=1/30 to 1/20) to obtain compound (13) (51 mg, 93%).

¹ H-NMR (400 MHz, DMSO-d ₆ )δ:7.61-7.57 (m, 2H), 7.27 (d, J=4.4 Hz, 1H), 7.22-7.10 ( m, 5H), 6.79 (d, J=3.6Hz, 1H), 4.99 (br, 2H, OH), 4.79 (br, 1H, OH), 4.45 (br, 1H, OH), 4.15 (d, J=16 Hz, 1H), 4.09 (d, J=16 Hz, 1H), 3.96 (d, J=9.6 Hz, 1H), 3.69 (d, J=11.2 Hz, 1H), 3.46-3.41 (m, 1H), 3.29-3.14 (m, 4H), 2.26 (s, 3H)
¹³ C-NMR (101 MHz, DMSO-d ₆ )δ: 161.4 (d, J=243 Hz), 143.63, 140.22, 138.21, 137.35, 134.93, 130.53 (d , J=3.1 Hz), 129.65, 129.05, 126.95 (d, J=8 Hz), 126.34, 126.23, 123.38, 115.86 (d, J=21.6 Hz). ), 81.31, 81.17, 78.48, 74.68, 70.44, 61.45, 33.44, 18.79.
HRMS [M+Na] ⁺ : C ₂₄ H ₂₅ FO ₅ SNa calc. 467.1304; found: 467.1299.

Example 26: Preparation of compound (15) (aryl zinc bromide)

A Schlenk tube dried in a hot oven was cooled under an argon atmosphere to give compound (14) (4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene: 0.163 g, 0.5 mmol) and magnesium-like cuttings. (0.1 g, 4.1 mmol) was added, followed by anhydrous THF (5 mL) and 1,2-dibromoethane (0.05 mL). The reaction was heated to reflux to start the reaction. After the reaction started, additional compound (8) (0.49 g, 1.5 mmol) in anhydrous THF (10 mL) was added dropwise to the reaction solution under an argon atmosphere, and the reaction solution was refluxed for 3 hours. The reaction mixture was then cooled to room temperature. The Grignard reagent just obtained was added to a solution of ZnBr ₂ (773 mg, 3.43 mmol, 1.1 eq) in dry THF at 25° C. and stirred for 1 hour to give compound (9), Used in the process.

Example 27: Compound (10) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 6-oxohexan-2-yl acetate)

A solution of compound (9) was added dropwise to a Schlenk tube containing a solution of compound (4) (756 mg, 1 mmol) in THF (5 mL), followed by 10 wt% Pd/C (22 mg, 0.02 mmol). It was The reaction was stirred for 48 hours at 40° C., quenched with water (1 mL), filtered the reaction through Celite™ and washed with ethyl acetate (3×100 mL). The filtrate was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/hexane=1/20 to 3/20) to give compound (16) ((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzyloxy) )-6-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-6-oxohexan-2-yl acetate; 588 mg, 0.71 mmol, 71%) was obtained.

Compound (16)
¹ H-NMR (400 MHz, CDCl ₃ ) δ:7.82 (d, J=1.3 Hz, 1 H), 7.68 (dd, J=8.3, 1.6 Hz, 1 H), 7.33- 7.12 (m, 19H), 6.99 (d, J=6.8Hz, 2H), 6.95 (d, J=8.5Hz, 2H), 6.71 (d, J=8.5Hz) , 2H), 5.24 (q, J=4.9 Hz, 1H), 4.73 (d, J=4.5 Hz, 1H), 4.62-4.42 (m, 7H), 4.31. (D, J=10.8 Hz, 1H), 4.13-4.09 (m, 1H), 4.02-3.99 (m, 1H), 3.94-3.88 (m, 4H) , 3.84 (dd, J=10.4, 5.0 Hz, 1H), 3.63 (dd, J=10.4, 5.5 Hz, 1H), 1.97 (s, 3H), 1. 34 (t, J=7.0Hz, 3H)
¹³ C-NMR (101 MHz, CDCl ₃ ) δ: 198.56, 170.09, 157.66, 139.53, 138.42, 138.00, 137.78, 137.12, 134.76, 131. 85, 130.70, 129.98, 129.56, 128.72, 128.57, 128.45, 128.40, 128.38, 128.32, 128.20, 128.07, 127.93, 127.87, 127.83, 127.68, 127.62, 114.65, 83.59, 80.59, 79.21, 77.36, 75.49, 74.60, 73.35, 72. 71, 68.15, 63.46, 38.45, 21.21, 14.96.
HRMS [M+Na] ⁺ : C ₅₁ H ₅₁ ClO ₈ Na calcd 849.3170; found 849.3165.

Example 28: Production of compound (17)

A Schlenk tube dried in a hot oven was cooled to room temperature and charged with compound (16) (166 mg, 0.2 mmol) in MeOH (5 mL). NaOMe (11 mg, 0.2 mmol) was added to the solution under an argon atmosphere and the reaction was stirred at 25° C. for 6 hours. Then, the reaction solution was neutralized with a 1N HCl (2 mL) aqueous solution. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane=2/20 to 8/20) to obtain compound (17) (145 mg, 0.184 mmol, 92%) as a colorless solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ:7.44 (d, J=1.9 Hz, 1 H), 7.37 (dd, J=8.3, 2.0 Hz, 1 H), 7.32- 7.12 (m, 19H), 7.01 (d, J=8.5Hz, 2H), 6.91 (d, J=6.7Hz, 2H), 6.71 (d, J=8.6Hz) , 2H), 4.86(s, 2H), 4.85(d, J=10.1Hz, 1H), 4.63(d, J=10.9Hz, 1H), 4.58(d, J =12.3 Hz, 1H), 4.49 (d, J=12.3 Hz, 1H), 4.42 (d, J=10.7 Hz, 1H), 4.14-3.85 (m, 7H) , 3.83-3.74 (m, 2H), 3.68-3.65 (m, 1H), 3.48 (d, J=9.3Hz, 1H), 3.12 (s, 1H) , 1.35 (t, J=7.0 Hz, 3H)
¹³ C-NMR (101 MHz, CDCl ₃ ) δ: 157.53, 141.37, 138.89, 138.72, 138.59, 138.38, 137.43, 134.50, 131.43, 129. 82, 129.44, 129.03, 128.53, 128.46, 128.31, 128.07, 127.86, 127.84, 127.79, 127.72, 127.69, 127.64, 125.72, 114.64, 97.77, 84.88, 83.66, 78.46, 75.84, 75.57, 75.17, 73.48, 72.36, 69.00, 63. 45, 38.60, 14.98
HRMS [M+Na] ⁺ : C ₄₉ H ₄₉ ClO ₇ Na calcd 807.3605; found 807.3060.

Example 29: Production of compound (18)

Under an argon atmosphere, Et ₃ SiH (88 μL, 0.55 mmol) was added to a solution of compound (17) (142 mg, 0.18 mmol) in acetonitrile/dichloromethane (3:2) (10 mL), and then the reaction solution was- After cooling to 30° C., BF ₃ .Et ₂ O (70 μL, 0.56 mmol) was added dropwise. After the addition was complete, the reaction was stirred for 4 hours, NaHCO ₃ aqueous solution (20 mL) was added slowly at 0° C., and the aqueous phase was extracted with dichloromethane (3×40 mL). After phase separation, the aqueous phase was discarded and the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate/hexane=2/20 to 6/20) to obtain compound (18) (105 mg, 0.137 mmol, 76%) as a colorless gum, as it was. Used in the next step.
HRMS [M+Na] ⁺ : C ₄₉ H ₄₉ ClO ₆ Na calc 791.3115; found 791.3109.

Example 30: Compound (19) ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- Production of 3,4,5-triol: Dapagliflozin)

To a solution of compound (18) (100 mg, 0.13 mmol) in EtOAc (4 mL) under argon atmosphere was added 5 wt% Pd/C (1.5 mg, 0.014 mmol, 11 mol% based on metal). The hydrogenation flask was purged with argon. The argon atmosphere was replaced with a hydrogen atmosphere, and the reaction solution was stirred at 30° C. for 24 hours. The reaction was then filtered through Celite, washed with EtOAc (3 x 40 mL), and all volatiles of the filtrate were removed under reduced pressure under reduced pressure and concentrated to give a crude product. The crude product was then purified by PTLC chromatography (hexane/EtOAc/MeOH, 10:10:1) to give compound (19) (42 mg, 79%).

Compound (19)
¹ H-NMR (400 MHz, methanol-d ₄ ) δ: 7.35-7.22 (m, 3H), 7.09 (d, J=8.4 Hz, 2H), 6.79 (d, J= 8.5 Hz, 2 H), 4.09 (d, J=9.5 Hz, 1 H), 4.03-3.95 (m, 3 H), 3.87 (d, J=12.6 Hz, 1 H), 3.69 (dd, J=11.9, 4.8 Hz, 1H), 3.48-3.26 (m, 5H), 1.35 (t, J=7.0 Hz, 3H)
¹³ C-NMR (101 MHz, MeOD) δ: 158.81, 139.97, 139.89, 134.45, 132.91, 131.91, 130.80, 130.11, 128.19, 115.47. , 82.86, 82.16, 79.73, 76.42, 71.86, 64.46, 63.10, 39.21, 15.18.
HRMS [M+Na] ⁺ : C ₂₁ H ₂₅ ClO ₆ Na calc. 431.1237; found 431.1231.

Claims

Formula (I) below:

[In the formula,
R 1 and R 2 each independently represent a hydroxyl-protecting group,
R 3 and R 4 each independently represent a hydroxyl group-protecting group or a hydrogen atom, and Ar contains an aromatic hydrocarbon ring group or an aromatic heterocyclic group as a functional group that bonds to the oxane ring in the formula. It represents an organic group, and the aromatic hydrocarbon ring group and the aromatic heterocyclic group each may have one or more substituents. ]
A method for producing a compound (I) represented by
Formula (II) below:

[In the formula,
R 1 to R 4 are as defined above,
R 5 represents a hydroxyl protecting group (however, the same hydroxyl protecting group as the hydroxyl protecting group represented by R 1 and the same hydroxyl protecting group as the hydroxyl protecting group represented by R 2 are excluded);
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 bonding to the sulfur atom in the formula, and the aliphatic carbon group Each of the hydrogen group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group may have one or more substituents. ]
A compound (II) represented by
The following formula (III-I):

[In the formula, Ar has the same meaning as described above, and X represents a halogen atom. ]
A compound (III-I) represented by
Formula (III-II) below:

[In the formula, Ar has the same meaning as described above. ]
Compound (III-II) represented by
At least one organozinc compound selected from the group consisting of:
In the presence of one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or a supported catalyst having the one or more transition metal catalysts and a carrier carrying the one or more transition metal catalysts. After reaction, the following formula (IV):

[In the formula, R 1 to R 5 and Ar have the same meanings as described above. ]
And a step of removing the hydroxyl-protecting group represented by R 5 from the compound (IV) to obtain the compound (I).
The method according to claim 1, wherein the reaction between the compound (II) and the at least one organozinc compound is performed at 0 to 80°C.
2. 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. Or the method described in 2.
The at least one organozinc compound comprises the compound (III-I),
The compound (III-I) has the following formula:

[In the formula, Ar and X are as defined above. ]
The method according to any one of claims 1 to 3, which is in a Schlenk equilibrium state represented by:
The method according to any one of claims 1 to 4, wherein R 3 and R 4 represent a hydroxyl-protecting group.
The method according to any one of claims 1 to 5, wherein the hydroxyl group-protecting group represented by R 5 is different from the hydroxyl group-protecting group represented by R 1 to R 4 .
The hydroxyl group-protecting groups represented by R 1 to R 5 are each independently an ester type protecting group, an arylalkyl type protecting group, an alkyl type protecting group, an arylalkyloxyalkyl type protecting group, an alkyloxyalkyl type protecting group, The method according to any one of claims 1 to 6, which is selected from the group consisting of a silyl type protecting group and an oxycarbonyl type protecting group.
The organic group represented by Q contains an alkyl group, an alkenyl group, an alkynyl group or an aryl group as a functional group that bonds to a sulfur atom in the formula, and the alkyl group, the alkenyl group, the alkynyl group and the aryl group The method according to any one of claims 1 to 7, wherein each may have one or more substituents.
The aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group or the aromatic heterocyclic group contained in the organic group represented by Q may have one or more of the above. The substituents are each independently a halogen atom, an optionally protected hydroxyl group, an optionally protected thiol group, an optionally protected amino group, an optionally protected formyl group, and a protected group. The method according to any one of claims 1 to 8, which is selected from the group consisting of an optionally carboxyl group and an optionally protected sulfonyl group.
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 that bonds to the oxane ring in the formula. The aromatic hydrocarbon ring group having 6 to 14 carbon atoms and the aromatic heterocyclic group having 3 to 12 carbon atoms each may have one or more substituents. The method according to any one of claims.
The organic group represented by Ar has the following formula (V):

