JPWO2020050361A1 - Method for Producing β-C-aryl Glycosid Derivative - Google Patents

Abstract

The reduction reaction of the C-aryl-hydroxyglycoside derivative represented by the formula (2) proceeds rapidly at a low temperature, and the β-C-aryl glycoside derivative represented by the formula (1) is highly selective and in high yield. An object of the present invention is to provide a method for producing, and in order to achieve such an object, the present invention contacts a C-aryl-hydroxyglycoside derivative represented by the formula (2) with a silane compound in the presence of a titanium compound. Provided is a method including a step of producing a β-C-arylglycoside derivative represented by the formula (1).

Description

The present invention relates to a method for producing an SGLT2 inhibitor useful as an antidiabetes drug or a β-C-arylglycoside derivative which is a synthetic intermediate thereof. Specifically, the present invention relates to a method for efficiently producing an SGLT2 inhibitor useful as an antidiabetes drug or a β-C-arylglycoside derivative which is a synthetic intermediate thereof under mild conditions. Throughout this specification, "β-C-arylglycoside derivative" means a compound represented by the formula (1) described later, and "C-aryl-hydroxyglycoside derivative" means the compound represented by the formula (2) described later. It means a compound represented by.

SGLT2 inhibitors are useful as anti-diabetic agents. In addition, "SGLT2" means sodium-glucose cotransporter-2. Examples of the SGLT2 inhibitor include canagliflozin (1- (β-D-glycopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene), empagliflozin ( (1S) -1,5-Anhydro-1-C- {4-chloro-3-[(4-{[(3S) -oxolan-3-yl] oxy} phenyl) methyl] phenyl} -D-glucitol) , Ipragliflozin ((1S) -1,5-anhydro-1-C- {3-[(1-benzothiophen-2-yl) methyl] -4-fluorophenyl} -D-glucitol- (2S)- Pyrrolidine-2-carboxylic acid), dapagliflozin ((2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethyloxybenzyl) phenyl] -6- (hydroxymethyl) tetrahydro-2H -Pyran-3,4,5-thiol) and the like are known.

The β-C-arylglycoside derivative has attracted attention as an SGLT2 inhibitor (antidiabetic drug) or a synthetic intermediate thereof (see Non-Patent Document 1 and Patent Document 1). As one of the methods for producing a β-C-arylglycoside derivative, a method for producing a β-C-arylglycoside derivative by reducing the C-aryl-hydroxyglycoside derivative has been reported (Non-Patent Document 1 and Non-Patent Document 2). And Patent Document 1).

In Non-Patent Documents 1 and 2, a C-aryl-hydroxyglycoside derivative is _{reduced using triethylsilane in the presence of a boron trifluoride diethyl ether complex (BF 3} , OEt ₂ ) and β-C-aryl. A method for producing a glycoside derivative is described. Further, in Patent Document 1, a C-aryl-hydroxyglycoside derivative is used in the presence of silanes such as triethylsilane, triisopropylsilane, and tetramethyldisiloxane in the presence of BF ₃ , OEt ₂ , and boron trifluoride tetrahydrofuran (BF _3). -A method for producing a β-C-arylglycoside derivative by reacting with a Lewis acid such as 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

However, since boron trifluoride is corrosive, the reaction vessel is corroded. Further, since aluminum chloride has low Lewis acidity, a relatively high temperature is required to allow the reaction to proceed, but the stereoselectivity (β-selectivity) of the reaction decreases as the reaction temperature increases. Furthermore, aluminum chloride is a solid Lewis acid, which is difficult to handle because it needs to be weighed under anhydrous conditions.

Therefore, an object of the present invention is to provide a method for producing a β-C-arylglycoside derivative in a highly selective manner and in a high yield, in which the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds rapidly at a low temperature. do.

The present inventors have made extensive studies to solve the above problems. As a result, by contacting the C-aryl-hydroxyglycoside derivative with the silane compound in the presence of the titanium compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative proceeds rapidly 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 equation (1):

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

[In the formula, 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 a step of contacting a C-aryl-hydroxyglycoside derivative represented by (1) 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 hydroxyl protecting groups selected from methyl group, benzyl group, acetyl group, pivaloyl group, trimethylsilyl group and tert-butyldimethylsilyl group, respectively. A method according to [1].
[3] The titanium compound is derived from triisopropoxy monochloride titanium (IV), diisopropoxy dichloride titanium (IV), monoisopropoxy trichloride titanium (IV), titanium chloride (III) and titanium chloride (IV). 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):

[During the ceremony,
^Ra 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, and non-substituted. Substituent 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 unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyloxy group, unsubstituted or substituted phenylalkyl group and unsubstituted or substituted phenylalkyloxy group. Is the basis for
n is an integer from 0 to 4 and
Ar'is a group selected from unsubstituted or substituted aromatic ring groups, unsubstituted or substituted aromatic heterocyclic groups and unsubstituted or substituted aliphatic heterocycles. ]
The method according to any one of [1] to [4], which is an organic group or a phenyl group represented by.
[6] Ar'is the following formula (Ar'-1), (Ar'-2) or (Ar'-3):

[During the ceremony,
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, and non-substituted. Substituent 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 unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyloxy group, unsubstituted or substituted phenylalkyl group and unsubstituted or substituted phenylalkyloxy group. Is the basis for
p is an integer from 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 in which the reduction reaction of a C-aryl-hydroxyglycoside derivative proceeds rapidly at a low temperature to produce a target β-C-aryl glycoside derivative in a highly selective manner and in a high yield. .. Since the obtained β-C-arylglycoside derivative is an SGLT2 inhibitor useful as an antidiabetes drug or a synthetic intermediate thereof, 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 this specification unless otherwise specified.

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

Unsubstituted or substituted alkyl group "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 chain alkyl group. The linear alkyl group usually has 1 to 20, preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 5, and even more preferably 1. ~ 4, even more preferably 1-3, even more preferably 1 or 2. The branched alkyl group usually has 3 to 20, preferably 3 to 10, more preferably 3 to 8, still more preferably 3 to 6, even more preferably 3 to 5, and even more preferably 3. Or 4. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, an isohexyl group, a heptyl group, and 4 , 4-Dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group, nonyl group, decyl group 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.

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

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 produced by removing one hydrogen atom from an alkyl group. The above description of the "alkyl group" also applies to the alkyl group that is the source of the alkylene group (the alkyl group from which one hydrogen atom is removed).

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

Unsubstituted or substituted alkoxy group "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 of "alkyl groups" also applies to alkyl groups contained in alkoxy groups.

In an alkoxy group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the alkoxy group. The number of substituents that the alkoxy group can have is preferably 1-3, more preferably 1 or 2. When the number of substituents is 2 or more, the 2 or more substituents may be the same or different. The one or more substituents that the alkoxy group can have can be independently selected from the 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 “heteroalkyl group” means an unsubstituted heteroalkyl group unless otherwise specified.

"Heteroalkyl group" means a linear 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 1 or 2, more preferably 1. The linear heteroalkyl group usually has 2 to 20, preferably 2 to 10, more preferably 2 to 8, even more preferably 2 to 6, even more preferably 2 to 5, and even more preferably. 2-4, more preferably 2 or 3. The branched heteroalkyl group usually has 3 to 20, preferably 3 to 10, more preferably 3 to 8, still more preferably 3 to 6, even more preferably 3 to 5, and even more preferably. 3 or 4. The heteroalkyl group, _{e.g., -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 2 -CH 3) -CH 3 CH ₃ ) -CH ₃ , -CH (-CH ₃ ) -CH _2- O-CH (-CH ₃ ) -CH _{3 and the} like can be mentioned.

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

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

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

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

Unsubstituted or substituted monoalkylamino group "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.

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

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

Unsubstituted or substituted dialkylamino group "Unsubstituted or substituted dialkylamino group" means a dialkylamino group or a dialkylamino group having one or more substituents. The "dialkylamino group" means an unsubstituted dialkylamino group unless otherwise specified.

The "dialkylamino group" is of the formula: -N (-Q ² ) ^{(-Q 3} ) [In the formula, Q ² and Q ³ are each independently an alkyl group. ] Is represented. The above description of "alkyl groups" also applies to alkyl groups contained in dialkylamino groups. The alkyl group contained in the dialkylamino group is preferably an alkyl group having 1 to 6 carbon atoms. The dialkylamino group usually has 2 to 20, preferably 2 to 12, more preferably 2 to 8, even more preferably 2 to 6, even more preferably 2 to 5, even more preferably 2 to 4. Even more preferably, it is 2 or 3.

In a dialkylamino group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the dialkylamino group. The number of substituents that the dialkylamino group can have is preferably 1-3, more preferably 1 or 2. When the number of substituents is 2 or more, the 2 or more substituents may be the same or different. The one or more substituents that the dialkylamino group can have can be independently selected from the 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. The "aliphatic ring group" means an unsubstituted aliphatic ring group unless otherwise specified.

The "aliphatic ring group" means a functional group produced 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 even 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, a cyclooctyl group and the like.

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

Unsubstituted or substituted aliphatic ring oxy group "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.

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

In the aliphatic ring oxy group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the aliphatic ring oxy group. The number of substituents that the aliphatic ring oxy group can have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the 2 or more substituents may be the same or different. One or more substituents that the aliphatic ring oxy group can have can be 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. The "aliphatic heterocyclic group" means an unsubstituted aliphatic heterocyclic group unless otherwise specified.

The "aliphatic heterocyclic group" is a monocyclic atom containing 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 as a ring-constituting atom. It means a functional group generated by removing one hydrogen atom from an aliphatic heterocycle (non-aromatic heterocycle).

The number of heteroatoms contained in the aliphatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of the aliphatic heterocyclic group is usually 3 to 8, preferably 4 to 8, more preferably 5 to 7, and even more preferably 5 or 6. 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 of the aliphatic heterocyclic group.

The aliphatic heterocyclic group is preferably a saturated aliphatic heterocyclic group. A saturated aliphatic heterocyclic group is an aliphatic heterocyclic group whose ring is composed only of saturated bonds. The aliphatic heterocyclic group includes, for example, one containing 1 to 2 oxygen atoms, one containing 1 to 2 sulfur atoms, 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. Those containing 1 to 4 nitrogen atoms, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or those containing 1 to 2 oxygen atoms, and the like. In the aliphatic heterocyclic group, the two carbon atoms constituting the ring may be crosslinked 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 can have is preferably 1 or 2. When the aliphatic heterocyclic group contains a sulfur atom, the aliphatic heterocyclic group may be a dioxide compound.

Examples of the aliphatic heterocyclic group include an aziridinyl group, an oxylanyl group, a thiylanyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a tetrahydrothienyl group, a tetrahydrofuranyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolinyl group, an imidazolidinyl group and an oxazolinyl group. , Oxazolydinyl group, pyrazolinyl group, pyrazolydinyl group, thiazolinyl group, thiazolidinyl group, tetrahydroisothiazolyl group, tetrahydrooxazolyl group, tetrahydroisooxazolyl group, piperidinyl group, piperazinyl group, tetrahydropyridinyl group, dihydropyridini Lu group, dihydrothiopyranyl group, tetrahydropyrimidinyl group, tetrahydropyridazinyl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group (sulfur atom on the ring is oxidized Azepanyl group, diazepanyl group, azepinyl group, oxepanyl group, azocanyl group, diazocanyl group and the like, and 3 to 8 member aliphatic heterocyclic groups can be mentioned.

The aliphatic heterocyclic group is preferably a tetrahydrofuranyl group.

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

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

The "aliphatic heterocyclic oxy group" means a group represented by the 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 a tetrahydrofuranyloxy group.

In the aliphatic heterocyclic oxy group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the aliphatic heterocyclic oxy group. The number of substituents that the aliphatic heterocyclic oxy group can have is preferably 1 to 3, more preferably 1 or 2. When the number of substituents is 2 or more, the 2 or more substituents may be the same or different. The one or more substituents that the aliphatic heterocyclic oxy group can have can be independently selected from the 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. The "phenyl group" means an unsubstituted phenyl group unless otherwise specified.

In a phenyl group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the phenyl group. The number of substituents that the phenyl group can have is preferably 1-4, more preferably 1-3, even more preferably 1 or 2. When the number of substituents is 2 or more, the 2 or more substituents may be the same or different. One or more substituents that the phenyl group can have can be 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 phenyl group having one or more substituents is preferably 10 or less, more preferably 9 or less, even more preferably 8. 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 one or more substituents. The "phenyloxy group" means an unsubstituted phenyloxy group unless otherwise specified.

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

In a phenyloxy group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the phenyloxy group. The number of substituents that the phenyloxy group can 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 2 or more substituents may be the same or different. One or more substituents that the phenyloxy group can have can be 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 phenyloxy group having one or more substituents is preferably 12 or less, more preferably 10 or less, even more preferably. It is 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 group-alkylene group. The above description of the "alkylene group" also applies to the alkylene group contained 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. It is a linear alkylene group of. The linear alkylene group preferably has 1 to 3 carbon atoms, and more preferably 1 or 2 carbon atoms. The phenylalkyl group preferably has 7 to 10 carbon atoms.

In a phenylalkyl group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the phenylalkyl group. The hydrogen atom to be substituted may be a hydrogen atom on the benzene ring or a hydrogen atom in the alkylene portion, but is preferably a hydrogen atom on the benzene ring. The number of substituents that the phenylalkyl group can have on the alkylene moiety is preferably 1-3, more preferably 1 or 2, and the number of substituents that the phenylalkyl group can 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 2 or more, the 2 or more substituents may be the same or different. One or more substituents that the phenylalkyl group can have can be 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 phenylalkyl group having one or more substituents is preferably 16 or less, more preferably 14 or less, even more preferably. It is 12 or less.

Unsubstituted or substituted phenylalkyloxy group "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 the phenylalkyl group -O-. The above description of the "phenylalkyl group" also applies to the phenylalkyl group contained in the phenylalkyloxy group.

In a phenylalkyloxy group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the phenylalkyloxy group. The hydrogen atom to be substituted may be a hydrogen atom on the benzene ring or a hydrogen atom in the alkylene portion, but is preferably a hydrogen atom on the benzene ring. The number of substituents that the phenylalkyloxy group can have on the alkylene moiety is preferably 1-3, more preferably 1 or 2, and the number of substituents that the phenylalkyloxy group can 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 2 or more, the 2 or more substituents may be the same or different. One or more substituents that the phenylalkyloxy group can have can be 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 phenylalkyloxy group having one or more substituents is preferably 16 or less, more preferably 14 or less, even more preferably. Is 12 or less.

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

"Aromatic ring group" means a group produced 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 type, preferably a 1 to 3 ring type, and more preferably a 1 or 2 ring type aromatic ring group. The number of ring-constituting carbon atoms in the aromatic ring group is usually 6 to 18, preferably 6 to 14, and more preferably 6 to 10. Examples of the monocyclic aromatic ring group include a phenyl group. Examples of the fused polycyclic aromatic ring group include a 2 to 4 cyclic aromatic ring group such as a naphthyl group, an anthryl group, a phenanthrenyl group, a tetrasenyl group and a pyrenyl group. The condensed polycyclic aromatic ring group may be a partially saturated condensed polycyclic aromatic ring group. A partially saturated condensed polycyclic aromatic ring group is a condensed polycyclic aromatic ring group in which a part of the bonds constituting the ring is hydrogenated.

The aromatic ring group is preferably a phenyl group.

In an aromatic ring group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the aromatic ring group. The number of substituents that the aromatic ring group can 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 can 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 2 or more substituents may be the same or different. One or more substituents that the aromatic ring group can have can be 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 the aromatic ring group having one or more substituents is preferably 20 or less, more preferably 19 or less, even more preferably. Is 18 or less, more preferably 17 or less.

Unsubstituted or substituted aromatic heterocyclic group "Unsubstituted or substituted aromatic heterocyclic group" means an aromatic heterocyclic group or an aromatic heterocyclic group having one or more substituents. The "aromatic heterocyclic group" means an unsubstituted aromatic heterocyclic group unless otherwise specified.

The "aromatic heterocyclic group" is a monocyclic atom or a monocyclic atom containing 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 as a ring-constituting atom. It means a group produced by removing one hydrogen atom from a fused polycyclic aromatic heterocycle. The aromatic heterocyclic group is usually a 1 to 4 ring type, preferably a 1 to 3 ring type, and more preferably a 1 or 2 ring type aromatic heterocyclic group. The number of heteroatoms contained in the aromatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and even more preferably 1 or 2. The number of members of the aromatic heterocyclic group is preferably 5 to 14 members, more preferably 5 to 10 members. The number of ring-constituting carbon atoms in the aromatic heterocyclic group is appropriately determined according to the number of heteroatoms and the number of members of 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. Examples of the monocyclic aromatic heterocyclic group include those containing 1 to 2 oxygen atoms, those containing 1 to 2 sulfur atoms, 1 to 2 oxygen atoms and 1 to 2 sulfur. Examples thereof include those containing atoms, those containing 1 to 4 nitrogen atoms, those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or those containing 1 to 2 oxygen atoms.

Examples of the monocyclic aromatic heterocyclic group include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group and an oxazolyl group. Isooxazolyl group, oxadiazolyl group (eg 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, etc.), thiadiazolyl group (eg 1,2,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group) Etc.), triazolyl groups (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.), tetrazolyl group, triazinyl group, etc. Can be mentioned. In a 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 a monocyclic aromatic heterocyclic group can 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 fused 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 oxygen atoms. Examples thereof include those containing sulfur atoms, those containing 1 to 5 nitrogen atoms, those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or those containing 1 to 3 oxygen atoms. ..

Examples of the fused polycyclic aromatic heterocyclic group include a benzothiophenyl group, a benzofuranyl group, a benzoimidazolyl group, a benzoxazolyl group, a benzoisooxazolyl group, a benzothiazolyl group, a benzoisothiazolyl group and a benzotoria. Zoryl group, imidazolipyridinyl group, thienopyridinyl group, flopyridinyl group, pyropyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazolopyrazine group, imidazolipyrimidinyl group, Thienopyrimidinyl group, flopyrimidinyl group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, oxazolopyrimidinyl group, thiazolopyrimidinyl group, pyrazorotriadinyl group, naphtho [2,3-b] thienyl group, phenoxatiynyl group , Indrill group, Isoindrill group, 1H-Indazolyl group, Prinyl group, Isoquinolyl group, Kinolyl group, Phthalazinyl group, Naftyridinyl group, Kinoxalinyl group, Kinazolinyl group, Synnolinyl group, Carbazolyl group, α-Carbolinyl group, Phenantridinyl group, Examples thereof include an 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group such as an acridinyl group, a phenazinyl group, a phenothiazinyl group and a phenoxadinyl group. In a 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 a 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 even more preferably a thienyl group or a benzothiophenyl group.

In an aromatic heterocyclic group having one or more substituents, each of the one or more substituents is substituted with a hydrogen atom of the aromatic heterocyclic group. The number of substituents that the aromatic heterocyclic group can 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 can have is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. Two or more substituents having two or more substituents may be the same or different. One or more substituents that the aromatic heterocyclic group can have can be 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 the aromatic heterocyclic group having one or more substituents is preferably 20 or less, more preferably 19 or less, even more. It is preferably 18 or less, and even 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 (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 Basic

"Halogen atom", "unsubstituted or substituted alkyl group", "unsubstituted or substituted alkoxy group", "unsubstituted or substituted heteroalkyl group", "unsubstituted or substituted heteroalkoxy group", "unsubstituted or substituted" 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 aliphatic ring oxy group. The above description of "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 group. It is preferably composed of a heterocyclic group and an unsubstituted or substituted aliphatic heterocyclic oxy group, preferably a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted hetero. It is more preferably composed of an alkyl group and an unsubstituted or substituted heteroalkoxy group, and further preferably composed of a halogen atom, an unsubstituted or substituted alkyl group, and an unsubstituted or substituted alkoxy group. preferable.

Substituent group β
The "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

Regarding "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 one or more substituents selected from halogen atoms. 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 one or more substituents selected from halogen atoms. 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 one or more substituents selected from halogen atoms. 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 one or more substituents selected from halogen atoms. 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 one or more substituents selected from the halogen atom and the aliphatic heterocyclic oxy group. , A halogen atom, an aliphatic heterocyclic oxy group, a phenyl group, and a phenyl group having one or more substituents selected from the halogen atom are more preferable.

<< Production method of β-C-arylglycoside derivative >>
The method for producing a β-C-arylglycoside derivative of the present invention includes a step of contacting a C-aryl-hydroxyglycoside derivative with a silane compound in the presence of a titanium compound to produce a β-C-arylglycoside derivative. ..

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

It is a compound represented by.

In formula (1), R ¹ , R ² , R ³ and R ⁴ are independently hydrogen atoms or hydroxyl protecting groups.

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, ^{1-3 of R 1} , R ² , R ³ and R ⁴ are hydroxyl protecting groups and the rest are hydrogen atoms.

It is preferable that at least one of ^{R 1} , R ² , R ³ and R ⁴ is a hydroxyl protecting group because the produced β-C-arylglycoside derivative can be 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, but of the hydroxyl protecting groups. From the viewpoint of efficient introduction and removal, they are preferably the same.

The hydroxyl protecting group can protect the hydroxyl group when the desired reaction is carried out, and is not particularly limited as long as it can be eliminated from the hydroxyl group after the completion of the desired reaction, and can be appropriately selected. Examples of the hydroxyl protecting group include an ester-type protecting group, an arylalkyl-type protecting group, an alkyl-type protecting group, an arylalkyloxyalkyl-type protecting group, an alkyloxyalkyl-type protecting group, a silyl-type protecting group, an oxycarbonyl-type protecting group, and the like. Can be mentioned.

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

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

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

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

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

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

The hydroxyl group protective 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 a benzyl group, an acetyl group and a pivaloyl group. These hydroxyl-protecting groups are preferable because they can easily protect and deprotect hydroxyl groups, and the reagents are 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 to be bonded to the oxane ring in the formula. be.

In one embodiment, Ar is an organic group comprising an unsubstituted or substituted aromatic ring group as a group to be attached to the oxane ring in the formula (1). Ar may be an unsubstituted or substituted aromatic ring group.

In another embodiment, Ar is an organic group comprising an unsubstituted or substituted aromatic heterocyclic group as a group to be attached 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 to be bonded to the oxane ring in the formula (1) include the formula: −J ¹ −J ² [in the formula, J ¹ is unsubstituted. Alternatively, it is a 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 aliphatic heterocyclic group. ], An aromatic ring group having a substituent represented by] can be mentioned. 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 the carbon atom of the oxane ring in the formula (I) include the formula: -K ^1- K ² [in the formula, K. 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. .. ], An aromatic heterocyclic group having a substituent represented by] can be mentioned. 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 aromatic heterocyclic group of the SGLT-2 inhibitor, or the aromatic ring group or aromatic heterocycle of the SGLT-2 inhibitor. It is preferably a group derived from the 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-[(also referred to as 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- ( SGLT-2 inhibitors such as (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-thiol ") have an organic group represented by the following formula (A).

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

It is an organic group represented by.

In formula (A), n is an integer from 0 to 4. n is preferably 1 to 3, more preferably 1 or 2, and even 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 Substituent 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 substituted aliphatic heterocyclic group, unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyloxy group, unsubstituted or substituted phenylalkyl group, and non-substituted or substituted phenylalkyl group. 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 formula (A), n pieces of R ^a are each independently a halogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkoxy group, substituted or unsubstituted heteroalkyl group, unsubstituted or substituted Heteroalkyl groups, unsubstituted or substituted aliphatic ring groups, unsubstituted or substituted aliphatic ring oxy groups, unsubstituted or substituted aliphatic heterocyclic groups, unsubstituted or substituted aliphatic heterocyclic oxy groups, non-substituted or substituted aliphatic heterocyclic oxy groups. It is preferably a group selected from a substituted or substituted phenyl group, an unsubstituted or substituted phenyloxy group, an unsubstituted or substituted phenylalkyl group, and an unsubstituted or substituted phenylalkyloxy group, preferably a halogen atom. More preferably, it is 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, preferably a fluorine atom and chlorine. It is more preferably a group selected from an 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 fluorine atom and a chlorine. It is even more preferable that the group is selected from an atom, a bromine atom, an iodine atom, a methyl group and a methoxy group.

In 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 preferably the following formula (Ar'-1). , (Ar'-2) or (Ar'-3) is preferable.

In the formulas (Ar'-1), (Ar'-2) and (Ar'-3), p is an integer from 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 formulas (Ar'-1), (Ar'-2) and (Ar'-3), p R ^bs are independently halogen atoms, amino groups, unsubstituted or substituted alkyl groups, non-substituted. Substituent 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 Group ring 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 Phenyloxy group, unsubstituted or substituted phenylalkyl group, and unsubstituted or substituted phenylalkyloxy group.

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

In 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 even more. Preferably, it is a phenyl group having a fluorine atom. The position to which the unsubstituted or substituted phenyl group is attached 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 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 the 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 the following formula (B):

It is preferably an organic group represented by.

In formula (B), ^Ra and Ar'are synonymous with formula (A).

Ar is preferably an organic group represented by the following formulas (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.

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

In the formula (2), R ⁵ represents 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 described above.

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 the titanium compound, the reduction reaction of the C-aryl-hydroxyglycoside derivative can be rapidly advanced at a low temperature, and the desired β-C-arylglycoside derivative can be obtained with high selectivity and high yield. Can be done.

As the titanium compound, for example, titanium is known to be 0-valent, titanium is divalent, trivalent, tetravalent, etc., but any titanium compound can be used. good. Titanium compounds include triisopropoxy titanium monochloride (IV), diisopropoxy dichloride titanium (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (IV), titanium bromide (IV), iodide. A tetravalent titanium salt such as titanium (IV) or titanium oxide (IV) or a solvent thereof; a trivalent titanium salt such as titanium chloride (III) or titanium bromide (III) or a solvent thereof; titanium chloride Divalent titanium salts such as (II) or a solvent product thereof; examples thereof include zero-valent titanium such as metallic Ti or a solvent product thereof. Examples of the solvate include those in which a solvent such as water or 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 It is an integer of 0 to 4 that satisfies 4. ], It is preferably a trivalent or tetravalent titanium salt represented by [] 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, and more preferably an alkyl group having 1 to 3 carbon atoms. ..

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

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

Silane Compound In the step of contacting the C-aryl-hydroxyglycoside derivative 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, tetramethyldisiloxane and the like. .. From the viewpoint of reactivity and price, the silane compound is preferably trimethoxyhydrosilane, triethoxyhydrosilane, tetramethyldisiloxane, or the like, and more preferably tetramethyldisiloxane.

The amount of the silane compound used is not particularly limited and can be adjusted as appropriate. The amount of the silane compound used is preferably 1 to 10 mol, more preferably 1 to 5 mol, still more preferably 1 to 3 mol, based on 1 mol of the C-aryl-hydroxyglycoside derivative, from the viewpoint of sufficiently advancing the reaction. It is a mole.

Reaction Solvent 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 is a solvent that does not adversely affect the C-aryl-hydroxyglycoside derivative, titanium compound and 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-butylmethyl ether, diisopropyl ether, dimethoxyethane, diglime and the like. Ethers, ketones such as acetone, methyl ethyl ketone, diethyl ketone, acetates such as methyl acetate, ethyl acetate, butyl acetate, hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and the like. Examples thereof include aromatic hydrocarbons such as hydrogens, 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 preferable in that they are less susceptible to silane reduction.

The amount of the reaction solvent used is not particularly limited and can be adjusted as appropriate. The amount of the reaction solvent used is preferably 1 to 100 times, more preferably 1 to 50 times, and 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 may satisfy the above range.

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

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

The temperature at the time of adding 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 even more preferably −60 ° C. to 10 ° C. By carrying out the reaction in the above temperature range, a β-C-arylglycoside derivative can be obtained with high selectivity and high yield.

The reaction time is not particularly limited, and can be appropriately adjusted, for example, while checking 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, and more preferably 1 hour or more and 17 hours or less.

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

The inside of the reaction system may be under atmospheric pressure, pressurization, or reduced pressure, but it is preferable to carry out the reaction under atmospheric pressure.

A β-C-arylglycoside derivative can be obtained by the reduction reaction. The products obtained by the reduction reaction are a β-C-arylglycoside derivative (hereinafter sometimes referred to as “β-form”) and an α-C-arylglycoside derivative (hereinafter sometimes referred to as “α-form”). Is a mixture of. According to the present invention, the β-C-arylglycoside derivative can be produced with high selectivity and high yield, so that the proportion of β-form in the product is high. The isomer ratio (β / α) in the product is usually 73/27 or higher, preferably 75/25 or higher, more preferably 77/23 or higher, even more preferably 80/20 or higher, even more preferably 85. It is / 15 or more, more preferably 90/10 or more. The isomer ratio is measured by the method described in Examples.

The β-C-arylglycoside derivative obtained by the reduction reaction is preferably taken out from the reaction system. The β-C-arylglycoside derivative obtained by the reduction reaction is, for example, added water to the reaction solution and then contacted with a poorly water-soluble organic solvent such as ethyl acetate, toluene, tert-butylmethyl ether, or methylene chloride. The β-C-arylglycoside derivative can be extracted from the reaction system by extracting it with the poorly water-soluble organic solvent.

Further, the obtained β-C-arylglycoside derivative can be further purified by using a known method such as column separation and recrystallization. However, it is difficult to separate the β-form and the α-form by column purification such as a silica gel column. Therefore, the usefulness of the present invention capable of producing a β-C-arylglycoside derivative with high selectivity and high yield is very high.

The obtained β-C-arylglycoside derivative is used as it is when all of ^{R 1 to} R ⁴ are hydrogen atoms, and as necessary when one or more of ^{R 1 to} R ^{4 are hydroxyl protecting groups.} After deprotection by a known method, it can be suitably used as an SGLT2 inhibitor useful as an antidiabetic agent or a synthetic intermediate thereof.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto, but is a specific example.

Production Example 1: Production of C-aryl-Hydroxyglycoside Derivative of Alcohol Compound The reaction represented by the following formula is carried out to carry out the reaction represented by the following formula, and ^{the C-aryl-hydroxyglycoside derivative of alcohol compound (in 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.

Phenyllithium (phenyllithium concentration: 16%, solvent: dibutyl ether) (1.3 g, 2.) In a solution of tetra-O-benzyl-D-gluconolactone (1.00 g, 1.86 mmol) in THF (5 mL). 47 mmol, 1.3 eq) was 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 give 3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl-6-hydroxy-6-phenyltetrahydropyran (hereinafter). (Alcohol compound) (1.20 g, yield: quant.) Was obtained.

Production Example 2: Production of methoxy C-aryl-hydroxyglycoside derivative The reaction represented by the following formula is carried out to carry out the reaction represented by the following formula, and the methoxy C-aryl-hydroxyglycoside derivative (in 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).

A solution of the alcohol compound (200 mg, 0.32 mmol) obtained in Production Example 1 in methanol (1 mL) was added to a solution of methanesulfonic acid (0.6 mg, 0.06 mmol) in methanol (2 mL) at room temperature, and the temperature was the same. Was stirred 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 mixture was concentrated under reduced pressure, and a mixed solution of ethyl acetate: water = 10 mL / 10 mL was added to the concentrated residue and separated. By concentrating the organic layer under reduced pressure, 3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl-6-methoxy-6-phenyltetrahydropyran (hereinafter, also referred to as methoxy form) (172 mg, yield: 84). %) Was obtained.

Production Example 3: Production of C-aryl-Hydroxyglycoside Derivative of Alcohol Compound The reaction represented by the following formula is carried out to carry out the reaction represented by the following formula, and ^{the C-aryl-hydroxyglycoside derivative of alcohol compound (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)).

(5-Iodo2-methylbenzyl) -2- (4-fluorophenyl) thiophene (765 mg, 1.86 mmol) in THF (5 mL) solution with butyllithium (1.6 M hexane solution) (1.16 mL, 1.86 mmol) ), Stir at −70 ° C. for 1 hour, and then add a solution of tetra-O-benzyl-D-gluconolactone (1.00 g, 1.86 mmol) in THF (5 mL) 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 resulting 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 a crude product without purification.

Example 1: Reduction with a titanium compound (Production of β-C-arylglycoside derivative from alcohol compound) Using a titanium compound, the reaction represented by the following formula was carried out, and β-C was obtained from the alcohol compound obtained in Production Example 1. -Aryl glycoside derivatives were produced.

Tetramethyldisiloxane (44 mg, 0.33 mmol) was added to an acetonitrile solution (2 mL) of the alcohol compound (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.

When the reaction solution was analyzed by HPLC, the alcohol form was completely consumed and the desired product was obtained. The isomer ratio of the product was β / α = 80/20.

Water (5 mL) was added to the reaction mixture, and the product was extracted 4 times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. The desired product (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 = 9.3Hz, 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 with a titanium compound (Production of β-C-arylglycoside derivative from methoxy compound) Using a titanium compound, the reaction represented by the following formula was carried out, and β-C was obtained from the methoxy compound obtained in Production Example 2. -Aryl glycoside derivatives were produced.

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.

When the reaction solution was analyzed by HPLC, the alcohol form was completely consumed and the desired product was obtained. The isomer ratio of the product was β / α = 75/25.

Water (5 mL) was added to the reaction mixture, 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 on 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 = 9.3Hz, 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 with a titanium compound (production of β-C-arylglycoside derivative from alcohol)
A β-C-arylglycoside derivative was produced from the alcohol compound obtained in Production Example 3 by carrying out the reaction represented by the following formula using a titanium compound.

Tetramethyldisiloxane (44 mg, 0.33 mmol) was added to an acetonitrile solution (2 mL) of the alcohol compound (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.

When the reaction solution was analyzed by HPLC, the alcohol form was completely consumed and the desired product was obtained. The isomer ratio of the product was β / α = 91/9.

Water (5 mL) was added to the reaction mixture, and the product was extracted 4 times with 5 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure. By purifying the concentrate with a silica gel column (developing solvent: hexane / ethyl acetate = 10/1), the desired product (3R, 4R, 5S-tribenzyloxy-2R-benzyloxymethyl-6S- (3- (5- (5- (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)
Using aluminum chloride, the reaction represented by the following formula was carried out to produce a β-C-arylglycoside derivative from the alcohol compound obtained in Production Example 1.

The alcohol compound (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. Aluminum chloride (6.5 mg, 0.05 mmol) was added thereto at −40 ° C., the temperature was gradually raised to room temperature, and the mixture was stirred at the same temperature for 18 hours.

When the reaction solution was analyzed by HPLC, the alcohol compound 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) Using aluminum chloride, the reaction represented by the following formula was carried out, and β-C was obtained from the methoxy form obtained in Production Example 2. -Aryl glycoside derivatives were produced.

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. 03 mmol) was added. Aluminum chloride (6.5 mg, 0.05 mmol) was added thereto at −40 ° C., the temperature was gradually raised to room temperature, and the mixture was stirred at the same temperature for 17 hours.

When the reaction solution was analyzed by HPLC, 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.

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 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. The ratio.

In addition, the yield in the examples was calculated from the amount of the raw material and the amount of the target product after collecting the target product. 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 product is the ratio of the peak area value of the target product to the total area value of all peaks (excluding the peak derived from the solvent).

<Recording conditions for HPLC>
Equipment: High Performance Liquid Chromatography (HPLC)
Detector: Ultraviolet absorptiometer (measurement wavelength: 210 nm)
Column: XBridge C18, 5 μm, inner diameter 4.8 mm, length 15 cm (manufactured by Waters)
Column temperature: 30 ° C (constant)
Flow velocity: 1.0 mL / min Mobile phase: Acetonitrile / water = 90/10 → 100/0 (0 → 10 min)
Retention time: Alcohol body of Production Example 1 4.5 minutes; methoxy body of Production Example 2 6.4 minutes; Alcohol body of Production Example 3 17.47 minutes; Example 1, Example 2, Comparative Example 1 and Comparative Example Β body of 2 5.7 minutes; α body of Example 1, Example 2, Comparative Example 1 and Comparative Example 2 5.4 minutes; β body of Example 3 18.31 minutes; α body of Example 3 18 .13 minutes

Claims (6)

The following formula (1):

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

[In the formula, 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 a step of contacting a C-aryl-hydroxyglycoside derivative represented by (1) with a silane compound in the presence of a titanium compound to produce the β-C-arylglycoside derivative. Claimed that R ¹ , R ² , R ³ and R ⁴ are hydroxyl protecting groups independently selected from a methyl group, a benzyl group, an acetyl group, a pivaloyl group, a trimethylsilyl group and a tert-butyldimethylsilyl group, respectively. Item 1. The method according to Item 1. The titanium compound is selected from triisopropoxy titanium monochloride (IV), diisopropoxy dichloride titanium (IV), monoisopropoxy titanium trichloride (IV), titanium chloride (III) and titanium chloride (IV). , The method according to claim 1 or 2. Claimed that the silane compound is selected from triethylsilane, triisopropylsilane, phenylsilane, dimethylphenylsilane, tert-butyldimethylsilane, triisobutylsilane, trichlorosilane, trimethoxyhydrosilane, triethoxyhydrosilane and tetramethyldisiloxane. Item 8. The method according to any one of Items 1 to 3. Ar is the following formula (A):

[During the ceremony,
^Ra 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, and non-substituted. Substituent 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 unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyloxy group, unsubstituted or substituted phenylalkyl group and unsubstituted or substituted phenylalkyloxy group. Is the basis for
n is an integer from 0 to 4 and
Ar'is a group selected from unsubstituted or substituted aromatic ring groups, unsubstituted or substituted aromatic heterocyclic groups and unsubstituted or substituted aliphatic heterocycles. ]
The method according to any one of claims 1 to 4, which is an organic group or a phenyl group represented by. Ar'is the following formula (Ar'-1), (Ar'-2) or (Ar'-3):

[During the ceremony,
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, and non-substituted. Substituent 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 unsubstituted or substituted aliphatic heterocyclic oxy group, unsubstituted or substituted phenyl group, unsubstituted or substituted phenyloxy group, unsubstituted or substituted phenylalkyl group and unsubstituted or substituted phenylalkyloxy group. Is the basis for
p is an integer from 0 to 5. ]
The method according to any one of claims 1 to 5, which is a group represented by.