TW202024046A - Production method for [beta]-C-aryl glycoside derivative - Google Patents

Abstract

The purpose of the present invention is to provide a method for quickly reducing a C-aryl-hydroxy glycoside derivative that is represented by formula (2) at a low temperature and highly selectively producing a [beta]-C-aryl glycoside derivative that is represented by formula (1) in high yield. To achieve said purpose, the present invention provides a method that includes a step for bringing a C-aryl-hydroxy glycoside derivative that is represented by formula (2) into contact with a silane compound in the presence of a titanium compound to produce a [beta]-C-aryl glycoside derivative that is represented by formula (1).

Description

Method for producing β-C-aryl glycoside derivative

The present invention relates to a method for producing β-C-aryl glycoside derivatives which are useful as antidiabetic drugs as SGLT2 inhibitors or synthetic intermediates thereof. In detail, the present invention relates to a method for efficiently producing β-C-aryl glycoside derivatives that are useful as antidiabetic drugs as SGLT2 inhibitors or synthetic intermediates thereof. In addition, throughout this specification, "β-C-aryl glycoside derivative" means the compound represented by formula (1) described later, and "C-aryl-hydroxyglycoside derivative" means the following compound The compound represented by formula (2).

SGLT2 inhibitors are useful as antidiabetic drugs. In addition, "SGLT2" means sodium-glucose co-delivery carrier-2. As SGLT2 inhibitors, for example, canagliflozin (1-(β-D-glucosepiperanyl)-4-methyl-3-[5-(4-fluorophenyl)-2- Thienylmethyl]benzene), empagliflozin ((1S)-1,5-dehydrate-1-C-{4-chloro-3-[(4-{[(3S)-oxoheterocycle Pent-3-yl]oxy)phenyl)methyl)phenyl)-D-glucitol), igragliflozin ((1S)-1,5-dehydrate-1-C-(3- [(1-Benzothien-2-yl)methyl]-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid), dapagliflozin (( 2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-piperan-3 ,4,5-thiol) and so on.

β-C-aryl glycoside derivatives are attracting attention as SGLT2 inhibitors (antidiabetic drugs) or synthetic intermediates thereof (see Non-Patent Document 1 and Patent Document 1). As one of the production methods of β-C-aryl glycoside derivatives, the production method of β-C-aryl glycoside derivatives via reduction of C-aryl-hydroxy glycoside derivatives has been reported (refer to Non-Patent Document 1, Non-Patent Document 2 and Patent Document 1).

In Non-Patent Documents 1 and 2, it is described that C-aryl-hydroxy glycoside derivatives are carried out using triethylsilane in the presence of boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ) Reduction, manufacturing method of β-C-aryl glycoside derivatives. In addition, in Patent Document 1, it is described that C-aryl-hydroxy glycoside derivatives are combined with BF ₃ · in the presence of silanes such as triethylsilane, triisopropylsilane, and tetramethyldisiloxane. OEt ₂ , boron trifluoride tetrahydrofuran (BF ₃ ·THF), aluminum chloride and other Lewis acids are reacted to produce β-C-aryl glycoside derivatives. [Prior Art Document] [Patent Document]

[Patent Document 1] International Publication No. 2010/043682 [Non-Patent Literature]

[Non-Patent Document 1] Wei Meng et al., "Journal of Medicinal Chemistry", 2008, Vol. 51, No. 5, p.1145-1149 [Non-Patent Document 2] S. Czernecki et al., "Journal of Organic Chemistry", 1989, Vol. 54, No. 3, p.610-612

[The problem to be solved by the invention]

However, due to the corrosive nature of boron trifluoride, the reactor will be corroded. In addition, the aluminum chloride-based Lewis is relatively low in acidity, so a relatively high temperature is required for the reaction to proceed. However, if the reaction temperature becomes higher, the stereoselectivity (β selectivity) of the reaction becomes lower. Furthermore, the Lewis acid whose aluminum chloride is a solid must be weighed under anhydrous conditions, which is difficult to handle.

Therefore, the object of the present invention is to provide a method for producing β-C-aryl glycoside derivatives with high selectivity and high yield by rapidly proceeding the reduction reaction of C-aryl-hydroxy glycoside derivatives at low temperature. [Means to solve the problem]

In order to solve the above-mentioned problems, the inventors of the present invention conducted in-depth reviews. As a result, it was found that by contacting the C-aryl-hydroxyglycoside derivative with a silane compound in the presence of a titanium compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative facilitates rapid progress at low temperatures and can achieve high selectivity. And the production of β-C-aryl glycoside derivatives in high yield, thus completing the present invention.

[式中，R¹ 、R² 、R³ 及R⁴ 各自獨立地為氫原子或羥基保護基，Ar為包含將選自未經取代或經取代之芳香族環基及未經取代或經取代之芳香族雜環基之基作為與式中之氧雜環己烷環進行鍵結之基之有機基]， 前述方法包含使下述式(2)所示之C-芳基-羥基糖苷衍生物在鈦化合物的存在下與矽烷化合物進行接觸，而製造前述β-C-芳基糖苷衍生物之步驟：

[式中，R¹ 、R² 、R³ 、R⁴ 及Ar係與前述同義，R⁵ 為氫原子、甲基、三甲基矽基或乙醯基]。 [2]如[1]所記載之方法，其中，R¹ 、R² 、R³ 及R⁴ 各自獨立地為選自甲基、苄基、乙醯基、三甲基乙醯基、三甲基矽基及第三丁基二甲基矽基之羥基保護基。 [3]如[1]或[2]所記載之方法，其中，前述鈦化合物係選自三異丙氧基一氯化鈦(IV)、二異丙氧基二氯化鈦(IV)、單異丙氧基三氯化鈦(IV)、氯化鈦(III)及氯化鈦(IV)。 [4]如[1]～[3]中任一項所記載之方法，其中，前述矽烷化合物係選自三乙基矽烷、三異丙基矽烷、苯基矽烷、二甲基苯基矽烷、第三丁基二甲基矽烷、三異丁基矽烷、三氯矽烷、三甲氧基氫矽烷、三乙氧基氫矽烷及四甲基二矽氧烷。 [5]如[1]～[4]中任一項所記載之方法，其中，Ar為下述式(A)所示之有機基或苯基：

[式中， R^a 各自獨立地為選自鹵素原子、胺基、未經取代或經取代之烷基、未經取代或經取代之烷氧基、未經取代或經取代之雜烷基、未經取代或經取代之雜烷氧基、未經取代或經取代之單烷胺基、未經取代或經取代之二烷胺基、未經取代或經取代之脂肪族環基、未經取代或經取代之脂肪族環氧基、未經取代或經取代之脂肪族雜環基、未經取代或經取代之脂肪族雜環氧基、未經取代或經取代之苯基、未經取代或經取代之苯氧基、未經取代或經取代之苯烷基及未經取代或經取代之苯烷氧基之基， n為0～4的整數， Ar’為選自未經取代或經取代之芳香族環基、未經取代或經取代之芳香族雜環基及未經取代或經取代之脂肪族雜環之基]。 [6]如[1]～[5]中任一項所記載之方法，其中，Ar’為下述式(Ar’-1)、(Ar’-2)或(Ar’-3)所示之基：

[式中， R^b 各自獨立地為選自鹵素原子、胺基、未經取代或經取代之烷基、未經取代或經取代之烷氧基、未經取代或經取代之雜烷基、未經取代或經取代之雜烷氧基、未經取代或經取代之單烷胺基、未經取代或經取代之二烷胺基、未經取代或經取代之脂肪族環基、未經取代或經取代之脂肪族環氧基、未經取代或經取代之脂肪族雜環基、未經取代或經取代之脂肪族雜環氧基、未經取代或經取代之苯基、未經取代或經取代之苯氧基、未經取代或經取代之苯烷基及未經取代或經取代之苯烷氧基之基， p為0～5的整數]。 [發明效果]That is, the present invention includes the following inventions. [1] A method for producing a β-C-aryl glycoside derivative represented by the following formula (1):

[In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom or a hydroxy protecting group, and Ar is an aromatic ring group that will be selected from unsubstituted or substituted and unsubstituted or substituted The group of the aromatic heterocyclic group is used as the organic group of the group bonded to the oxane ring in the formula], the aforementioned method includes derivatizing the C-aryl-hydroxy glycoside represented by the following formula (2) The steps of making the aforementioned β-C-aryl glycoside derivatives by contacting the silane compound with the silane compound in the presence of the titanium compound:

[In the formula, R ¹ , R ² , R ³ , R ⁴ and Ar have the same meaning as above, and R ⁵ is a hydrogen atom, a methyl group, a trimethylsilyl group, or an acetyl group]. [2] The method as described in [1], wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of methyl, benzyl, acetyl, trimethylacetyl, trimethyl Hydroxy protecting groups for silyl and tert-butyldimethylsilyl. [3] The method according to [1] or [2], wherein the titanium compound is selected from triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), Monoisopropoxy titanium(IV) trichloride, titanium(III) chloride and titanium(IV) chloride. [4] The method according to any one of [1] to [3], wherein the silane compound is selected from triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, Tertiary butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane, and tetramethyldisiloxane. [5] The method according to any one of [1] to [4], wherein Ar is an organic group represented by the following formula (A) or a phenyl group:

[In the formula, each R ^{a is} independently selected from a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, Unsubstituted or substituted heteroalkoxy, unsubstituted or substituted monoalkylamino, unsubstituted or substituted dialkylamino, unsubstituted or substituted aliphatic cyclic group, unsubstituted Substituted or substituted aliphatic epoxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted aliphatic heterocyclic group The group of substituted or substituted phenoxy, unsubstituted or substituted phenalkyl and unsubstituted or substituted phenalkoxy, n is an integer from 0 to 4, Ar' is selected from unsubstituted Or substituted aromatic ring group, unsubstituted or substituted aromatic heterocyclic group and unsubstituted or substituted aliphatic heterocyclic group]. [6] The method according to any one of [1] to [5], wherein Ar' is represented by the following formula (Ar'-1), (Ar'-2) or (Ar'-3) Foundation:

[In the formula, R ^{b is} each independently selected from a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, Unsubstituted or substituted heteroalkoxy, unsubstituted or substituted monoalkylamino, unsubstituted or substituted dialkylamino, unsubstituted or substituted aliphatic cyclic group, unsubstituted Substituted or substituted aliphatic epoxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted aliphatic heterocyclic group The group of substituted or substituted phenoxy, unsubstituted or substituted phenylalkyl and unsubstituted or substituted phenylalkoxy, p is an integer of 0-5]. [Invention Effect]

According to the present invention, there is provided a method for the reduction reaction of C-aryl-hydroxy glycoside derivatives to proceed rapidly at low temperature, and to produce the target β-C-aryl glycoside derivatives with high selectivity and high yield. The obtained β-C-aryl glycoside derivative is an SGLT2 inhibitor or its synthesis intermediate useful as an antidiabetic drug, so the industrial utility value of the present invention is very high.

≪Explanation of terms≫

The following describes the terms used in this manual. The following instructions are applicable throughout this manual unless otherwise specified.

(Halogen atom) "Halogen atom" means fluorine atom, chlorine atom, bromine atom or iodine atom.

(Unsubstituted or substituted alkyl) "Unsubstituted or substituted alkyl" means an alkyl group or an alkyl group having one or more substituents. In addition, unless otherwise specified, "alkyl" means an unsubstituted alkyl group.

"Alkyl" means a linear alkyl group or a branched chain alkyl group. The carbon number of the linear alkyl group is usually from 1 to 20, preferably from 1 to 10, more preferably from 1 to 8, still more preferably from 1 to 6, still more preferably from 1 to 5, and still more preferably from 1 to 4. More preferably 1 to 3, still more preferably 1 or 2. The carbon number of the branched chain alkyl group is usually 3-20, preferably 3-10, more preferably 3-8, still more preferably 3-6, still more preferably 3-5, still more preferably 3 Or 4. As the alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl, tertiary butyl, pentyl, hexyl, isohexyl, heptyl, 4 ,4-Dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, etc.

The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms. The "alkyl group having 1 to 6 carbons" means a linear alkyl group having 1 to 6 carbons or a branched chain alkyl group having 3 to 6 carbons.

In an alkyl group having one or more substituents, one or more substituents are each substituted with a hydrogen atom of the alkyl group. The number of substituents that the alkyl group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the alkyl group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted alkylene) The "unsubstituted or substituted alkylene group" means an alkylene group or an alkylene group having one or more substituents. In addition, unless otherwise specified, "alkylene" means unsubstituted alkylene.

"Alkylene group" means a divalent functional group generated by removing one hydrogen atom from an alkyl group. The above description of "alkyl" also applies to the alkyl group (an alkyl group with one hydrogen atom removed) that is the source of the alkylene group.

In an alkylene group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the alkylene group. The number of substituents that the alkylene group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the alkylene group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted alkoxy) "Unsubstituted or substituted alkoxy" means an alkoxy group or an alkoxy group having one or more substituents. In addition, unless otherwise specified, "alkoxy" means an unsubstituted alkoxy group.

"Alkoxy" means a group represented by alkyl-O-. The above description of "alkyl" also applies to the alkyl group contained in the alkoxy group.

In the alkoxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the alkoxy group. The number of substituents that the alkoxy group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents which the alkoxy group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted heteroalkyl) "Unsubstituted or substituted heteroalkyl" means heteroalkyl or heteroalkyl having one or more substituents. In addition, unless otherwise specified, "heteroalkyl" means an unsubstituted heteroalkyl.

"Heteroalkyl" means straight-chain heteroalkyl or branched heteroalkyl. "Heteroalkyl" means an alkyl group having an oxygen atom (-O-) between carbon atoms. The number of oxygen atoms is preferably 1 or 2, more preferably 1. The carbon number of the linear heteroalkyl group is usually 2-20, preferably 2-10, more preferably 2-8, still more preferably 2-6, still more preferably 2-5, and still more preferably 2 ~4, more preferably 2 or 3. The carbon number of the branched chain heteroalkyl group is usually 3-20, preferably 3-10, more preferably 3-8, still more preferably 3-6, still more preferably 3-5, and still more preferably 3 or 4. Examples of heteroalkyl groups include -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -CH ₂ -O-CH ₃ , -CH(-CH ₃ ) -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -O-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CH ₂ -O-CH ₂ -CH ₃ , -CH(-CH ₃ )-CH ₂ -O-CH ₂ -CH ₃ , -CH ₂ -O-CH ₂ -CH ₂ -CH ₃ , -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -CH ₃ , -CH(-CH ₃ )-CH ₂ -O-CH ₂ -CH ₂ -CH ₃ , -CH ₂ -O-CH(-CH ₃ )-CH ₃ , -CH ₂ -CH ₂ -O-CH(-CH ₃ )-CH ₃ , -CH ₂ -CH ₂ -CH ₂ -O-CH(- CH ₃ )-CH ₃ , -CH(-CH ₃ )-CH ₂ -O-CH(-CH ₃ )-CH ₃ and so on.

In a heteroalkyl group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the heteroalkyl group. The number of substituents that the heteroalkyl group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the heteroalkyl group may have may each independently be selected from halogen atoms.

(Unsubstituted or substituted heteroalkoxy) "Unsubstituted or substituted heteroalkoxy" means heteroalkoxy or heteroalkoxy having one or more substituents. In addition, unless otherwise specified, "heteroalkoxy" means an unsubstituted heteroalkoxy.

"Heteroalkoxy" means a group represented by heteroalkyl-O-. The above description of "heteroalkyl" also applies to the heteroalkyl contained in the heteroalkoxy.

In the heteroalkoxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the heteroalkoxy group. The number of substituents that the heteroalkoxy group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the heteroalkoxy group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted monoalkylamino group) The "unsubstituted or substituted monoalkylamino group" means a monoalkylamino group or a monoalkylamino group having one or more substituents. In addition, unless otherwise specified, "monoalkylamino" means an unsubstituted monoalkylamino group.

The "monoalkylamino group" has the formula: -NH(-Q ¹ ) [where Q ¹ is an alkyl group. ] Said. The above description of "alkyl" also applies to the alkyl group contained in the monoalkylamino group. The alkyl group contained in the monoalkylamino group is preferably an alkyl group having 1 to 6 carbon atoms.

In the monoalkylamino group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the monoalkylamino group. The number of substituents that the monoalkylamino group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the monoalkylamino group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted dialkylamino group) The "unsubstituted or substituted dialkylamino group" means a dialkylamino group or a dialkylamino group having one or more substituents. In addition, unless otherwise specified, "dialkylamino" means an unsubstituted dialkylamino group.

The "dialkylamino group" has the formula: -N(-Q ² )(-Q ³ ) [wherein, Q ² and Q ³ are each independently an alkyl group. ] Said. The above description of "alkyl" also applies to the alkyl group contained in the dialkylamino group. The alkyl group contained in the dialkylamino group is preferably an alkyl group having 1 to 6 carbon atoms. The carbon number of the dialkylamino group is usually 2-20, preferably 2-12, more preferably 2-8, still more preferably 2-6, still more preferably 2-5, still more preferably 2-4 , And more preferably 2 or 3.

In the dialkylamino group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the dialkylamino group. The number of substituents that the dialkylamino group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the dialkylamino group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted aliphatic ring group) "Unsubstituted or substituted aliphatic ring group" means an aliphatic ring group or an aliphatic ring group having one or more substituents. In addition, unless otherwise specified, "aliphatic ring group" means an unsubstituted aliphatic ring group.

"Aliphatic cyclic group" means a functional group generated by removing one hydrogen atom from a monocyclic aliphatic hydrocarbon ring. The aliphatic cyclic group is preferably a cycloalkyl group having 3 to 10 carbons, more preferably a cycloalkyl group having 3 to 8 carbons, and still more preferably a cycloalkyl group having 3 to 6 carbons. Examples of cycloalkyl groups having 3 to 10 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In the aliphatic ring group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the aliphatic ring group. The number of substituents that the aliphatic ring group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the aliphatic cyclic group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted aliphatic epoxy group) The "unsubstituted or substituted aliphatic epoxy group" means an aliphatic epoxy group or an aliphatic epoxy group having one or more substituents. In addition, unless otherwise specified, "aliphatic epoxy group" means an unsubstituted aliphatic epoxy group.

"Aliphatic epoxy group" means a group represented by an aliphatic ring group -O-. The above description of "aliphatic ring group" also applies to the aliphatic ring group contained in the aliphatic epoxy group.

In the aliphatic epoxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the aliphatic epoxy group. The number of substituents that the aliphatic epoxy group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents which the aliphatic epoxy group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted aliphatic heterocyclic group) "Unsubstituted or substituted aliphatic heterocyclic group" means an aliphatic heterocyclic group or an aliphatic heterocyclic group having one or more substituents. In addition, unless otherwise specified, "aliphatic heterocyclic group" means an unsubstituted aliphatic heterocyclic group.

"Aliphatic heterocyclic group" means a monocyclic formula that includes, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms as ring constituent atoms Aliphatic heterocycles (non-aromatic heterocycles) are functional groups generated by removing one hydrogen atom.

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 3-8 members, preferably 4-8 members, more preferably 5-7 members, and still more preferably 5 or 6 members. The number of ring constituent carbon atoms in the aliphatic heterocyclic group can be appropriately determined according to the number of heteroatoms and the number of members of the aliphatic heterocyclic group.

The aliphatic heterocyclic group is preferably a saturated aliphatic heterocyclic group. The saturated aliphatic heterocyclic group is an aliphatic heterocyclic group composed of only saturated bonds. Examples of the aliphatic heterocyclic group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, and those containing 1 to 4 nitrogen atoms. Atoms, including 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms, and/or 1 to 2 oxygen atoms, etc. In the aliphatic heterocyclic group, the two carbon atoms constituting the ring can also be bridged by alkylation. In an aliphatic heterocyclic group, two adjacent carbon atoms among the carbon atoms constituting the ring may also form a double bond. In an aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the aliphatic heterocyclic group may have is preferably 1 or 2. In the case where the aliphatic heterocyclic group contains a sulfur atom, the aliphatic heterocyclic group may also be a dioxide.

As the aliphatic heterocyclic group, for example, aziridinyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl , Tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolinyl, tetrahydro Isothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridine Group, dihydropiperanyl, tetrahydropiperanyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl (the sulfur atom on the ring can also be oxidized), azepanyl, diaza Aliphatic heterocyclic groups with 3 to 8 members such as cycloheptyl, azepanyl, oxepanyl, azepinyl, and diazacyclooctyl.

The aliphatic heterocyclic group is preferably tetrahydrofuranyl.

In an aliphatic heterocyclic group having one or more substituents, one or more substituents are each substituted with a hydrogen atom of the aliphatic heterocyclic group. The number of substituents that the aliphatic heterocyclic group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the aliphatic heterocyclic group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted aliphatic heterocyclic oxy group) The "unsubstituted or substituted aliphatic heterocyclic oxy group" means an aliphatic heterocyclic oxy group or an aliphatic heterocyclic oxy group having one or more substituents. In addition, unless otherwise specified, "aliphatic heterocyclic oxy group" means an unsubstituted aliphatic heterocyclic oxy group.

"Aliphatic heterocyclic oxy group" means a group represented by aliphatic heterocyclic group -O-. The above description of the "aliphatic heterocyclic group" also applies to the aliphatic heterocyclic group contained in the aliphatic heterocyclic oxy group.

The aliphatic heterocyclic oxy group is preferably tetrahydrofuranoxy group.

In the aliphatic heterocyclic oxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the aliphatic heterocyclic oxy group. The number of substituents that the aliphatic heterocyclic oxy group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the aliphatic heterocyclic oxy group may have may be each independently selected from halogen atoms.

(Unsubstituted or substituted phenyl) "Unsubstituted or substituted phenyl" means a phenyl group or a phenyl group having one or more substituents. In addition, unless otherwise specified, "phenyl" means unsubstituted phenyl.

In the phenyl group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the phenyl group. The number of substituents that the phenyl group may have is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. The one or more substituents that the phenyl group may have may each independently be selected from the substituent group α described later. When one or more substituents are selected from groups containing carbon atoms, the total number of carbons in the phenyl group having one or more substituents is preferably 10 or less, more preferably 9 or less, and even more preferably 8 or less, More preferably, it is 7 or less.

(Unsubstituted or substituted phenoxy) The "unsubstituted or substituted phenoxy group" means a phenoxy group or a phenoxy group having one or more substituents. In addition, unless otherwise specified, "phenoxy" means unsubstituted phenoxy.

"Phenoxy" means a group represented by phenyl-O-.

In the phenoxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the phenoxy group. The number of substituents that the phenoxy group may have is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. The one or more substituents that the phenoxy group may have may be each independently selected from the substituent group α described later. When one or more substituents are selected from groups containing carbon atoms, the total number of carbons in the phenoxy group having one or more substituents is preferably 12 or less, more preferably 10 or less, and even more preferably 8 or less .

(Unsubstituted or substituted phenalkyl) The "unsubstituted or substituted phenalkyl group" means a phenalkyl group or a phenalkyl group having one or more substituents. In addition, unless otherwise specified, "phenalkyl" means unsubstituted phenalkyl.

"Phenylalkyl" means a group represented by phenyl-alkylene. The above description of "alkylene" also applies to the alkylene contained in the phenalkylene group. The alkylene group contained in the phenalkylene group is preferably a linear alkylene having 1 to 4 carbons or a branched alkylene having 3 to 4 carbons, and more preferably a straight alkylene having 1 to 4 carbons. Chain alkylene. The carbon number of the linear alkylene group is preferably 1 to 3, more preferably 1 or 2. The carbon number of the phenylalkyl group is preferably 7-10.

In the phenalkyl group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the phenalkyl group. The hydrogen atom to be substituted may be a hydrogen atom on the benzene ring or a hydrogen atom on the alkylene moiety, and is preferably a hydrogen atom on the benzene ring. The number of substituents that the phenylalkyl group may have on the alkylene part is preferably 1 to 3, more preferably 1 or 2, and the number of substituents that the phenylalkyl group may have on the benzene ring is preferably 1 to 4. It is more preferably 1 to 3, and still more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the phenalkyl group may have may be each independently selected from the substituent group α described later. When one or more substituents are selected from groups containing carbon atoms, the total number of carbons in the phenalkyl group having one or more substituents is preferably 16 or less, more preferably 14 or less, and even more preferably 12 or less .

(Unsubstituted or substituted phenalkoxy) "Unsubstituted or substituted phenylalkoxy" means a phenylalkoxy group or a phenylalkoxy group having one or more substituents. In addition, unless otherwise specified, "phenylalkoxy" means unsubstituted phenylalkoxy.

"Phenylalkoxy" means a group represented by phenylalkyl-O-. The above description of "phenylalkyl" also applies to the phenylalkyl group contained in the phenylalkoxy group.

In the phenylalkoxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the phenylalkoxy group. The hydrogen atom to be substituted may be a hydrogen atom on the benzene ring or a hydrogen atom on the alkylene moiety, and is preferably a hydrogen atom on the benzene ring. The number of substituents that the phenylalkoxy group may have on the alkylene moiety is preferably 1 to 3, more preferably 1 or 2, and the number of substituents that the phenylalkoxy group may have on the benzene ring is preferably 1 to 4, more preferably 1 to 3, still more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents which the phenalkoxy group may have may be each independently selected from the substituent group α described later. When one or more substituents are selected from groups containing carbon atoms, the total number of carbon atoms in the phenalkoxy group having one or more substituents is preferably 16 or less, more preferably 14 or less, and even more preferably 12 the following.

(Unsubstituted or substituted aromatic ring group) The "unsubstituted or substituted aromatic ring group" means an aromatic ring group or an aromatic ring group having one or more substituents. In addition, unless otherwise specified, "aromatic ring group" means an unsubstituted aromatic ring group.

"Aromatic ring group" means a group generated by removing one hydrogen atom from a monocyclic or condensed polycyclic aromatic hydrocarbon ring. The aromatic ring group is usually 1 to 4 ring types, preferably 1 to 3 ring types, and more preferably 1 or 2 ring type aromatic ring groups. The number of ring constituent carbon atoms in the aromatic ring group is usually 6-18, preferably 6-14, and more preferably 6-10. As a monocyclic aromatic ring group, a phenyl group can be mentioned, for example. Examples of the condensed polycyclic aromatic ring group include 2 to 4 ring aromatic ring groups such as naphthyl, anthracenyl, phenanthryl, fused tetraphenyl, and pyrenyl. The condensed polycyclic aromatic ring group may also be a partially saturated condensed polycyclic aromatic ring group. The partially saturated condensed polycyclic aromatic ring group is a condensed polycyclic aromatic ring group in which a part of the bond constituting the ring is hydrogenated.

The aromatic ring group is preferably a phenyl group.

In the aromatic ring group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the aromatic ring group. The number of substituents that the aromatic ring group may have can be appropriately determined according to the carbon number and the number of members of the aromatic ring group. The number of substituents that the aromatic ring group may have is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents which the aromatic ring group may have may be each independently selected from the substituent group β described later. When one or more substituents are selected from groups containing carbon atoms, the total number of carbon atoms in an aromatic ring group having one or more substituents is preferably 20 or less, more preferably 19 or less, and even more preferably 18 Below, more preferably 17 or less.

(Unsubstituted or substituted aromatic heterocyclic group) The "unsubstituted or substituted aromatic heterocyclic group" means an aromatic heterocyclic group or an aromatic heterocyclic group having one or more substituents. In addition, unless otherwise specified, "aromatic heterocyclic group" means an unsubstituted aromatic heterocyclic group.

"Aromatic heterocyclic group" means a monocyclic formula that includes, in addition to carbon atoms, one or more heteroatoms independently selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms as ring constituent atoms Or condensate a polycyclic aromatic heterocyclic ring to remove one hydrogen atom. The aromatic heterocyclic group is usually 1 to 4 cyclic, preferably 1 to 3 cyclic, and more preferably 1 or 2 cyclic aromatic heterocyclic group. 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 from 5 to 14 members, more preferably from 5 to 10 members. The number of ring constituent carbon atoms in the aromatic heterocyclic group can be appropriately determined according to the number of heteroatoms and the number of members of the aromatic heterocyclic group. In the aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups.

The aromatic heterocyclic group is, for example, a monocyclic aromatic heterocyclic group. The monocyclic aromatic heterocyclic group is, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group. Examples of the monocyclic aromatic heterocyclic group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, those containing 1 to 2 oxygen atoms, and those containing 1 to 2 sulfur atoms, and those containing 1 to 2 sulfur atoms. 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, etc.

The monocyclic aromatic heterocyclic group includes, for example, pyridyl, tiazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, Oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.), thiadiazolyl (e.g. 1,2,4 -Thiadiazolyl, 1,3,4-thiadiazolyl, etc.), triazolyl (e.g. 1,2,3-triazolyl, 1,2,4-triazolyl, etc.), tetrazolyl, A 5- to 7-membered monocyclic aromatic heterocyclic group such as triazinyl group. In the monocyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted by pendant oxy groups. The number of pendant oxy groups that the monocyclic aromatic heterocyclic group may have is preferably 1 or 2.

The aromatic heterocyclic group is, for example, a condensed polycyclic aromatic heterocyclic group. The condensed polycyclic aromatic heterocyclic group is, for example, an 8- to 14-membered 2-ring or 3-ring aromatic heterocyclic group. Examples of the condensed polycyclic aromatic heterocyclic group include those containing 1 to 3 oxygen atoms, those containing 1 to 3 sulfur atoms, those containing 1 to 3 oxygen atoms and 1 to 3 sulfur atoms, and those containing 1 -5 nitrogen atoms, 1 to 4 nitrogen atoms, 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, etc.

Examples of the condensed polycyclic aromatic heterocyclic group include benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, and benziso Thiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyrazine Group, imidazopyrimidinyl, thienopyrimidinyl, furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2 ,3-b]thienyl, phenoxathiyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolinyl, quinolinyl, azizinyl, naphthyridinyl, quinoxa Polyline, quinazolinyl, cinnoline, carbazolyl, α-carboline, phenanthridinyl, acridinyl, phenanthrazinyl, phenanthiazinyl, phenanthrazinyl, etc. 8 to 14-member condensation Cyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group and the like. In the polycyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the polycyclic aromatic heterocyclic group may have is preferably 1, 2, or 3.

The aromatic heterocyclic group is preferably thienyl, benzothienyl, furyl, pyrrolyl, imidazolyl, or pyridyl, and more preferably thienyl or benzothienyl.

In the aromatic heterocyclic group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the aromatic heterocyclic group. The number of substituents that the aromatic heterocyclic group may have can be appropriately determined in accordance with the carbon number and the number of members of the aromatic heterocyclic group. The number of substituents that the aromatic heterocyclic group may have is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2. When the number of substituents is 2 or more, the two or more substituents may be the same or different. One or more substituents that the aromatic heterocyclic group may have may be each independently selected from the substituent group β described later. When one or more substituents are selected from groups containing carbon atoms, the total number of carbon atoms in an aromatic heterocyclic group having one or more substituents is preferably 20 or less, more preferably 19 or less, and even more preferably 18 or less, more preferably 17 or less.

(Substituent group α) The "substituent group α" is composed of the following substituents. (α-1) halogen atom (α-2) Amino (α-3) Unsubstituted or substituted alkyl (α-4) Unsubstituted or substituted alkoxy (α-5) Unsubstituted or substituted heteroalkyl (α-6) Unsubstituted or substituted heteroalkoxy (α-7) Unsubstituted or substituted monoalkylamino group (α-8) Unsubstituted or substituted dialkylamino group (α-9) Unsubstituted or substituted aliphatic ring group (α-10) Unsubstituted or substituted aliphatic epoxy group (α-11) Unsubstituted or substituted aliphatic heterocyclic group (α-12) Unsubstituted or substituted aliphatic heterocyclic oxy

Regarding "halogen atom", "unsubstituted or substituted alkyl", "unsubstituted or substituted alkoxy", "unsubstituted or substituted heteroalkyl", "unsubstituted or substituted Substituted heteroalkoxy", "unsubstituted or substituted monoalkylamino group", "unsubstituted or substituted dialkylamino group", "unsubstituted or substituted aliphatic cyclic group", The above descriptions of "unsubstituted or substituted aliphatic epoxy group", "unsubstituted or substituted aliphatic heterocyclic group" and "unsubstituted or substituted aliphatic heterocyclic group" also apply In the substituent group α.

Substituent group α preferably consists of halogen atom, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted heteroalkyl, unsubstituted or substituted Heteroalkoxy group, unsubstituted or substituted aliphatic heterocyclic group and unsubstituted or substituted aliphatic heterocyclic oxy group, more preferably composed of halogen atom, unsubstituted or substituted alkane Group, unsubstituted or substituted alkoxy group, unsubstituted or substituted heteroalkyl group and unsubstituted or substituted heteroalkoxy group, and more preferably by halogen atom, unsubstituted or It is composed of substituted alkyl and unsubstituted or substituted alkoxy.

(Substituent group β) The "substituent group β" is composed of the following substituents. (β-1) Substituent group α (β-2) Unsubstituted or substituted phenyl (β-3) Unsubstituted or substituted phenoxy (β-4) Unsubstituted or substituted phenylalkyl (β-5) Unsubstituted or substituted phenylalkoxy

Regarding "substituent group α", "unsubstituted or substituted phenyl", "unsubstituted or substituted phenoxy", "unsubstituted or substituted phenalkyl" and "unsubstituted The above description of "or substituted phenalkoxy" also applies to the substituent group β.

(β-2) is preferably a phenyl group having one or more substituents selected from halogen atoms. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2.

(β-3) is preferably a phenoxy group having one or more substituents selected from halogen atoms. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2.

(β-4) Preferably, it is a phenalkyl group having one or more substituents selected from halogen atoms. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2.

(β-5) is preferably a phenylalkoxy group having one or more substituents selected from halogen atoms. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2.

Substituent group β is preferably composed of halogen atoms, aliphatic heterocyclic oxy groups, phenyl groups, and phenyl groups having one or more substituents selected from halogen atoms and aliphatic heterocyclic oxy groups, more preferably It consists of a halogen atom, an aliphatic heterocyclic oxy group, a phenyl group, and a phenyl group having one or more substituents selected from halogen atoms.

≪Method for producing β-C-aryl glycoside derivatives≫ The method for producing a β-C-aryl glycoside derivative of the present invention includes contacting a C-aryl-hydroxy glycoside derivative with a silane compound in the presence of a titanium compound to produce a β-C-aryl glycoside derivative step.

(β-C-aryl glycoside derivative) β-C-aryl glycoside derivative is a compound represented by the following formula (1):

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

In one embodiment, all of R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms.

In another embodiment, all of R ¹ , R ² , R ³ and R ⁴ are hydroxyl protecting groups.

In yet another embodiment, 1 to 3 of R ¹ , R ² , R ³ and R ⁴ are hydroxyl protecting groups, and the rest are hydrogen atoms.

In terms of easy separation of the produced β-C-aryl glycoside derivative from the reaction system, it is preferable that one or more of R ¹ , R ² , R ³ and R ⁴ is a hydroxyl protecting group , more preferably Department of R ^1, R ^2, R ^3, and R of two or more hydroxy-protecting groups ^4, and still more preferably based R ^1, R ^2, R ³ and R ⁴ are both hydroxy protecting groups all.

In the case where two or more of R ¹ , R ² , R ³ and R ⁴ are hydroxyl protecting groups, these hydroxyl protecting groups may be the same or different, and are based on the viewpoint of efficient introduction and removal of hydroxyl protecting groups In other words, they are preferably the same.

The hydroxyl protecting group can protect the hydroxyl group when the target reaction is performed, and it can be removed from the hydroxyl group after the target reaction is completed. It is not particularly limited and can be selected appropriately. Examples of the hydroxy protecting group include ester type protecting groups, aralkyl type protecting groups, alkyl type protecting groups, aralkoxyalkyl type protecting groups, alkoxyalkyl type protecting groups, silyl type protecting groups, oxygen Carbonyl type protecting group, etc.

As the ester-type protecting group, for example, acetyl, propyl, butyryl, isopropyl, trimethyl acetyl, benzyl, 4-nitrobenzyl, 4-methyloxy Benzyl, 4-methylbenzyl, 4-tert-butylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, 4-methyloxycarbonylbenzyl and the like. The ester-type protecting groups are preferably acetyl and trimethyl acetyl.

Examples of the aralkyl-type protective group include benzyl, 1-phenylethyl, diphenylmethyl, 1,1-diphenylethyl, and naphthylmethyl. The aralkyl type protecting group is preferably benzyl.

Examples of the alkyl-type protective group include methyl, ethyl, and tertiary butyl. The alkyl-type protecting group is preferably methyl.

As an aralkoxyalkyl type protecting group, benzyloxymethyl etc. are mentioned, for example.

As an alkoxyalkyl type protective group, a methyloxymethyl group etc. are mentioned, for example.

Examples of the silyl-type protecting group include trimethylsilyl, triethylsilyl, tertiary butyldimethylsilyl, and tertiary butyldiphenylsilyl. The silyl protecting group is preferably trimethylsilyl and tert-butyldimethylsilyl.

Examples of the oxycarbonyl-type protective group include alkoxycarbonyl groups such as methyloxycarbonyl and aralkyloxycarbonyl groups such as benzyloxycarbonyl.

The hydroxyl protecting group is preferably selected from methyl, benzyl, acetyl, trimethyl acetyl, trimethylsilyl and tert-butyldimethylsilyl, more preferably selected from benzyl, ethyl Acetyl and trimethyl acetyl. These hydroxyl protecting groups are preferable in terms of easier protection and deprotection of the hydroxyl group, and inexpensive reagents.

In the formula (1), Ar is a group containing a group selected from an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic heterocyclic group as the oxane ring in the formula The organic base for bonding.

In one embodiment, Ar is an organic group including an unsubstituted or substituted aromatic ring group as a group for bonding with the oxane ring in formula (1). Ar may also be an unsubstituted or substituted aromatic ring group.

In another embodiment, Ar is an organic group containing an unsubstituted or substituted aromatic heterocyclic group as a group bonding to the oxane ring in formula (1). Ar may also be an unsubstituted or substituted aromatic heterocyclic group.

As an organic group containing an unsubstituted or substituted aromatic ring group as a group bonding to the oxane ring in the formula (1), for example, the organic group having the formula: -J ¹ -J ² [ In the formula, J ¹ is an unsubstituted or substituted alkylene group, and J ² is an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, or an unsubstituted or substituted A substituted aliphatic heterocyclic group. ] The aromatic ring group of the substituent shown. J ^{1 is} preferably an unsubstituted alkylene group. J ^{2 is} preferably an unsubstituted or substituted aromatic ring group or an unsubstituted or substituted aromatic heterocyclic group.

As an organic group containing an unsubstituted or substituted aromatic heterocyclic group as a functional group bonded to the carbon atom of the oxane ring in formula (I), for example, the organic group having the formula: -K ¹ -K ² [In the formula, K ¹ is an unsubstituted or substituted alkylene group, K ² is an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group or Unsubstituted or substituted aliphatic heterocyclic group. ] The aromatic heterocyclic group of the substituent shown. K ^{1 is} preferably an unsubstituted alkylene group. K ^{2 is} preferably an unsubstituted or substituted aromatic ring group or an unsubstituted or substituted aromatic heterocyclic group.

The organic group shown by Ar is preferably the same as the aromatic ring group or aromatic heterocyclic group of the SGLT-2 inhibitor, or it is the same as the aromatic ring group or aromatic group of the SGLT-2 inhibitor. The heterocyclic group is derived from induction.

Here, Cannagliflozin (1-(β-D-glucosepiperanyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene ), Enpagliflozin (also known as "(1S)-1,5-dehydrate-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl ]Oxy}phenyl)methyl]phenyl}-D-glucitol”), Igligliflozin (also known as “(1S)-1,5-dehydrate-1-C-{3-[(1 -Benzothiophen-2-yl)methyl)-4-fluorophenyl}-D-glucitol-(2S)-pyrrolidine-2-carboxylic acid'') and dapagliflozin (also known as “(2S ,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-piperan-3, SGLT-2 inhibitors headed by "4,5-thiol") have an organic group represented by the following formula (A).

Therefore, in a preferred embodiment, Ar is an organic group represented by the following formula (A):

In formula (A), n is an integer of 0-4. n is preferably 1 to 3, more preferably 1 or 2, and still more preferably 1.

In formula (A), n ^Ra are each independently selected from halogen atoms, amino groups, unsubstituted or substituted alkyl groups, unsubstituted or substituted alkoxy groups, unsubstituted or substituted Heteroalkyl, unsubstituted or substituted heteroalkoxy, unsubstituted or substituted monoalkylamino, unsubstituted or substituted dialkylamino, unsubstituted or substituted aliphatic Cyclic group, unsubstituted or substituted aliphatic epoxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted The group of phenyl, unsubstituted or substituted phenoxy, unsubstituted or substituted phenalkyl, and unsubstituted or substituted phenalkoxy.

When n is 2 or more, n ^Ras may be the same or different.

In formula (A), n is preferably a R ^a are each independently selected from halogen atoms, the unsubstituted or substituted alkyl, of unsubstituted or substituted alkoxy, unsubstituted or substituted with the Heteroalkyl, unsubstituted or substituted heteroalkoxy, unsubstituted or substituted aliphatic cyclic group, unsubstituted or substituted aliphatic epoxy group, unsubstituted or substituted aliphatic Heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenoxy group, unsubstituted or substituted phenalkyl group and The group of unsubstituted or substituted phenalkoxy is more preferably selected from halogen atoms, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted The phenyl group and the unsubstituted or substituted phenalkyl group are more preferably selected from fluorine atom, chlorine atom, bromine atom, iodine atom, methyl, ethyl, isopropyl, tertiary butyl, methyl The group of oxy, ethoxy, phenyl and benzyl is more preferably a group selected from fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group and methoxy group.

In formula (A), Ar' is selected from the group consisting of unsubstituted or substituted aromatic ring groups, unsubstituted or substituted aromatic heterocyclic groups and unsubstituted or substituted aliphatic heterocyclic groups base.

In formula (A), Ar' is preferably a group selected from an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic heterocyclic group, preferably the following formula (Ar'- 1) The group represented by (Ar'-2) or (Ar'-3).

In formulas (Ar'-1), (Ar'-2) and (Ar'-3), p is an integer of 0-5. p is preferably an integer of 0-3, more preferably an integer of 0-2, and still more preferably 0 or 1.

In formulas (Ar'-1), (Ar'-2) and (Ar'-3), each of p R ^{b is} independently selected from halogen atoms, amino groups, unsubstituted or substituted alkyl groups, Unsubstituted or substituted alkoxy, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heteroalkoxy, unsubstituted or substituted monoalkylamino, unsubstituted or A substituted dialkylamino group, an unsubstituted or substituted aliphatic ring group, an unsubstituted or substituted aliphatic epoxy group, an unsubstituted or substituted aliphatic heterocyclic group, an unsubstituted or Substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenoxy group, unsubstituted or substituted phenalkyl group and unsubstituted or substituted benzene Alkoxy group.

When p is 2 or more, p R ^b may be the same or different.

In the formula (Ar'-1), p is preferably 1, and R ^{b is} preferably an unsubstituted or substituted phenyl group, more preferably a phenyl group having a halogen atom, and still more preferably a benzene having a fluorine atom base. The position to which the unsubstituted or substituted phenyl group is bonded is preferably the 2-position of the thiophene ring. In the phenyl group having a halogen atom, the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.

In formula (Ar'-2), p is preferably zero.

In formula (Ar'-3), p is preferably 1, and R ^{b is} preferably an unsubstituted or substituted alkoxy group or an unsubstituted or substituted aliphatic heterocyclic oxy group. The unsubstituted or substituted alkoxy group is preferably an alkoxy group having 1 to 3 carbon atoms, more preferably a methoxy group or an ethoxy group. The unsubstituted or substituted aliphatic heterocyclic oxy group is preferably tetrahydrofuranoxy. The position to which the unsubstituted or substituted alkoxy group or the unsubstituted or substituted aliphatic heterocyclic oxy group is bonded is preferably the 4-position of the benzene ring.

When n is 1, Ar is preferably an organic group represented by the following formula (B):

In Formula (B), R ^a and Ar 'is synonymous with the system of formula (A).

Ar is preferably an organic group represented by the following formula (Ar-1), (Ar-2), (Ar-3) or (Ar-4).

(C-Aryl-Hydroxy Glycoside Derivatives) C-Aryl-Hydroxy Glycoside Derivatives are compounds represented by the following formula (2):

In formula (2), R ¹ , R ² , R ³ , R ⁴ and Ar are synonymous with formula (1).

In the formula (2), R ⁵ is a hydrogen atom, a methyl group, a trimethylsilyl group or an acetyl group.

In the formula (2), R ^{5 is} preferably a methyl group, a trimethylsilyl group or an acetyl group.

In formula (2), when R ⁵ is a methyl group, it is preferable that none of R ¹ to R ⁴ is a methyl group. Thereby, in the reduction reaction of the C-aryl-hydroxyglycoside derivative, -OR ¹ , -OR ² , -OR ³ and -OR ⁴ can be maintained while -OR ^{5 can be} released.

In formula (2), when R ⁵ is a trimethylsilyl group, it is preferable that none of R ¹ to R ⁴ is a trimethylsilyl group. Thereby, in the reduction reaction of the C-aryl-hydroxyglycoside derivative, -OR ¹ , -OR ² , -OR ³ and -OR ⁴ can be maintained while -OR ^{5 can be} released.

In formula (2), when R ⁵ is an acetyl group, it is preferable that none of R ¹ to R ⁴ is an acetyl group. Thereby, in the reduction reaction of the C-aryl-hydroxyglycoside derivative, -OR ¹ , -OR ² , -OR ³ and -OR ⁴ can be maintained while -OR ^{5 can be} released.

The C-aryl-hydroxy glycoside derivative can be obtained by the known methods described in the aforementioned Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2, etc.

(Titanium compound) In the step of bringing the C-aryl-hydroxy glycoside derivative into contact with the silane compound in the presence of the titanium compound, the titanium compound acts as Lewis acid. By using a titanium compound, the reduction reaction of the C-aryl-hydroxy glycoside derivative can proceed rapidly at low temperature, and the target β-C-aryl glycoside derivative can be obtained with high selectivity and high yield.

As the titanium compound, for example, titanium is 0-valent, titanium is divalent, trivalent, tetravalent, etc., and any titanium compound may be used. As the titanium compound, triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV) ), titanium bromide (IV), titanium iodide (IV), titanium oxide (IV) and other tetravalent titanium salts or their solvents; titanium (III) chloride, titanium (III) bromide and other trivalent titanium salts Or its solvent; divalent titanium salt such as titanium(II) chloride or its solvent; 0-valent titanium such as metal Ti or its solvent. Examples of the solvent include those obtained by coordination with a solvent such as water and tetrahydrofuran.

The titanium compound preferably has the formula: TiR ^c _r (OR ^d ) _s [wherein R ^c is a halogen atom, R ^d is a substituted or unsubstituted alkyl group, and r and s satisfy r+s=3 or 4 The integer of 0～4. ] As shown in the trivalent or tetravalent titanium salt or its solvent. R ^{c is} preferably a chlorine atom, a bromine atom or an iodine atom, and R ^{d is} preferably an alkyl group having 1 to 6 carbons, and more preferably an alkyl group having 1 to 3 carbons.

The titanium compound is preferably triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV) , Titanium (III) chloride, etc., more preferably titanium (IV) chloride. Titanium(IV) chloride has a low melting point and is liquid at room temperature, so it is better in terms of easy handling and low price.

The amount of the titanium compound used is not particularly limited, and can be appropriately adjusted. The amount of the titanium compound used is relative to 1 mol of the C-aryl-hydroxyglycoside derivative represented by formula (1), preferably 0.05-10 mol, more preferably 0.1-7 mol, and still more Preferably, it is 1 to 5 moles.

(Silane compound) In the step of bringing the C-aryl-hydroxy glycoside derivative into contact with the silane compound in the presence of the titanium compound, the silane compound acts as a reducing agent.

As the silane compound, for example, triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tertiary butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxy Hydrogen silane, triethoxy silane, tetramethyldisiloxane, etc. In terms of reactivity or price, the silane compound is preferably trimethoxyhydrosilane, triethoxyhydrosilane, tetramethyldisiloxane, etc., and more preferably tetramethyldisiloxane.

The amount of the silane compound used is not particularly limited, and can be appropriately adjusted. The amount of the silane compound used is from the aspect of allowing the reaction to proceed sufficiently, relative to 1 mol of the C-aryl-hydroxy glycoside derivative, preferably 1-10 mol, more preferably 1-5 mol , More preferably 1～3 mol.

(Reaction solvent) In the step of bringing the C-aryl-hydroxy glycoside derivative into contact with the silane compound in the presence of the titanium compound, it is preferable to stir the C-aryl-hydroxy glycoside derivative, the titanium compound and the silane compound in a reaction solvent mixing.

The reaction solvent is recommended before it is a solvent that does not adversely affect C-aryl-hydroxy glycoside derivatives, titanium compounds and silane compounds, and can smoothly reduce C-aryl-hydroxy glycoside derivatives. It is not particularly limited. Examples of the reaction solvent include aliphatic nitriles such as acetonitrile and propionitrile, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, tert-butyl methyl ether, and diisopropyl. Ether, dimethoxyethane, diglyme and other ethers, acetone, methyl ethyl ketone, diethyl ketone and other ketones, methyl acetate, ethyl acetate, butyl acetate and other acetates , Dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and other halogenated hydrocarbons, toluene, xylene and other aromatic hydrocarbons, hexane, heptane and other aliphatic hydrocarbons. These reaction solvents can be used alone or in the form of mixed solvents. The reaction solvent is preferably acetonitrile, methylene chloride or a mixed solvent of these. In terms of not being easily subjected to silane reduction, these are preferably aprotic polar solvents.

The amount of the reaction solvent used is not particularly limited, and can be appropriately adjusted. The amount of the reaction solvent used is preferably 1 to 100 times the capacity relative to the C-aryl-hydroxyglycoside derivative, more preferably 1 to 50 times the capacity, and even more preferably 2 to 20 times the capacity. In addition, when a mixed solvent is used as the reaction solvent, the total amount of the mixed solvent may satisfy the above range.

(Reduction reaction) In the step of bringing the C-aryl-hydroxy glycoside derivative into contact with the silane compound in the presence of the titanium compound, the reduction reaction of the C-aryl-hydroxy glycoside derivative proceeds. The reduction reaction can be performed by mixing a C-aryl-hydroxy glycoside derivative, a titanium compound, a silane compound, and a reaction solvent if necessary.

The method of mixing each component is not specifically limited, For example, it can implement in the reaction container equipped with a stirring device. The order of adding the components to the reaction vessel is not particularly limited. It is more preferable to put the C-aryl-hydroxyglycoside derivative, the silane compound, and the reaction solvent if necessary into the reaction vessel in advance, and add the titanium compound while stirring. And the method of mixing.

The temperature when the titanium compound is added and the reaction temperature after the addition are not particularly limited, and can be adjusted appropriately. The temperature when the titanium compound is added and the reaction temperature after addition are preferably in the range of -100°C to 100°C, more preferably -78°C to 50°C, and still more preferably -60°C to 10°C. By performing the reaction in the above temperature range, β-C-aryl glycoside derivatives can be obtained with high selectivity and high yield.

The reaction time is not particularly limited, and for example, it can be appropriately adjusted while confirming the conversion rate of the raw material C-aryl-hydroxyglycoside derivative. The reaction time is usually 10 minutes or more and 48 hours or less, preferably 0.5 hours or more and 24 hours or less, more preferably 1 hour or more and 17 hours or less.

The reaction environment is not particularly limited. In order to suppress the incorporation of moisture, it is preferably under an inert gas environment or an air environment.

The reaction system may be under atmospheric pressure, under pressure, or under reduced pressure. Among these, the reaction is preferably carried out under atmospheric pressure.

Through the reduction reaction, β-C-aryl glycoside derivatives can be obtained. The product obtained by the reduction reaction is β-C-aryl glycoside derivative (hereinafter, sometimes referred to as "β body") and α-C-aryl glycoside derivative (hereinafter, sometimes referred to as " Alpha body".) A mixture. According to the present invention, β-C-aryl glycoside derivatives can be produced with high selectivity and high yield, so the ratio of β-body in the product is high. The isomer ratio (β-form/α-form) in the product is usually 73/27 or more, preferably 75/25 or more, more preferably 77/23 or more, still more preferably 80/20 or more, and still more preferably It is 85/15 or more, more preferably 90/10 or more. In addition, the isomer ratio was measured by the method described in the examples.

The β-C-aryl glycoside derivative obtained by the reduction reaction is preferably taken out of the reaction system. The β-C-aryl glycoside derivative obtained by the reduction reaction can be hardly water-soluble with ethyl acetate, toluene, tert-butyl methyl ether, dichloromethane, etc., by adding water to the reaction solution, for example. The organic solvent is contacted, and the β-C-aryl glycoside derivative is extracted with the poorly water-soluble organic solvent, and taken out of the reaction system.

In addition, the obtained β-C-aryl glycoside derivative can also be purified with higher purity by using known methods such as column separation and recrystallization. However, it is difficult to separate the β-body from the α-body by refining the column such as a silica gel column. Therefore, the usefulness of the present invention which can produce β-C-aryl glycoside derivatives with high selectivity and high yield is very high.

The β-C-aryl glycoside derivative obtained is the case where R ¹ to R ⁴ are all hydrogen atoms as it is, and the case where one or more of R ¹ to R ⁴ is a hydroxyl protecting group is known as necessary After being deprotected by the method, it can be suitably used as an SGLT2 inhibitor or its synthetic intermediate useful as an antidiabetic drug. [Example]

Hereinafter, the present invention will be explained in detail with examples, but these are specific examples and the present invention is not limited by these.

(Production Example 1: Production of C-aryl-hydroxyglycoside derivative of alcohol body) The reaction shown in the following formula was performed to produce the C-aryl-hydroxyglycoside derivative of alcohol body (in formula (2), Compounds in which R ¹ , R ² , R ³ and R ⁴ are benzyl, R ⁵ is a hydrogen atom, and Ar is a phenyl group). In addition, Bn represents a benzyl group. The following is the same.

In the THF (5mL) solution of tetra-O-benzyl-D-gluconolactone (1.00g, 1.86mmol), phenyllithium (phenyllithium concentration) was added dropwise at -63℃～-67℃ for 30 minutes. : 16%, solvent: dibutyl ether) (1.3g, 2.47mmol, 1.3eq). After stirring at the same temperature for 1 hour, water (5 mL) was added, and it took 1 hour to warm up to room temperature.

The product was extracted with ethyl acetate (20 mL), and the obtained organic layer was concentrated under reduced pressure to obtain 3R,4S,5R-tribenzyloxy-6R-benzyloxymethyl-6-hydroxy -6-Phenyltetrahydropiperan (hereinafter, also referred to as an alcohol body.) (1.20 g, yield: quant.).

(Production Example 2: Production of C-Aryl-Hydroxy Glycoside Derivative of Methoxylate) The reaction shown in the following formula was carried out to produce C-aryl-hydroxyglycoside derivative of Methoxylate (in formula (2) Where R ¹ , R ² , R ³ and R ⁴ are benzyl groups, R ⁵ is a methyl group, and Ar is a phenyl group).

To a methanol (2 mL) solution of methanesulfonic acid (0.6 mg, 0.06 mmol), the alcohol (200 mg, 0.32 mmol) obtained in Production Example 1 in methanol (1 mL) was added at room temperature, and stirred at the same temperature for 21 hours . Triethylamine (50mg, 0.49mmol) was added to the reaction solution at room temperature and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and a mixed solution of ethyl acetate: water = 10 mL/10 mL was added to the concentrated residue to perform liquid separation. By concentrating the organic layer under reduced pressure, 3R,4S,5R-tribenzyloxy-6R-benzyloxymethyl-6-methoxy-6-phenyltetrahydropiperan (hereinafter, Also known as methoxy body.) (172 mg, yield: 84%).

(Production Example 3: Production of C-aryl-hydroxy glycoside derivative of alcohol body) The reaction shown in the following formula was performed to produce the C-aryl-hydroxy glycoside derivative of alcohol body (in formula (2), R ¹ , R ² , R ³ and R ⁴ are a benzyl group, R ⁵ is a hydrogen atom, and Ar is an organic compound represented by the above formula (Ar-1)).

To (5-iodo-2-methylbenzyl)-2-(4-fluorophenyl)thiophene (765mg, 1.86mmol) in THF (5mL) was added butyl lithium (1.6M hexane solution) (1.16 mL, 1.86mmol), after stirring at -70℃ for 1 hour, add Tetra-O-benzyl-D-gluconolactone (1.00g, 1.86mmol) in THF (5mL) solution at the same temperature and stir for 1 hour , Add water (5mL) to stop the reaction.

The product was extracted with ethyl acetate (20 mL), and the obtained organic layer was concentrated under reduced pressure to obtain 3R,4R,5S-tribenzyloxy-2R-benzyloxymethyl-6-hydroxy -6-(3-(5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydropiperan (hereinafter, also referred to as alcohol) (1.53g , Yield: quant.). This strain was not refined and the bold was used as it was in the next step (Example 3).

(Example 1: Reduction via titanium compound (manufacturing of β-C-aryl glycoside derivative from alcohol)) Using a titanium compound, the reaction shown in the following formula was performed to produce a β-C-aryl glycoside derivative from the alcohol body obtained in Production Example 1.

Tetramethyl disiloxane (44 mg, 0.33 mmol) was added to the acetonitrile solution (2 mL) of the alcohol body (100 mg, 0.16 mmol) obtained in Production Example 1. After cooling to -40°C in a dry ice/acetone bath, a solution of titanium tetrachloride (92 mg, 0.49 mmol) in dichloromethane (1 mL) was added, and the mixture was stirred at the same temperature for 3 hours.

The reaction solution was analyzed by HPLC. As a result, the alcohol body was completely consumed and the target product was obtained. The isomer ratio of the product is β/α=80/20.

Water (5 mL) was added to the reaction solution, and the product was extracted 4 times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. The concentrated solution was purified by a silica gel column (developing solvent: hexane/ethyl acetate=10/1) to obtain the target product (3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl) 2-S-phenyltetrahydropiperan) (64 mg, yield: 66%). The isomer ratio of the product is β/α=80/20.

1H-NMR(CDCl3)δ: 3.50-3.55(m, 1H), 3.60-3.61(m, 1H), 3.73-3.82(m, 5H), 4.25(d, J=9.3Hz, 1H), 4.36(d , J=10.3Hz, 1H), 4.55-4.68(m, 3H), 4.86-4.98(m, 3H), 6.91-6.93(m, 2H), 7.14-7.53(m, 23H).

(Example 2: Reduction via titanium compound (manufacture of β-C-aryl glycoside derivative from methoxy compound) Using a titanium compound, the reaction shown in the following formula was performed to produce a β-C-aryl glycoside derivative from the methoxy body obtained in Production Example 2.

Tetramethyl disiloxane (44 mg, 0.33 mmol) was added to the acetonitrile solution (2 mL) of the methoxy compound (103 mg, 0.16 mmol) obtained in Production Example 2. After cooling to -40°C in a dry ice/acetone bath, a solution of titanium tetrachloride (92 mg, 0.49 mmol) in dichloromethane (1 mL) was added, and the mixture was stirred at the same temperature for 3 hours.

The reaction solution was analyzed by HPLC. As a result, the alcohol body was completely consumed and the target product was obtained. The isomer ratio of the product is β/α=75/25.

Water (5 mL) was added to the reaction solution, and the product was extracted 4 times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. The concentrate was purified with a silica gel column (developing solvent: hexane/ethyl acetate=10/1) to obtain the target product (60 mg, yield: 62%). The isomer ratio of the product is β/α=75/25.

1H-NMR(CDCl3)δ: 3.50-3.55(m, 1H), 3.60-3.61(m, 1H), 3.73-3.82(m, 5H), 4.25(d, J=9.3Hz, 1H), 4.36(d , J=10.3Hz, 1H), 4.55-4.68(m, 3H), 4.86-4.98(m, 3H), 6.91-6.93(m, 2H), 7.14-7.53(m, 23H).

(Example 3: Reduction via titanium compound (manufacturing of β-C-aryl glycoside derivative from alcohol)) Using a titanium compound, the reaction shown in the following formula was performed to produce a β-C-aryl glycoside derivative from the alcohol body obtained in Production Example 3.

Tetramethyl disiloxane (44 mg, 0.33 mmol) was added to the acetonitrile solution (2 mL) of the alcohol body (131 mg, 0.16 mmol) obtained in Production Example 3. After cooling to -40°C in a dry ice/acetone bath, add a solution of titanium tetrachloride (92 mg, 0.49 mmol) in dichloromethane (1 mL), and stir at the same temperature for 3 hours.

The reaction solution was analyzed by HPLC. As a result, the alcohol body was completely consumed and the target product was obtained. The isomer ratio of the product is β/α=91/9.

Water (5 mL) was added to the reaction solution, and the product was extracted 4 times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. Purify the concentrated solution with a silica gel column (developing solvent: hexane/ethyl acetate=10/1) to obtain the target product (3R, 4R, 5S-tribenzyloxy-2R-benzyloxymethyl) Benzyl-6S-(3-(5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydropiperan) (106 mg, yield: 82%). The isomer ratio of the product is β/α=>95/5.

1H-NMR(CDCl3): 2.24(s, 3H), 3.04-3.18(m, 2H), 3.22-3.30(m, 2H), 3.33-3.47(m, 1H), 3.55-3.74(m, 1H), 3.88-3.92(m, 1H), 4.00-4.62(m, 8H), 4.73-4.93(m, 2H), 6.80-6.88(m, 1H), 7.04-7.21(m, 12H), 7.28-7.40(m , 14H), 7.52-7.62(m, 2H).

(Comparative Example 1: Reduction via aluminum chloride (manufacturing of β-C-aryl glycoside derivative from alcohol)) Using aluminum chloride, the reaction shown in the following formula was performed to produce a β-C-aryl glycoside derivative from the alcohol body obtained in Production Example 1.

After dissolving the alcohol body (10 mg, 0.02 mmol) obtained in Production Example 1 in a mixed solution of dichloromethane (0.5 mL) and acetonitrile (1 mL), tetramethyl disiloxane (4.4 mg, 0.03 mmol) was added . Aluminum chloride (6.5 mg, 0.05 mmol) was added to it at -40°C, slowly raised to room temperature, and stirred at the same temperature for 18 hours.

The reaction liquid was analyzed by HPLC. As a result, the alcohol body was completely consumed and the target product was obtained (yield: 76%). The isomer ratio of the product is β/α=71/29.

(Comparative Example 2: Reduction via aluminum chloride (manufacturing of β-C-aryl glycoside derivative from methoxy compound) Using aluminum chloride, the reaction shown in the following formula was performed to produce a β-C-aryl glycoside derivative from the methoxy compound obtained in Production Example 2.

After dissolving the methoxy compound (10 mg, 0.02 mmol) obtained in Production Example 2 in a mixed solution of dichloromethane (0.5 mL) and acetonitrile solution (1 mL), tetramethyldisiloxane (4.4 mg, 0.03 mmol). Aluminum chloride (6.5mg, 0.05mmol) was added to it at -40°C, slowly raised to room temperature, and stirred at the same temperature for 17 hours.

The reaction solution was analyzed by HPLC. As a result, the methoxy body was completely consumed and the target product was obtained (yield: 41%). The isomer ratio of the product is β/α=68/32.

In addition, the evaluation of the isomer ratio in the examples and comparative examples was performed by a method using high performance liquid chromatography (HPLC). The HPLC system was performed under the following measurement conditions. The isomer ratio of α-form and β-form is the ratio of the peak area values of α-form and β-form measured by HPLC to the sum of the peak area values of α-form and β-form measured by HPLC Ratio.

In addition, the yield in the examples is based on the recovery of the target, which is calculated from the amount of raw materials and the amount of the target. The yield in the comparative example was calculated by the method using HPLC. The HPLC system was performed under the following measurement conditions. The yield of the target product is the ratio of the peak area value of the target product to the total area value of all peaks (except the peak derived from the solvent).

<HPLC measurement conditions> Device: high performance liquid chromatography (HPLC) Detector: UV absorbance photometer (measurement wavelength: 210nm) Column: XBridge C18, 5μm, inner diameter 4.8mm, length 15cm (made by Waters) Column temperature: 30℃ (definitely) Flow rate: 1.0mL/min Mobile phase: acetonitrile/water=90/10→100/0 (0→10 minutes) Holding time: 4.5 minutes for the alcohol of Production Example 1; 6.4 minutes for the methoxy compound of Production Example 2; 17.47 minutes for the alcohol of Production Example 3; β-form 5.7 of Example 1, Example 2, Comparative Example 1 and Comparative Example 2 Minutes; Example 1, Example 2, Comparative Example 1 and Comparative Example 2's α-body 5.4 minutes; Example 3 β-body 18.31 minutes; Example 3 α-body 18.13 minutes

Claims (6)

A method for producing β-C-aryl glycoside derivatives represented by the following formula (1):

[In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom or a hydroxy protecting group, and Ar is an aromatic ring group that will be selected from unsubstituted or substituted and unsubstituted or substituted The group of the aromatic heterocyclic group is used as the organic group of the group bonded to the oxane ring in the formula], the aforementioned method includes derivatizing the C-aryl-hydroxy glycoside represented by the following formula (2) The steps of making the aforementioned β-C-aryl glycoside derivatives by contacting the silane compound with the silane compound in the presence of the titanium compound:

[In the formula, R ¹ , R ² , R ³ , R ⁴ and Ar have the same meaning as above, and R ⁵ is a hydrogen atom, a methyl group, a trimethylsilyl group, or an acetyl group]. The method of claim 1, wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from methyl, benzyl, acetyl, trimethylacetoxy, trimethylsilyl and the third The hydroxyl protecting group of tributyldimethylsilyl. According to the method of claim 1 or 2, wherein the aforementioned titanium compound is selected from triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy trichloride Titanium (IV), titanium (III) chloride and titanium (IV) chloride. The method according to any one of claims 1 to 3, wherein the aforementioned silane compound is selected from the group consisting of triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tertiary butyldimethyl Silane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane, and tetramethyldisiloxane. The method according to any one of claims 1 to 4, wherein Ar is an organic group or a phenyl group represented by the following formula (A):

[In the formula, each R ^{a is} independently selected from a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, Unsubstituted or substituted heteroalkoxy, unsubstituted or substituted monoalkylamino, unsubstituted or substituted dialkylamino, unsubstituted or substituted aliphatic cyclic group, unsubstituted Substituted or substituted aliphatic epoxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted aliphatic heterocyclic group The group of substituted or substituted phenoxy, unsubstituted or substituted phenalkyl and unsubstituted or substituted phenalkoxy, n is an integer from 0 to 4, Ar' is selected from unsubstituted Or substituted aromatic ring group, unsubstituted or substituted aromatic heterocyclic group and unsubstituted or substituted aliphatic heterocyclic group]. For example, the method according to any one of claims 1 to 5, wherein Ar' is a group represented by the following formula (Ar'-1), (Ar'-2) or (Ar'-3):

[In the formula, R ^{b is} each independently selected from a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, Unsubstituted or substituted heteroalkoxy, unsubstituted or substituted monoalkylamino, unsubstituted or substituted dialkylamino, unsubstituted or substituted aliphatic cyclic group, unsubstituted Substituted or substituted aliphatic epoxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted aliphatic heterocyclic group The group of substituted or substituted phenoxy, unsubstituted or substituted phenylalkyl and unsubstituted or substituted phenylalkoxy, p is an integer of 0-5].