[In the formula,
R a is each independently 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, or aryloxy. Group, an arylalkyloxy group, an arylalkenyloxy group and a functional group selected from the group consisting of an arylalkynyloxy group, the alkyl group, the alkenyl group, the alkynyl group, the aryl group, the arylalkyl group, the The arylalkenyl group, the arylalkynyl group, the alkyloxy group, the alkenyloxy group, the alkynyloxy group, the aryloxy group, the arylalkyloxy group, the arylalkenyloxy group and the arylalkynyloxy group are each 1 May have one or more substituents,
n is an integer of 0 to 4,
Ar′ represents an aromatic hydrocarbon ring group, an aliphatic heterocycle or an aromatic heterocycle group, and each of the aromatic hydrocarbon ring group, the aliphatic heterocycle group and the aromatic heterocycle group is 1 It may have the above substituents. ]
The method according to any one of claims 1 to 10, represented by:
The method according to claim 11, wherein the functional groups represented by R a are each independently selected from an alkyl group and a halogen atom, and the alkyl group may have one or more substituents. ..
The organic group represented by Ar has the following formula (Va):

[In the formula,
Ra is as defined above,
Ar' is represented by the following formulas (Va-I), (Va-II) and (Va-III):

[Wherein each R b 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 heterocycle each may have one or more substituents, and p is an integer of 0 to 5 Represents. ]
Represents a functional group selected from the group consisting of: ]
The method according to claim 11 or 12, represented by:
The functional groups represented by R b are each independently an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, and an aromatic group having 6 to 14 carbon atoms. Selected from the group consisting of a hydrocarbon ring group, an aliphatic heterocyclic group having 2 to 12 carbon atoms and an aromatic heterocyclic group having 3 to 12 carbon atoms, the alkyl group, the alkenyl group, the alkynyl group, the aromatic group 14. The method according to claim 13, wherein the hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group each may have one or more substituents.
The one or more substituents which the aromatic hydrocarbon ring group or the aromatic heterocyclic group contained in the organic group represented by Ar may have, are each independently a halogen atom or a protected group. Optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally protected formyl group, optionally protected carboxyl group, optionally protected sulfonyl group The method according to any one of claims 1 to 14, wherein the method is selected from the group consisting of an alkyl group, an alkenyl group and an alkynyl group.
Formula (VI) below:

[In the formula, R 1 to R 4 have the same meanings as described above. ]
A compound (VI) represented by
The following formula (VII):

[In the formula, Q has the same meaning as described above. ]
By reacting with a compound (VII) represented by the following formula (VIII):

[In the formula, R 1 to R 4 have the same meanings as described above. ]
16. The method according to claim 1, further comprising a step of obtaining a compound (VIII) represented by: and a step of protecting the hydroxyl group in the compound (VIII) with R 5 to obtain the compound (II). The method described in the section.
The method according to claim 16, wherein the reaction between the compound (VI) and the compound (VII) is performed at -30 to 40°C.
The reaction of the compound (VI) with the compound (VII) is represented by the following formula (IX):

[In the formula,
R c and R d each independently represent 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. The aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group and the aromatic heterocyclic group each may have one or more substituents,
q represents an integer of 0 to 3,
r represents an integer of 0 to 3, provided that q+r=3. ]
The method according to claim 16 or 17, which is carried out in the presence of a compound (IX) represented by:
The functional groups represented by R c and R d are each independently selected from the group consisting of an alkyl group, an aryl group and an arylalkyl group, wherein the alkyl group, the aryl group and the arylalkyl group are each 1 19. The method according to claim 18, which may have one or more substituents.
Formula (II) below:

[In the formula, R 1 to R 5 and Q have the same meanings as described above. ]
A compound represented by the following formula (XI):

[In the formula, Ar has the same meaning as described above, and R 1 ′ to R 4 ′ each independently represent a hydrogen atom or a hydroxyl group-protecting group. ]
A reagent for producing a compound (XI) represented by:
The following formula compound (XI):

[In the formula, Ar and R 1 ′ to R 4 ′ have the same meanings as described above. ]
As an intermediate for the production of compound (XI) represented by
Formula (II) below:

[In the formula, R 1 to R 5 and Q have the same meanings as described above. ]
Use of the compound (II) represented by: