WO2020050361A1 - PRODUCTION METHOD FOR β-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 β-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 β-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 a SGLT2 inhibitor useful as an antidiabetic agent or a β-C-arylglycoside derivative which is a synthetic intermediate thereof. Specifically, the present invention relates to a method for efficiently producing a SGLT2 inhibitor useful as an antidiabetic agent or a β-C-arylglycoside derivative which is a synthetic intermediate thereof under mild conditions. Throughout this specification, “β-C-aryl glycoside derivative” means a compound represented by the formula (1) described below, and “C-aryl-hydroxyglycoside derivative” means a compound represented by the formula (2) described later. Means a compound represented by

SGLT2 inhibitors are useful as antidiabetic agents. “SGLT2” means sodium-glucose cotransport carrier-2. Examples of SGLT2 inhibitors include canagliflozin (1- (β-D-glycopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene), empagliflozin ( (1S) -1,5-anhydro-1-C- {4-chloro-3-[(4-{[(3S) -oxolan-3-yl] oxy} phenyl) methyl] phenyl} -D-glucitol , Ipragliflozin ((1S) -1,5-anhydro-1-C- {3-[(1-benzothiophen-2-yl) methyl] -4-fluorophenyl} -D-glucitol- (2S)- Pyrrolidine-2-carboxylic acid), dapagliflozin ((2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethyloxybenzyl) phenyl] -6- (hydroxy Chill) tetrahydro -2H- pyran-3,4,5-thiol), and the like are known.

Β-C-aryl glycoside derivatives have received attention as SGLT2 inhibitors (antidiabetic agents) or synthetic intermediates thereof (see Non-Patent Document 1 and Patent Document 1). As one method for producing a β-C-aryl glycoside derivative, a method for producing a β-C-aryl glycoside derivative by reducing a C-aryl-hydroxy glycoside derivative has been reported (Non-Patent Documents 1 and 2). And Patent Document 1).

Non-patent Documents 1 and 2 disclose that a C-aryl-hydroxyglycoside derivative is reduced using triethylsilane in the presence of boron trifluoride diethyl ether complex (BF ₃ .OEt ₂ ) to give β-C-aryl Methods for producing glycoside derivatives have been described. Further, Patent Document 1 discloses that a C-aryl-hydroxyglycoside derivative is prepared by converting BF ₃ .OEt ₂ , boron trifluoride tetrahydrofuran (BF ₃ ) in the presence of silanes such as triethylsilane, triisopropylsilane, and tetramethyldisiloxane A process for producing a β-C-arylglycoside derivative by reacting with a Lewis acid such as THF (THF) and aluminum chloride is described.

International Publication No. 2010/043682

Wei @ Meng et al., "Journal of Medicinal Chemistry", 2008, Vol. 51, No. 5, p. 1145-1149 S. Czernecki et al., "Journal of Organic Chemistry", 1989, Vol. 54, No. 3, p. 610-612

ホ ウ 素 However, the reaction vessel is corroded because boron trifluoride is corrosive. Also, aluminum chloride requires a relatively high temperature for the reaction to proceed because of its low Lewis acidity. However, as the reaction temperature increases, the stereoselectivity (β selectivity) of the reaction decreases. Further, aluminum chloride is a solid Lewis acid, and it is necessary to weigh it under anhydrous conditions, so that handling is difficult.

Accordingly, an object of the present invention is to provide a method for producing a β-C-aryl glycoside derivative with high selectivity and high yield, in which the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds rapidly at a low temperature. I do.

The present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, by bringing the C-aryl-hydroxyglycoside derivative into contact with the silane compound in the presence of the titanium compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative rapidly proceeds at a low temperature, and the β-C-arylglycoside They have found that derivatives can be produced with high selectivity and high yield, and have completed the present invention.

［式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は、それぞれ独立して、水素原子又は水酸基保護基であり、Ａｒは、非置換又は置換の芳香族環基及び非置換又は置換の芳香族複素環基から選択される基を、式中のオキサン環と結合する基として含む有機基である。］
で表されるβ－Ｃ－アリールグリコシド誘導体を製造する方法であって、
　下記式（２）：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＡｒは、前記と同義であり、Ｒ^５は、水素原子、メチル基、トリメチルシリル基又はアセチル基である。］
で表されるＣ－アリール－ヒドロキシグリコシド誘導体を、チタン化合物の存在下、シラン化合物と接触させて、前記β－Ｃ－アリールグリコシド誘導体を製造する工程を含む、前記方法。
［２］Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４が、それぞれ独立して、メチル基、ベンジル基、アセチル基、ピバロイル基、トリメチルシリル基及びｔｅｒｔ－ブチルジメチルシリル基から選択される水酸基保護基である、［１］に記載の方法。
［３］前記チタン化合物が、トリイソプロポキシ一塩化チタン（ＩＶ）、ジイソプロポキシ二塩化チタン（ＩＶ）、モノイソプロポキシ三塩化チタン（ＩＶ）、塩化チタン（ＩＩＩ）及び塩化チタン（ＩＶ）から選択される、［１］又は［２］に記載の方法。
［４］前記シラン化合物が、トリエチルシラン、トリイソプロピルシラン、フェニルシラン、ジメチルフェニルシラン、ｔｅｒｔ－ブチルジメチルシラン、トリイソブチルシラン、トリクロロシラン、トリメトキシヒドロシラン、トリエトキシヒドロシラン及びテトラメチルジシロキサンから選択される、［１］～［３］のいずれかに記載の方法。
［５］Ａｒが、下記式（Ａ）：

［式中、
　Ｒ^ａは、それぞれ独立して、ハロゲン原子、アミノ基、非置換又は置換のアルキル基、非置換又は置換のアルコキシ基、非置換又は置換のヘテロアルキル基、非置換又は置換のヘテロアルコキシ基、非置換又は置換のモノアルキルアミノ基、非置換又は置換のジアルキルアミノ基、非置換又は置換の脂肪族環基、非置換又は置換の脂肪族環オキシ基、非置換又は置換の脂肪族複素環基、非置換又は置換の脂肪族複素環オキシ基、非置換又は置換のフェニル基、非置換又は置換のフェニルオキシ基、非置換又は置換のフェニルアルキル基及び非置換又は置換のフェニルアルキルオキシ基から選択される基であり、
　ｎは、０～４の整数であり、
　Ａｒ’は、非置換又は置換の芳香族環基、非置換又は置換の芳香族複素環基及び非置換又は置換の脂肪族複素環から選択される基である。］
で表される有機基又はフェニル基である、［１］～［４］のいずれかに記載の方法。
［６］Ａｒ’が、下記式（Ａｒ’－１）、（Ａｒ’－２）又は（Ａｒ’－３）：

［式中、
　Ｒ^ｂは、それぞれ独立して、ハロゲン原子、アミノ基、非置換又は置換のアルキル基、非置換又は置換のアルコキシ基、非置換又は置換のヘテロアルキル基、非置換又は置換のヘテロアルコキシ基、非置換又は置換のモノアルキルアミノ基、非置換又は置換のジアルキルアミノ基、非置換又は置換の脂肪族環基、非置換又は置換の脂肪族環オキシ基、非置換又は置換の脂肪族複素環基、非置換又は置換の脂肪族複素環オキシ基、非置換又は置換のフェニル基、非置換又は置換のフェニルオキシ基、非置換又は置換のフェニルアルキル基及び非置換又は置換のフェニルアルキルオキシ基から選択される基であり、
　ｐは、０～５の整数である。］
で表される基である、［１］～［５］のいずれかに記載の方法。 That is, the present invention includes the following inventions.
[1] The following formula (1):

[Wherein, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom or a hydroxyl-protecting group, and Ar is an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic ring group. It is an organic group containing a group selected from a group heterocyclic group as a group bonded to an oxane ring in the formula. ]
A method for producing a β-C-aryl glycoside derivative represented by the formula:
The following equation (2):

[Wherein, R ¹ , R ² , R ³ , R ⁴ and Ar have the same meanings as described above, and R ⁵ is a hydrogen atom, a methyl group, a trimethylsilyl group or an acetyl group. ]
The method comprising the step of contacting a C-aryl-hydroxyglycoside derivative represented by the formula with a silane compound in the presence of a titanium compound to produce the β-C-arylglycoside derivative.
[2] R ¹ , R ² , R ³ and R ⁴ are each independently a hydroxyl protecting group selected from a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group and a tert-butyldimethylsilyl group. The method according to [1].
[3] The titanium compound is selected from triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (III) and titanium (IV) chloride. The method according to [1] or [2], which is selected.
[4] The silane compound is selected from triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane and tetramethyldisiloxane. The method according to any one of [1] to [3].
[5] Ar is the following formula (A):

[Where,
^Ra is each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, Substituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, Selected from an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and an unsubstituted or substituted phenylalkyloxy group. Group
n is an integer from 0 to 4,
Ar ′ is a group selected from an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, and an unsubstituted or substituted aliphatic heterocyclic ring. ]
The method according to any one of [1] to [4], which is an organic group or a phenyl group represented by:
[6] Ar ′ is represented by the following formula (Ar′-1), (Ar′-2) or (Ar′-3):

[Where,
R ^b is independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, Substituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, Selected from an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and an unsubstituted or substituted phenylalkyloxy group. Group
p is an integer of 0 to 5. ]
The method according to any one of [1] to [5], which is a group represented by:

According to the present invention, there is provided a method for producing a desired β-C-aryl glycoside derivative with high selectivity and high yield, in which the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds rapidly at a low temperature. . The obtained β-C-arylglycoside derivative is a SGLT2 inhibitor useful as an antidiabetic drug or a synthetic intermediate thereof, and therefore, the industrial utility value of the present invention is very high.

≪ Explanation of terms ≪
Hereinafter, terms used in the present specification will be described. The following description applies throughout the specification unless otherwise specified.

Halogen atom “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

An unsubstituted or substituted alkyl group “an unsubstituted or substituted alkyl group” means an alkyl group or an alkyl group having one or more substituents. The “alkyl group” means an unsubstituted alkyl group unless otherwise specified.

"Alkyl group" means a linear alkyl group or a branched alkyl group. The number of carbon atoms of the linear alkyl group is usually 1 to 20, preferably 1 to 10, more preferably 1 to 8, still more preferably 1 to 6, even more preferably 1 to 5, and still more preferably 1 to 5. To 4, more preferably 1 to 3, even more preferably 1 or 2. The number of carbon atoms of the branched alkyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, still more preferably 3 to 6, still more preferably 3 to 5, and even more preferably 3 to 5. Or 4. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, , 4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl and the like.

The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms. The “alkyl group having 1 to 6 carbon atoms” means a linear alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms.

に お い て In the alkyl group having one or more substituents, the 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 two or more, the two or more substituents may be the same or different. The one or more substituents that the alkyl group may have may each independently be selected from halogen atoms.

An unsubstituted or substituted alkylene group “unsubstituted or substituted alkylene group” means an alkylene group or an alkylene group having one or more substituents. The “alkylene group” means an unsubstituted alkylene group unless otherwise specified.

"Alkylene group" means a divalent functional group generated by removing one hydrogen atom from an alkyl group. The above description regarding the “alkyl group” also applies to the alkyl group from which the alkylene group is derived (the alkyl group from which one hydrogen atom is removed).

に お い て In the 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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.

An unsubstituted or substituted alkoxy group “an unsubstituted or substituted alkoxy group” means an alkoxy group or an alkoxy group having one or more substituents. The “alkoxy group” means an unsubstituted alkoxy group unless otherwise specified.

"Alkoxy group" means a group represented by an alkyl group -O-. The above description regarding the “alkyl group” also applies to the alkyl group included in the alkoxy group.

に お い て 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different. The one or more substituents that the alkoxy group may have may each independently be selected from halogen atoms.

Unsubstituted or substituted heteroalkyl group “unsubstituted or substituted heteroalkyl group” means a heteroalkyl group or a heteroalkyl group having one or more substituents. The term “heteroalkyl group” means an unsubstituted heteroalkyl group unless otherwise specified.

“Heteroalkyl group” means a straight-chain heteroalkyl group or a branched-chain heteroalkyl group. “Heteroalkyl group” means an alkyl group having an oxygen atom (—O—) between carbon atoms. The number of oxygen atoms is preferably one or two, more preferably one. The carbon number of the linear heteroalkyl group is usually 2 to 20, preferably 2 to 10, more preferably 2 to 8, still more preferably 2 to 6, still more preferably 2 to 5, and still more preferably It is 2 to 4, more preferably 2 or 3. The number of carbon atoms of the branched heteroalkyl group is usually 3 to 20, preferably 3 to 10, more preferably 3 to 8, still more preferably 3 to 6, still more preferably 3 to 5, and still more preferably. 3 or 4. Examples of the heteroalkyl group 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 _{) -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 or the like Is mentioned.

に お い て In the 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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.

An unsubstituted or substituted heteroalkoxy group “an unsubstituted or substituted heteroalkoxy group” means a heteroalkoxy group or a heteroalkoxy group having one or more substituents. In addition, a "heteroalkoxy group" means an unsubstituted heteroalkoxy group unless otherwise specified.

{"Heteroalkoxy group" means a group represented by heteroalkyl group -O-. The above description regarding the “heteroalkyl group” also applies to the heteroalkyl group included in the heteroalkoxy group.

に お い て 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 can have is preferably from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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.

An unsubstituted or substituted monoalkylamino group “an unsubstituted or substituted monoalkylamino group” means a monoalkylamino group or a monoalkylamino group having one or more substituents. The “monoalkylamino group” means an unsubstituted monoalkylamino group unless otherwise specified.

A “monoalkylamino group” has the formula: —NH (—Q ¹ ), wherein Q ¹ is an alkyl group. ]. The above description regarding the “alkyl group” 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.

に お い て 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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.

An unsubstituted or substituted dialkylamino group “an unsubstituted or substituted dialkylamino group” means a dialkylamino group or a dialkylamino group having one or more substituents. In addition, "dialkylamino group" means an unsubstituted dialkylamino group unless otherwise specified.

“Dialkylamino group” has the formula: —N (—Q ² ) (— Q ³ ) wherein Q ² and Q ³ are each independently an alkyl group. ]. The above description regarding the “alkyl group” also applies to the alkyl group included 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 to 20, preferably 2 to 12, more preferably 2 to 8, still more preferably 2 to 6, even more preferably 2 to 5, and still more preferably 2 to 4, Even more preferably, it is 2 or 3.

に お い て 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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.

An unsubstituted or substituted aliphatic cyclic group “unsubstituted or substituted aliphatic cyclic group” means an aliphatic cyclic group or an aliphatic cyclic group having at least one substituent. The “aliphatic ring group” means an unsubstituted aliphatic ring group, unless otherwise specified.

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

に お い て 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 which the aliphatic ring group may have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different. One or more substituents that the aliphatic ring group may have may be each independently selected from halogen atoms.

An unsubstituted or substituted aliphatic ring oxy group “an unsubstituted or substituted aliphatic ring oxy group” means an aliphatic ring oxy group or an aliphatic ring oxy group having one or more substituents. The “aliphatic ring oxy group” means an unsubstituted aliphatic ring oxy group, unless otherwise specified.

"Aliphatic ring oxy group" means a group represented by an aliphatic ring group -O-. The above description regarding the “aliphatic ring group” also applies to the aliphatic ring group included in the aliphatic ring oxy group.

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

An unsubstituted or substituted aliphatic heterocyclic group “unsubstituted or substituted aliphatic heterocyclic group” means an aliphatic heterocyclic group or an aliphatic heterocyclic group having at least one substituent. The “aliphatic heterocyclic group” means an unsubstituted aliphatic heterocyclic group unless otherwise specified.

"Aliphatic heterocyclic group" is a monocyclic monocyclic ring containing, as a ring-constituting atom, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to a carbon atom. It means a functional group formed by removing one hydrogen atom from an aliphatic heterocycle (non-aromatic heterocycle).

The number of hetero atoms contained in the aliphatic heterocyclic group is usually 1 to 4, preferably 1 to 3, more preferably 1 or 2. The number of members of the aliphatic heterocyclic group is usually 3 to 8, preferably 4 to 8, more preferably 5 to 7 members, and still more preferably 5 or 6 members. The number of ring-constituting carbon atoms in the aliphatic heterocyclic group is appropriately determined according to the number of heteroatoms and the number of members in 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 in which a ring is constituted only by a saturated bond. As the aliphatic heterocyclic group, for example, 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, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, and the like. In the aliphatic heterocyclic group, two carbon atoms constituting the ring may be bridged with an alkylene group. In the aliphatic heterocyclic group, two adjacent carbon atoms among the carbon atoms constituting the ring may form a double bond. In the 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 aliphatic heterocyclic group may have is preferably one or two. When the aliphatic heterocyclic group contains a sulfur atom, the aliphatic heterocyclic group may be in the form of a dioxide.

Examples of the aliphatic heterocyclic group include, for example, an aziridinyl group, an oxiranyl group, a thiranyl 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, an imidazolidinyl group, and an 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 , Dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl A 3- to 8-membered aliphatic heterocyclic group such as a morpholinyl group, a thiomorpholinyl group (a sulfur atom on the ring may be oxidized), an azepanyl group, a diazepanyl group, an azepinyl group, an oxepanyl group, an azocanyl group, or a diazocanyl group. No.

The aliphatic heterocyclic group is preferably a tetrahydrofuranyl group.

に お い て In the aliphatic heterocyclic group having one or more substituents, the 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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.

An unsubstituted or substituted aliphatic heterocyclic oxy group “an unsubstituted or substituted aliphatic heterocyclic oxy group” means an aliphatic heterocyclic oxy group or an aliphatic heterocyclic oxy group having at least one substituent. The “aliphatic heterocyclic oxy group” means an unsubstituted aliphatic heterocyclic oxy group unless otherwise specified.

"Aliphatic heterocyclic oxy group" means a group represented by an aliphatic heterocyclic group -O-. The above description regarding the “aliphatic heterocyclic group” also applies to the aliphatic heterocyclic group included in the aliphatic heterocyclic oxy group.

(4) The aliphatic heterocyclic oxy group is preferably a tetrahydrofuranyloxy group.

に お い て 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 from 1 to 3, more preferably 1 or 2. When the number of substituents is two 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 group “Unsubstituted or substituted phenyl group” means a phenyl group or a phenyl group having one or more substituents. Here, “phenyl group” means an unsubstituted phenyl group unless otherwise specified.

に お い て 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 even more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different. The one or more substituents that the phenyl group may have can be independently selected from the substituent group α described below. When one or more substituents are selected from groups containing carbon atoms, the total number of carbon atoms in the phenyl group having one or more substituents is preferably 10 or less, more preferably 9 or less, even more preferably 8 or less. Hereinafter, it is even more preferably 7 or less.

Unsubstituted or substituted phenyloxy group “Unsubstituted or substituted phenyloxy group” means a phenyloxy group or a phenyloxy group having at least one substituent. The “phenyloxy group” means an unsubstituted phenyloxy group unless otherwise specified.

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

に お い て In the phenyloxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the phenyloxy group. The number of substituents that the phenyloxy 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 two or more, the two or more substituents may be the same or different. One or more substituents that the phenyloxy group may have can be independently selected from the substituent group α described below. When one or more substituents are selected from groups containing carbon atoms, the total carbon number in the phenyloxy group having one or more substituents is preferably 12 or less, more preferably 10 or less, even more preferably 8 or less.

Unsubstituted or substituted phenylalkyl group “Unsubstituted or substituted phenylalkyl group” means a phenylalkyl group or a phenylalkyl group having one or more substituents. The “phenylalkyl group” means an unsubstituted phenylalkyl group, unless otherwise specified.

"Phenylalkyl group" means a group represented by a phenyl-alkylene group. The above description regarding the “alkylene group” also applies to the alkylene group included in the phenylalkyl group. The alkylene group contained in the phenylalkyl group is preferably a linear alkylene group having 1 to 4 carbon atoms or a branched alkylene group having 3 to 4 carbon atoms, and more preferably 1 to 4 carbon atoms. Is a linear alkylene group. The number of carbon atoms in the linear alkylene group is preferably from 1 to 3, more preferably 1 or 2. The phenylalkyl group preferably has 7 to 10 carbon atoms.

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

An unsubstituted or substituted phenylalkyloxy group “an unsubstituted or substituted phenylalkyloxy group” means a phenylalkyloxy group or a phenylalkyloxy group having one or more substituents. The “phenylalkyloxy group” means an unsubstituted phenylalkyloxy group unless otherwise specified.

"Phenylalkyloxy group" means a group represented by phenylalkyl group -O-. The above description regarding the “phenylalkyl group” also applies to the phenylalkyl group included in the phenylalkyloxy group.

に お い て In the phenylalkyloxy group having one or more substituents, the one or more substituents are each substituted with a hydrogen atom of the phenylalkyloxy group. The hydrogen atom to be substituted may be a hydrogen atom on a benzene ring or a hydrogen atom in an alkylene portion, but is preferably a hydrogen atom on a benzene ring. The number of substituents that the phenylalkyloxy group may have on the alkylene moiety is preferably from 1 to 3, more preferably 1 or 2. The number of substituents that the phenylalkyloxy group may have on the benzene ring is It is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. When the number of substituents is two or more, the two or more substituents may be the same or different. The one or more substituents that the phenylalkyloxy group may have can be independently selected from the substituent group α described below. When one or more substituents are selected from groups containing a carbon atom, the total carbon number in the phenylalkyloxy group having one or more substituents is preferably 16 or less, more preferably 14 or less, even more preferably. Is 12 or less.

An unsubstituted or substituted aromatic ring group “an unsubstituted or substituted aromatic ring group” means an aromatic ring group or an aromatic ring group having at least one substituent. The term “aromatic ring group” means an unsubstituted aromatic ring group, unless otherwise specified.

"Aromatic ring group" means a group formed by removing one hydrogen atom from a monocyclic or condensed polycyclic aromatic hydrocarbon ring. The aromatic ring group is usually a 1 to 4 ring, preferably 1 to 3 ring, more preferably a 1 or 2 ring aromatic ring group. The number of ring-constituting carbon atoms in the aromatic ring group is usually from 6 to 18, preferably from 6 to 14, and more preferably from 6 to 10. Examples of the monocyclic aromatic ring group include a phenyl group. Examples of the condensed polycyclic aromatic ring group include 2- to 4-cyclic aromatic ring groups such as a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group, and a pyrenyl group. The fused polycyclic aromatic ring group may be a partially saturated fused polycyclic aromatic ring group. The partially saturated condensed polycyclic aromatic ring group is a condensed polycyclic aromatic ring group in which some of the bonds constituting the ring are hydrogenated.

The aromatic ring group is preferably a phenyl group.

に お い て 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 number of carbon atoms, the number of members, and the like 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 two or more, the two or more substituents may be the same or different. One or more substituents that the aromatic ring group may have can be independently selected from the substituent group β described below. When one or more substituents are selected from groups containing carbon atoms, the total number of carbon atoms in the aromatic ring group having one or more substituents is preferably 20 or less, more preferably 19 or less, and still more preferably. Is 18 or less, even more preferably 17 or less.

An unsubstituted or substituted aromatic heterocyclic group “an unsubstituted or substituted aromatic heterocyclic group” means an aromatic heterocyclic group or an aromatic heterocyclic group having at least one substituent. The “aromatic heterocyclic group” means an unsubstituted aromatic heterocyclic group unless otherwise specified.

“Aromatic heterocyclic group” is a monocyclic or heterocyclic group containing, as a ring-constituting atom, one or more heteroatoms independently selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to a carbon atom. It means a group formed by removing one hydrogen atom from a condensed polycyclic aromatic heterocycle. The aromatic heterocyclic group is usually a 1 to 4 cyclic, preferably 1 to 3 cyclic, more preferably a 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 aromatic heterocyclic groups is preferably from 5 to 14 members, more preferably from 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 in the aromatic heterocyclic group. In the aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group.

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. The monocyclic aromatic heterocyclic group includes, for example, those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. Examples include an atom-containing compound, a compound containing 1 to 4 nitrogen atoms, a compound containing 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms, and / or 1 to 2 oxygen atoms.

As the monocyclic aromatic heterocyclic group, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, 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) And a 5- to 7-membered monocyclic aromatic heterocyclic group such as a triazolyl group (eg, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group), a tetrazolyl group, a triazinyl group and the like. No. 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 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 fused polycyclic aromatic heterocyclic group is, for example, an 8- to 14-membered bicyclic or tricyclic 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, 1 to 3 oxygen atoms and 1 to 3 A compound containing a sulfur atom, a compound containing 1 to 5 nitrogen atoms, a compound containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, and the like. .

Examples of the condensed polycyclic aromatic heterocyclic group include a benzothiophenyl group, a benzofuranyl group, a benzoimidazolyl group, a benzooxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzoisothiazolyl group, and a benzotria Zolyl group, imidazopyridinyl group, thienopyridinyl group, flopyridinyl 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, phenoxathiinyl group , Indolyl group, isoindolyl group, 1 -Indazolyl group, purinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, carbazolyl group, α-carbolinyl group, phenanthridinyl group, acridinyl group, phenazinyl group, phenothiazinyl And a 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group such as 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 that the polycyclic aromatic heterocyclic group can have is preferably 1, 2 or 3.

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

に お い て 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 according to the number of carbon atoms, the number of members, and the like 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 even 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 can be independently selected from the substituent group β described below. When one or more substituents are selected from groups containing carbon atoms, the total number of carbon atoms in the aromatic heterocyclic group having one or more substituents is preferably 20 or less, more preferably 19 or less, and even more. It is 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 group (α-3) unsubstituted or substituted alkyl group (α-4) unsubstituted or substituted alkoxy group (α-5) unsubstituted or substituted heteroalkyl Group (α-6) unsubstituted or substituted heteroalkoxy group (α-7) unsubstituted or substituted monoalkylamino group (α-8) unsubstituted or substituted dialkylamino group (α-9) unsubstituted or substituted Aliphatic group (α-10) unsubstituted or substituted aliphatic ring oxy group (α-11) unsubstituted or substituted aliphatic heterocyclic group (α-12) unsubstituted or substituted aliphatic heterocyclic oxy Base

"Halogen atom", "unsubstituted or substituted alkyl group", "unsubstituted or substituted alkoxy group", "unsubstituted or substituted heteroalkyl group", "unsubstituted or substituted heteroalkoxy group", "unsubstituted" Or a substituted monoalkylamino group, an unsubstituted or substituted dialkylamino group, an unsubstituted or substituted aliphatic ring group, an unsubstituted or substituted aliphatic ring oxy group, an unsubstituted or substituted The above description regarding the “aliphatic heterocyclic group” and “unsubstituted or substituted aliphatic heterocyclic oxy group” also applies to the substituent group α.

Substituent group α is a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, an unsubstituted or substituted aliphatic It is preferable that the heterocyclic group is composed of a heterocyclic group and an unsubstituted or substituted aliphatic heterocyclic oxy group, a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted hetero group. More preferably, it is composed of an alkyl group and an unsubstituted or substituted heteroalkoxy group, and more preferably it is composed of a halogen atom, an unsubstituted or substituted alkyl group, and an unsubstituted or substituted alkoxy group. preferable.

Substituent group β
“Substituent group β” is composed of the following substituents.
(Β-1) Substituent group α
(Β-2) unsubstituted or substituted phenyl group (β-3) unsubstituted or substituted phenyloxy group (β-4) unsubstituted or substituted phenylalkyl group (β-5) unsubstituted or substituted phenylalkyl Oxy group

"Substituent group α", "unsubstituted or substituted phenyl group", "unsubstituted or substituted phenyloxy group", "unsubstituted or substituted phenylalkyl group" and "unsubstituted or substituted phenylalkyloxy group" The above description also applies to the substituent group β.

(Β-2) is preferably a phenyl group having at least one substituent selected from a halogen atom. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.

(Β-3) is preferably a phenyloxy group having at least one substituent selected from a halogen atom. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.

(Β-4) is preferably a phenylalkyl group having at least one substituent selected from a halogen atom. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.

(Β-5) is preferably a phenylalkyloxy group having at least one substituent selected from a halogen atom. The number of halogen atoms is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.

The substituent group β is preferably composed of a halogen atom, an aliphatic heterocyclic oxy group, a phenyl group, and a phenyl group having at least one substituent selected from a halogen atom and an aliphatic heterocyclic oxy group. , A halogen atom, an aliphatic heterocyclic oxy group, a phenyl group, and a phenyl group having at least one substituent selected from a halogen atom.

<< Method for producing β-C-aryl glycoside derivative >>
The method for producing a β-C-aryl glycoside derivative of the present invention includes a step of producing a β-C-aryl glycoside derivative by contacting the C-aryl-hydroxy glycoside derivative with a silane compound in the presence of a titanium compound. .

で表される化合物である。 β-C-aryl glycoside derivatives β-C-aryl glycoside derivatives have the following formula (1):

It is a compound represented by these.

In the 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, R ¹ , R ² , R ³ and R ⁴ are all hydrogen atoms.

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

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

Preferably, at least one of R ¹ , R ² , R ³ and R ⁴ is a hydroxyl-protecting group in that the β-C-aryl glycoside derivative to be produced is easily separated from the reaction system. ^1, more preferably ^R 2, 2 or more of ^{R 3} and ^{R 4} are hydroxyl-protecting ^group, it is preferably further all R ^1, R 2, ^{R 3} and ^{R 4} are hydroxyl protecting group .

When 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. It is preferable that they are the same from the viewpoint of efficient introduction and removal.

The hydroxyl-protecting group is not particularly limited and can be appropriately selected as long as it can protect the hydroxyl group when performing the desired reaction and can be eliminated from the hydroxyl group after the completion of the desired reaction. Examples of the hydroxyl 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, and oxycarbonyl-type protecting groups. Is mentioned.

Examples of the ester-type protecting group include acetyl, propanoyl, butanoyl, isopropanoyl, pivaloyl, benzoyl, 4-nitrobenzoyl, 4-methyloxybenzoyl, 4-methylbenzoyl, Examples include a tert-butylbenzoyl group, a 4-fluorobenzoyl group, a 4-chlorobenzoyl group, a 4-bromobenzoyl group, a 4-phenylbenzoyl group, and a 4-methyloxycarbonylbenzoyl group. The ester-type protecting groups are preferably an acetyl group and a pivaloyl group.

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

Examples of the alkyl-type protecting group include a methyl group, an ethyl group and a tert-butyl group. The alkyl-type protecting group is preferably a methyl group.

Examples of the arylalkyloxyalkyl type protecting group include a benzyloxymethyl group.

Examples of the alkyloxyalkyl-type protecting group include a methyloxymethyl group.

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

Examples of the oxycarbonyl-type protecting group include an alkyloxycarbonyl group such as methyloxycarbonyl and an arylalkyloxycarbonyl group such as benzyloxycarbonyl.

The hydroxyl protecting group is preferably selected from a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group and a tert-butyldimethylsilyl group, and more preferably selected from a benzyl group, an acetyl group and a pivaloyl group. These hydroxyl group-protecting groups are preferable in that the protection and deprotection of the hydroxyl group are easy and the reagent is inexpensive.

In the formula (1), Ar is an organic group containing a group selected from an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic heterocyclic group as a group bonded to the oxane ring in the formula. is there.

In one embodiment, Ar is an organic group that contains an unsubstituted or substituted aromatic ring group as a group that bonds to the oxane ring in Formula (1). Ar may 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 bonded to the oxane ring in the formula (1). Ar may be an unsubstituted or substituted aromatic heterocyclic group.

Examples of the organic group containing an unsubstituted or substituted aromatic ring group as a group bonded to the oxane ring in the formula (1) include, for example, a compound represented by the formula: -J ¹ -J ² [wherein J ¹ is an unsubstituted Or a substituted alkylene group; J ² is an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, or an unsubstituted or substituted aliphatic heterocyclic group. And an aromatic ring group having a substituent represented by the formula: 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.

Examples of the organic group containing an unsubstituted or substituted aromatic heterocyclic group as a functional group bonded to a carbon atom of an oxane ring in the formula (I) include, for example, a compound represented by the formula: -K ¹ -K ^{2 1} is an unsubstituted or substituted alkylene group, and K ² is an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group or an unsubstituted or substituted aliphatic heterocyclic group. . And an aromatic heterocyclic group having a substituent represented by the formula: 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 represented by Ar is the same as the aromatic ring group or the aromatic heterocyclic group of the SGLT-2 inhibitor, or the aromatic group or the aromatic heterocyclic group of the SGLT-2 inhibitor. It is preferable that the group is derived from a 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-carboxylic acid ") and dapagliflozin (" (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethyloxybenzyl) phenyl] -6- ( Hi Rokishimechiru) tetrahydro -2H- pyran-3,4,5 thiol "as SGLT-2 inhibitors, including referred) also has an organic group represented by the following formula (A).

で表される有機基である。 Thus, in a preferred embodiment, Ar is of the following formula (A):

Is an organic group represented by

に お い て In the formula (A), n is an integer of 0 to 4. n is preferably 1 to 3, more preferably 1 or 2, and still more preferably 1.

In formula (A), n pieces of R ^a are each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, substituted or unsubstituted heteroalkyl group, non Substituted or substituted heteroalkoxy group, unsubstituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted Or a substituted aliphatic heterocyclic group, an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and It is a group selected from a substituted or substituted phenylalkyloxy group.

When n is 2 or more, n pieces of R ^a may be the same or different.

In the formula (A), n ^Ra are each independently a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted A heteroalkoxy group, an unsubstituted or substituted aliphatic ring group, an unsubstituted or substituted aliphatic ring oxy group, an unsubstituted or substituted aliphatic heterocyclic group, an unsubstituted or substituted aliphatic heterocyclic oxy group, It is preferably a substituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and a group selected from an unsubstituted or substituted phenylalkyloxy group, a halogen atom, A group selected from an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted phenylalkyl group. And more preferably a group selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a methoxy group, an ethoxy group, a phenyl group and a benzyl group. And more preferably a group selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group and a methoxy group.

In the formula (A), Ar 'is a group selected from an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, and an unsubstituted or substituted aliphatic heterocyclic group.

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

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

In the formulas (Ar′-1), (Ar′-2) and (Ar′-3), p R ^b are each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, Substituted or substituted alkoxy group, unsubstituted or substituted heteroalkyl group, unsubstituted or substituted heteroalkoxy group, unsubstituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted fat Aliphatic group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted A phenyloxy group, an unsubstituted or substituted phenylalkyl group, and an unsubstituted or substituted phenylalkyloxy 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. Preferably, it is a phenyl group having a fluorine atom. The position where 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 where the halogen atom is bonded is preferably the 4-position of the benzene ring.

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

In the 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, and more preferably a methoxy group or an ethoxy group. The unsubstituted or substituted aliphatic heterocyclic oxy group is preferably a tetrahydrofuranyloxy group. The position to which the unsubstituted or substituted alkoxy group or unsubstituted or substituted aliphatic heterocyclic oxy group is bonded is preferably the 4-position of the benzene ring.

で表される有機基であることが好ましい。 When n is 1, Ar is represented by the following formula (B):

It is preferably an organic group represented by

In the formula (B), ^Ra and Ar ′ have the same meaning as in the formula (A).

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

で表される化合物である。 C-aryl-hydroxyglycoside derivative The C-aryl-hydroxyglycoside derivative has the following formula (2):

It is a compound represented by these.

In the formula (2), R ¹ , R ² , R ³ , R ⁴ and Ar have the same meanings as in the 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 the 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 ⁵ can be eliminated while maintaining -OR ¹ , -OR ² , -OR ³ and -OR ⁴ .

In the 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 ⁵ can be eliminated while maintaining -OR ¹ , -OR ² , -OR ³ and -OR ⁴ .

In the 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 ⁵ can be eliminated while maintaining -OR ¹ , -OR ² , -OR ³ and -OR ⁴ .

The C-aryl-hydroxyglycoside derivative can be obtained by a known method described in Patent Document 1, Non-Patent Document 1, Non-Patent Document 2, and the like.

In the step of contacting the titanium compound C-aryl-hydroxyglycoside derivative with the silane compound in the presence of the titanium compound, the titanium compound acts as a Lewis acid. By using a titanium compound, a reduction reaction of a C-aryl-hydroxyglycoside derivative can be rapidly advanced at a low temperature, and a desired β-C-arylglycoside derivative can be obtained with high selectivity and high yield. Can be.

Known titanium compounds include, for example, those in which titanium is zero-valent, those in which titanium is divalent, those in which trivalent is tetravalent, those in which tetravalent is tetravalent, etc. Good. Examples of the titanium compound include triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV), titanium bromide (IV), and iodide. Tetravalent titanium salts such as titanium (IV) and titanium oxide (IV) or solvates thereof; Trivalent titanium salts such as titanium (III) chloride and titanium (III) bromide or solvates thereof; titanium chloride Divalent titanium salts such as (II) or solvates thereof; zero-valent titanium such as metallic Ti or solvates thereof. Examples of the solvate include those in which a solvent such as water and tetrahydrofuran is coordinated.

Titanium compounds have the ^formula: _TiR c r in ^(OR _{d) s} [wherein, ^{R c} is a halogen atom, ^{R d} is a substituted or unsubstituted alkyl group, r and s, r + s = 3, or An integer from 0 to 4 that satisfies 4. ], Or a trivalent or tetravalent titanium salt or a solvate thereof. 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 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms. .

The titanium compound is preferably triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV), titanium (III) chloride or the like. And more preferably titanium (IV) chloride. Titanium (IV) chloride has a low melting point and is a liquid at room temperature, and thus is preferable in that it is easy to handle and inexpensive.

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

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

Examples of the silane compound include triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane, and tetramethyldisiloxane. . In terms of reactivity and cost, the silane compound is preferably trimethoxyhydrosilane, triethoxyhydrosilane, tetramethyldisiloxane, or the like, and more preferably tetramethyldisiloxane.

使用 The amount of the silane compound used is not particularly limited, and can be appropriately adjusted. The amount of the silane compound to be used is preferably 1 to 10 mol, more preferably 1 to 5 mol, and still more preferably 1 to 3 mol, per mol of the C-aryl-hydroxyglycoside derivative, from the viewpoint of sufficiently proceeding the reaction. Is a mole.

In the step of contacting the C-aryl-hydroxyglycoside derivative with the silane compound in the presence of the titanium compound, it is preferable to stir and mix the C-aryl-hydroxyglycoside derivative, the titanium compound and the silane compound in the reaction solvent.

The reaction solvent is not particularly limited as long as it does not adversely affect the C-aryl-hydroxyglycoside derivative, the titanium compound and the silane compound and can smoothly reduce the C-aryl-hydroxyglycoside derivative. 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, diisopropyl ether, dimethoxyethane, diglyme and the like. Ethers, ketones such as acetone, methyl ethyl ketone and diethyl ketone, acetates such as methyl acetate, ethyl acetate and butyl acetate, and halogenated carbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and chlorobenzene Examples thereof include hydrogens, aromatic hydrocarbons such as toluene and xylene, and aliphatic hydrocarbons such as hexane and heptane. These reaction solvents can be used alone or as a mixed solvent. The reaction solvent is preferably acetonitrile, methylene chloride or a mixed solvent thereof. These are aprotic polar solvents and are preferred because they are less susceptible to silane reduction.

使用 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, more preferably 1 to 50 times, even more preferably 2 to 20 times the volume of the C-aryl-hydroxyglycoside derivative. When a mixed solvent is used as the reaction solvent, the total amount of the mixed solvent should satisfy the above range.

Reduction Reaction In the step of contacting a C-aryl-hydroxyglycoside derivative with a silane compound in the presence of a titanium compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds. The reduction reaction can be advanced by mixing a C-aryl-hydroxyglycoside derivative, a titanium compound, a silane compound and, if necessary, a reaction solvent.

方法 The method of mixing the components is not particularly limited, and can be carried out, for example, in a reaction vessel equipped with a stirring device. The procedure for adding each component to the reaction vessel is not particularly limited, but a C-aryl-hydroxyglycoside derivative, a silane compound and, if necessary, a reaction solvent are charged in the reaction vessel in advance, and the titanium compound is added with stirring. And a method of mixing.

温度 The temperature at the time of addition of the titanium compound and the reaction temperature after the addition are not particularly limited, and can be appropriately adjusted. The temperature at the time of addition of the titanium compound and the reaction temperature after the 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, a β-C-aryl glycoside derivative can be obtained with high selectivity and high yield.

The reaction time is not particularly limited, and can be adjusted as appropriate, for example, while checking the conversion of the C-aryl-hydroxyglycoside derivative as a raw material. The reaction time is generally from 10 minutes to 48 hours, preferably from 0.5 hours to 24 hours, more preferably from 1 hour to 17 hours.

The reaction atmosphere is not particularly limited, but is preferably under an inert gas atmosphere or an air atmosphere in order to suppress mixing of moisture.

内 The reaction system may be under atmospheric pressure, under pressure, or under reduced pressure, and among these, it is preferable to carry out the reaction under atmospheric pressure.

Β A β-C-aryl glycoside derivative can be obtained by the reduction reaction. The products obtained by the reduction reaction are a β-C-aryl glycoside derivative (hereinafter sometimes referred to as “β-form”) and an α-C-aryl glycoside derivative (hereinafter sometimes referred to as “α-form”). Is a mixture of According to the present invention, a β-C-aryl glycoside derivative can be produced with high selectivity and high yield, so that the ratio of β-form 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 even more preferably 85 or more. / 15 or more, more preferably 90/10 or more. The isomer ratio is measured by the method described in the examples.

Β 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 is, for example, after adding water to the reaction solution, contacting with a poorly water-soluble organic solvent such as ethyl acetate, toluene, tert-butyl methyl ether, and methylene chloride, The β-C-aryl glycoside derivative can be extracted from the reaction system by extracting with the poorly water-soluble organic solvent.

ΒThe obtained β-C-arylglycoside derivative can be further purified by a known method such as column separation and recrystallization. However, it is difficult to separate β-form and α-form by column purification using a silica gel column or the like. Therefore, the usefulness of the present invention, in which a β-C-aryl glycoside derivative can be produced with high selectivity and high yield, is extremely high.

The resulting β-C-arylglycoside derivative may be used as it is when R ¹ to R ⁴ are all hydrogen atoms, or as needed when at least one of R ¹ to R ⁴ is a hydroxyl protecting group. After deprotection by a known method, it can be suitably used as an SGLT2 inhibitor useful as an antidiabetic drug or a synthetic intermediate thereof.

The present invention will be described in detail with reference to examples below, but the present invention is a specific example and the present invention is not limited to these examples.

Production Example 1: Production of C-aryl-hydroxyglycoside derivative of alcohol derivative The reaction represented by the following formula was carried out to obtain a C-aryl-hydroxyglycoside derivative of an alcohol derivative (in the formula (2), R ¹ , R ² , R ³ And R ⁴ is a benzyl group, R ⁵ is a hydrogen atom, and Ar is a phenyl group). Bn represents a benzyl group. The same applies hereinafter.

To a solution of tetra-O-benzyl-D-gluconolactone (1.00 g, 1.86 mmol) in THF (5 mL), phenyllithium (phenyllithium concentration: 16%, solvent: dibutyl ether) (1.3 g, 2. 47 mmol, 1.3 eq) were added dropwise at -63 ° C to -67 ° C over 30 minutes. After stirring at the same temperature for 1 hour, water (5 mL) was added, and the temperature was raised to room temperature over 1 hour.

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-phenyltetrahydropyran (hereinafter, referred to as “3R, 4S, 5R-benzyl”). , Alcohol product) (1.20 g, yield: quant.).

Production Example 2: Production of methoxy C-aryl-hydroxyglycoside derivative The reaction represented by the following formula was carried out to obtain a methoxy C-aryl-hydroxyglycoside derivative (in the formula (2), R ¹ , R ² , R ³ And R ⁴ is a benzyl group, 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), a methanol (1 mL) solution of the alcohol compound (200 mg, 0.32 mmol) obtained in Production Example 1 was added at room temperature, and the same temperature was applied. For 21 hours. Triethylamine (50 mg, 0.49 mmol) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, a mixed solution of ethyl acetate: water = 10 mL / 10 mL was added to the concentrated residue, and the mixture was separated. The organic layer was concentrated under reduced pressure to give 3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl-6-methoxy-6-phenyltetrahydropyran (hereinafter also referred to as a methoxy compound) (172 mg, yield: 84). %).

Production Example 3: Production of C-aryl-hydroxyglycoside derivative of alcohol derivative The reaction represented by the following formula was carried out to obtain a C-aryl-hydroxyglycoside derivative of an alcohol derivative (in the formula (2), R ¹ , R ² , R ³ And R ⁴ is a benzyl group, R ⁵ is a hydrogen atom, and Ar is an organic group represented by the above formula (Ar-1).

Butyl lithium (1.6 M in hexane) (1.16 mL, 1.86 mmol) was added to a solution of (5-iodo-2-methylbenzyl) -2- (4-fluorophenyl) thiophene (765 mg, 1.86 mmol) in THF (5 mL). ) And stirred at -70 ° C for 1 hour. At the same temperature, a THF (5 mL) solution of tetra-O-benzyl-D-gluconolactone (1.00 g, 1.86 mmol) was added at the same temperature. After stirring for 1 hour, water (5 mL) was added to stop the reaction.

The product was extracted with ethyl acetate (20 mL), and the obtained organic layer was concentrated under reduced pressure to give 3R, 4R, 5S-tribenzyloxy-2R-benzyloxymethyl-6-hydroxy-6- (3- (5 -(4-Fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydropyran (hereinafter also referred to as alcohol) (1.53 g, yield: quant.) Was obtained. This product was used in the next step (Example 3) as it was without purification.

Example 1 Reduction with Titanium Compound (Production of β-C-Aryl Glycoside Derivative from Alcohol Form ) Using a titanium compound, a reaction represented by the following formula was carried out, and β-C was obtained from the alcohol form obtained in Production Example 1. -An aryl glycoside derivative was prepared.

に Tetramethyldisiloxane (44 mg, 0.33 mmol) was added to an acetonitrile solution (2 mL) of the alcohol (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 methylene chloride (1 mL) was added, and the mixture was stirred at the same temperature for 3 hours.

(7) The reaction mixture was analyzed by HPLC, and the alcohol was completely consumed, and the desired product was obtained. The isomer ratio of the product was β / α = 80/20.

水 Water (5 mL) was added to the reaction solution, and the product was extracted four times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. The concentrate (3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl-2S-phenyltetrahydropyran) is obtained by purifying the concentrate with a silica gel column (developing solvent: hexane / ethyl acetate = 10/1). (64 mg, yield: 66%). The isomer ratio of the product was 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 = 9.3 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 2 Reduction with Titanium Compound (Production of β-C-aryl Glycoside Derivative from Methoxy Form) A reaction represented by the following formula was carried out using a titanium compound, and β-C was obtained from the methoxy form obtained in Production Example 2. -An aryl glycoside derivative was prepared.

に Tetramethyldisiloxane (44 mg, 0.33 mmol) was added to an 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 methylene chloride (1 mL) was added, and the mixture was stirred at the same temperature for 3 hours.

(7) The reaction mixture was analyzed by HPLC, and the alcohol was completely consumed, and the desired product was obtained. The isomer ratio of the product was β / α = 75/25.

水 Water (5 mL) was added to the reaction solution, and the product was extracted four times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. The concentrate was purified by a silica gel column (developing solvent: hexane / ethyl acetate = 10/1) to obtain the desired product (60 mg, yield: 62%). The isomer ratio of the product was 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 = 9.3 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 3 Reduction with Titanium Compound (Production of β-C-aryl Glycoside Derivative from Alcohol Form)
Using a titanium compound, a reaction represented by the following formula was carried out, and a β-C-arylglycoside derivative was produced from the alcohol obtained in Production Example 3.

に Tetramethyldisiloxane (44 mg, 0.33 mmol) was added to an acetonitrile solution (2 mL) of the alcohol (131 mg, 0.16 mmol) obtained in Production Example 3. After cooling to −40 ° C. in a dry ice / acetone bath, a solution of titanium tetrachloride (92 mg, 0.49 mmol) in methylene chloride (1 mL) was added, and the mixture was stirred at the same temperature for 3 hours.

(7) The reaction mixture was analyzed by HPLC, and the alcohol was completely consumed, and the desired product was obtained. The isomer ratio of the product was β / α = 91/9.

水 Water (5 mL) was added to the reaction solution, and the product was extracted four times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. The concentrate is purified by a silica gel column (developing solvent: hexane / ethyl acetate = 10/1) to give the desired product (3R, 4R, 5S-tribenzyloxy-2R-benzyloxymethyl-6S- (3- (5- (4-Fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydropyran) was obtained (106 mg, yield: 82%). The isomer ratio of the product was 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 with aluminum chloride (production of β-C-aryl glycoside derivative from alcohol form)
The reaction represented by the following formula was carried out using aluminum chloride, and a β-C-aryl glycoside derivative was produced from the alcohol obtained in Production Example 1.

The alcohol (10 mg, 0.02 mmol) obtained in Production Example 1 was dissolved in a mixed solution of methylene chloride (0.5 mL) and acetonitrile (1 mL), and then tetramethyldisiloxane (4.4 mg, 0.03 mmol) was dissolved. ) Was added. Here, aluminum chloride (6.5 mg, 0.05 mmol) was added at −40 ° C., gradually raised to room temperature, and stirred at the same temperature for 18 hours.

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

Comparative Example 2: Reduction with aluminum chloride (Production of β-C-arylglycoside derivative from methoxy form) A reaction represented by the following formula was carried out using aluminum chloride, and β-C was obtained from the methoxy form obtained in Production Example 2. -An aryl glycoside derivative was prepared.

The methoxy compound (10 mg, 0.02 mmol) obtained in Production Example 2 was dissolved in a mixed solution of methylene chloride (0.5 mL) and an acetonitrile solution (1 mL), and then tetramethyldisiloxane (4.4 mg, 0.4 mL) was dissolved. 03 mmol) was added. Here, aluminum chloride (6.5 mg, 0.05 mmol) was added at −40 ° C., gradually raised to room temperature, and stirred at the same temperature for 17 hours.

(5) HPLC analysis of the reaction mixture revealed that the methoxy compound was completely consumed, and the desired product was obtained (yield: 41%). The isomer ratio of the product was β / α = 68/32.

異性 The isomer ratios in Examples and Comparative Examples were evaluated by a method using high performance liquid chromatography (HPLC). HPLC was performed according to the following measurement conditions. The isomer ratio of α-form and β-form is the ratio of the peak area value of each of the 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.

収率 Further, the yield in the examples was calculated from the amount of the raw material and the amount of the target substance after recovering the target substance. The yield in the comparative example was calculated by a method using HPLC. HPLC was performed according to the following measurement conditions. The yield of the target substance is a ratio of the peak area value of the target substance to the sum of the area values of all peaks (excluding the peak derived from the solvent).

<HPLC measurement conditions>
Equipment: High Performance Liquid Chromatography (HPLC)
Detector: UV absorption photometer (measurement wavelength: 210 nm)
Column: XBridge C18, 5 μm, inner diameter 4.8 mm, length 15 cm (Waters)
Column temperature: 30 ° C (constant)
Flow rate: 1.0 mL / min Mobile phase: acetonitrile / water = 90/10 → 100/0 (0 → 10 minutes)
Retention time: 4.5 minutes of alcohol compound of Production Example 1; 6.4 minutes of methoxy compound of Production Example 2; 17.47 minutes of alcohol compound of Production Example 3; Example 1, Example 2, Comparative Example 1, and Comparative Example Β-form of Example 5.7 minutes; α-form of Example 1, Example 2, Comparative Example 1 and Comparative Example 2 5.4 minutes; β-form of Example 3 18.31 minutes; α-form 18 of Example 3 .13 minutes

Claims (6)

The following equation (1):

[Wherein, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom or a hydroxyl-protecting group, and Ar is an unsubstituted or substituted aromatic ring group and an unsubstituted or substituted aromatic ring group. It is an organic group containing a group selected from a group heterocyclic group as a group bonded to an oxane ring in the formula. ]
A method for producing a β-C-aryl glycoside derivative represented by the formula:
The following equation (2):

[Wherein, R ¹ , R ² , R ³ , R ⁴ and Ar have the same meanings as described above, and R ⁵ is a hydrogen atom, a methyl group, a trimethylsilyl group or an acetyl group. ]
The method comprising the step of contacting a C-aryl-hydroxyglycoside derivative represented by the formula with a silane compound in the presence of a titanium compound to produce the β-C-arylglycoside derivative. R ¹ , R ² , R ³ and R ⁴ are each independently a hydroxyl protecting group selected from a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group and a tert-butyldimethylsilyl group. Item 1. The method according to Item 1. The titanium compound is selected from triisopropoxy titanium monochloride (IV), diisopropoxy titanium dichloride (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (III) and titanium chloride (IV). The method according to claim 1. Wherein the silane compound is selected from triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane and tetramethyldisiloxane. Item 4. The method according to any one of Items 1 to 3. Ar is the following formula (A):

[Where,
^Ra is each independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, Substituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, Selected from an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and an unsubstituted or substituted phenylalkyloxy group. Group
n is an integer from 0 to 4,
Ar ′ is a group selected from an unsubstituted or substituted aromatic ring group, an unsubstituted or substituted aromatic heterocyclic group, and an unsubstituted or substituted aliphatic heterocyclic ring. ]
5. The method according to claim 1, wherein the method is an organic group or a phenyl group. Ar ′ is represented by the following formula (Ar′-1), (Ar′-2) or (Ar′-3):

[Where,
R ^b is independently a halogen atom, an amino group, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted heteroalkyl group, an unsubstituted or substituted heteroalkoxy group, Substituted or substituted monoalkylamino group, unsubstituted or substituted dialkylamino group, unsubstituted or substituted aliphatic ring group, unsubstituted or substituted aliphatic ring oxy group, unsubstituted or substituted aliphatic heterocyclic group, Selected from an unsubstituted or substituted aliphatic heterocyclic oxy group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and an unsubstituted or substituted phenylalkyloxy group. Group
p is an integer of 0 to 5. ]
The method according to any one of claims 1 to 5, which is a group represented by the following formula: