HK1103393B

HK1103393B - Cyclohexane derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes

Info

Publication number: HK1103393B
Application number: HK07111803.7A
Authority: HK
Inventors: 松冈宏治; 佐藤勉; 西本昌弘; 新间信夫
Original assignee: 中外制药株式会社
Priority date: 2004-07-26
Filing date: 2005-07-26
Publication date: 2011-08-26

Description

Cyclohexane derivative, prodrug thereof, salt thereof, and therapeutic agent for diabetes containing same

Technical Field

The present invention relates to a cyclohexane derivative useful as a pharmaceutical, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a compound which is capable of inhibiting Na⁺Glucose co-transporter 2(SGLT2) as insulin-dependent diabetes mellitus (type 1 diabetes), insulin-independent diabetes mellitus (type 2 diabetes) and the likeA cyclohexane derivative, a prodrug thereof, and a salt thereof, which are useful as a prophylactic or therapeutic agent for a disease caused by hyperglycemia such as diabetes, diabetic complications, and obesity.

Background

In recent years, diabetic patients have been increasing due to westernization of dietary life, chronic lack of exercise, and the like. In diabetic patients, chronic hyperglycemia causes both insulin secretion and insulin sensitivity to decrease, which further increases blood glucose levels, leading to worsening of symptoms. Heretofore, biguanides, sulfonylureas, glycosidase inhibitors, insulin resistance improvers, and the like have been used as diabetes therapeutic agents. However, biguanides have been reported to have side effects of lactic acidosis; sulfonylureas have hypoglycemic side effects; glycosidase inhibitors have side effects such as diarrhea; therefore, it is the current situation that people urgently hope to develop a class of diabetes therapeutic drugs with a new action mechanism different from the drugs.

It has been reported that phlorizin, which is a natural glucose derivative, inhibits the reabsorption of excess glucose in the kidney by inhibiting sodium-dependent glucose co-transporter 2(SGLT2) present at the S1 site of the renal tubule in the vicinity of the kidney, promotes the excretion of glucose, and exhibits an action of lowering blood glucose (see non-patent document 1), and since then, studies on therapeutic agents for diabetes based on the inhibition of SGLT2 have been actively conducted.

For example, Japanese patent laid-open No. 2000-80041 (patent document 1), International publication No. 01/068660 (patent document 2), International publication No. 04/007517 (patent document 3), and the like have reported compounds used as SGLT2 inhibitors. However, phlorizin and the compounds described in the above patent applications have glucose as a partial structure, and if they are orally administered, hydrolysis is likely to occur due to glycosidase present in the small intestine, and the pharmacological effects are rapidly lost. Further, it is reported that phloretin as an aglycon moiety strongly inhibits a sugar transporter of a diffusion-promoting type in the case of phlorizin, and for example, it is reported that when phloretin is administered intravenously to rats, adverse effects of a decrease in the brain glucose concentration occur (for example, see non-patent document 2).

Therefore, attempts have been made to convert the compound into a prodrug in order to prevent such decomposition and improve the absorption efficiency. However, when a prodrug is administered, it is desired that the prodrug be reliably metabolized and converted into an active compound in or near a target organ, but various metabolic enzymes exist in the living body, and the individual difference is large, and it is often difficult to cause the prodrug to exert a stable action. In addition, attempts have been made to convert the glycosidic bond of a compound into a carbon-carbon bond (see patent documents 4 to 8), and further improvement of properties including activity and metabolic stability as a drug has been desired.

[ patent document 1]

Japanese laid-open patent publication No. 2000-080041

[ patent document 2]

International publication No. 01/068660 pamphlet [ パンフレツト ]

[ patent document 3]

International publication No. 04/007517 pamphlet

[ patent document 4]

U.S. patent application publication No. 2001/041674

[ patent document 5]

U.S. patent application publication No. 2002/137903

[ patent document 6]

International publication No. 01/027128 pamphlet

[ patent document 7]

International publication No. 02/083066 pamphlet

[ patent document 8]

International publication No. 04/013118 pamphlet

[ non-patent document 1]

Clin. invest, volume 93, page 1037, 1994

[ non-patent document 2]

Stroke, volume 14, page 388, 1983

Disclosure of Invention

The present invention aims to provide a cyclohexane derivative having excellent properties as a drug. Another object of the present invention is to provide a cyclohexane derivative having a blood glucose-lowering action and further having excellent properties as a drug, such as drug efficacy persistence, metabolic stability, or safety. It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating diseases caused by hyperglycemia such as diabetes including insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), diabetic complications, and obesity.

The present inventors have made intensive studies in order to achieve the above object and, as a result, have obtained knowledge that a cyclohexane derivative represented by the formula (I) has excellent SGLT2 inhibitory activity, and have thus completed the present invention.

That is, according to 1 aspect of the present invention, there is provided a cyclohexane derivative represented by the formula (I):

[ solution 1]

[ wherein A is-O-, -CH ]₂-, or-NH-;

n is an integer selected from 0 and 1;

R⁶and R⁷Each independently is a hydrogen atom or C₁-C₆An alkyl group;

m is an integer selected from 1 to 3;

q is selected from Q represented by the following formula¹～Q⁵：

[ solution 2]

R¹、R²、R³、R⁴And R⁵Each independently selected from hydrogen atom, hydroxyl group, C which may be substituted by 1 or more Ra₁-C₆Alkyl, C which may be substituted by 1 or more Ra₁-C₆Alkoxy, C which may be substituted by 1 or more Rb₇-C₁₄Aralkoxy, and-OC (═ O) Rx;

rx is C which may be substituted by 1 or more Ra₁-C₆Alkyl, aryl which may be substituted by 1 or more Rb, heteroaryl which may be substituted by 1 or more Rb, C which may be substituted by 1 or more Ra₁-C₆Alkoxy, or-nredrf;

Ar¹is arylene which can be substituted by more than 1 Rb, or heteroarylene which can be substituted by more than 1 Rb, and the heteroarylene can also form a condensed ring with an aromatic carbocycle or an aromatic heterocycle;

Ar²is aryl which may be substituted by 1 or more Rb, or heteroaryl which may be substituted by 1 or more Rb;

ra eachIndependently selected from halogen atom, hydroxyl, cyano, nitro, carboxyl, C which can be substituted by more than 1 Rc₁-C₆Alkoxy, aryl which may be substituted with 1 or more Rd, aryloxy which may be substituted with 1 or more Rd, heteroaryl which may be substituted with 1 or more Rd, heteroaryloxy which may be substituted with 1 or more Rd, mercapto, C₁-C₆Alkylthio radical, C₁-C₆Alkylsulfinyl radical, C₁-C₆Alkylsulfonyl, -NRfRg, and C which may be substituted by 1 or more Rc₁-C₆An alkylcarbonyl group;

each Rb is independently selected from C which may be substituted by 1 or more Rc₁-C₆Alkyl, C which may be substituted by 1 or more Rc₁-C₆Alkenyl, C which may be substituted by 1 or more Rc₃-C₈Cycloalkyl, C which may be substituted by more than 1 Rd₇-C₁₄Aralkyl group, halogen atom, hydroxyl group, cyano group, nitro group, carboxyl group, C which may be substituted with 1 or more Rc₁-C₆Alkoxy, aryl which may be substituted with 1 or more Rd, aryloxy which may be substituted with 1 or more Rd, heteroaryl which may be substituted with 1 or more Rd, heteroaryloxy which may be substituted with 1 or more Rd, mercapto, C₁ -C₆Alkylthio radical, C₁-C₆Alkylsulfinyl radical, C₁-C₆Alkylsulfonyl, -NRfRg, C which may be substituted by 1 or more Rc₁-C₆Alkylcarbonyl group, C₁-C₃Alkylenedioxy, heterocyclic radical, -CO₂Ri, and-CONRiRj;

rc is independently selected from halogen atom, hydroxyl, cyano, nitro, carboxyl, C which can be substituted by more than 1 halogen atom₁-C₆Alkoxy, aryl which may be substituted with 1 or more Rd, aryloxy which may be substituted with 1 or more Rd, heteroaryl which may be substituted with 1 or more Rd, heteroaryloxy which may be substituted with 1 or more Rd, amino, C₁-C₆Alkylamino group, and di (C)₁-C₆Alkyl) amino;

rd are each independentlyIs selected from C which may be substituted by 1 or more halogen atoms₁-C₆Alkyl, C which may be substituted by 1 or more halogen atoms₁-C₆Alkoxy, C which may be substituted by 1 or more halogen atoms₇-C₁₄Aralkyl group, halogen atom, hydroxy group, cyano group, nitro group, amino group, C₁-C₆Alkylamino group, and di (C)₁-C₆Alkyl) amino;

re is a hydrogen atom, C which may be substituted by 1 or more Rc₁-C₆Alkyl, aryl which may be substituted with 1 or more Rd, or heteroaryl which may be substituted with 1 or more Rd;

rf is a hydrogen atom or C which may be substituted by 1 or more Rc₁-C₆An alkyl group;

rg is hydrogen atom, C which may be substituted by more than 1 Rc₁-C₆Alkyl, C which may be substituted by 1 or more Rc₁-C₆Alkylcarbonyl, aryl which may be substituted with 1 or more Rd, heteroaryl which may be substituted with 1 or more Rd, carbamoyl, C which may be substituted with 1 or more Rc₁-C₆Alkoxycarbonyl or C which may be substituted by 1 or more Rc₁-C₆An alkylsulfonyl group; or

Re and Rf, and Rf and Rg can also form a 4-7-membered heterocyclic ring together with the nitrogen atom bonded with Re and Rf and Rg;

ri and Rj are each independently selected from a hydrogen atom, C which may be substituted with 1 or more Rc₁-C₆Alkyl, C which may be substituted by 1 or more Rc₃-C₈Cycloalkyl, and C which may be substituted by 1 or more Rd₇-C₁₄Aralkyl radical]。

According to another aspect of the present invention, there is provided a cyclohexane derivative represented by the formula (I) wherein n is 1, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Here, A is preferably-O-or-NH-. In addition, in Ar¹The substitution pattern above is preferably, the substituent- (CR)⁶R⁷)_m-Ar²Bonded to ring atoms adjacent to the ring atom to which substituent A is bonded, e.g. in Ar¹In the case of phenylene, ortho-substituted forms are preferred; in addition, for example in Ar¹In the case of thienylene, 2, 3-substitution or 3, 4-substitution is preferred; further, for example, in Ar¹Is pyridinylene [ pyridinylene ]]In the case of (3), 2, 3, 4, 5, or 5, 6 substitution is preferred. In addition, in Ar¹Is pyrazolylene [ pyrazolylene ]]In the case of (2), 3, 4, 5, or 1, 5 substitution is preferred. Note that the substituent A and the substituent- (CR)⁶R⁷)_m -Ar²May also be bonded to a ring nitrogen atom.

According to another aspect of the present invention, there is provided a cyclohexane derivative represented by the formula (I) wherein n is 0, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Here, in Ar¹The substitution pattern above is preferably, the substituent- (CR)⁶R⁷)_m-Ar²Bonded to ring atoms 2 atoms away from the ring atom to which Q is bonded, e.g. in Ar¹In the case of phenylene, a meta-substituent is preferred; in addition, for example in Ar¹In the case of a pyridylene group, a 2, 4-substitution, 3, 5-substitution, 4, 6-substitution, or 1, 6-substitution is preferred; further, for example, in Ar¹Is indolyl [ indolyl ene ]]In the case of (3), 1, 3 substitution, 3, 4 substitution, 4, 6 substitution, or 5, 7 substitution is preferable. In addition, in Ar¹In the case of a pyrazolylene group, 1, 3-substitution, 3, 5-substitution, or 1, 4-substitution is preferable. Note that the substituent A and the substituent- (CR)⁶R⁷)_m-Ar²May also be bonded to a ring nitrogen atom.

In the above formula (I), m is preferably 1. In addition, Ar¹Preferably a phenylene group, a naphthylene group, a thienylene group, a pyridylene group, an indolyl group, or a pyrazolylene group, and particularly preferably a phenylene group, a thienylene group, a pyridylene group, or an indolyl group (these groups may be substituted with 1 or more Rb).

In the above formula (I), m is preferably 1, and，Ar²preferably phenyl, naphthyl, thienyl, benzofuranyl, benzothienyl, benzodioxolyl]2, 3-dihydrobenzofuranyl or 2, 3-dihydrobenzothienyl, particularly preferably phenyl, benzodioxolyl or 2, 3-dihydrobenzofuranyl (these radicals may also be substituted by more than 1 Rb).

In the above formula Q¹～Q⁵In, R¹、R²、R³、R⁴And R⁵Preferably each independently is a group selected from hydroxy and-OC (═ O) Rx.

According to other aspects of the present invention, there is provided a compound wherein m is 1, n is 1, A is-O-or-NH-, Ar¹Selected from phenylene, naphthylene, thienylene, pyridinylene, indolylene, or pyrazolylene (these groups may be substituted by more than 1 Rb), Ar²Is phenyl, naphthyl, thienyl, benzofuranyl, benzothienyl, benzodioxolyl, 2, 3-dihydrobenzofuranyl, or 2, 3-dihydrobenzothienyl (these groups may be substituted by more than 1 Rb), R¹、R²、R³、R⁴And R⁵A compound of formula (I) as hereinbefore described, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, each independently selected from hydroxy and-OC (═ O) Rx.

According to other aspects of the present invention, there is provided a composition wherein m is 1, n is 0, Ar¹Is phenylene, naphthylene, thienylene, pyridinylene, indolylene or pyrazolylene (these groups can be substituted by more than 1 Rb), Ar²Is phenyl, naphthyl, thienyl, benzofuranyl, benzothienyl, benzodioxolyl, 2, 3-dihydrobenzofuranyl, or 2, 3-dihydrobenzothienyl (these groups may be substituted by more than 1 Rb), R¹、R²、R³、R⁴And R⁵A compound of formula (I) as hereinbefore described, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, each independently selected from hydroxy and-OC (═ O) Rx.

Further, according to another aspect of the present invention, there is provided a compound selected from the following, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[2- (4-methoxybenzyl) phenyl ] -5 a-carbon [ carba ] - β -D-glucopyranoside [ グルコピラノシド glucopyranoside ];

[1S, 2R, 3R, 4R, 6S ] -4-hydroxymethyl-6- [3- (4-methoxybenzyl) phenyl ] cyclohexane-1, 2, 3-triol;

[2- (4-trifluoromethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclopentylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-chlorobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

(2-benzylphenyl) -5 a-carbon- β -D-glucopyranoside;

[2- (4-isopropylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclopropylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-n-propylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-trifluoromethylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methylsulfanyl [ sulfanyl ] benzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 3-fluoro-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-trifluoromethylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -4-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -4-methoxyphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -6-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -4-fluorophenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-fluorobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 5-fluoro-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methylsulfonylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-fluorobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3, 4-dimethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-hydroxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyanobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-trifluoromethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-aminomethylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 5-methoxy-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxycarbonylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-carbamoylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-N, N-dimethylcarbamoylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-difluoromethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-tert-butylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -5-trifluoromethylthiophen-3-yl ] -5 a-carbon- β -D-glucopyranoside;

[ 3-methoxy-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -3-methylphenyl ] -5 a-carbon- β -D-glucopyranoside; and

[2- (3-fluoro-4-methoxybenzyl) phenyl ] -5 a-carbon- α -D-glucopyranoside;

[4- (4-cyclopropylbenzyl) pyridin-3-yl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-carboxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-vinylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

{2- [4- (2, 2-difluorovinyl) benzyl ] phenyl } -5 a-carbon- β -D-glucopyranoside;

[2- (2, 3-dihydrobenzofuran-5-ylmethyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-fluoro-4-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxy-3-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-pyrazol-1-ylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-chloro-4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3, 4-methylenedioxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclobutylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-acetylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -5-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethylbenzyl) thiophen-3-yl ] -5 a-carbon- β -D-glucopyranoside;

[2- (benzothien-2-yl) methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

(R) - {2- [1- (4-cyclopropylphenyl) ethyl ] phenyl } -5 a-carbon- β -D-glucopyranoside;

(S) - {2- [1- (4-cyclopropylphenyl) ethyl ] phenyl } -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclopropylbenzyl) -5-methylthiophen-3-yl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethylbenzyl) -5-methylthiophen-3-yl ] -5 a-carbon- β -D-glucopyranoside;

[ 5-chloro-2- (4-cyclopropylbenzyl) thiophen-3-yl ] -5 a-carbon- β -D-glucopyranoside;

(1R, 2S, 3R, 6R) -6- [2- (4-cyclopropylbenzyl) phenoxy ] -4- (hydroxymethyl) cyclohex-4-ene-1, 2, 3-triol;

(1R, 2S, 3R, 6R) -4-hydroxymethyl-6- [2- (4-methoxybenzyl) phenoxy ] cyclohex-4-ene-1, 2, 3-triol;

(1R, 2S, 3S, 6R) -4- [3- (4-ethylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohex-4-ene-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] -5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-ethylbenzyl) -4-methoxyphenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] -5- (hydroxymethyl) cyclohexane-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2, 4-dimethoxyphenyl ] -5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2, 4-dimethoxyphenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-methylphenyl ] -5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-methylphenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-methoxyphenyl ] hydroxymethylcyclohexane-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-methoxyphenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-trifluoromethoxyphenyl ] -5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-isopropylbenzyl) -2-methoxyphenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-ethylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-hydroxybenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-hydroxyphenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-cyclopropylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol;

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-fluorophenyl ] -5- (hydroxymethyl) cyclohexane-1, 2, 3, 4-tetraol;

(1S, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-fluorophenyl ] -5- (hydroxymethyl) cyclohexane-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4R, 5R) -5-hydroxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexa-1, 2, 3, 4-tetraol;

(1S, 2R, 3S, 4R, 5R) -5-hydroxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexa-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4S, 6R) -4- [1- (4-ethylbenzyl) -1H-indol-3-yl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol.

According to other aspects of the invention, there is provided a compound which acts as Na⁺-glucose co-transporter inhibitors pharmaceutical compositions containing the compounds of formula (I) above.

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating diabetes such as insulin-dependent diabetes (type 1 diabetes) or insulin-independent diabetes (type 2 diabetes), diabetic complications due to hyperglycemia, or obesity, comprising the compound of the above formula (I).

According to another aspect of the present invention, there is provided a method for preventing or treating diabetes such as insulin-dependent diabetes mellitus (type 1 diabetes) and insulin-independent diabetes mellitus (type 2 diabetes), diabetic complications due to hyperglycemia, and obesity, which comprises administering a therapeutically effective amount of the compound of the formula (I) or a salt thereof to a patient.

In the above formula Q¹～Q⁵In, R¹、R²、R³And R⁴Or may each independently be selected from, for example, hydroxy, C₁-C₆Alkoxy radical, C₇-C₁₄Aralkoxy, or-OC (═ O) Rx, in particular R¹、R²、R³、R⁴And R⁵Preferably both are hydroxyl groups.

In the compound of the present invention, n is preferably 1, and in this case, A is preferably-O-, -NH-, and particularly preferably-O-.

In the above formula (I), Ar¹And Ar²Each of which may be substituted with 1 to 4 independently selected substituents Rb; and as Rb, a halogen atom is preferable; a hydroxyl group; c which may be substituted with 1 to 4 substituents selected from halogen atom, hydroxyl group or amino group₁-C₆Alkyl and C₃-C₈A cycloalkyl group; c which may be substituted with 1 to 4 substituents selected from halogen atom, hydroxyl group or amino group₁-C₆Alkoxy and C₁-C₆An alkylthio group; a cyano group; c₁-C₆An alkylsulfonyl group; a nitro group; a carboxyl group; -NReRf (where Re is a hydrogen atom, C₁-C₆Alkyl radical, C₁-C₆Alkylcarbonyl, carbamoyl, C₁-C₆Alkylsulfonyl, or C₁-C₆An alkoxycarbonyl group; rf is a hydrogen atom or C₁-C₆Alkyl groups); 5 or 6 membered heteroaryl; or a 4-to 6-membered heterocyclic group.

From Ar¹In the group represented, the arylene group is a 2-valent group consisting of an aromatic carbon ring, preferably an aromatic carbon ring having 6 to 10 carbon atoms, and includes, for example, phenylene, naphthylene and the like. Heteroarylene means a 2-valent group containing an aromatic heterocycle, preferably a 6-to 10-membered aromatic heterocycle, and includes heteroarylene containing, for example, a pyrrole ring, an indole ring, a thiophene ring, a benzothiophene ring, a furan ring, a benzofuran ring, a pyridine ring, a quinoline ring, an isoquinoline ring, a thiazole ring, a benzothiazole ring, an isothiazole ring, a benzisothiazole ring, a pyrazole ring, an indazole ring, an oxazole ring, a benzoxazole ring, an isoxazole ring, a benzisoxazole ring, an imidazole ring, a benzimidazole ring, a triazole ring, a benzotriazole ring, a pyrimidine ring, a uracil ring, a pyrazine ring, a pyridazine ring, and the like. In particular, Ar¹Preferably a phenylene group, a naphthylene group, or a heteroarylene group containing a pyridine ring, a pyrrole ring, an indole ring, a thiophene ring, a benzothiophene ring, a furan ring, a benzofuran ring, a pyrazole ring, and more preferably a phenylene group, a thienylene group, a pyridylene group, and an indolyl group.

From Ar²In the groups, aryl means phenyl, naphthyl, azulenyl [ azulenyl ]](ii) a Heteroaryl means pyrrolyl, indolyl, pyridyl, quinolyl, isoquinolyl, thienyl, benzothienyl, furyl, benzofuryl, thiazolyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzoisoxazolyl, imidazolyl, benzimidazolyl, triazolyl, benzotriazolyl, pyrimidinyl, uracil, pyrazinyl, pyridazinyl and the like; ar (Ar)²Preferably phenyl, naphthyl, thienyl, benzothienyl, benzodioxolyl, furyl, benzofuryl or 2, 3-dihydrobenzofuryl, more preferably phenyl, benzodioxolyl or 2, 3-dihydrobenzofuryl.

In the present specification, "C" or "C" is used₁-C₆The "alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butylButyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl and the like. As preferred C₁-C₆Examples of the alkyl group include straight-chain or branched-chain alkyl groups having 1 to 3 carbon atoms, and particularly preferably methyl and ethyl groups.

In the present specification, "C" or "C" is used₃-C₈The cycloalkyl group means a cyclic alkyl group having 3 to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

In the present specification, "C" or "C" is used₁-C₆The "alkoxy group" refers to an alkoxy group having a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms as an alkyl moiety, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, 3-methylbutyloxy, 2-methylbutyloxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3-ethylbutoxy and the like.

In the present specification, "aryl" refers to an aryl group having an aromatic hydrocarbon group having 6 to 10 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

In the present specification, "C" or "C" is used₇-C₁₄The "aralkyl group" refers to an aralkyl group having 7 to 14 carbon atoms and containing an aryl group as defined above, and means, for example, a benzyl group, a 1-phenethyl group, a 2-phenethyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group and the like.

In the present specification, "C" or "C" is used₇-C₁₄The aralkyloxy group "means an aralkyloxy group having 7 to 14 carbon atoms containing the aralkyl group as defined above, for example, benzyloxy group, 1-phenethyloxy group, 2-phenethyloxy group, 1-naphthylmethoxy group, 2-naphthylmethoxy group and the like.

In the present specification, "heteroaryl" refers to a 5 to 10-membered aromatic heterocyclic group containing 1 or more heteroatoms independently selected from oxygen atom, nitrogen atom and sulfur atom, and includes, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl and the like. Preferred heteroaryl groups are 5-to 6-membered heteroaryl groups such as pyrrolyl, pyrazolyl, imidazolyl and pyridyl, and pyrazolyl is particularly preferred.

In the present specification, "aryloxy group" means an aryloxy group having an aromatic hydrocarbon group having 6 to 10 carbon atoms as defined above as an aryl moiety, and includes, for example, phenoxy, 1-naphthoxy, 2-naphthoxy and the like.

In the present specification, "heteroaryloxy" refers to a heteroaryloxy group having a 5-to 10-membered aromatic heterocyclic group containing 1 or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom as defined above as a heteroaryl moiety, and includes, for example, furan oxy, thiophene oxy, pyrrole oxy, imidazole oxy, pyrazole oxy, oxazole oxy, isoxazole oxy, thiazole oxy, isothiazole oxy, oxadiazole oxy, thiadiazole oxy, triazole oxy, tetrazole oxy, pyridine oxy, pyrimidine oxy, pyrazine oxy, pyridazine oxy, indole oxy, quinoline oxy (キノリニルオキシ), isoquinoline oxy and the like. Preferred heteroaryloxy groups are 5-to 6-membered ring heteroaryloxy groups.

In the present specification, "C" or "C" is used₁-C₆The "alkylamino group" refers to an alkylamino group having a linear or branched alkyl group having 1 to 6 carbon atoms as an alkyl moiety, and includes, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, 3-methylbutylamino, 2-methylbutylamino, 1-ethylpropylamino, n-hexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3-ethylbutylamino, and 2-ethylbutylamino.

In the present specification, "two (C)₁-C₆Alkyl) amino "refers to a dialkylamino group having 2 linear or branched alkyl groups of 1 to 6 carbon atoms as alkyl moieties, and the 2 alkyl moieties may be the same or different. The second (C)₁-C₆Alkyl) amino "includes, for example, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, methyl-sec-butylamino, methyl-isobutylamino, methyl-tert-butylamino, ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino and the like.

In the present specification, "C" or "C" is used₁-C₆The "alkylthio group" refers to an alkylthio group having a straight-chain or branched alkyl group having 1 to 6 carbon atoms as an alkyl moiety, and includes, for example, a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, a sec-butylthio group, an isobutylthio group, a tert-butylthio group, a n-pentylthio group, a 3-methylbutylthio group, a 2-methylbutylthio group, a 1-ethylpropylthio group, a n-hexylthio group, a 4-methylpentylthio group, a 3-methylpentylthio group, a 2-methylpentylthio group, a 1-methylpentylthio group, a 3-ethylbutylthio group, and.

In the present specification, "C" or "C" is used₁-C₆The alkylsulfinyl group "refers to an alkylsulfinyl group (-SO-R) having a linear or branched alkyl group having 1 to 6 carbon atoms as an alkyl moiety, and includes, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, isobutylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, 3-methylbutylsulfinyl, 2-methylbutylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3-ethylbutylsulfinyl, and 2-ethylbutylsulfinyl, and the like.

In the present specification, "C" or "C" is used₁-C₆The alkylsulfonyl group means a linear or branched alkyl group having 1 to 6 carbon atoms as the alkyl moietyThe alkylsulfonyl group of the alkyl group includes, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, sec-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, 3-methylbutylsulfonyl group, 2-methylbutylsulfonyl group, 1-ethylpropylsulfonyl group, n-hexylsulfonyl group, 4-methylpentylsulfonyl group, 3-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 1-methylpentylsulfonyl group, 3-ethylbutylsulfonyl group, 2-ethylbutylsulfonyl group and the like.

In the present specification, "-OC (═ O) -Rx" includes, for example, C₁-C₆Alkyl carbonyloxy group]、C₇-C₁₄Aralkyl carbonyloxy, C₁-C₆Alkoxycarbonyloxy, C₇-C₁₄Aralkyloxycarbonyloxy, and the like. Here, as C₁-C₆Examples of the alkylcarbonyloxy group include an acetoxy group, propionyloxy group, butyryloxy group, pivaloyloxy group and the like, and particularly preferred is an acetoxy group. As C₇-C₁₄Examples of the aralkylcarbonyloxy group include benzylcarbonyloxy group and naphthylmethylcarbonyloxy group, and benzylcarbonyloxy group is preferable.

As C₁-C₆Examples of the alkoxycarbonyloxy group include methoxycarbonyloxy group and ethoxycarbonyloxy group, and methoxycarbonyloxy group is preferable. As C₇-C₁₄Examples of the aralkyloxycarbonyloxy group include benzyloxycarbonyloxy group and naphthylmethoxycarbonyloxy group, and benzyloxycarbonyloxy group is preferable.

In the present specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

In the present specification, the 4-to 7-membered heterocyclic ring is a heterocyclic ring which may be completely saturated or partially saturated or completely unsaturated and may contain 1 or more nitrogen atoms and further 1 or more heteroatoms independently selected from oxygen atoms, nitrogen atoms and sulfur atoms, and includes, for example, azetidine, pyrrolidine, piperidine, morpholine and the like, and piperidine is particularly preferable.

In the present specification, the "aromatic carbocyclic ring" refers to a 6-to 10-membered aromatic carbocyclic ring, and includes, for example, a benzene ring, a naphthalene ring, and the like.

In the present specification, the "aromatic heterocycle" refers to a 5-to 6-membered aromatic heterocycle containing 1 or more heteroatoms independently selected from an oxygen atom, a nitrogen atom and a sulfur atom, and includes, for example, a pyrrole ring, an indole ring, a thiophene ring, a benzothiophene ring, a furan ring, a benzofuran ring, a pyridine ring, a quinoline ring, an isoquinoline ring, a thiazole ring, a benzothiazole ring, an isothiazole ring, a benzisothiazole ring, a pyrazole ring, an indazole ring, an oxazole ring, a benzoxazole ring, an isoxazole ring, a benzisoxazole ring, an imidazole ring, a benzimidazole ring, a triazole ring, a benzotriazole ring, a pyrimidine ring, a uracil ring, a pyrazine ring, a pyridazine ring and the like.

The "heterocyclic group" as used herein means a 4-to 7-membered heterocyclic group which may be completely saturated or partially saturated or completely unsaturated and contains 1 or more heteroatoms independently selected from oxygen atom, nitrogen atom and sulfur atom, and includes, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxazolinyl, morpholinyl, thiomorpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, hexamethyleneimino, furanyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, dioxolanyl, oxathiolanyl (オキサチオラニル), dioxanyl and the like. The linking position of the heterocyclic group is not particularly limited as long as it is a position that can be substituted on a carbon atom or a nitrogen atom.

In the present specification, "C" or "C" is used₁-C₃Alkylenedioxy "is of the formula-O- (C)₁-C₃Alkylene) -O-represents a 2-valent group, and includes, for example, methylenedioxy, ethylenedioxy, dimethylmethylenedioxy, and the like.

In addition, the compounds of the present invention include mixtures of various stereoisomers such as tautomers and optical isomers, and isolated isomers.

The compounds of the present invention sometimes form acid addition salts. Further, depending on the kind of the substituent, a salt may be formed with a base. Specific examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and the like; acid addition salts of acidic amino acids such as aspartic acid and glutamic acid. Examples of the salt with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, etc.; salts and ammonium salts with basic amino acids such as lysine and ornithine.

Further, the compound of the present invention includes hydrates, various pharmaceutically acceptable solvates and polymorphs.

The compounds of the present invention are not limited to the compounds described in the following examples, but include all of the cyclohexane derivatives represented by the above formula (I) and pharmaceutically acceptable salts thereof.

In addition, the present invention also includes so-called prodrugs belonging to compounds which are metabolized in the living body and converted into the above-mentioned compounds of the formula (I) and into pharmaceutically acceptable salts thereof. Examples of the group forming the prodrug of the compound of the present invention include those described in prog.med. Vol.5, pp.2157-2161 (1985), and those described in 1990 of Guanchuan bookstore, Vol.7, pp.163-198 of molecular design.

The compound of the present invention can be produced by various known synthetic methods according to the characteristics based on the basic skeleton or the kind of the substituent. In this case, depending on the kind of the functional group, it may be preferable in terms of production technology to protect the functional group with an appropriate protecting group at the stage of the raw material or the intermediate, and then the protecting group is removed in a subsequent step, whereby a desired compound can be obtained. Examples of the functional group to be protected in the preparation step include a hydroxyl group and a carboxyl group, and examples of the above-mentioned protecting group include protecting Groups described in "Protective Groups in Organic Synthesis" 2 nd edition by Greene and Wuts. The protecting group to be used and the reaction conditions for introducing and removing the protecting group can be appropriately selected based on known techniques such as those described in the above-mentioned documents.

The compounds of the present invention have inhibitory activity against sodium-dependent glucose transporter 2(SGLT2) (j. clin. invest., volume 93, page 397, 1994) which is involved in glucose reabsorption in the kidney. Since SGLT2 is inhibited, the reabsorption of sugar is inhibited, and thus the excess sugar is excreted, so that the effect of treating diabetes and the effect of improving insulin resistance are achieved by restoring hyperglycemia without increasing the load on pancreatic β cells.

Therefore, according to 1 aspect of the present invention, there is provided an agent for preventing or treating, for example, diabetes-related diseases and diabetic complications, which can improve a disease or condition by inhibiting the activity of SGLT 2.

Here, "diabetes" includes type 1 diabetes, type 2 diabetes, and other types of diabetes due to specific causes. In addition, "diabetes-related diseases" include, for example, obesity, hyperinsulinemia, sugar metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, hyperuricemia, gout, and the like.

In addition, "diabetic complications" include any of acute complications and chronic complications. Examples of the "acute complications" include hyperglycemia (ketoacidosis in the blood, etc.), infectious diseases (skin, soft tissue, biliary tract, respiratory system, urinary tract infection, etc.), and the like; examples of the "chronic complications" include capillary diseases (nephropathy, retinopathy), arteriosclerosis (atherosclerotic arteriosclerosis, myocardial infarction, cerebral infarction, arterial occlusion of lower limbs, etc.), neuropathy (sensory nerve, motor nerve, autonomic nerve, etc.), and gangrene of feet. The main diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

The compound of the present invention may be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension, etc., which have different mechanisms of action other than SGLT2 activity inhibitors. By combining the compound of the present invention with other agents, it is expected that a synergistic effect can be obtained when the compounds are used in combination, compared with the effect obtained when the above-mentioned diseases are treated with a single agent.

Examples of the "therapeutic agents for diabetes and therapeutic agents for diabetic complications" which can be used in combination include insulin sensitivity enhancers (PPAR γ agonists, PPAR α/γ agonists, PPAR δ agonists, PPAR α/γ/δ agonists and the like), glycosidase inhibitors, biguanides, insulin secretion promoters, insulin preparations, glucagon receptor antagonists, insulin receptor kinase promoters, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glyconeogenesis inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, glucokinase activators, D-inositol, glycogen synthase kinase 3 inhibitors, glucagon-like peptide-1, glucose-6-phosphatase inhibitors, glucose-producing inhibitors, fructose bisphosphatase inhibitors, glucose dehydrogenase inhibitors, glucose kinase activators, D-alpha-inositol, glycogen synthase kinase 3 inhibitors, glucose-like peptide-1, glucose-like-2-alpha-glucosidase inhibitors, glucose-producing inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, coumarins analogs, coumarins agonists, glucocorticoid receptor antagonists, 11 beta-hydroxysteroid dehydrogenase inhibitors, aldose reductase inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kb inhibitors, IKK beta inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acidic-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor (PDGF) analogs, Epidermal Growth Factor (EGF), nerve growth factor (gff), insulin receptor antagonists, and inhibitors of the like, Carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, ビモクロモル [ bimoclomol ], sulodexide, Y-128, TAR-428, etc.

The therapeutic agents for diabetes and the therapeutic agents for diabetic complications include the following agents.

Examples of the biguanide include metformin hydrochloride and phenformin.

Examples of the sulfonylurea type of the "insulin secretion-promoting agent" include glibenclamide (glibenclamide), glipizide, gliclazide, chlorpropamide, and the like; examples of the nonsulfonylurea include nateglinide, repaglinide, and mitiglinide.

"insulin preparations" include genetically recombinant human insulin and insulin from animals. The drug is classified into 3 types according to the action time, and examples thereof include a rapid-acting type (human insulin and human neutral insulin), an intermediate type (insulin-human protamine zinc insulin aqueous suspension, human neutral insulin-human protamine zinc insulin aqueous suspension, human insulin zinc aqueous suspension, insulin zinc aqueous suspension), and a long-acting type (human crystalline insulin zinc suspension).

Examples of the "glycosidase inhibitor" include acarbose, voglibose, and miglitol.

Examples of PPAR γ agonists in the "insulin sensitivity enhancers" include troglitazone, pioglitazone, rosiglitazone, and the like; examples of PPAR α/γ dual agonists include MK-767(KRP-297), Tesaglitazar, LM4156, LY510929, DRF-4823, TY-51501, etc.; examples of the PPAR δ agonist include GW-501516 and the like.

Examples of the "tripeptidyl peptidase II inhibitor" include UCL-139 and the like.

Examples of the "dipeptidyl peptidase IV inhibitor" include NVP-DPP728A, LAF-237, MK-0431, P32/98, TSL-225, and the like.

Examples of the "aldose reductase inhibitor" include vecgamate, tolrestat, epalrestat, fadesistat, sorbinil, ponalrestat, lisacostat, and zenalstat.

Examples of the "gamma-aminobutyric acid receptor antagonist" include topiramate and the like.

Examples of the "sodium channel antagonist" include mexiletine hydrochloride.

Examples of the "transcription factor NF-. kappa.B inhibitor" include dexlipotam.

Examples of the "lipid peroxidase inhibitor" include tirapartat mesylate and the like.

Examples of the "N-acetylated- α -linked-acidic-dipeptidase inhibitor" include GPI-5693.

Examples of the "carnitine derivative" include carnitine and レバセカルニン [ levacecarnitine ] hydrochloride [ レバセカルニン hydrochloride ].

Examples of the "hyperlipemia therapeutic agent and hypertension therapeutic agent" which can be used in combination include hydroxymethylglutaryl-CoA reductase inhibitor, fibrate compound and beta₃-adrenoceptor agonists, AMPK activators, acyl-coa: cholesterol acyltransferase inhibitors, probucol (probucol), thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor promoters, nicotinic acid derivatives, bile acid adsorbents, sodium-conjugated bile acid transport (transporter) inhibitors, cholesteryl ester transport protein inhibitors, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilating hypotensives, sympathetic nerve blocking agents, central hypotensives, alpha-agonists, calcium antagonists, vasodilating hypotensives, anti-hypertensive agents, anti-inflammatory agents, anti₂-adrenoceptorAgonists, antiplatelet agents, uric acid production inhibitors, uricosuric agents, urine alkalinizing agents, appetite suppressants, adiponectin receptor agonists, GPR40 agonists, GPR40 antagonists, and the like.

Examples of the hyperlipemia therapeutic agent and the hypertension therapeutic agent include the following agents.

Examples of the "hydroxymethylglutaryl-coenzyme a reductase inhibitor" include fluvastatin, lovastatin, pravastatin, cerivastatin, and pitavastatin.

Examples of the fibrate compound include bezafibrate, binifibrate, and binifibrate.

Examples of the "squalene synthetase inhibitor" include TAK-475 and α -phosphonosulfonate derivatives (see U.S. Pat. No. 5712396).

As "acyl-coa: examples of the cholesterol acyltransferase inhibitor include CI-1011, NTE-122, FCE-27677, RP-73163, MCC-147, and DPU-129.

Examples of the "low-density lipoprotein receptor agonist" include MD-700 and LY-295427.

Examples of the "microsomal triglyceride transfer protein inhibitor (MTP inhibitor)" include compounds described in, for example, U.S. Pat. No. 5739135, U.S. Pat. No. 5712279, and U.S. Pat. No. 5760246.

Examples of the "appetite suppressant" include adrenaline-noradrenaline agonists (e.g., mazindol and ephedrine), serotonin agonists (selective serotonin re-recording inhibitors, such as fluvoxamine), adrenaline-serotonin agonists (e.g., sibutramine), melatonin 4 receptor (MC4R) agonists, α -melanocyte stimulating hormone (α -MCH), leptin, cocaine-and amphetamine-regulated transcript (CART).

Examples of the "thyroid hormone receptor agonist" include iodomethylamine sodium and levothyroxine sodium.

Examples of the "cholesterol absorption inhibitor" include ezetimibe and the like.

Examples of the "lipase inhibitor" include orlistat and the like.

Examples of the "carnitine palmitoyltransferase inhibitor" include etomoxider.

Examples of the "nicotinic acid derivative" include nicotinic acid, nicotinamide, nicormor, nicorandil and the like.

Examples of the "bile acid adsorbent" include cholestyramine, cholestilan, and コレセベラム [ cholesevelam ].

Examples of the "angiotensin converting enzyme inhibitor" include captopril, enalapril maleate, alacepril, cilazapril, and the like.

Examples of the "angiotensin II receptor antagonist" include candesartan cilexetil, losartan potassium, eprosartan mesylate, and the like.

Examples of the "endothelin-converting enzyme inhibitor" include CGS-31447 and CGS-35066.

Examples of the "endothelin receptor antagonist" include L-749805, TBC-3214, and BMS-182874.

For example, in the treatment of diabetes and the like, it is considered preferable to use the compound of the present invention in combination with at least 1 agent selected from the group consisting of insulin sensitivity enhancers (PPAR γ agonists, PPAR α/γ agonists, PPAR δ agonists, PPAR α/γ/δ agonists and the like), glycosidase inhibitors, biguanides, insulin secretion promoters, insulin preparations and dipeptidyl peptidase IV inhibitors.

Furthermore, it is preferably contemplated that the compounds of the invention are mixed with a compound selected from the group consisting of hydroxymethylglutaryl-coenzyme a reductase inhibitors, fibrates, squalene synthetase inhibitors, acetyl-coenzyme a: at least 1 agent selected from the group consisting of cholesterol acyltransferase inhibitors, low density lipoprotein receptor agonists, microsomal triglyceride transfer protein inhibitors, and appetite suppressants.

The drug of the present invention can be administered systemically or locally orally or parenterally such as intrarectally, subcutaneously, intramuscularly, intravenously, or transdermally.

The compound of the present invention can be used as a pharmaceutical in any form of a solid composition, a liquid composition, and other compositions, and the most suitable form can be selected as needed. The pharmaceutical of the present invention can be prepared by formulating a pharmaceutically acceptable carrier into the compound of the present invention. Specifically, a conventional excipient, an extender, a binder, a disintegrating agent, a coating agent, a sugar coating agent, a pH adjuster, a dissolving agent, an aqueous or non-aqueous solvent, or the like may be added, and the mixture may be prepared into tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, injections, and the like by a conventional preparation technique. Examples of the excipient and the extender include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cacao butter, ethylene glycol and the like, and other commonly used excipients.

The compound of the present invention may be formulated with α, β, or γ -cyclodextrin, methylated cyclodextrin, or the like to form an inclusion compound.

The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, administration route and the like, and is preferably 0.1 to 1000mg/kg body weight/day, more preferably 0.1 to 200mg/kg body weight/day for an adult, and the compound of the present invention may be administered 1 time or several times per day.

The compound of the present invention can be synthesized, for example, by the following production method. In the following schemes, "Bn" represents a benzyl group.

The 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon- α -D-glucopyranose (IV) as a bond intermediate can be produced, for example, as follows.

Scheme 1

[ solution 3]

First, after protecting the primary hydroxyl group of D-hexenose (for example, with t-butyldimethylsilyl group), 2 secondary hydroxyl groups are protected with benzyl group, and then the protecting group of the primary hydroxyl group is removed (for example, in the case where the protecting group is t-butyldimethylsilyl group, with tetrabutylammonium fluoride), 3, 4-di-O-benzyl-D-hexenose (II) can be synthesized.

Compound (II) can then be converted in 5 steps into 3, 4, 6-tri-O-benzyl-5 a-carbon-D-hexenose (III) (chem. commun., p.925, 1998).

Can be converted from compound (III) in 2 steps into 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon- α -D-glucopyranose (IV) (liebig an. chem., page 267, 1995).

The compound (V) can be prepared by a method described in the literature (j. chem. soc. perkin trans.1, p 3287, 1991). Alternatively, as shown in the following scheme 2, compound (V) can also be prepared from compound (IV) using an appropriate oxidizing reagent (e.g., activated DMSO by the Swern method, etc., or PCC, PDC, Dess-Martin periodinane, etc.):

scheme 2

[ solution 4]

The compound (IV) can be converted into the compound (VII) as follows.

Scheme 3

[ solution 5]

Compound (IV) can be hydrolyzed, for example after a mitsunobu reaction with benzoic acid, to derive 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon- β -D-glucopyranose (VI).

Then, compound (VII) in which X is a halogen atom can be produced by reacting compound (VI) with an appropriate halogenating agent (for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine, N-chlorosuccinimide [ スクシニド succinimide ] -triphenylphosphine, N-bromosuccinimide-triphenylphosphine, iodine-triphenylphosphine, or the like).

Further, compound (VII) in which X is methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, or the like can be prepared by allowing compound (IV) to act on methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, or the like in an appropriate solvent under basic conditions.

For example, compounds of the following formula (la) are intermediates for compounds of formula (I):

[ solution 6]

(VIII)

(in the formula, R¹¹And as defined aboveRb has the same meaning, Ar²The same as the above), the synthesis can be carried out with reference to the following documents: international publication No. 01/68660, International publication No. 01/074834, International publication No. 01/074835, International publication No. 02/28872, International publication No. 02/44192, International publication No. 02/064606, International publication No. 03/011880, and International publication No. 04/014931.

[ solution 7]

(in the formula, R¹²Ar has the same meaning as Rb as defined above²The same as the above), the synthesis can be carried out with reference to the following documents: international publication No. 04/007517.

[ solution 8]

(in the formula, R¹³Ar has the same meaning as Rb as defined above²The same as the above), the synthesis can be carried out with reference to the following documents: international publication No. WO01/16147, International publication No. 02/36602, International publication No. 02/053573, International publication No. 02/068439, International publication No. 02/068440, International publication No. 02/088157, International publication No. 02/098893, International publication No. 03/020737, and International publication No. 03/090783.

[ solution 9]

(in the formula, X¹、X²、X³And X⁴Each represents a nitrogen atom, or C-R¹⁴，X¹、X²、X³And X⁴1 or 2 in (A) are nitrogen atoms, R¹⁴The same meaning as Rb defined above), synthesis can be carried out with reference to the following: international publication No. 03/000712.

[ solution 10]

(in the formula, R¹⁵Ar has the same meaning as Rb as defined above²The same as described above), can be prepared, for example, according to the following scheme 4:

scheme 4

[ solution 11]

(in the formula, R¹⁶M-alkyl [ M-alkyl ] having the same meaning as Rb as defined above]And M-aryl [ M-aryl ]]Respectively represent organometallic reagents such as n-butyllithium, phenyllithium, phenylmagnesium bromide, etc.; x is halogen such as chlorine, bromine, iodine and the like; ar (Ar)²The same as described above).

That is, the compound (XIV) can be reacted with an appropriate organometallic reagent (e.g., n-butyllithium, phenyllithium, phenylmagnesium bromide, etc.), and then reacted with Ar²-CHO reaction, thereby deriving compound (XV), and then, using an appropriate reduction reaction (catalytic hydrogenation using a palladium catalyst or the like, or the like).

The compounds of the invention can be prepared, for example, according to scheme 5 shown below:

scheme 5

[ solution 12]

(in the formula, R¹¹Ar has the same meaning as Rb as defined above²The same as described above).

That is, the compound (IV) and the compound (VIII) are condensed under a mitsunobu reaction condition using an azo reagent and a phosphine, and then deprotected under a catalytic hydrogenation condition using a palladium catalyst or the like, or deprotected using boron trifluoride-dimethylsulfide or the like. Here, as the azo reagent which can be used for synthesizing the compound of the present invention, diethyl azodicarboxylate and tetramethyl azodicarboxamide [ カルボキサミド ] can be mentioned]1, 6-dimethyl-1, 5, 7-hexahydro-1, 4, 6, 7-disazo [ テトラゾシン ]]And (e) 2, 5-diketones, and the phosphines include triphenylphosphine, tributylphosphine, 2- (dicyclohexylphosphino) biphenyl, and tri (tert-butyl) phosphine. In addition, a mitsunobu reaction using a phosphorane reagent may also be employed to synthesize the compound of the present invention. Examples of the phosphorane reagent that can be used herein include (cyanomethylene) tributylphosphorane, and (cyanomethylene) trimethylphosphine. Further, substituent R of Compound (XVII)¹¹Or Ar²(iii) a substituent (in the case of halogen, or hydroxy, converted to トリフレ - ト [ triflate ]]Etc.) or may be inIn the presence of a palladium catalyst, a tin reagent, boric acid, or the like is used for conversion.

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 6 shown below:

scheme 6

[ solution 13]

(in the formula, X⁵Halogen such as chlorine, bromine, iodine, etc., or leaving group such as methane sulfonate, trifluoromethane sulfonate, etc.; r¹¹Ar has the same meaning as Rb as defined above²The same as described above).

That is, the compound (XVI) can also be produced by condensing the compound (VII) with the compound (VIII) in an appropriate solvent under basic conditions. Examples of the base that can be used herein include sodium hydride, potassium carbonate, and potassium tert-butoxide.

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 7 shown below:

scheme 7

[ solution 14]

(in the formula, R¹¹The same as Rb as defined above; r' is C₁-C₆Alkyl radical, C₇-C₁₄Aralkyl or aryl; ar (Ar)²The same as described above).

That is, the reaction conditions of the mitsunobu reaction using the azo reagent and the phosphine may be employed,compound (XX) is prepared by condensing Compound (IV) with Compound (XVIII), converting alkoxycarbonyl to formyl according to a conventional method, and then reacting it with Ar²Compound (XVII) of the present invention can be prepared by reacting (A) with (B) M (M represents a halide of lithium, magnesium, or the like) to convert the compound into (XXI), and then removing the hydroxyl group and the benzyl group simultaneously by catalytic hydrogenation conditions using a palladium catalyst or the like, or reducing the hydroxyl group with triethylsilane or the like, and then removing the benzyl group with boron trifluoride-dimethylsulfide or the like.

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 8 shown below:

scheme 8

[ solution 15]

(in the formula, X¹¹Represents a halogen atom; r¹¹Ar has the same meaning as Rb as defined above²The same as described above).

That is, compound (IV) and compound (XXII) may be derivatized by a mitsunobu reaction to compound (XXIII), and then reacted with an organometallic reagent (e.g., lower alkyllithium such as n-butyllithium) to react with Ar²-CHO, whereby compound (XXI) is synthesized.

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 9 shown below:

scheme 9

[ solution 16]

(in the formula, X²¹And X²²Represents a halogen atom; each R' is independently selected from C₁-C₆An alkyl group; r¹¹Ar has the same meaning as Rb as defined above²The same as described above).

That is, compound (XXIV) may be derived by reacting compound (XXIII) with hexaalkylditin in the presence of a palladium catalyst, and then reacting compound (XXIII) with Ar²-CH₂X²²The reaction is carried out in the presence of a palladium catalyst, whereby compound (XVI) is synthesized. Examples of the hexaalkylditin which can be used herein include hexamethylditin and hexabutylditin, and examples of the palladium catalyst include tetrakis (triphenyl) phosphine palladium (0) and 1, 2-bis (diphenylphosphinoethane) dichloropalladium (II).

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 10 shown below:

scheme 10

[ solution 17]

(in the formula, R¹²Ar has the same meaning as Rb as defined above²The same as described above).

That is, compound (IV) and compound (IX) may be condensed to give compound (XXV) under the mitsunobu reaction conditions using an azo reagent and phosphines, and then ketone reduction and benzyl group removal may be performed simultaneously or ketone reduction by sodium borohydride or the like and benzyl group removal by a palladium catalyst may be performed in stages under the catalytic hydrogenation conditions using a palladium catalyst or the like, thereby producing compound (XXVI) of the present invention.

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 11 shown below:

scheme 11

[ solution 18]

That is, the compound (IV) and the compound (X) may be condensed to give the compound (XXVII) under the conditions of the mitsunobu reaction using an azo reagent and phosphines, and then the compound (XXVII) may be derivatized with Ar²M (M represents a halide of lithium, magnesium, or the like) is reacted to thereby convert into compound (XXI), and then, hydroxyl group and benzyl group are removed simultaneously or stepwise using catalytic hydrogenation conditions using a palladium catalyst or the like, thereby producing compound (XXVI) of the present invention.

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 12 shown below:

scheme 12

[ solution 19]

(in the formula, X⁵The same as defined above, R¹³Ar has the same meaning as Rb as defined above²The same as described above).

That is, the compound (XXX) of the present invention can also be prepared by reacting the compound (VII) with the compound (XI) in an appropriate solvent in the presence of a base to derive the compound (XXIX), and then removing the benzyl group using catalytic hydrogenation conditions using a palladium catalyst or the like.

Further, in the production process of scheme 10, compound (XXXI) (X) of the present invention can be synthesized by using compound (XII) in place of compound (IX)¹、X²、X³、X⁴And Ar²The same as described above).

[ solution 20]

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 13 shown below:

scheme 13

[ solution 21]

(wherein X is a halogen atom; R)¹⁷Ar has the same meaning as Rb as defined above²The same as described above).

That is, the compound (XXXV) of the present invention can be prepared by subjecting the compound (IV) to a mitsunobu reaction with phthalimide, then reacting hydrazine or methylamine to derive the compound (XXXII), then converting the compound (xxxvi) to the compound (XXXII) by a coupling reaction with the compound (XXXIII) in the presence of a palladium catalyst (for example, tris (dibenzylideneacetone) dipalladium (0), 1' -bis (diphenylphosphinoferrocene) dichloropalladium (II), etc.) or a copper reagent (for example, copper iodide (I), etc.), and then removing the benzyl group by catalytic hydrogenation conditions using a palladium catalyst, etc.

The compound (XXXII) can also be synthesized by subjecting the compound (IV) to a mitsunobu reaction with sodium azide or the like, and then reacting the resultant with triphenylphosphine or the like.

Further, compound (XXXIII) compound (XXXVI) can be prepared by reacting compound (XXXVI) with Ar according to the following scheme 14²-M is reacted to derive compound (XXXVII), and then treated with triethylsilane in the presence of boron trifluoride-diethyl ether complex or trifluoroacetic acid or the like to prepare:

scheme 14

[ solution 22]

(wherein X is as defined above and R is¹⁷Ar has the same meaning as Rb as defined above²The same as described above).

In addition, the compounds of the present invention can also be prepared according to, for example, scheme 15 shown below:

scheme 15

[ solution 23]

(in the formula, R¹⁸Ar has the same meaning as Rb as defined above²The same as described above).

That is, compound (XXXX-I) can be produced by reacting compound (XXXVIII) with an appropriate alkyllithium (e.g., n-butyllithium) and compound (V), and catalytically hydrogenating the resulting compound (XXXIX-I) with a palladium catalyst or the like. Similarly, the compound (XXXX-II) can be produced by subjecting the compound (XXXIX-II) to catalytic hydrogenation directly with a palladium catalyst or acetylating a hydroxyl group, followed by catalytic hydrogenation using a palladium catalyst or the like (adding an acid such as hydrochloric acid if necessary), thereby removing an acetoxy group and a benzyl group. Here, compound (XXXVIII) can be synthesized, for example, according to the method described in international publication No. 01/27128.

Compound (XXXX) can also be prepared according to the procedure shown in scheme 16 below:

scheme 16

[ solution 24]

(in the formula, X²³And X²⁴Is a halogen atom; r¹⁸Ar has the same meaning as Rb as defined above²The same as described above).

That is, compound (xxxx) can be synthesized by reacting compound (xxxxxi) with an appropriate alkyllithium (e.g., n-butyllithium or the like), then reacting it with compound (V) to derive compound (xxxxxii), converting the generated hydroxyl group into a thiocarbonyloxy group by, for example, methylthiocarbonylation or imidazolylthiocarbonylation, and then dehydroxylating it by reacting it with an appropriate radical reactant (e.g., a tin hydride reagent such as tributyltin hydride, a silane reagent such as diphenylsilane, diphosphorous acid and diethyl phosphite in combination with a tertiary amine) in the presence of an appropriate radical initiator (e.g., 2, 2' -azobisisobutyronitrile or benzoyl peroxide). Next, it is converted into a benzyl halide (XXXXIV) using an appropriate halogenation condition (for example, N-bromosuccinimide, bromine, hydrogen bromide, etc.), reacted with an aryl halide (including heteroaryl halide) in the presence of an appropriate palladium catalyst (for example, tetrakis (triphenyl) phosphine palladium (0), 1, 2-bis (diphenylphosphinoethane) dichloropalladium (II), etc.), and then debenzylated, thereby deriving the compound (XXXX).

Intermediate (XXXXIV) may also be prepared according to the procedure shown in scheme 17 below:

scheme 17

[ solution 25]

(in the formula, R¹⁸The same as Rb as defined above; p is a protecting group; x is a halogen atom; ar (Ar)²The same as described above. )

That is, compound (xxxxxvii) is derived by protecting the hydroxyl group of compound (xxxvi) with an appropriate protecting group (e.g., tert-butyldimethylsilyl group, tetrahydropyranyl group, etc.), reacting it with an appropriate alkyllithium (e.g., n-butyllithium, etc.), and reacting it with compound (V). The tertiary hydroxyl group is then converted to a thiocarbonyloxy group, for example, by methylthiothiocarbonylation or imidazolylthiocarbonylation, and reacted with an appropriate radical reactant (for example, tin hydride reagent such as tributyltin hydride or the like, silane reagent such as diphenylsilane or the like, or the condition of a combination of diphosphorous acid or diethyl phosphite with a tertiary amine) in the presence of an appropriate radical initiator (for example, 2, 2' -azobisisobutyronitrile or benzoyl peroxide), thereby converting to the compound (xxxviii). Then, after deprotection to obtain compound (XXXXIX), compound (xxxxxiv) can be synthesized by using appropriate halogenation conditions (for example, when X is a bromine atom, conditions using N-bromosuccinimide, bromine, carbon tetrabromide, or the like in the presence of triphenylphosphine).

Compound (L) can also be prepared according to the procedure shown in scheme 18 below:

scheme 18

[ solution 26]

(in the formula, R¹¹Ar has the same meaning as Rb as defined above²The same as described above. )

That is, in the production method of scheme 5, compound (L) of the present invention can be produced by using compound (LI) or compound (LII) in place of compound (IV). Compound (LI) can be synthesized by a method described in literature (j. org. chem., volume 63, page 5668, 1998); the compound (LII) can be synthesized by a method described in literature (Tetrahedron, volume 56, page 7109, year 2000).

Alternatively, the compounds of the invention can be prepared according to the method of scheme 19.

Scheme 19

[ solution 27]

(in the formula, R¹⁷The same as Rb as defined above; x is as defined above; tf is trifluoromethanesulfonyl; ar (Ar)²The same as described above. )

That is, compound (LV) can be obtained by treating (LIV) obtained by converting compound (V) トリフレ - ト with compound (LVII) obtained by treating compound (XXXIII) with a borate ester (trimethyl borate or the like) by using an appropriate alkyllithium (n-butyllithium or the like), in the presence of a palladium catalyst (tetrakis (triphenyl) phosphine palladium or the like). This is further treated with boron trichloride or the like in the presence of pentamethylbenzene or the like, whereby compound (LVI) can be produced.

The method for producing the compound of the present invention is not limited to the above-mentioned method. The compound of the present invention can also be synthesized by appropriately combining the steps included in schemes 1 to 19, for example.

The compound of the present invention has not only SGLT2 inhibitory activity but also excellent properties as a drug, such as metabolic stability, oral absorbability, drug efficacy duration, safety, and the like. Therefore, according to the present invention, there can be provided a pharmaceutical composition having a blood sugar-lowering effect for the prevention or treatment (particularly treatment) of diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), diabetic complications due to hyperglycemia, and obesity.

[ examples ]

The present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these.

In the following examples, the abbreviations have the following meanings:

NMR: nuclear magnetic resonance spectroscopy (TMS internal standard), MS: mass analysis value, HPLC: high performance liquid chromatography.

NMR, MS, and HPLC were measured using the following instruments:

NMR: JEOL JNM-EX-270(270MHz), Varian mercury 300(300MHz), or JEOL JNM-ECP400(400 MHz);

MS: LCQ manufactured by Thermo Finigan or micromassZQ manufactured by Waters;

HPLC: waters corporation 2690/2996 (Detector).

The following conditions were used for HPLC unless otherwise specified.

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Mobile phase: elution was performed according to a gradient that took 20 minutes to change from 0.1% TFA/MeCN (5%) + 0.1% TFA/H2O (95%) to 0.1% TFA/MeCN (100%), followed by 5 minutes of elution under the same conditions (0.1% TFA/MeCN (100%)).

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Detection conditions are as follows: a total amount curve chart of all bands of 230-400 nm.

Example 1

[2- (4-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of methyl 2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranosyl) benzoate

Triphenylphosphine (146mg, 0.557mmol) and 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (200mg, 0.371mmol) were added to a THF solution (400. mu.L) of methyl salicylate (72. mu.L, 0.557mmol), and then diethyl azodicarboxylate (DEAD, 88. mu.L, 0.557mmol) was added dropwise and stirred at room temperature for 10.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 3)) to give the title compound (123mg, 49%).

¹H-NMR(CDCl₃)δ：1.60-1.80(2H，m)、2.15-2.24(1H，m)、3.48-3.64(4H，m)、3.75-3.90(1H，m)、3.83(3H，s)、4.43(3H，s)、4.53(1H，d，J＝10.7Hz)、4.51-4.98(6H，m)、6.95-7.02(1H，m)、7.10-7.50(22H，m)、7.78(1H，dd，J＝1.65，7.75Hz)

MS(ESI⁺)：695[M+Na]⁺

2) Synthesis of 2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranosyl) benzyl alcohol

Lithium aluminum hydride (10.4mg, 0.274mmol) was added little by little to a THF solution (360. mu.L) of methyl 2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranosyl) benzoate (123mg, 0.183mmol), and the mixture was stirred in an oil bath (55 ℃ C.) for 3 hours. After the reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 3)) to obtain the title compound (95mg, 81%).

¹H-NMR(CDCl₃)δ：1.60-1.80(2H，m)、2.16-2.22(1H，m)、3.46-3.74(5H，m)、4.43(3H，s)、4.54(1H，d，J＝10.7Hz)、4.66(2H，br s)、4.81-4.96(5H，m)、6.94-7.31(24H，m)

MS(ESI⁺)：667[M+Na]⁺

3) Synthesis of 2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranosyl) benzaldehyde

To a solution of 2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranosyl) benzyl alcohol (95mg, 0.147mmol) in methylene chloride (1.5mL) was added Dess-Martin reagent (94mg, 0.221mmol), and the mixture was stirred at room temperature for 45 minutes. Insoluble matter was removed by filtration from the reaction mixture, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 3)) to obtain the title compound (77mg, 81%).

¹H-NMR(CDCl₃)δ：1.60-1.80(2H，m)、2.17-2.23(1H，m)、3.48-3.78(5H，m)、4.44(3H，s)、4.54(1H，d，J＝10.7Hz)、 4.73-4.97(5H，m)、7.00-7.32(22H，m)、7.50(1H，dd，J＝1.48，7.83Hz)、7.83(1H，dd，J＝1.49，7.58Hz)、10.4(1H，s)

4) Synthesis of [2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranosyl) phenyl ] - (4-methoxyphenyl) methanol

To a solution of 2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranosyl) benzaldehyde (77mg, 0.119mmol) in diethyl ether (120. mu.L) was added a 0.5M THF solution of 4-methoxyphenylmagnesium bromide (480. mu.L, 0.238mmol), and the mixture was stirred at room temperature for 13 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), and the solvent was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 3)) to obtain the title compound (66mg, 74%).

¹H-NMR(CDCl₃)δ：1.60-1.80(2H，m)、1.95-2.09(1H，m)、2.66(1H，d，J＝4.78Hz)、3.38-3.79(5H，m)、3.65(1.2H，s)、3.69(1.8H，s)、4.33-4.93(9H，m)、5.96-6.16(1H，m)、6.73-7.42(28H，m)

MS(ESI⁺)：773[M+Na]⁺

5) Synthesis of [2- (4-methoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

To [2- (2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranosyl) ] - (4-methoxyphenyl) methanol (66mg, 0.0879mmol) was added a 20% palladium hydroxide in carbon (10mg) in methanol hydrochloride (2mL), and the mixture was stirred for 3 hours under a hydrogen atmosphere. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 10)) to obtain the title compound (20mg, 61%).

¹H-NMR(CD₃OD)δ：0.89-1.03(1H，m)、1.40-1.60(1H，m)、2.02-2.10(1H，m)、3.18-3.34(2H，m)、3.45-3.51(2H，m)、3.67-3.71(1H，m)、3.73(3H，s)、3.82-3.99(2H，m)、4.13-4.22(1H，m)、6.78(2H，d，J＝8.57Hz)、6.80-6.86(1H，m)、6.99-7.16(5H，m)

MS(ESI⁺)：397[M+Na]⁺

HPLC retention time: 10.6 minutes

Example 2

[1S，2R，3R，4R，6S]-4-hydroxymethyl-6- [3- (4-methoxybenzyl) phenyl]Cyclohexane-1, 2, 3-triol

1) Synthesis of [2R, 3S, 4R, 5R ] -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexanol

To a solution of 3- (4-methoxybenzyl) -1-bromobenzene (155mg, 0.559mmol) in THF (0.80mL) at-78 deg.C was added dropwise a 2.44M hexane solution of n-butyllithium (0.23mL, 0.559mmol) and the mixture was stirred for 25 minutes. Subsequently, a solution of 2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexanone (200mg, 0.373mmol) in THF (0.70mL) was added dropwise thereto, and the mixture was stirred for 75 minutes. Saturated aqueous ammonium chloride was added thereto, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate-n-hexane (2: 5)) to obtain the title compound (80mg, 27%) as a mixture of 1R-and 1S-forms.

¹H-NMR(CDCl₃)δ：1.82-1.92(1H，m)、2.39-2.44(1H，m)、2.56-2.64(1H，m)、3.34-3.39(1H，m)、3.55-3.80(2H，m)、3.66(3H，s)、3.78(2H，s)、3.87-3.94(2H，m)、4.42-5.04(8H，m)、6.61-6.84(4H，m)、7.06-7.40(23H，m)、7.55-7.66(1H，m)

2) Synthesis of [2R, 3S, 4R, 5R ] -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexyl acetate

Acetic anhydride (0.003mL) was added to a solution of [2R, 3S, 4R, 5R ] -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexanol (20mg), triethylamine (0.008mL), and 4-dimethylaminopyridine (0.7mg) in methylene chloride (0.10mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Subsequently, acetyl chloride (0.003mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated, and the obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (2: 5)) to obtain the title compound (4.2 mg).

¹H-NMR(CDCl₃)δ：1.85(3H，s)、2.03-2.17(2H，s)、3.20-3.49(3H，m)、3.60-3.72(2H，m)、3.67(3H，s)、3.87(2H，s)、4.07(1H，d，J＝9.9Hz)、4.39-4.95(8H，m)、6.72(2H，d，J＝8.6Hz)、6.99-7.40(24H，m)、7.54(1H，d，J＝7.8Hz)、7.65(1H，s)

MS(ESI⁺)：794[M+H₂O]⁺

3) Synthesis of [1S, 2R, 3R, 4R, 6S ] -4-hydroxymethyl-6- [3- (4-methoxybenzyl) phenyl ] cyclohexane-1, 2, 3-triol

To a solution of [2R, 3S, 4R, 5R ] -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexyl acetate (4.2mg) in methanol (0.2mL) -THF (0.2mL) was added 20% palladium hydroxide-carbon (3mg), and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by preparative TLC (developing solution ═ dichloromethane: methanol (9: 1)) to give the title compound (1.7mg) as a single diastereomer.

¹H-NMR(DMSO-d₆)δ：1.24(1H，dd，J＝12.9Hz，12.6Hz)、1.48(1H，m)、1.65(1H，dt，J＝13.8Hz，3.3Hz)、2.43(1H，dt，J＝10.4Hz，4.2Hz)、3.05-3.17(2H，m)、3.26-3.40(2H，m)、3.60(1H，m)、3.71(3H，s)、3.83(2H，s)、4.15(1H，d，J＝4.8Hz)、4.21(1H，t，J＝5.1Hz)、4.45(1H，br)、4.60(1H，br)、6.84(2H，m)、6.93-7.08(3H，m)、7.10-7.20(3H，m)

MS(ESI⁺)：376[M+H₂O]⁺

Example 3

[2- (4-trifluoromethoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-trifluoromethoxyphenyl) methanol

To a solution of 1-benzyloxy-2-bromobenzene (3.3g, 12.64mmol) in THF (126mL) was added dropwise a solution of n-butyllithium in hexane (1.59M, 8.7mL) under a nitrogen stream at-78 deg.C, and the mixture was stirred at the same temperature for 15 minutes. To this solution was added dropwise a THF solution (42mL) of 4-trifluoromethoxybenzaldehyde (2.0g, 10.52mmol) at-78 ℃. After stirring at the same temperature for 40 minutes and further at 0 ℃ for 45 minutes, a saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (3.03g, 77%) as a colorless oil.

¹H-NMR(CDCl₃)δ：2.98(1H，d，J＝5.8Hz)、5.01(2H，s)、6.02(1H，d，J＝5.6Hz)、6.84-7.00(2H，m)、7.03-7.37(11H，m)

2) Synthesis of 2- (4-trifluoromethoxybenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (4-trifluoromethoxyphenyl) methanol (1.5g, 4.01mmol) in methanol (27mL) was added 20% palladium hydroxide catalyst (150mg), followed by 36% HCl (0.33 mL). After stirring for 16 hours under a hydrogen atmosphere, it was cooled to 0 ℃ and potassium carbonate (0.54g) was added, and after stirring for 30 minutes, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (1.05g, 97%) as a white solid.

¹H-NMR(CDCl₃)δ：3.98(2H，s)、4.83(1H，s)、6.77(1H，d，J＝7.7Hz)、6.89(1H，t，J＝7.3Hz)、6.99-7.13(4H，m)、7.23(2H，d，J＝8.1Hz)

3) Synthesis of [2- (4-trifluoromethoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (400mg, 0.74mmol) and tributylphosphine (0.28mL, 1.11mmol) were added to a toluene solution (2.5mL) of 2- (4-trifluoromethoxybenzyl) phenol (298mg, 1.11mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 191mg, 1.11mmol) at the same temperature. The reaction mixture was stirred overnight while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)), followed by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 5)). The obtained crude product was dissolved in tetrahydrofuran (1.4mL) and methanol (2.8mL), and 20% palladium hydroxide catalyst (20mg) was added thereto, followed by stirring for 1 hour and 45 minutes under a hydrogen atmosphere, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (67mg, 21%).

¹H-NMR(CD₃OD)δ：0.85-0.99(1H，m)、1.44-1.61(1H，m)、2.00-2.11(1H，m)、3.12-3.33(2H，m)、3.38-3.48(2H，m)、3.64-3.73(1H，m)、3.93(1H，d，J＝14.8Hz)、4.07(1H，d，J＝14.8Hz)、4.12-4.23(1H，m)、6.86(1H，t，J＝7.3Hz)、6.96-7.17(5H，m)、7.29(2H，d，J＝8.6Hz)

MS(ESI⁺)：428[M]⁺

HPLC retention time: 12.7 minutes

Example 4

[2- (4-Cyclopentylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-bromophenyl) methanol

A solution of n-butyllithium in hexane (1.59M, 11.57mL) was added dropwise to a THF solution (168mL) of 1-benzyloxy-2-bromobenzene (4.4g, 16.72mmol) at-78 deg.C under a nitrogen stream, and the mixture was stirred at the same temperature for 15 minutes. To this solution was added dropwise a solution of 4-bromobenzaldehyde (2.47g, 13.34mmol) in THF (50mL) at-78 deg.C. After stirring at the same temperature for 30 minutes and further at 0 ℃ for 30 minutes, a saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (4.08g, 83%) as a colorless oil.

¹H-NMR(CDCl₃)δ：2.96(1H，d，J＝6.1Hz)、5.01(2H，s)、5.97(1H，d，J＝5.9Hz)、6.86-6.99(2H，m)、7.09-7.39(11H，m)

2) Synthesis of 1-benzyloxy-2- (4-bromobenzyl) benzene

Triethylsilane (1.84mL, 11.55mmol) and boron trifluoride etherate (1.33mL, 10.5mmol) were added to a solution of (2-benzyloxyphenyl) - (4-bromophenyl) methanol (3.88g, 10.5mmol) in acetonitrile (19.5mL) at-40 ℃ in a nitrogen stream, and stirred at the same temperature for 0.5 hour. Saturated aqueous potassium carbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (2.86g, 77%).

¹H-NMR(CDCl₃)δ：3.95(2H，s)、5.03(2H，s)、6.81-6.92(2H，m)、6.96-7.36(11H，m)

3) Synthesis of 1- [4- (2-benzyloxybenzyl) phenyl ] cyclopentanol

To a THF solution (16.5mL) of 1-benzyloxy-2- (4-bromobenzyl) benzene (1.5g, 4.25mmol) was added dropwise a hexane solution of n-butyllithium (1.59M, 2.94mL) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of cyclopentanone (357mg, 4.25mmol) in THF (4mL) at-78 ℃. After stirring at the same temperature for 50 minutes and further at 0 ℃ for 1 hour, a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (1.14g, 75%) as a colorless oil.

¹H-NMR(CDCl₃)δ：1.47-2.02(8H，m)、4.00(2H，s)、5.03(2H，s)、6.79-6.89(2H，m)、7.02-7.36(11H，m)

4) Synthesis of 2- (4-cyclopentylbenzyl) phenol

To a solution of 1- [4- (2-benzyloxybenzyl) phenyl ] cyclopentanol (1.14g, 3.19mmol) in methanol (21mL) was added 20% palladium hydroxide catalyst (114mg), followed by 36% HCl (0.255 mL). After stirring overnight under hydrogen atmosphere, it was cooled to 0 ℃ and potassium carbonate (425mg) was added, and after stirring for 20 minutes, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 20)) to obtain the title compound (744mg, 92%) as a white solid.

¹H-NMR(CDCl₃)δ：1.44-1.84(6H，m)、1.93-2.09(2H，m)、2.84-3.00(1H，m)、3.95(2H，s)、4.76(1H，s)、6.76 (1H，d，J＝8.1Hz)、6.87(1H，t，J＝7.3Hz)、7.02-7.20(6H，m)

5) Synthesis of [2- (4-cyclopentylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3.1mL) of 2- (4-cyclopentylbenzyl) phenol (351mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred overnight while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ n-hexane: dichloromethane: acetone (12: 3: 1)) to obtain a crude product (555 mg). The obtained crude product (100mg) was dissolved in tetrahydrofuran (0.9mL) and methanol (1.8mL), and a 20% palladium hydroxide catalyst (12.6mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere for 7 hours, followed by filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (40mg, 58%).

¹H-NMR(CD₃OD)δ：0.79-0.96(1H，m)、1.44-1.86(7H，m)、1.93-2.07(3H，m)、2.84-2.99(1H，m)、3.12-3.31(2H，m)、3.37-3.48(2H，m)、3.62-3.71(1H，m)、3.86(1H，d，J＝14.8Hz)、3.98(1H，d，J＝14.8Hz)、4.08-4.20(1H，m)、6.83(1H，t，J＝7.3Hz)、6.93-7.14(7H，m)

MS(ESI⁺)：413[M+H]⁺

HPLC retention time: 14.5 minutes

Example 5

[2- (4-chlorobenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-chlorophenyl) methanol

A solution of n-butyllithium in hexane (2.44M, 10.3mL) was added dropwise to a THF solution (228mL) of 1-benzyloxy-2-bromobenzene (6.0g, 22.8mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 4-chlorobenzaldehyde (2.67g, 19.0mmol) in THF (76mL) at-78 ℃. After stirring at the same temperature for 2 hours, further stirring at 0 ℃ for 1 hour, then adding water, and extracting with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (4.76g, 77%).

¹H-NMR(CDCl₃)δ：2.94(1H，s)、5.01(2H，s)、5.99(1H，s)、6.92-7.00(22H，m)、7.17-7.41(11H，m)

2) Synthesis of 1-benzyloxy-2- (4-chlorobenzyl) benzene

To a solution of (2-benzyloxyphenyl) - (4-chlorophenyl) methanol (4.76g, 14.6mmol) in acetonitrile (150mL) at-40 ℃ in a nitrogen stream were added triethylsilane (2.8mL, 17.6mmol) and boron trifluoride diethyl etherate (1.84mL, 14.6mmol), and the mixture was stirred at the same temperature for 2 hours. After stirring at 0 ℃ for 1 hour, water was added and extraction was performed with methylene chloride. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (3.83g, 85%).

¹H-NMR(CDCl₃)δ：3.97(2H，s)、5.03(2H，s)、6.87-6.92(2H，m)、7.08-7.37(11H，m)

3) Synthesis of 2- (4-chlorobenzyl) phenol

To a solution of 1-benzyloxy-2- (4-chlorobenzyl) benzene (50.0mg, 0.16mmol) in methylene chloride (2.0mL) was added dimethyl sulfide (105.1. mu.L, 2.43mmol) and boron trifluoride diethyl etherate (51.3. mu.L, 0.4mmol) under a nitrogen stream under ice cooling. The reaction mixture was stirred while slowly warmed to room temperature for 19 hours, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (33.4mg, 94%).

¹H-NMR(CDCl₃)δ：3.95(2H，s)、4.60(1H，s)、6.75-6.78(1H，m)、6.86-6.92(1H，m)、7.07-7.27(6H，m)

4) Synthesis of [2- (4-chlorobenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 2- (4-chlorobenzyl) phenol (304.5mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in methylene chloride (8mL), and dimethyl sulfide (2.17mL, 50.2mmol) and boron trifluoride diethyl etherate (1.08mL, 8.51mmol) were added under ice cooling. The reaction mixture was stirred for 25 hours while slowly being warmed to room temperature, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (122.6mg, 35%).

¹H-NMR(CD₃OD)δ：0.95(1H，dd，J＝13.2，11.1Hz)、1.53(1H，m)、2.00-2.09(1H，m)、3.20(1H，d，J＝8.7Hz)、3.25(1H，d，J＝5.1Hz)、3.43-3.51(2H，m)、3.68-3.71(1H，dd，J＝3.9，3.9Hz)、3.91(1H，d，J＝14.7Hz)、3.99(1H，d，J＝15Hz)、4.15-4.23(1H，m)、6.85(1H，t，J＝7.5Hz)、7.03(1H，d，J＝9.0Hz)、7.08-7.23(6H，m)

MS(ESI⁺)：379[M+H]⁺

HPLC retention time: 11.7 minutes

Example 6

(2-benzylphenyl) -5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2-benzylphenol

To a solution of 2- (4-chlorobenzyl) phenol (618.5mg, 2.83mmol) in methanol (20mL) was added 20% palladium hydroxide catalyst (240 mg). After stirring for 3 days under hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (348.4mg, 67%).

¹H-NMR(CDCl₃)δ：3.99(2H，s)、4.65(1H，s)、6.79(1H，d，J＝8.1Hz)、6.89(1H，t，J＝7.5Hz)、7.09-7.31(6H，m)

2) Synthesis of (2-benzylphenyl) -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon- α -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) are added to a toluene solution (2mL) of 2-benzylphenol (256.5mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 21 hours while slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (14mL) of methanol-THF (1: 1), and 20% palladium hydroxide catalyst (118.8mg) was added thereto, followed by stirring under a hydrogen atmosphere for 15 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (84mg, 26%).

¹H-NMR(CD₃OD)δ：0.95(1H，dd，J＝12.0，11.7Hz)、1.49-1.59(1H，m)、2.03-2.09(1H，m)、3.20(1H，d，J＝9.0Hz)、3.25(1H，d，J＝5.7Hz)、3.34(4H，s)、3.44-3.50(2H，m)、3.68(1H，dd，J＝3.9，4.2Hz)、3.94(1H，d，J＝15Hz)、4.0(1H，d，J＝15Hz)、4.13-4.22(1H，m)、6.84(1H，t，J＝6.3Hz)、7.03(1H，d，J＝6.3Hz)、7.06-7.24(7H，m)

MS(ESI⁺)：345[M+H]⁺

HPLC retention time: 10.6 minutes

Example 7

[2- (4-Isopropylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-isopropylphenyl) methanol

A solution of n-butyllithium in hexane (2.44M, 5.14mL) was added dropwise to a THF solution (114mL) of 1-benzyloxy-2-bromobenzene (3.0g, 11.4mmol) at-78 deg.C under a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a THF solution (38mL) of 4-isopropylbenzaldehyde (1.41g, 9.49mmol) at-78 ℃. After stirring at the same temperature for 1 hour, and further stirring at 0 ℃ for 1 hour, water was added and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.63g, 84%).

¹H-NMR(CDCl₃)δ：1.26(6H，d，J＝7.8Hz)、2.84-2.94(1H，m)、5.02(2H，s)、6.02(1H，s)、6.90-7.00(2H，m)、7.15-7.34(11H，m)

2) Synthesis of 2- (4-isopropylbenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (4-isopropylphenyl) methanol (2.63g, 7.92mmol) in methanol (50mL) was added 20% palladium hydroxide catalyst (263mg), followed by 2N-HCl (0.4 mL). After stirring for 15 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.31g, 73%).

¹H-NMR(CDCl₃)δ：1.24(6H，d，J＝7.8Hz)、2.82-2.92(1H，m)、3.96(2H，s)、4.67(1H，s)、6.79(1H，d，J＝9.0Hz)、6.88(1H，t，J＝8.4Hz)、7.10-7.15(6H，m)

3) Synthesis of [2- (4-isopropylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 2- (4-isopropylbenzyl) phenol (315.1mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (14mL) of methanol-THF (1: 1), and a 20% palladium hydroxide catalyst (127.8mg) was added thereto, followed by stirring under a hydrogen atmosphere for 17 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (97.1mg, 27%).

¹H-NMR(CD₃OD)δ：0.94(1H，dd，J＝12.9，12.0Hz)、1.22(6H，d，J＝6.9Hz)、1.48-1.58(1H，m)、2.02-2.09(1H，dt，J＝3.9，4.2Hz)、2.78-2.87(1H，m)、3.12-3.24(2H，m)、3.43-3.49(2H，m)、3.68(1H，dd，J＝6.6，4.2Hz)、3.89(1H，d，J＝14.4Hz)、4.01(1H，d，J＝14.7Hz)、4.13-4.21(1H，m)、6.84(1H，t，J＝6.3Hz)、7.02(1H，d，J＝6.3Hz)、7.06-7.15(6H，m)

MS(ESI⁺)：387[M+H]⁺

HPLC retention time: 13.1 minutes

Example 8

[2- (4-Cyclopropylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-cyclopropylphenyl) methanol

A solution of n-butyllithium in hexane (2.6M, 3.5mL) was added dropwise to a THF solution (83mL) of 1-benzyloxy-2-bromobenzene (2.2g, 8.3mmol) at-78 deg.C in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a THF solution (28mL) of 4-cyclopropylbenzaldehyde (1.1g, 6.9mmol) at-78 ℃. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (1.7g, 75%).

¹H-NMR(CDCl₃)δ：0.65-0.69(2H，m)、0.92-0.97(2H，m)、1.86-1.90(1H，m)、2.88(1H，d，J＝6Hz)、5.03(2H，s)、6.03(1H，d，J＝6Hz)、7.17-7.26(5H，m)、7.32-7.35(4H，m)

MS(ESI⁺)：315[M+Na]⁺

2) Synthesis of 1-benzyloxy-2- (4-cyclopropylbenzyl) benzene

Triethylsilane (0.73mL, 4.6mmol) and boron trifluoride diethyl etherate (0.5mL, 4.0mmol) were added to a solution of (2-benzyloxyphenyl) - (4-cyclopropylphenyl) methanol (1.3g, 4.0mmol) in acetonitrile (7mL) at-40 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 1.5 hours. After stirring at 0 ℃ for 30 minutes, water was added and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 7)) to obtain the title compound (1.2g, 95%).

¹H-NMR(CDCl₃)δ：0.63-0.67(2H，m)、0.89-0.94(2H，m)、1.84-1.87(1H，m)、3.98(2H，s)、5.06(2H，s)、6.87-6.97(4H，m)、7.08-7.26(4H，m)、7.31-7.37(5H，m)

MS(ESI⁺)：332[M+H₂O]⁺

3) Synthesis of 2- (4-cyclopropylbenzyl) phenol

To a solution of 1-benzyloxy-2- (4-cyclopropylbenzyl) benzene (1.1g, 3.5mmol) in methylene chloride (24mL) was added dimethyl sulfide (2.2mL, 51.7mmol) and boron trifluoride diethyl etherate (1.1mL, 8.8mmol) under a nitrogen stream under ice-cooling. The reaction mixture was stirred for 23 hours while slowly being warmed to room temperature, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (620.7mg, 79%).

¹H-NMR(CDCl₃)δ：0.65-0.67(2H，m)、0.90-0.94(2H，m)、1.85-1.86(1H，m)、3.95(2H，s)、4.90(1H，s)、6.79(1H，d，J＝8.1Hz)、6.88(1H，t，J＝7.7Hz)、7.11(2H，d，J＝8.1Hz)、7.20(4H，d，J＝7.7Hz)

MS(ESI⁺)：247[M+Na]⁺

4) Synthesis of [2- (4-cyclopropylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (557mg, 1.03mmol) and tributylphosphine (0.37mL, 1.55mmol) were added to a toluene solution (3.5mL) of 2- (4-cyclopropylbenzyl) phenol (348mg, 1.55mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 267mg, 1.55mmol) at the same temperature. The reaction mixture was stirred for 15 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in methylene chloride (3.5mL), and dimethyl sulfide (1.3mL, 30.3mmol) and boron trifluoride diethyl etherate (0.65mL, 5.1mmol) were added under ice cooling. The reaction mixture was stirred for 14 hours while slowly being warmed to room temperature, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (9: 1)), and recrystallized from acetone to obtain the title compound (97.8mg, 25%).

¹H-NMR(CD₃OD)δ：0.57-0.61(2H，m)、0.81-0.95(3H，m)、1.50(1H，s)、1.79-1.85(1H，m)、1.99-2.03(1H，m)、3.15-3.33(2H，m)、3.42-3.48(2H，m)、3.66-3.72(1H，m)、3.81-3.99(2H，q，J＝14.7Hz)、4.41-4.85(1H，m)、6.80-7.15(8H，m)

MS(ESI⁺)：407[M+Na]⁺

HPLC retention time: 12.3 points

Example 9

2- (4-n-propylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (4-n-propylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

1-benzyloxy-2- (4-cyclopropylbenzyl) benzene (640.8mg, 2.0mmol) synthesized in example 8 was dissolved in 2, 2-dimethylpropanol (12mL), and 20% palladium hydroxide catalyst (64mg) was added thereto, followed by stirring under a hydrogen atmosphere for 2 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)). To a toluene solution (3.5mL) of the obtained crude product (348mg) was added 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (557mg, 1.03mmol) and tributylphosphine (0.39mL, 1.55mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 267mg, 1.55mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)). The obtained crude product was dissolved in 2, 2-dimethylpropanol (15mL), and 20% palladium hydroxide catalyst (159mg) was added thereto, followed by stirring under a hydrogen atmosphere for 17 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (9: 1)) to obtain the title compound (164.4 mg).

¹H-NMR(CD₃OD)δ：0.88-0.94(4H，m)、1.48-1.63(3H，m)、2.05-2.09(1H，m)、2.52(2H，t，J＝7.7Hz)、3.13-3.30(2H，m)、3.46(2H，m)、3.70(1H，m)、3.87(1H，d，J＝15Hz)、3.98(1H，d，J＝15Hz)、4.60-4.88(1H，m)、6.84(1H，t，J＝7.3Hz)、7.00-7.16(7H，m)

MS(ESI⁺)：387[M+H]⁺

HPLC retention time: 13.3 minutes

Example 10

[2- (4-trifluoromethylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-trifluoromethylphenyl) methanol

A solution of n-butyllithium in hexane (2.44M, 4.0mL) was added dropwise to a THF solution (100mL) of 1-benzyloxy-2-bromobenzene (2.6g, 9.9mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise 4-trifluoromethylbenzaldehyde (1.6g, 9.0mmol) at-78 ℃. After stirring at the same temperature for 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.6g, 82%).

¹H-NMR(CDCl₃)δ：3.01(1H，d，J＝6.3Hz)、5.02(2H，dd，J＝11.4，4.8Hz)、6.05(1H，d，J＝6.3Hz)、6.94-7.02(2H，m)、6.96-7.16(2H，m)、7.24-7.33(5H，m)、7.44(2H，d，J＝7.1Hz)、7.53(2H，d，J＝8.7Hz)

MS(ESI⁺)：359[M+H]⁺

2) Synthesis of 2- (4-trifluoromethylbenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (4-trifluoromethylphenyl) methanol (2.46g, 6.85mmol) in methanol (68.5mL) was added 20% palladium hydroxide catalyst (246mg), followed by 36% HCl (0.59 mL). After stirring for 3.5 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 8)) to obtain the title compound (1.49g, 86%).

¹H-NMR(CDCl₃)δ：4.03(2H，s)、4.72(1H，s)、6.77(1H，d，J＝6.0Hz)、6.89(1H，t，J＝4.8Hz)、7.08-7.15(2H，m)、7.33(2H，d，J＝6.0Hz)、7.52(2H，d，J＝6.0Hz)

MS(ESI⁺)：275[M+Na]⁺

3) Synthesis of [2- (4-trifluoromethylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (4-trifluoromethylbenzyl) phenol (351mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (5mL) of methanol-THF (1: 1), and a 20% palladium hydroxide catalyst (20mg) was added thereto, followed by stirring under a hydrogen atmosphere for 2 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (74mg, 19%).

¹H-NMR(CD₃OD)δ：0.89(1H，dd，J＝11.7，12.9Hz)、1.48-1.61(1H，m)、2.05(1H，dt，J＝13.2，4.2Hz)、3.15-3.34(2H，m)、3.42-3.49(2H，m)、3.69(1H，dd，J＝3.9，10.5Hz)、3.96-4.15(2H，dd，J＝14.7，28.2Hz)、4.17-4.24(1H，m)、6.87(1H，dt，J＝1.2，7.5Hz)、7.02-7.20(3H，m)、7.38(2H，d，J＝8.1Hz)、7.51(2H，d，J＝8.4Hz)

MS(ESI⁺)：435[M+Na]⁺

HPLC retention time: 12.3 minutes

Example 11

[2- (4-Methylsulfanylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-methylsulfanylphenyl) methanol

A solution of n-butyllithium in hexane (1.59M, 6.92mL) was added dropwise to a THF solution (38mL) of 1-benzyloxy-2-bromobenzene (2.89g, 11.0mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a THF solution (12mL) of 4-methylsulfanylbenzaldehyde (1.67g, 11.0mmol) at-78 ℃. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.14g, 58%).

¹H-NMR(CDCl₃)δ：2.47(3H，s)、2.92(1H，d，J＝6.0Hz)、5.03(2H，s)、6.02(1H，d，J＝6.0Hz)、6.92-7.00(2H，m)、7.21-7.34(11H，m)

2) Synthesis of 1-benzyloxy-2- (4-methylsulfanylbenzyl) benzene

Triethylsilane (1.23mL, 7.72mmol) and boron trifluoride etherate (0.88mL, 5.48mmol) were added to a solution of (2-benzyloxyphenyl) - (4-methylsulfanylphenyl) methanol (2.13g, 6.3mmol) in acetonitrile (15mL) at-40 ℃ in a nitrogen stream, and stirred at the same temperature for 1.5 hours. After stirring at 0 ℃ for 30 minutes, water was added and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (1.9g, 95%).

¹H-NMR(CDCl₃)δ：2.46(3H，s)、3.97(2H，s)、5.05(2H，s)、6.85-6.95(2H，m)、7.10-7.35(11H，m)

3) Synthesis of 2- (4-methylsulfanylbenzyl) phenol

To a solution of 1-benzyloxy-2- (4-methylsulfanylbenzyl) benzene (1.9g, 5.9mmol) in methylene chloride (15mL) was added dimethyl sulfide (7.25mL, 138mmol) and boron trifluoride diethyl etherate (2.1mL, 13mmol) under a nitrogen stream under ice-cooling. The reaction mixture was stirred for 48 hours while slowly being warmed to room temperature, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (1.19g, 91%).

¹H-NMR(CDCl₃)δ：2.46(3H，s)、3.95(2H，s)、4.65-4.75(1H，br s)、6.78(1H，d，J＝7.6Hz)、6.89(1H，t，J＝7.6Hz)、7.09-7.21(6H，m)

4) Synthesis of [2- (4-methylsulfanylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 2- (4-methylsulfanylbenzyl) phenol (320mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in methylene chloride (10mL), and dimethyl sulfide (3.28mL, 63mmol) and boron trifluoride diethyl etherate (0.94mL, 5.9mmol) were added under ice cooling. The reaction mixture was stirred for 20 hours while slowly being warmed to room temperature, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (102mg, 28%).

¹H-NMR(CD₃OD)δ：0.80-0.95(1H，m)、1.45-1.60(1H，m)、2.00-2.10(1H，m)、2.42(3H，s)、3.12-3.33(2H，m)、3.40-3.50(2H，m)、3.63-3.70(1H，m)、3.86(1H，d，J＝15Hz)、4.00(1H，d，J＝15Hz)、4.15-4.23(1H，m)、6.84(1H，t，J＝7.0Hz)、7.00-7.18(7H，m)

MS(ESI⁺)：391[M+H]⁺

HPLC retention time: 11.6 minutes

Example 12

[ 3-fluoro-2- (4-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxy-6-fluorophenyl) - (4-methoxyphenyl) methanol

A THF solution (0.5M, 21.5mL) of 4-methoxyphenylmagnesium bromide was added dropwise to a THF solution (50mL) of 2-benzyloxy-6-fluorobenzaldehyde (2.25g, 9.8mmol) described in International publication WO04/048335 at room temperature under a nitrogen stream. After stirring at room temperature for 1.5 hours, a saturated aqueous ammonium chloride solution was added under ice-cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.82g, 85%).

¹H-NMR(CDCl₃)δ：3.78(1H，d，J＝12Hz)、3.80(3H，s)、4.98(1H，d，J＝12Hz)、5.05(1H，d，J＝12Hz)、6.20(1H，d，J＝12Hz)、6.74-6.84(4H，m)、7.11-7.31(8H，m)

2) Synthesis of 3-fluoro-2- (4-methoxybenzyl) phenol

To a solution of 2-benzyloxy-6-fluorophenyl) - (4-methoxyphenyl) methanol (2.54g, 7.51mmol) in methanol (20mL) was added 20% palladium hydroxide catalyst (381mg), followed by 2N-HCl (2 mL). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.48g, 85%).

¹H-NMR(CDCl₃)δ：3.76(3H，s)、3.96(2H，s)、4.90(1H，br s)、6.57(1H，d，J＝8.0Hz)、6.67(1H，t，J＝8.0Hz)、6.82(2H，d，J＝9.0Hz)、7.06(1H，dd，J＝8.0，8.0Hz)、7.19(2H，d，J＝9.0Hz)

3) Synthesis of [ 3-fluoro-2- (4-methoxybenzyl) -phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 3-fluoro-2- (4-methoxybenzyl) phenol (323mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (5mL) of methanol-THF (1: 4), and a 20% palladium hydroxide catalyst (63mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (86mg, 24%).

¹H-NMR(CD₃OD)δ：0.90-1.05(1H，m)、1.45-1.60(1H，m)、2.00-2.10(1H，m)、3.17-3.35(2H，m)、3.45-3.52(2H，m)、3.65-3.70(1H，m)、3.72(3H，s)、3.93(2H，s)、4.15-4.25(1H，m)、6.67(1H，t，J＝8.0Hz)、6.76(2H，d，J＝9.0Hz)、6.86(1H，d，J＝8.0Hz)、7.09-7.18(3H，m)

MS(ESI^-)：391[M-H]^-

HPLC retention time: 10.8 points

Example 13

[2- (3-trifluoromethylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (3-trifluoromethylphenyl) methanol

A solution of n-butyllithium in hexane (2.7M, 3.4mL) was added dropwise to a THF solution (50mL) of 1-benzyloxy-2-bromobenzene (2.0g, 7.6mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise 4-trifluoromethylbenzaldehyde (2.0g, 11.4mmol) at-78 ℃. After stirring at the same temperature for 3 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (2.2g, 80%).

¹H-NMR(CDCl₃)δ：3.03(1H，d，J＝6.3Hz)、4.97-5.07(2H，m)、6.06(1H，d，J＝6.3Hz)、6.95-7.03(2H，m)、7.16-7.20 (2H，m)、7.26(1H，dd，J＝7.7，2.0Hz)、7.29-7.36(4H，m)、7.39(1H，d，J＝7.7Hz)、7.46-7.55(2H，m)、7.67(1H，s)

2) Synthesis of 2- (3-trifluoromethylbenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (3-trifluoromethylphenyl) methanol (3.32g, 9.3mmol) in methanol (50mL) was added 20% palladium hydroxide catalyst (166mg), followed by 36% HCl (0.2 mL). After stirring for 72 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (2.26g, 96%).

¹H-NMR(CDCl₃)δ：4.04(2H，s)、4.90(1H，d，J＝2.0Hz)、6.76(1H，d，J＝8.1Hz)、6.86-6.90(1H，m)、7.09-7.16(2H，m)、7.34-7.46(3H，m)、7.50(1H，s).

3) Synthesis of [2- (3-trifluoromethylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (3-trifluoromethylbenzyl) phenol (351mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (5: 2), and a 20% palladium hydroxide catalyst (45mg) was added thereto, followed by stirring under a hydrogen atmosphere for 15 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (56mg, 14%).

¹H-NMR(CD₃OD)δ：0.88-1.02(1H，m)、1.52-1.68(1H，m)、2.10(1H，dt，J＝13.4，3.9Hz)、3.20-3.38(2H，m)、3.45-3.55(2H，m)、3.74(1H，dd，J＝4.1，10.8Hz)、3.99(1H，d，J＝14.7Hz)、4.18(1H，d，J＝15.4Hz)、4.20-4.32(1H，m)、6.89-6.95(1H，m)、7.08(1H，d，J＝7.7Hz)、7.16-7.26(2H， m)、7.42-7.58(4H，m)

MS(ESI⁺)：413[M+H]⁺

HPLC retention time: 12.0 minutes

Example 14

[2- (4-methoxybenzyl) -4-methylphenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 1-benzyloxy-2-bromo-4-methylbenzene

To a solution of 2-bromo-4-methylphenol (1.5g, 8.0mmol) in N, N-dimethylformamide (40mL) was added potassium carbonate (1.32g, 9.6mmol), followed by benzyl bromide (1.05mL, 8.8 mmol). After stirring at room temperature for 12 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.72g, 77%).

¹H-NMR(CDCl₃)δ：2.30(3H，s)、5.12(2H，s)、6.82(1H，d，J＝8.4Hz)、6.99-7.03(1H，m)、7.28-7.41(4H，m)、7.45-7.48(2H，m)

2) Synthesis of (2-benzyloxy-5-methylphenyl) - (4-methoxyphenyl) methanol

To a THF solution (50mL) of 1-benzyloxy-2-bromo-4-methylbenzene (1.72g, 6.2mmol) was added dropwise a hexane solution of n-butyllithium (2.7M, 2.75mL) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added 4-methoxybenzaldehyde (1.27g, 9.3mmol) dropwise at-78 ℃. After stirring at the same temperature for 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.46g, 70%).

¹H-NMR(CDCl₃)δ：2.28(3H，s)、2.88(1H，d，J＝9.2Hz)、3.80(3H，s)、5.00(2H，s)、5.99(1H，d，J＝5.6Hz)、6.80-6.88(3H，m)、7.00-7.05(1H，m)、7.13(1H，d，J＝1.8Hz)、 7.19-7.34(7H，m)

3) Synthesis of 2- (4-methoxybenzyl) -4-methylphenol

To a solution of (2-benzyloxy-5-methoxyphenyl) - (4-methoxyphenyl) methanol (1.46g, 4.3mmol) in methanol (20mL) was added 20% palladium hydroxide catalyst (73mg), followed by 36% HCl (0.1 mL). After stirring for 72 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (0.8g, 80%).

¹H-NMR(CDCl₃)δ：2.24(3H，s)、3.77(3H，s)、3.89(2H，s)、4.55-4.56(1H，m)、6.65-6.69(1H，m)、6.80-6.86(2H，m)、6.88-6.94(2H，m)、7.11-7.16(2H，m)

4) Synthesis of [2- (4-methoxybenzyl) -4-methylphenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (4-methoxybenzyl) -4-methylphenol (317mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (5: 2), and a 20% palladium hydroxide catalyst (44mg) was added thereto, followed by stirring under a hydrogen atmosphere for 4 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (88mg, 24%).

¹H-NMR(CD₃OD)δ：0.88-1.02(1H，m)、1.42-1.60(1H，m)、2.04(1H，dt，J＝13.4，4.0Hz)、2.21(3H，s)、3.17-3.32(2H，m)、3.43-3.51(2H，m)、3.70(1H，dd，J＝4.1，10.7Hz)、3.74(3H，s)、3.82(1H，d，J＝14.7Hz)、3.92(1H，d，J＝14.7Hz)、4.06-4.16(1H，m)、6.77-6.82(2H，m)、6.86-6.96(3H，m)、7.06-7.15(2H，m)

MS(ESI⁺)：389[M+H]⁺

HPLC retention time: 11.2 minutes

Example 15

[2- (3-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (3-methoxyphenyl) methanol

A THF solution (1.0M, 17.0mL) of 3-methoxyphenylmagnesium bromide was added dropwise to a THF solution (50mL) of 2-benzyloxybenzaldehyde (3.0g, 14.1mmol) under a nitrogen stream under ice cooling. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution was added under ice-cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (4.92g, 100%).

¹H-NMR(CDCl₃)δ：2.97(1H，dd，J＝1.1，6.0Hz)、3.73(3H，s)、4.98-5.10(2H，m)、6.03(1H，d，J＝6.0Hz)、6.77-6.82(1H，m)、6.88-7.01(4H，m)、7.19-7.35(9H，m)

2) Synthesis of 2- (3-methoxybenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (3-methoxyphenyl) methanol (1.68g, 5.24mmol) in methanol (50mL) was added 20% palladium hydroxide catalyst (168mg), followed by 36% HCl (0.2 mL). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.29g, 100%).

¹H-NMR(CDCl₃)δ：3.76(3H，s)、3.97(2H，s)、4.69(1H，s)、6.73-6.92(5H，m)、7.10-7.23(3H，m)

3) Synthesis of [2- (3-methoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (3-methoxybenzyl) phenol (298mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (5: 2), and a 20% palladium hydroxide catalyst (55mg) was added thereto, followed by stirring under a hydrogen atmosphere for 4 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (111mg, 32%).

¹H-NMR(CD₃OD)δ：0.97-1.11(1H，m)、1.52-1.68(1H，m)、2.12(1H，dt，J＝13.4，4.0Hz)、3.22-3.39(2H，m)、3.49-3.56(2H，m)、3.72-3.78(1H，m)、3.78(3H，s)、3.92(1H，d，J＝14.8Hz)、4.05(1H，d，J＝14.8Hz)、4.18-4.27(1H，m)、6.72-6.92(4H，m)、7.05-7.22(4H，m)

MS(ESI⁺)：375[M+H]⁺

HPLC retention time: 10.6 minutes

Example 16

[2- (4-methoxybenzyl) -4-methoxyphenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2-benzyloxy-5-methoxybenzaldehyde

To a solution of 2-hydroxy-5-methoxybenzaldehyde (3.0g, 19.7mmol) in N, N-dimethylformamide (50mL) was added potassium carbonate (3.27g, 23.6mmol), followed by benzyl bromide (2.6mL, 21.7 mmol). After stirring at room temperature for 24 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (4.8g, 100%).

¹H-NMR(CDCl₃)δ：3.80(3H，s)、5.15(2H，s)、6.99(1H，d，J＝9.0Hz)、7.11(1H，dd、J＝3.4，9.1Hz)、7.32-7.44(6H，m)、10.50(1H，s)

2) Synthesis of (2-benzyloxy-5-methoxyphenyl) - (4-methoxyphenyl) methanol

A THF solution (0.5M, 19.8mL) of 4-methoxyphenylmagnesium bromide was added dropwise to a THF solution (50mL) of 2-benzyloxy-5-methoxybenzaldehyde (2.0g, 8.25mmol) under ice-cooling in a nitrogen stream. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution was added under ice-cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 1)) to obtain the title compound (2.9g, 100%).

¹H-NMR(CDCl₃)δ：2.85(1H，d，J＝5.4Hz)、3.76(3H，s)、3.79(3H，s)、4.96(2H，s)、5.99(1H，d，J＝5.4Hz)、6.74(1H，dd，J＝2.8，9.0Hz)、6.81-6.87(3H，m)、6.94(1H，d，J＝4.1Hz)、7.19-7.36(7H，m)

3) Synthesis of 2- (4-methoxybenzyl) -4-methoxyphenol

To a solution of (2-benzyloxy-5-methoxyphenyl) - (4-methoxyphenyl) methanol (2.54g, 7.25mmol) in methanol (50mL) was added 20% palladium hydroxide catalyst (250mg), followed by 36% HCl (0.25 mL). After stirring for 14 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.62g, 91%).

¹H-NMR(CDCl₃)δ：3.74(3H，s)、3.78(3H，s)、3.90(2H，s)、4.41(1H，br s)、6.64-6.86(5H，m)、7.11-7.16(2H，m)

4) Synthesis of [2- (4-methoxybenzyl) -4-methoxyphenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (4-methoxybenzyl) -4-methoxyphenol (340mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (5: 2), and a 20% palladium hydroxide catalyst (40mg) was added thereto, followed by stirring under a hydrogen atmosphere for 6 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (128mg, 34%).

¹H-NMR(CD₃OD)δ：0.94-1.08(1H，m)、1.45-1.62(1H，m)、2.06(1H，dt，J＝13.0，4.0Hz)、3.20-3.34(2H，m)、3.46-3.56(2H，m)、3.70-3.80(1H，m)、3.73(3H，s)、3.79(3H，s)、3.88(1H，d，J＝14.8Hz)、3.96(1H，d，J＝14.8Hz)、4.04-4.14(1H，m)、6.67(1H，d，J＝3.1Hz)、6.74(1H，dd，J＝3.1，8.7Hz)、6.80-6.88(2H，m)、7.00(1H，d，J＝8.7Hz)、7.12-7.18(2H、m)

MS(ESI⁺)：405[M+H]⁺

HPLC retention time: 10.2 minutes

Example 17

[2- (4-methoxybenzyl) -6-methylphenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2-benzyloxy-3-methylbenzaldehyde

To a solution of 2-hydroxy-3-methylbenzaldehyde (3.0g, 22.07mmol) in N, N-dimethylformamide (50mL) was added potassium carbonate (3.65g, 26.4mmol), followed by benzyl bromide (2.9mL, 24.2 mmol). After stirring at room temperature for 26 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (5.0g, 100%).

¹H-NMR(CDCl₃)δ：2.36(3H，s)、4.97(2H，s)、7.16(1H，t，J＝7.4Hz)、7.36-7.49(6H，m)、7.68(1H，dd，J＝1.4，7.8Hz)、10.26(1H，d，J＝0.5Hz)

2) Synthesis of (2-benzyloxy-3-methylphenyl) - (4-methoxyphenyl) methanol

A THF solution (0.5M, 19.8mL) of 4-methoxyphenylmagnesium bromide was added dropwise to a THF solution (50mL) of 2-benzyloxy-3-methylbenzaldehyde (1.87g, 8.25mmol) under a nitrogen stream under ice cooling. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution was added under ice-cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.76g, 100%).

¹H-NMR(CDCl₃)δ：2.36(3H，s)、2.63(1H，d，J＝5.0Hz)、3.78(3H，s)、4.64-4.73(2H，m)、6.02(1H，d，J＝5.0Hz)、6.77-6.86(2H，m)、7.02-7.08(1H，m)、7.15-7.21(2H，m)、7.22-7.28(2H，m)、7.34-7.40(5H，m)

3) Synthesis of 2- (4-methoxybenzyl) -6-methylphenol

To a solution of (2-benzyloxy-3-methylphenyl) - (4-methoxyphenyl) methanol (2.76g, 8.25mmol) in methanol (30mL) was added 20% palladium hydroxide catalyst (276mg), and concentrated hydrochloric acid (0.27mL) was added. After stirring for 18 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.75g, 93%).

¹H-NMR(CDCl₃)δ：2.22(3H，s)、3.78(3H，s)、3.93(2H，s)、4.63(1H，br s)、6.77-6.86(3H，m)、6.96-7.05(2H，m)、7.11-7.17(2H，m)

4) Synthesis of [2- (4-methoxybenzyl) -6-methylphenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (4-methoxybenzyl) -6-methylphenol (318mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 48 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (5: 2), and a 20% palladium hydroxide catalyst (72mg) was added thereto, followed by stirring under a hydrogen atmosphere for 4 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (180mg, 50%).

¹H-NMR(CD₃OD)δ：1.16-1.35(2H，m)、1.74-1.88(1H，m)、2.33(3H，s)、3.16-3.26(2H，m)、3.42-3.52(1H，m)、3.54-3.68(2H，m)、3.74(3H，s)、3.92-4.02(2H，m)、4.08(1H，d，J＝15.3Hz)、6.77-6.83(2H，m)、6.86-6.91(2H，m)、6.96-7.04(1H，m)、7.05-7.12(2H，m)

MS(ESI⁺)：411[M+Na]⁺

HPLC retention time: 10.8 minutes

Example 18

[2- (4-methoxybenzyl) -4-fluorophenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxy-5-fluorophenyl) - (4-methoxyphenyl) methanol

To a solution of 1-benzyloxy-2-bromo-4-fluorobenzene (1.5g, 5.33mmol) in THF (60mL) at-78 deg.C in a nitrogen stream was added dropwise a solution of n-butyllithium in hexane (2.44M, 2.4mL) and stirred at the same temperature for 30 minutes. To this solution was added dropwise a THF solution (20mL) of 4-methoxybenzaldehyde (0.6g, 4.42mmol) at-78 ℃. After stirring at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (0.98g, 66%).

¹H-NMR(CDCl₃)δ：2.66(1H，dd，J＝0.8，4.9Hz)、3.80(3H，s)、4.98(2H，s)、6.01(1H，d，J＝4.9Hz)、6.83-6.90(4H，m)、7.14(1H，dd，J＝3.0，9.0Hz)、7.20-7.34(7H，m)

2) Synthesis of 4-fluoro-2- (4-methoxybenzyl) phenol

To a solution of (2-benzyloxy-5-fluorophenyl) - (4-methoxyphenyl) methanol (0.98g, 2.90mmol) in methanol (18.6mL) was added 20% palladium hydroxide catalyst (98mg), followed by 2N-HCl (1 mL). After stirring for 15 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 6)) to obtain the title compound (0.55g, 82%).

¹H-NMR(CDCl₃)δ：3.78(3H，s)、3.89(2H，s)、4.65(1H，br s)、6.68-6.73(1H，m)、6.77-6.87(4H，m)、7.11-7.12(2H，m)

3) Synthesis of [2- (4-methoxybenzyl) -4-fluorophenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (4-methoxybenzyl) -4-fluorophenol (323mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 48 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (5: 2), and a 20% palladium hydroxide catalyst (22mg) was added thereto, followed by stirring under a hydrogen atmosphere for 4 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (103mg, 29%).

¹H-NMR(CD₃OD)δ：0.99-1.13(1H，m)、1.50-1.65(1H，m)、2.08(1H，dt，J＝13.4，4.0Hz)、3.22-3.35(2H，m)、3.50-3.57(2H，m)、3.75(1H，dd，J＝4.0，10.7Hz)、3.79(3H，s)、3.87-4.02(2H，m)、4.11-4.21(1H，m)、6.79(1H，dd，J＝3.1，9.4Hz)、6.83-6.92(3H，m)、7.06(1H，dd，J＝4.7，8.9Hz)、7.12-7.20(2H，m)

MS(ESI⁺)：415[M+Na]⁺

HPLC retention time: 10.9 minutes

Example 19

[2- (3-Fluorobenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (3-fluorophenyl) methanol

A solution of n-butyllithium in hexane (2.44M, 5.65mL) was added dropwise to a THF solution (40mL) of 1-benzyloxy-2-bromobenzene (3.3g, 12.5mmol) at-78 deg.C under a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 3-fluorobenzaldehyde (1.40g, 11.3mmol) in THF (5mL) at-78 ℃. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (2.26g, 65%).

¹H-NMR(CDCl₃)δ：3.00(1H，d，J＝6.3Hz)、5.57(1H，d，J＝11.5Hz)、5.60(1H，d，J＝11.5Hz)、6.01(1H，d，J＝6.3Hz)、6.85-7.15(5H，m)、7.17-7.4(7H，m)

MS(ESI⁺)：308[M]⁺

2) Synthesis of 2- (3-fluorobenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (3-fluorophenyl) methanol (2.54g, 7.51mmol) in methanol (30mL) was added 20% palladium hydroxide catalyst (300mg), followed by 2N-HCl (0.3 mL). After stirring for 5 days under hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (620mg, 42%).

¹H-NMR(CDCl₃)δ：3.98(2H，s)、4.70(1H，s)、6.75-7.3(8H，m)

MS(ESI^-)：201[M-H]^-

3) [2- (3-Fluorobenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranose (400mg, 0.743mmol) and tributylphosphine (0.278mL, 1.11mmol) were added to a toluene solution (2.5mL) of 2- (3-fluorobenzyl) phenol (225mg, 1.11mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 192mg, 1.11mmol) at the same temperature. The reaction mixture was stirred at 0 ℃ for 5 hours, and then stirred for 14 hours while slowly raising the temperature to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (2: 5), and a 20% palladium hydroxide catalyst (40mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (76mg, 28%).

¹H-NMR(CD₃OD)δ：0.99(1H，dd，J＝24.7Hz，13.2Hz)、1.45-1.62(1H，m)、2.09(1H，dt，J＝12.6Hz，4Hz)、3.16-3.3(2H，m)、3.4-3.55(2H，m)、3.71(1H，dd，J＝10.7，3.8Hz)、3.93(1H，d，J＝14.9Hz)、4.05(1H，d，J＝14.9Hz)、4.1-4.3(1H，m)、6.8-6.95(3H，m)、7.0-7.06(2H，m)、7.08-7.27(3H，m).

MS(ESI⁺)：363[M+H]⁺、385[M+Na]⁺

HPLC retention time: 10.9 minutes

Example 20

[2- (3-methylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (3-methylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

Under a nitrogen stream, 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranose (413mg, 0.743mmol) and tributylphosphine (0.233mL, 1.15mmol) were added to a toluene solution (2.5mL) of 2- (3-methylbenzyl) phenol (228mg, 1.15mmol) described in Uzbekskii Khimiceskii Zhurnal (1984), (6), 31-4, etc., under ice cooling, and then tetramethylazodicarboxamide (TMAD, 198mg, 1.15mmol) was added at the same temperature. The reaction mixture was stirred for 15 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (2: 5), and a 20% palladium hydroxide catalyst (40mg) was added thereto, followed by stirring under a hydrogen atmosphere for 6 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (109mg, 40%).

¹H-NMR(CD₃OD)δ：0.95(1H，dd，J＝24.4Hz，12.9Hz)、1.45 -1.62(1H，m)、2.06(1H，dt，J＝13.1，4.0Hz)、2.27(3H，s)、3.15-3.30(2H，m)、3.42-3.52(2H，m)、3.70(1H，dd，J＝10.7，3.9Hz)、3.87(1H，d，J＝14.8Hz)、3.98(1H，d，J＝14.8Hz)、4.1-4.25(1H，m)、6.81-6.88(1H，m)、6.9-7.2(7H，m)

MS(ESI⁺)：376[M+NH₄]⁺、359[M+H]⁺

HPLC retention time: 11.4 minutes

Example 21

[ 5-fluoro-2- (4-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2-benzyloxy-1-bromo-4-fluorobenzene

To a solution of 2-bromo-5-fluorophenol (3.0g, 15.7mmol) in DMF (15.7mL) was added potassium carbonate (2.61g, 18.8mmol) and stirred at room temperature for 15 minutes under a stream of nitrogen. To the solution was added dropwise benzyl bromide (2.69g, 15.7mmol) at the same temperature, and stirred at the same temperature overnight. Aqueous potassium hydrogen sulfate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ n-hexane) to obtain the title compound (4.31g, 98%) as a colorless oil.

¹H-NMR(CDCl₃)δ：5.14(2H，s)、6.56-6.72(2H，m)、7.31-7.52(6H，m)

2) Synthesis of (2-benzyloxy-4-fluorophenyl) - (4-methoxyphenyl) methanol

To a solution of 2-benzyloxy-1-bromo-4-fluorobenzene (1.4g, 5.0mmol) in THF (50mL) at-78 deg.C in a nitrogen stream was added dropwise a solution of n-butyllithium in hexane (1.59M, 3.14mL) and stirred at the same temperature for 15 minutes. To this solution was added dropwise a solution of 4-methoxybenzaldehyde (680mg, 4.99mmol) in THF (15mL) at-78 ℃. After stirring at the same temperature for 1.5 hours, a saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ n-hexane: dichloromethane: acetone (12: 3: 1)) to obtain the title compound (1.41g, 83%) as a colorless oil.

¹H-NMR(CDCl₃)δ：2.67(1H，d，J＝5.0Hz)、3.79(3H，s)、4.99(2H，s)、6.00(1H，d，J＝3.8Hz)、6.62-6.70(2H，m)、6.81-6.86(2H，m)、7.19-7.38(8H，m)

3) Synthesis of 2- (4-methoxybenzyl) -5-fluorophenol

To a solution of (2-benzyloxy-4-fluorophenyl) - (4-methoxyphenyl) methanol (2.095g, 6.19mmol) in methanol (20mL) was added 20% palladium hydroxide catalyst (200mg), followed by 2N-HCl (0.3 mL). After stirring for 16 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (489mg, 34%).

¹H-NMR(CDCl₃)δ：3.78(3H，s)、3.89(2H，s)、4.88(1H，s)、6.50-6.40(2H，m)、6.80-6.88(2H，m)、7.04(1H，dd，J＝6.6，8.2Hz)、7.08-7.15(2H，m)

MS(ESI^-)：231[M-H]^-

4) Synthesis of [ 5-fluoro-2- (4-methoxybenzyl) phenyl ] -5 a-carbon (carba) -beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranose (500mg, 0.928mmol) and tributylphosphine (0.346mL, 1.39mmol) were added to a toluene solution (2.5mL) of 2- (4-methoxybenzyl) -5-fluorophenol (323mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 240mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 17 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (7mL) of methanol-THF (2: 5), and a 20% palladium hydroxide catalyst (40mg) was added thereto, followed by stirring under a hydrogen atmosphere for 22 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (59mg, 16%).

¹H-NMR(CD₃OD)δ：1.00(1H，dd，J＝24.4，12.9Hz)、1.5-1.65(1H，m)、2.04(1H，dt，J＝13.4，4.1Hz)、3.17-3.35(2H，m)、3.43-3.55(2H，m)、3.65-3.75(1H，m)、3.73(3H，s)、3.81(1H，d，J＝15.1Hz)、3.90(1H，d，J＝15.1Hz)、4.1-4.22(1H，m)、6.56(1H，dt，J＝8.5，2.7Hz)、6.75-6.88(3H，m)、7.0-7.13(3H，m)

MS(ESI⁺)：415[M+Na]⁺

HPLC retention time: 11.0 minutes

Example 22

[2- (4-Methylsulfonylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-methylsulfanylphenyl) methanol

A THF solution (0.5M, 35mL) of 4-methylsulfanylphenylmagnesium bromide was added dropwise to a THF solution (24mL) of 2-benzyloxybenzaldehyde (2.60g, 12.2mmol) at 0 ℃ in a nitrogen stream. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added under ice-cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (3.91g, 95%).

¹H-NMR(CDCl₃)δ：2.47(3H，s)、2.91(1H，d，J＝5.8Hz)、5.03(2H，s)、6.01(1H，d，J＝6.0Hz)、6.90-7.00(2H，m)、7.15-7.35(11H，m)

2) Synthesis of (2-benzyloxyphenyl) - (4-methanesulfonylphenyl) methanol

To a solution of (2-benzyloxyphenyl) - (4-methylsulfanylphenyl) methanol (3.00g, 8.92mmol) in methylene chloride (25mL) at 0 ℃ in a nitrogen stream was added m-chloroperbenzoic acid (4.40g, 22.2mmol) and the mixture was stirred at the same temperature for 30 minutes. After removing the precipitate by filtration, the filtrate was washed with a 2N aqueous solution of sodium hydroxide. The washing solution was extracted with dichloromethane, and the combined organic layers were washed with water and saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound (3.18g, 97%).

¹H-NMR(CDCl₃)δ：3.02(3H，s)、3.03(1H，d，J＝6.3Hz)、5.00(1H，J＝11.4Hz)、5.04(1H，d，J＝11.5Hz)、6.09(1H，d，J＝6.2Hz)、6.95-7.03(2H，m)、7.16-7.22(2H，m)、7.24-7.38(5H，m)、7.53(2H，d，J＝8.1Hz)、 7.84(2H，d，J＝8.6Hz)

3) Synthesis of 2- (4-methanesulfonylbenzyl) phenol

To a mixed solution of (2-benzyloxyphenyl) - (4-methanesulfonylphenyl) methanol (3.00g, 8.14mmol) in methanol (30mL) -ethyl acetate (30mL) was added 20% palladium hydroxide catalyst (299mg) and 36% HCl (150. mu.L, 1.78mmol) in a nitrogen stream, and the mixture was stirred under a hydrogen atmosphere for 6 hours. Sodium bicarbonate was added, stirred for 30 minutes and after neutralization the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 2)) to obtain the title compound (1.81g, 85%).

¹H-NMR(CDCl₃)δ：3.02(3H，s)、4.06(2H，s)、5.00(1H，s)、6.77(1H，d，J＝7.9Hz)、6.89(1H，dt，J＝7.5，1.2Hz)、7.08-7.17(2H，m)、7.42(2H，d，J＝8.6Hz)、7.82(2H，d，J＝8.4Hz)

4) Synthesis of [2- (4-methanesulfonylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.928mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a mixed solution of 2- (4-methanesulfonylbenzyl) phenol (365mg, 1.39mmol) in toluene (2mL) -THF (1mL) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 242mg, 1.41mmol) at the same temperature. The reaction mixture was stirred for 25 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4 → 1: 2)). The obtained crude product was dissolved in a mixed solvent of methanol (3mL) -THF (2mL), and 20% palladium hydroxide catalyst (27.2mg) and 1 drop of 2N hydrochloric acid were added and stirred under a hydrogen atmosphere for 2.5 hours. After adding saturated aqueous sodium bicarbonate solution for neutralization, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (8: 1)) to obtain the title compound (120mg, 31%).

¹H-NMR(CD₃OD)δ：0.91(1H，ddd，J＝13.0，13.0，13.0Hz)、1.53(1H，m)、2.03(1H，ddd，J＝13.0，4.0，4.0Hz)、3.07(3H，s)、3.19(1H，dd，J＝8.9，8.9Hz)、3.28(1H，dd，J＝9.0，9.0Hz)、3.43(1H，dd，J＝9.0，9.0Hz)、3.50(1H，dd，J＝10.7，6.1Hz)、3.67(1H，dd，J＝10.7， 4.0Hz)、4.02(1H，d，J＝14.5Hz)、4.16(1H，d，J＝14.5Hz)、4.14-4.26(1H，m)、6.88(1H，t，J＝6.2Hz)、7.04(1H，d，J＝8.1Hz)、7.17(1H，d，J＝7.5Hz)、7.18(1H，t，J＝7.5Hz)、7.48(1H，d，J＝8.4Hz)、7.80(1H，d，J＝8.4Hz)

MS(ESI⁺)：423[M+H]⁺，440[M+NH₄]⁺，445[M+Na]⁺

HPLC retention time: 9.0 minutes

Example 23

[2- (4-Fluorobenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2- (4-fluorobenzyl) phenol

A solution of n-butyllithium in hexane (1.59M, 4.9mL) was added dropwise to a THF solution (60mL) of 1-benzyloxy-2-bromobenzene (2.04g, 7.75mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 20 minutes. To the solution was added dropwise a solution of 4-fluorobenzaldehyde (801mg, 6.45mmol) in THF (10mL) at-78 ℃. After stirring at the same temperature for 1.5 hours, a saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (2.35 g). To a methanol solution (15mL) of the resulting crude product was added 20% palladium hydroxide catalyst (186mg), followed by 2N-HCl (400. mu.L). After stirring for 3 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (996mg, 77%).

¹H-NMR(CDCl₃)δ：3.95(2H，s)、4.72(1H，s)、7.77(1H，dd，J＝7.9，1.1Hz)、6.88(1H，td，J＝7.5，1.1Hz)、6.96(1H，dd，J＝8.7，8.7Hz)、7.06-7.20(4H，m)

2) Synthesis of [2- (4-fluorobenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.928mmol) and tributylphosphine (0.35mL, 1.40mmol) were added to a toluene solution (3mL) of 2- (4-fluorobenzyl) phenol (284mg, 1.40mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 241mg, 1.40mmol) at the same temperature. The reaction mixture was stirred for 21 hours while slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 8 → 1: 3)). The obtained crude product was dissolved in a mixed solvent of methanol (4mL) -THF (2mL), and 20% palladium hydroxide catalyst (18.4mg) and 1 drop of 2N hydrochloric acid were added and stirred for 1.5 hours under a hydrogen atmosphere. Saturated sodium bicarbonate was added for neutralization and the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1 → 8: 1)) to obtain the title compound (153mg, 46%).

¹H-NMR(CD₃OD)δ：0.99(1H，ddd，J＝12.9，12.9，12.9Hz)、1.55(1H，m)、2.08(1H，ddd，J＝13.2，3.9，3.9Hz)、3.22(1H，dd，J＝9.0，9.0Hz)、3.30(1H，dd，J＝9.0，9.0Hz)、3.48(1H，dd，J＝8.7，8.7Hz)、3.51(1H，dd，J＝10.8，6.0Hz)、3.70(1H，dd，J＝10.8，4.2Hz)、3.90(1H，d，J＝14.7Hz)、4.02(1H，d，J＝14.7Hz)、4.20(1H，ddd，J＝11.4，9.0，4.8Hz)、6.85(1H，t，J＝7.5Hz)、6.93(1H，dd，J＝8.9，8.9Hz)、7.02(1H，d，J＝8.1Hz)、7.06-7.23(4H，m)

MS(ESI⁺)：363[M+H]⁺

HPLC retention time: 10.9 minutes

Example 24

[2- (3, 4-Dimethoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2- (3, 4-dimethoxybenzyl) phenol

A solution of n-butyllithium in hexane (1.59M, 4.4mL) was added dropwise to a THF solution (30mL) of 1-benzyloxy-2-bromobenzene (1.74g, 6.61mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 1 hour. To the solution was added dropwise a THF solution (8mL) of 3, 4-dimethoxybenzaldehyde (1.00g, 6.02mmol) at-78 ℃. After stirring at the same temperature for 1.5 hours, a saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure to obtain a crude product (2.38 g). The crude product was dissolved in methanol (20mL), and 20% palladium hydroxide catalyst (196mg) was added followed by 2N-HCl (30. mu.l). After stirring for 23 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (653mg, 44%).

¹H-NMR(CDCl₃)δ：3.82(3H，s)、3.85(3H，s)、3.94(2H，s)、4.73(1H，s)、6.74-6.82(2H，m)、6.78(1H，s)、6.89(1H，td，J＝7.5，1.1Hz)、 7.08-7.17(2H，m)

2) Synthesis of [2- (3, 4-dimethoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (504mg, 0.936mmol) and tributylphosphine (0.35mL, 1.40mmol) were added to a mixed solution of 2- (3, 4-dimethoxybenzyl) phenol (342mg, 1.40mmol) in toluene (2.5mL) -THF (1.0mL) under ice-cooling in a nitrogen stream, and then tetramethylazodicarboxamide (TMAD, 242mg, 1.41mmol) was added at the same temperature. The reaction mixture was stirred for 22 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 3)). The obtained crude product was dissolved in a mixed solvent of methanol (2mL) -THF (2mL), and 20% palladium hydroxide catalyst (21.9mg) was added thereto, followed by stirring under a hydrogen atmosphere for 5 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (108mg, 38%).

¹H-NMR(CD₃OD)δ：1.01(1H，ddd，J＝13.1，13.1，11.6Hz)、1.55(1H，m)、2.08(1H，ddd，J＝13.3，3.8，3.8Hz)、3.21(1H，dd，J＝9.2，9.2Hz)、3.29(1H，dd，J＝8.9，8.9Hz)、3.48(1H，dd，J＝9.2，9.2Hz)、3.49(1H，dd，J＝10.7，6.3Hz)、3.70(1H，dd，J＝10.7，4.1Hz)、3.76(3H，s)、3.78(3H，s)、3.87(1H，d，J＝14.8Hz)、3.96(1H，d，J＝14.8Hz)、4.19(1H，ddd，J＝11.5，9.0，4.6Hz)、6.73(1H，dd，J＝8.3，2.0Hz)、6.81(1H，s)、6.82(1H，d，J＝8.3Hz)、6.84(1H，td，J＝7.5，1.2Hz)、7.02(1H，d，J＝7.5Hz)、7.08(1H，dd，J＝7.5，1.5Hz)、7.14(1H，td，J＝7.2，1.7Hz)

MS(ESI⁺)：405[M+H]⁺

HPLC retention time: 9.7 minutes

Example 25

[2- (4-ethylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (4-ethylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

Under a nitrogen stream, 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (400mg, 0.74mmol) and tributylphosphine (0.28mL, 1.11mmol) were added to a toluene solution (2.5mL) of 2- (4-ethylbenzyl) phenol (236mg, 1.11mmol) described in International publication No. WO04/052902 or WO01/074834, etc., under ice cooling, followed by addition of tetramethylazodicarboxamide (TMAD, 191mg, 1.11mmol) at the same temperature. The reaction mixture was stirred for 25 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (4mL) of methanol-THF (1: 2), and 20% palladium hydroxide catalyst (20mg) was added thereto, followed by stirring under a hydrogen atmosphere for 1.5 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by TLC (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (40mg, 14%).

¹H-NMR(CD₃OD)δ：0.86-1.00(1H，m)、1.19(3H，t，J＝7.6Hz)、1.45-1.62(1H，m)、2.00-2.11(1H，m)、2.57(2H，q，J＝7.6Hz)、3.16-3.30(2H，m)、3.43-3.49(2H，m)、3.70(1H，dd，J＝10.6，4.1Hz)、3.84-4.02(2H，m)、4.12-4.24(1H，m)、6.83(1H，t，J＝7.4Hz)、6.99-7.16(7H，m)

MS(ESI⁺)：395[M+Na]⁺

HPLC retention time: 12.3 minutes

Example 26

[2- (4-hydroxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (4-hydroxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

To a dichloromethane solution (1.3mL) of [2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside (100mg, 0.27mmol) obtained in example 1 was added a dichloromethane solution (1.0M, 0.80mL, 0.80mmol) of boron tribromide at-78 ℃ under a nitrogen atmosphere, and after removing the cooling bath, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by HPLC (developing solution ═ methanol: 20mM aqueous ammonium acetate solution) to obtain the title compound (45mg, 47%).

¹H-NMR(CD₃OD)δ：0.92-1.06(1H，m)、1.47-1.67(1H，m)、2.03-2.11(1H，m)、3.18-3.34(2H，m)、3.45-3.52(2H，m)、3.71(1H，dd，J＝10.7，4.1Hz)、3.79-3.95(2H，m)、4.12-4.22(1H，m)、6.65(2H，d，J＝8.4Hz)、6.83(1H，t，J＝7.3Hz)、6.99-7.16(5H，m)

MS(ESI⁺)：361[M+H]⁺

HPLC retention time: 8.9 minutes

Example 27

[2- (4-cyanobenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (4-cyanobenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a mixture of 2- (4-cyanobenzyl) phenol (291mg, 1.39mmol) in toluene (2mL) -THF (1mL) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 14 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) and preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 3)) to obtain a crude product (130 mg). The obtained crude product (55mg) was dissolved in methylene chloride (0.50mL), and dimethyl sulfide (0.19mL, 4.4mmol) and boron trifluoride diethyl etherate (0.095mL, 0.75mmol) were added under ice cooling. After the reaction mixture was stirred at room temperature for 5 hours, water was added under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by TLC (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (17.5mg, 12%).

¹H-NMR(CD₃OD)δ：0.83-0.96(1H，m)、1.44-1.60(1H，m)、1.99-2.07(1H，m)、3.14-3.32(2H、m)、3.38-3.50(2H，m)、3.67(1H，dd，J＝10.7，4.0Hz)、3.93-4.13(2H，m)、4.15-4.22(1H，m)、6.85(1H，t，J＝7.3Hz)、7.01(1H，d，J＝7.9Hz)、7.11-7.18(2H，m)、7.37(2H，d，J＝8.2Hz)、7.55(2H，d，J＝8.1Hz)

MS(ESI⁺)：392[M+Na]⁺

HPLC retention time: 10.2 minutes

Example 28

[2- (3-trifluoromethoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2- (3-trifluoromethoxybenzyl) phenol

A solution of n-butyllithium in hexane (2.44M, 4.3mL) was added dropwise to a THF solution (95mL) of 1-benzyloxy-2-bromobenzene (2.5g, 9.5mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 3-trifluoromethoxybenzaldehyde (1.5g, 7.9mmol) in THF (32mL) at-78 ℃. After stirring at the same temperature for 2 hours, further stirring at 0 ℃ for 1 hour, then adding water, and extracting with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)). The resulting crude product was dissolved in methanol (20mL), and 20% palladium hydroxide catalyst (200mg) and 2N-HCl (0.187mL) were added. Stirred under hydrogen atmosphere for 13 hours. To the reaction mixture was added potassium carbonate (850mg), and after stirring at room temperature for 30 minutes, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (1.40g, 99%).

¹H-NMR(CDCl₃)δ：3.99(2H，s)、4.71(1H，br s)、6.76(1H，d，J＝7.9Hz)、6.92-6.86(1H，m)、7.02-7.15(5H，m)、7.29(1H，d，J＝7.3Hz)

2) Synthesis of [2- (3-trifluoromethoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

Under a nitrogen stream, 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 2- (3-trifluoromethoxybenzyl) phenol (373mg, 1.39mmol) under ice cooling, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (10mL) of methanol-THF (1: 2), and a 20% palladium hydroxide catalyst (100mg) was added thereto, followed by stirring under a hydrogen atmosphere for 13 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by TLC (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (104mg, 26%).

¹H-NMR(CD₃OD)δ：0.86-1.00(1H，m)、1.45-1.60(1H，m)、2.01-2.09(1H，m)、3.15-3.31(2H，m)、3.41-3.48(2H，m)、3.68(1H，dd，J＝10.7，4.1Hz)、3.88-4.11(2H，m)、4.13-4.95(1H，m)、6.82-6.87(1H，m)、7.00-7.30(7H，m)

MS(ESI⁺)：429[M+H]⁺

HPLC retention time: 12.4 minutes

Example 29

[2- (4-Aminomethylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside acetate

1) Synthesis of [2- (4-aminomethylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside acetate

The crude product of [2- (4-cyanobenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (63mg) obtained in example 27 was dissolved in a mixed solution (1mL) of methanol-THF (1: 2), a 20% palladium hydroxide catalyst (10mg) was added, and after stirring for 23 hours in a hydrogen atmosphere, the catalyst was filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of [2- (4-aminomethylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside. This crude product was dissolved in methylene chloride (0.55mL), dimethyl sulfide (0.22mL, 5.1mmol) and boron trifluoride diethyl etherate (0.11mL, 0.86mmol) were added under ice cooling, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by HPLC (developing solution ═ methanol: 20mM aqueous ammonium acetate solution) to give the title compound (19 mg).

¹H-NMR(CD₃OD)δ：0.85-0.99(1H，m)、1.42-1.58(1H，m)、1.88(3H，s)、1.93-2.01(1H，m)、3.14-3.67(5H，m)、3.87-4.07(2H，m)、4.01(2H，s)、4.11-4.20(1H，m)、6.79-6.85(1H，m)、6.99(1H，d，J＝4.1H)、7.01-7.16(2H，m)、7.25(2H，d，J＝8.4Hz)、7.29(2H，d，J＝8.5Hz)

MS(ESI⁺)：374[M+H]⁺

HPLC retention time: 7.3 minutes

Example 30

[ 5-methoxy-2- (4-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [ 5-methoxy-2- (4-methoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon- α -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) are added to a toluene solution (3mL) of 5-methoxy-2- (4-methoxybenzyl) phenol (340mg, 1.39mmol) described in International publication WO04/058682, WO02/064606, WO02/044192, etc. under ice cooling in a nitrogen stream, and then tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) is added at the same temperature. The reaction mixture was stirred for 17 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 3)). The obtained crude product was dissolved in a mixed solution (5mL) of methanol-THF (1: 2), and a 20% palladium hydroxide catalyst (50mg) was added thereto, followed by stirring under a hydrogen atmosphere for 3 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by TLC (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (119mg, 32%).

¹H-NMR(CD₃OD)δ：0.84-0.98(1H，m)、1.44-1.60(1H，m)1.98-2.06(1H，m)、3.13-3.47(5H，m)、3.77(3H，s)、3.82(3H，s)、3.71-3.88(2H，m)、4.06-4.16(1H，m)、6.41(1H，dd，J＝2.3，8.2Hz)、6.58(1H，d，J＝2.1Hz)、6.75(2H，d，J＝8.7Hz)、6.94(1H，d，J＝8.2Hz)、7.05(2H，d，J＝8.6Hz)

MS(ESI⁺)：405[M+H]⁺

HPLC retention time: 10.7 minutes

Example 31

[2- (4-Methoxycarbonylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of methyl 4- [ (2-benzyloxyphenyl) hydroxymethyl ] benzoate

A solution of n-butyllithium in hexane (2.71M, 12.1mL) was added dropwise to a THF solution (300mL) of 1-benzyloxy-2-bromobenzene (7.84g, 29.8mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a THF solution (100mL) of 4-methoxycarbonylbenzaldehyde (4.78g, 29.1mmol) at-78 ℃. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (4.15g, 41%).

¹H-NMR(CDCl₃)δ：3.06(1H，d，J＝6.2Hz)、3.91(3H，s)、5.02(2H，dd，J＝5.8，11.4Hz)、6.07(1H，d，J＝6.2Hz)、6.94-7.00(2H，m)、7.18-7.42(9H，m)、7.96(2H，d，J＝8.4Hz)

2) Synthesis of methyl 4- (2-benzyloxybenzyl) benzoate

Triethylsilane (2.27mL, 13.5mmol) and boron trifluoride diethyl etherate (1.52mL, 11.88mmol) were added to a solution of methyl 4- [ (2-benzyloxyphenyl) -hydroxymethyl ] benzoate (4.15g, 11.9mmol) in acetonitrile (22.7mL) at-40 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 1.5 hours. After stirring at 0 ℃ for 30 minutes, water was added and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (2.39g, 62%).

¹H-NMR(CDCl₃)δ：3.89(3H，s)、4.05(2H，s)、5.02(2H，d、J＝5.8Hz)、6.92(2H，d、J＝7.9Hz)、7.12-7.36(9H，m)、7.91(2H，d，J＝8.0Hz)

MS(ESI⁺)：333[M+H]⁺

3) Synthesis of methyl 4- (2-hydroxybenzyl) benzoate

To a solution of methyl 4- (2-benzyloxybenzyl) benzoate (2.39g, 7.19mmol) in methanol (70mL) was added 20% palladium hydroxide catalyst (239 mg). After stirring for 5 hours under hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure to give the title compound (1.16g, 96%).

¹H-NMR(CDCl₃)δ：3.89(3H，s)、4.04(2H，s)、4.76(1H，s)、6.77(1H，d、J＝8.0Hz)、6.89(1H，t、J＝7.3Hz)、7.13(2H，m)、7.29(2H，d，J＝8.4Hz)、7.94(2H，d，J＝8.0Hz)

MS(ESI⁺)：243[M+H]⁺

4) Synthesis of [2- (4-methoxycarbonylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (1.10g, 2.04mmol) and tributylphosphine (0.77mL, 3.06mmol) were added to a toluene solution (6.9mL) of methyl 4- (2-hydroxybenzyl) benzoate (741.4mg, 3.06mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 526.5mg, 3.06mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (429.0mg, 28%).

¹H-NMR(CD₃OD)δ：1.40(1H，dd、J＝12.0，12.0Hz)、1.65-1.74(1H，m)、2.00-2.09(1H，m)、3.43-3.59(2H，m)、3.84(3H，s)、 4.00(2H，s)、4.32-3.92(8H，m)、6.91(1H，t，J＝8.0Hz)、7.04-7.32(25H，m)，7.87(2H，d，J＝8.0Hz)

5) Synthesis of [2- (4-methoxycarbonylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

[2- (4-Methoxycarbonylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (38.1mg, 0.05mmol) was dissolved in a mixed solution (1.5mL) of methanol-THF (2: 1), and 20% palladium hydroxide catalyst (5mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (12.9mg, 65%).

¹H-NMR(CD₃OD)δ：0.89-1.00(1H，m)、1.47-1.62(1H，m)、2.03-2.09(1H，m)、3.16-3.23(2H，m)、3.42-3.49(2H，m)、3.51-3.87(1H，m)、3.95(3H，s)、4.00-4.17(2H，m)、4.19-4.23(1H，m)、6.87(1H，d，J＝7.4Hz)、7.31(1H，d，J＝7.6Hz)、7.12-7.20(2H，m)、7.32(2H，d，J＝8.4Hz)、7.88(2H，d，J＝8.4Hz)

MS(ESI⁺)：403[M+Na]⁺

Example 32

[2- (4-carbamoylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (4-carboxybenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranoside

To a solution of [2- (4-methoxycarbonylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (100.0mg, 0.13mmol) in ethanol-THF (4: 1) (1.5mL) was added an aqueous 5N-sodium hydroxide solution (0.15mL) under a nitrogen atmosphere at room temperature, and the mixture was stirred for 22 hours. Then, under ice-cooling, 5N-hydrochloric acid aqueous solution was added to neutralize. Extraction with dichloromethane, drying (sodium sulfate) and concentration under reduced pressure gave the title compound (91.3mg, 94%).

¹H-NMR(CDCl₃)δ：1.42(1H，ddd、J＝12.4，12.4，12.4Hz)、1.55-1.67(1H，m)、2.00-2.04(1H，m)、3.41-3.61(2H，m)、4.02(2H，s)、4.35-3.92(8H，m)、6.92(1H，t，J＝7.3Hz)、7.05-7.32(25H，m)，7.92(2H，d， J＝7.7Hz)

MS(ESI⁺)：749[M+H]⁺

2) Synthesis of [2- (4-carbamoylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranoside

To a solution of [2- (4-hydroxycarbonylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (45.0mg, 0.06mmol) in N, N-dimethylformamide (1.2mL) was added 1-hydroxybenzotriazole 1 hydrate (9.0mg, 0.07mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12.0mg, 0.07mmol) under nitrogen at room temperature, followed by stirring for 1 hour, adding aqueous ammonia (0.5mL) under ice-cooling, and stirring for 27 hours. Concentrated under reduced pressure, and purified by preparative TLC (developing solution: methanol: dichloromethane: 1: 10) to give the title compound (39.1mg, 89%).

¹H-NMR(CDCl₃)δ：1.31-1.49(1H，m)、1.62-1.76(1H，m)、1.96-2.08(1H，m)、3.39-3.66(2H，m)、4.02(2H，s)、4.33-4.96(8H，m)、6.88-6.97(1H，m)、7.04-7.39(25H，m)，7.54-7.61(2H，m)

MS(ESI⁺)：748[M+H]⁺

3) Synthesis of [2- (4-carbamoylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

To a solution of [2- (4-carbamoylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (39.1mg, 0.05mmol) in methanol-THF (2: 1) (3mL) was added 20% palladium hydroxide catalyst (5 mg). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 5)) to obtain the title compound (19.2g, 99%).

¹H-NMR(CD₃OD)δ：0.92(1H，dd，J＝11.7，11.7Hz)、1.48-1.62(1H，m)、1.96-2.08(1H，m)、3.16-3.33(4H，m)、3.42-3.59(2H，m)、3.65-3.73(1H，m)、3.93-4.26(3H，m)、6.87(1H，t、J＝7.3Hz)，7.02-7.21(3H，m)、7.31(2H，d，J＝8.2Hz)、7.74(2H，d，J＝8.1Hz)

MS(ESI⁺)：388[M+H]⁺

HPLC retention time: 8.0 minutes

Example 33

[2- (4-N, N-dimethylcarbamoylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of [2- (4-N, N-dimethylcarbamoylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranoside

To a solution of [2- (4-carboxybenzyl) phenyl ] - ]2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (45.0mg, 0.06mmol) obtained in example 32 in N, N-dimethylformamide (1.2mL) was added ] -hydroxybenzotriazole 1 hydrate (9.0mg, 0.07mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12.0mg, 0.07mmol) under a nitrogen atmosphere at room temperature, followed by stirring for 1 hour, adding an aqueous solution of N, N-dimethylamine (0.5mL) under ice-cooling and stirring for 27 hours. Concentrated under reduced pressure, and purified by preparative TLC (methanol: dichloromethane ═ 1: 10) to give the title compound (44.1mg, 96%).

¹H-NMR(CDCl₃)δ：1.42-1.52(1H，m)、1.66-1.78(1H，m)、2.05-2.14(1H，m)、2.83(3H，s)、3.04(3H，s)、3.44-3.68(5H，m)、3.99(2H，s)、4.35-4.53(1H，m)、4.68(2H，s)、4.83-4.94(3H，m)、6.91(1H，t，J＝7.3Hz)、7.04-7.36(27H，m)

MS(ESI⁺)：776[M+H]⁺

2) Synthesis of [2- (4-N, N-dimethylcarbamoylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

To a solution of [2- (4-N, N-dimethylcarbamoylbenzyl) phenyl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon- β -D-glucopyranoside (44.1mg, 0.06mmol) in methanol-THF (2: 1) (3mL) was added 20% palladium hydroxide catalyst (5 mg). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 5)) to obtain the title compound (20.1mg, 87%).

¹H-NMR(CD₃OD)δ：0.86-1.00(1H，m)、1.45-1.58(1H，m)、1.98-2.06(1H，m)、2.95(3H，s)、3.03(3H，s)、3.13-3.49(5H，m)、3.62-3.68(1H，m)、3.88-4.21(3H，m)、6.91(1H，t，J＝7.2Hz)、6.98-7.15(3H，m)、7.26(4H，s)

MS(ESI⁺)：416[M+H]⁺

HPLC retention time: 8.9 minutes

Example 34

[2- (4-ethoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2- (4-ethoxybenzyl) -phenol

A solution of n-butyllithium in hexane (2.71M, 3.8mL) was added dropwise to a THF solution (90mL) of 1-benzyloxy-2-bromobenzene (2.5g, 9.5mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 4-ethoxybenzaldehyde (1.29mL, 1.86mmol) in THF (30mL) at-78 ℃. After stirring at the same temperature for 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)). To a solution of the resulting crude product in methanol (26.8mL) was added 20% palladium hydroxide catalyst (147mg), followed by 36% HCl (0.4 mL). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (828.1mg, 38%).

¹H-NMR(CDCl₃)δ：1.39(3H，t、J＝7.0Hz)、3.93(2H，s)、3.99(2H，q、J＝7.0Hz)、6.77-6.90(4H，m)、7.09-7.14(4H，m)

2) Synthesis of [2- (4-ethoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3.2mL) of 2- (4-ethoxybenzyl) phenol (319.6mg, 1.4mmol) under ice-cooling in a nitrogen stream, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in methanol (5mL), and a 20% palladium hydroxide catalyst (56mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (133.5mg, 36%).

¹H-NMR(CD₃OD)δ：0.89-1.03(1H，m)、1.35(3H，t，J＝7.1Hz)，1.48-1.62(1H，m)、2.02-2.11(1H，m)、3.18-3.33(3H，m)、3.35(2H，s)， 3.44-3.52(2H，m)、3.68-3.74(1H，m)、3.81-4.02(4H，m)、4.13-4.23(1H，m)、6.74-6.87(4H，m)、6.99-7.17(4H、m)

MS(ESI⁺)：411[M+Na]⁺

HPLC retention time: 11.4 minutes

Example 35

[2- (4-Difluoromethoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2- (4-difluoromethoxybenzyl) phenol

A solution of n-butyllithium in hexane (2.71M, 3.8mL) was added dropwise to a THF solution (90mL) of 1-benzyloxy-2-bromobenzene (2.5g, 9.5mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 4-difluoromethoxybenzaldehyde (1.23mL, 1.86mmol) in THF (30mL) at-78 ℃. After stirring at the same temperature for 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)). To a methanol solution (26.8mL) of the resulting crude product was added 20% palladium hydroxide catalyst (147mg), and concentrated hydrochloric acid (0.4mL) was added. After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (1.03g, 42%).

¹H-NMR(CDCl₃)δ：3.97(2H，s)、6.46(1H，t，J＝74.4Hz)6.77(1H，d、J＝8.0Hz)、6.87-6.91(1H，t，J＝7.3Hz)、7.03(2H，d，J＝8.4Hz)、7.09-7.15(2H，m)、7.21(2H，d，J＝8.0Hz)

2) Synthesis of [2- (4-difluoromethoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3.2mL) of 2- (4-difluoromethoxybenzyl) phenol (350.0mg, 1.4mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in methanol (5mL), and a 20% palladium hydroxide catalyst (69mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (153.1mg, 40%).

¹H-NMR(CD₃OD)δ：0.87-1.01(1H，m)、1.48-1.62(1H，m)、2.01-2.11(1H，m)、3.17-3.34(2H，m)、3.43-3.54(2H，m)、3.67-3.73(1H，m)、3.96(2H，dd、J＝22.9，14.7Hz)、4.14-4.26(1H，m)、6.72(1H，t，J＝74.5Hz)、6.83-7.25(8H，m)

MS(ESI⁺)：433[M+Na]⁺

HPLC retention time: 11.6 minutes

Example 36

[2- (4-tert-butylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (4-tert-butylphenyl) methanol

A solution of n-butyllithium in hexane (2.44M, 5.65mL) was added dropwise to a THF solution (126mL) of 1-benzyloxy-2-bromobenzene (3.3g, 12.5mmol) at-78 deg.C under a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 4-tert-butylbenzaldehyde (1.68g, 10.4mmol) in THF (42mL) at-78 ℃. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.17g, 60%).

¹H-NMR(CDCl₃)δ：1.32(9H，s)、2.86(1H，br s)、5.02(2H，s)、6.03(1H，s)、6.03-7.00(2H，m)、7.13-7.39(11H，m)

2) Synthesis of 2- (4-tert-butylbenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (4-tert-butylphenyl) methanol (2.17g, 6.26mmol) in methanol (27mL) was added a 20% palladium hydroxide catalyst (217mg), followed by 2N-HCl (0.52 mL). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (1.3g, 86%).

¹H-NMR(CDCl₃)δ：1.29(9H，s)、3.96(2H，s)、4.65(1H，s)、 6.75-6，91(2H，m)、7.09-7.32(6H，m)

3) Synthesis of [2- (4-tert-butylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

Under a nitrogen stream, 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 2- (4-tert-butylbenzyl) phenol (334mg, 1.39mmol) under ice cooling, followed by the addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (12mL) of methanol-THF (1: 1), and a 20% palladium hydroxide catalyst (60mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (57mg, 15%).

¹H-NMR(CD₃OD)δ：0.89-1.01(1H，m)、1.29(9H，s)、1.53-1.59(1H，m)、2.04-2.11(1H，m)、3.19-3.34(2H，m)、3.45-3.51(2H，m)、3.71(1H，dd，10.8，4.5Hz)、3.95(2H，m)、4.19(1H，m)、6.84(1H，m)、7.01-7.17(5H，m)、7.26-7.28(2H，m)

MS(ESI⁺)：401[M+H]⁺

HPLC retention time: 13.7 minutes

Example 37

[2- (4-methylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) p-tolylmethanol

A solution of n-butyllithium in hexane (2.44M, 5.65mL) was added dropwise to a THF solution (126mL) of 1-benzyloxy-2-bromobenzene (3.3g, 12.54mmol) at-78 deg.C under a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 4-methylbenzaldehyde (1.28g, 10.6mmol) in THF (42mL) at-78 ℃. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.3g, 71%).

¹H-NMR(CDCl₃)δ：2.33(3H，s)、2.87(1H，s)、5.02(2H，s)、 6.03(1H，s)、6.09-6.99(2H，m)、7.09-7.34(11H，m)

2) Synthesis of 2- (4-methylbenzyl) phenol

To a solution of (2-benzyloxyphenyl) p-tolylmethanol (1.5g, 4.43mmol) in methanol (27mL) was added a 20% palladium hydroxide catalyst (150mg), followed by 2N-HCl (0.37 mL). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (617mg, 70%).

¹H-NMR(CDCl₃)δ：1.55(3H，s)、3.95(2H，s)、4.65(1H，s)、6.75-6，90(2H，m)、7.09-7.25(6H，m)

3) Synthesis of [2- (4-methylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

Under a nitrogen flow, 2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (2mL) of 2- (4-methylbenzyl) phenol (275mg, 1.39mmol) under ice cooling, followed by addition of tetramethylazodicarboxamide (TMAD, 239mg, 1.39mmol) at the same temperature. The reaction mixture was stirred for 20 hours while slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)). The obtained crude product was dissolved in a mixed solution (8mL) of methanol-THF (1: 1), and a 20% palladium hydroxide catalyst (44mg) was added thereto, followed by stirring under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (20mg, 6%).

¹H-NMR(CD₃OD)δ：0.84-0.97(1H，m)、1.44-2.03(1H，m)、1.96-2.03(1H，m)、2.22(3H，s)、3.13-3.30(2H，m)、3.39-3.46(2H，m)、3.64(1H，dd，J＝10.8，4.5Hz)、3.95(2H，m)、4.12(1H，m)、6.76-6.81(1H，m)、6.92-7.03(5H，m)、7.06-7.11(2H，m)

MS(ESI⁺)：381[M+Na]⁺

HPLC retention time: 11.4 minutes

Example 38

[2- (4-methoxybenzyl) -5-trifluoromethylthiophen-3-yl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 3-benzyloxy-2- (4-methoxybenzyl) -5-trifluoromethylthiophene

Trifluoroacetic acid (3mL) was added dropwise to a solution of (3-benzyloxy-5-trifluoromethylthiophen-2-yl) - (4-methoxyphenyl) methanone [ methanone ] (220.2mg, 0.56mmol) and triethylsilane (1.34mL, 8.41mmol) in methylene chloride (1.1mL) synthesized according to the method described in International publication WO 04/007517 at 0 ℃ over 5 minutes in a nitrogen stream. After stirring at the same temperature for 6 hours and 45 minutes, triethylsilane (0.9mL, 5.61mmol) was added. After stirring at the same temperature for 16 hours and 45 minutes, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (108.8mg, 51%).

¹H-NMR(CDCl₃)δ：3.79(3H，s)、3.96(2H，s)、5.04(2H，s)、6.82(2H，d，J＝8.6Hz)、7.11(2H，d，J＝8.6Hz)、7.16(1H，s)、7.30-7.41(5H，m)

2) Synthesis of 2- (4-methoxybenzyl) -5-trifluoromethylthiophene-3-ol [ thiophen-3-ol ]

To a dichloromethane solution (4.5mL) of (3-benzyloxy-2- (4-methoxybenzyl) -5-trifluoromethylthiophene (170.5mg, 0.45mmol) was added a dichloromethane solution (0.47mL, 0.47mmol) of boron tribromide dimethyl sulfide complex at-78 ℃ in a nitrogen stream, the mixture was stirred at the same temperature for 5 minutes and at 0 ℃ for 11 hours, water was added to the reaction mixture, the mixture was extracted with dichloromethane, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, the solvent was removed by drying (anhydrous sodium sulfate), and the resulting residue was purified by silica gel column chromatography (developing solution: ethyl acetate: n-hexane (1: 5)) to obtain the title compound (117.0mg, 90%).

¹H-NMR(CDCl₃)δ：3.80(3H，s)、3.97(2H，s)、4.47(1H，s)、6.87(2H，d，J＝8.6Hz)、6.98(1H，s)、7.19(2H，d，J＝8.6Hz)

3) Synthesis of [2- (4-methoxybenzyl) -5-trifluoromethylthiophen-3-yl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (146mg, 0.27mmol) and tributylphosphine (0.10mL, 0.41mmol) were added to a toluene solution (0.85mL) of 2- (4-methoxybenzyl) -5-trifluoromethylthiophene-3-ol (117mg, 0.41mmol) under ice-cooling in a nitrogen stream, and then tetramethylazodicarboxamide (TMAD, 70mg, 0.41mmol) was added at the same temperature. The reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10 to 1: 8)). The obtained product was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 8)) to obtain the title compound (47.2 mg).

¹H-NMR(CDCl₃)δ：1.56-1.80(2H，m)、1.96-2.10(1H，m)、3.40-3.70(5H，m)、3.75(3H，s)、3.96(2H，s)、3.96-4.16(1H，m)、4.44(2H，s)、4.53(1H，d，J＝11.0Hz)、4.70-5.00(5H，m)、6.79(2H，d，J＝8.6Hz)、7.06-7.38(23H，m)

4) Synthesis of [2- (4-methoxybenzyl) -5-trifluoromethylthiophen-3-yl ] -5 a-carbon-beta-D-glucopyranoside

[2- (4-methoxybenzyl) -5-trifluoromethylthiophen-3-yl ] -2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. beta. -D-glucopyranoside (45.2mg, 0.056mmol) was dissolved in dichloromethane (0.5mL) under a nitrogen flow, and dimethylsulfide (0.145mL, 3.35mmol) and boron trifluoride diethyl etherate (0.07mL, 0.56mmol) were added under ice cooling. The reaction mixture was stirred at the same temperature for 5 minutes and at room temperature for 19 hours, and then saturated aqueous sodium bicarbonate solution and water were added under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (developing solution ═ n-hexane: acetone (1: 1)) to obtain the title compound (12.2mg, 49%).

¹H-NMR(CD₃OD)δ：1.15-1.35(1H，m)、1.40-1.65(1H，m)、1.95-2.15(1H，m)、3.15-3.35(2H，m)、3.35-3.60(2H，m)、3.65-3.80(1H，m)、3.75(3H，m)、3.90-4.06(1H，m)、4.01(2H，m)、6.84(2H，d，J＝8.3Hz)、7.16(2H，d，J＝8.3Hz)、7.40(1H，s)

MS(ESI⁺)：448[M]⁺

HPLC retention time: 12.4 minutes

Example 39

[ 3-methoxy-2- (4-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of benzyl 2-benzyloxy-6-methoxybenzoate

DMF (30mL) was added under a nitrogen stream while stirring a mixture of 6-methoxysalicylic acid (5.07g, 30.15mmol) and sodium hydride (60% w/w, 3.02g, 75.38mmol) under ice cooling. After stirring at the same temperature for 10 minutes, benzyl bromide (8.95mL, 75.38mmol) was added over 5 minutes, and the reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 2.5 hours. Saturated aqueous ammonium chloride and water were added under ice-cooling, and extracted with ether. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride, dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10 to 1: 5)) to obtain the title compound (6.24g, 59%).

¹H-NMR(CDCl₃)δ：3.81(3H，s)、5.08(2H，s)、5.35(2H，s)、6.55(1H，d，J＝5.9Hz)、6.58(1H，d，J＝5.9Hz)、7.15-7.45(11H，m)

2) Synthesis of (2-benzyloxy-6-methoxyphenyl) methanol

To a suspension of lithium aluminum hydride (0.88g, 23.14mmol) in diethyl ether (35mL) at room temperature under a stream of nitrogen was added a solution of benzyl 2-benzyloxy-6-methoxybenzoate (6.2g, 17.80mmol) in diethyl ether (20mL) over 15 minutes. The reaction mixture was stirred under heating reflux for 2 hours. After ethyl acetate (2mL) was added dropwise under ice-cooling, a saturated aqueous Rochelle [ Rochelle ] salt solution (20mL) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. After filtration through celite, a saturated aqueous Rochelle's salt solution (15mL) was added to the filtrate, followed by extraction with ether. The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ diethyl ether: n-hexane (1: 1)) to obtain the title compound (4.75g, 100%).

¹H-NMR(CDCl₃)δ：2.48(1H，t，J＝6.8Hz)、3.85(3H，s)、4.84(2H，d，J＝6.8Hz)、5.10(2H，s)、6.58(1H，d，J＝8.4Hz)、6.62(1H，d，J＝8.2Hz)、7.20(1H，dd，J＝8.4Hz，8.2Hz)、7.28-7.47(5H，m)

3) Synthesis of (2-benzyloxy-6-methoxyphenyl) - (4-methoxyphenyl) methanol

A solution of (2-benzyloxy-6-methoxyphenyl) methanol (3.52g, 14.41mmol) and N-methylmorpholine N-oxide (NMO, 2.53g, 21.61mmol) in dichloromethane (14.5mL) was cooled in a nitrogen stream in a water bath and ammonium tetra-N-propylperruthenate (TPAP, 152mg, 0.43mmol) was added. The reaction mixture was stirred at the same temperature for 20 minutes, at room temperature for 1.75 hours, then filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 3 to 1: 2.5)). The resulting compound was dissolved in THF, cooled with a water bath, and a THF solution of 4-methoxyphenylmagnesium bromide (0.5M, 30.3mL) was added dropwise under a nitrogen stream. After stirring at room temperature for 1.25 hours, a saturated aqueous ammonium chloride solution was added at room temperature, followed by extraction with diethyl ether. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4 to 1: 3.5)) to obtain the title compound (3.66g, 72%).

¹H-NMR(CDCl₃)δ：3.78(3H，s)、3.81(3H，s)、4.28(1H，d，J＝11.7Hz)、4.99(1H，d，J＝11.5Hz)5.06(1H，d，J＝11.5Hz)、6.33(1H，d，J＝11.7Hz)、6.61(1H，d，J＝7.6Hz)、6.64(1H，d，J＝7.6Hz)、6.80(2H，d，J＝8.7Hz)、7.10-7.40(8H，m)

4) Synthesis of 3-methoxy-2- (4-methoxybenzyl) phenol

To a solution of (2-benzyloxy-6-methoxyphenyl) - (4-methoxyphenyl) methanol (2.13g, 6.08mmol) in methanol (50mL) was added 20% palladium hydroxide catalyst (0.32g), followed by 2N-HCl (1.8 mL). After stirring for 24 hours in a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (1.31g, 89%).

¹H-NMR(CDCl₃)δ：3.76(3H，s)、3.82(3H，s)、3.98(2H，s)、4.67(1H，s)、6.45(1H，d，J＝8.1Hz)、6.52(1H，d，J＝8.2Hz)、6.79(1H，d，J＝8.6Hz)、7.07(1H，dd，J＝8.1Hz，8.2Hz)、7.17(1H，d，J＝8.6Hz)

5) Synthesis of [ 3-methoxy-2- (4-methoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (504mg, 0.94mmol) and tributylphosphine (0.35mL, 1.40mmol) were added to a toluene-THF solution (toluene 2.5mL, THF 0.3mL) of 3-methoxy-2- (4-methoxybenzyl) phenol (343mg, 1.40mmol) under ice-cooling in a nitrogen stream, and then tetramethylazodicarboxamide (TMAD, 242mg, 1.40mmol) was added at the same temperature. The reaction mixture was stirred under ice-cooling for 1.25 hours and at room temperature for 22 hours. The reaction solution was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10 to 1: 5)). The obtained crude product was dissolved in a mixed solution (10mL) of methanol-THF (1: 4), and a 20% palladium hydroxide catalyst (94mg) was added thereto, followed by stirring under a hydrogen atmosphere for 5 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (15: 1 to 10: 1)) to obtain the title compound (121mg, 32%).

¹H-NMR(CD₃OD)δ：0.85-1.05(1H，m)、1.40-1.65(1H，m)、1.95-2.15(1H，m)、3.10-3.30(2H，m)、3.40-3.55(2H，m)、3.60-3.75(1H，m)、3.71(3H，s)、3.79(3H，s)、3.92(2H，s)、4.05-4.25(1H，m)、6.59(1H，d，J＝8.2Hz)、6.65-6.75(3H，m)、7.05-7.15(3H，m)

MS(ESI⁺)：405[M+H]⁺

HPLC retention time: 10.6 minutes

Example 40

[2- (4-methoxybenzyl) -3-methylphenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (2-benzyloxy-6-methylphenyl) methanol

To a suspension of lithium aluminum hydride (0.82g, 21.50mmol) in diethyl ether (30mL) at room temperature over 10 minutes under a stream of nitrogen was added a solution of ethyl 2-benzyloxy-6-methylbenzoate (4.47g, 16.54mmol) in diethyl ether (15 mL). The reaction mixture was stirred under heating under reflux for 1 hour. After ethyl acetate (2mL) was added dropwise under ice-cooling, a saturated aqueous Rochelle salt solution (20mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After filtration through Celite, a saturated aqueous Rochelle's salt solution (10mL) was added to the filtrate, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (3.84g, 100%).

¹H-NMR(CDCl₃)δ：2.20(1H，d，J＝6.6Hz)、2.40(3H，s)、4.79(2H，d，J＝6.6Hz)、5.11(2H，s)、6.83(2H，d，J＝7.9Hz)、7.15(1H，t，J＝7.9Hz)、7.25-7.50(5H，m)

2) Synthesis of 2-benzyloxy-6-methylbenzaldehyde

A solution of (2-benzyloxy-6-methylphenyl) methanol (3.46g, 15.16mmol) and N-methylmorpholine N-oxide (NMO, 2.66g, 22.73mmol) in dichloromethane (10mL) was cooled in a nitrogen stream with a water bath, and ammonium tetra-N-propylperruthenate (TPAP, 152mg, 0.43mmol) was added. After the reaction mixture was stirred at the same temperature for 1.75 hours, it was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (3.08g, 90%).

¹H-NMR(CDCl₃)δ：2.59(3H，s)、5.16(2H，s)、6.82(1H，d，J＝7.3Hz)、6.90(1H，d，J＝8.4Hz)、7.25-7.50(6H，m)、10.73(1H，s)

3) Synthesis of (2-benzyloxy-6-methylphenyl) - (4-methoxyphenyl) methanol

A THF solution (10mL) of 2-benzyloxy-6-methylbenzaldehyde (3.08g, 13.6mmol) was cooled in a nitrogen stream in a water bath, and a THF solution of 4-methoxyphenylmagnesium bromide (0.5M, 30.3mL) was added dropwise. After stirring at room temperature for 1.75 hours, a saturated aqueous ammonium chloride solution was added under ice-cooling, and extraction was performed with diethyl ether. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 6 to 1: 5)) to obtain the title compound (4.57g, 100%).

¹H-NMR(CDCl₃)δ：2.38(3H，s)、3.80(3H，s)、4.09(1H，d，J＝11.2Hz)、4.88(1H，d，J＝11.5Hz)、5.00(1H，d，J＝11.5Hz)、6.03(1H，d，J＝11.2Hz)、6.75-6.90(4H，m)、6.90-7.05(2H，m)、7.10-7.35(6H，m)

4) Synthesis of 2- (4-methoxybenzyl) -3-methylphenol

To a solution of (2-benzyloxy-6-methylphenyl) - (4-methoxyphenyl) methanol (2.39g, 7.15mmol) in methanol (50mL) was added 20% palladium hydroxide catalyst (0.36g), followed by 36% HCl (0.36 mL). After stirring for 11 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (1.40g, 86%).

¹H-NMR(CDCl₃)δ：2.28(3H，s)、3.76(3H，s)、3.99(2H，s)、4.61(1H，s)、6.67(1H，d，J＝8.1Hz)、6.70-6.85(3H，m)、6.95-7.15(3H，m)

5) Synthesis of [2- (4-methoxybenzyl) -3-methylphenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene-THF solution of 2- (4-methoxybenzyl) -3-methylphenol (318mg, 1.39mmol) in toluene (1mL of toluene, 0.1mL of THF) under ice-cooling in a nitrogen stream, and then tetramethylazodicarboxamide (TMAD, 242mg, 1.40mmol) was added at the same temperature. The reaction mixture was stirred under ice-cooling for 10 minutes and at room temperature for 23 hours. The reaction solution was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 7 to 1: 6)). The obtained crude product was dissolved in a mixed solution (4mL) of methanol-THF (1: 3), and a 20% palladium hydroxide catalyst (66mg) was added thereto, followed by stirring under a hydrogen atmosphere for 6.5 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (55mg, 15%).

¹H-NMR(CD₃OD)δ：0.85-1.05(1H，m)、1.45-1.65(1H，m)、2.00-2.15(1H，m)、2.21(3H，s)、3.15-3.30(2H，m)、3.40-3.55(2H，m)、3.65-3.75(1H，m)、3.72(3H，s)、3.94(1H，d，J＝15.0Hz)、4.06(1H，d，J＝15.0Hz)、4.05-4.20(1H，m)、6.70-6.80(3H，m)、6.91(1H，d，J＝8.2Hz)、6.95-7.10(3H，m)

MS(ESI⁺)：411[M+Na]⁺

HPLC retention time: 11.2 minutes

EXAMPLE 41

[2- (3-fluoro-4-methoxybenzyl) phenyl]-5 a-carbon-alpha-D-glucopyranoside

1) Synthesis of (2-benzyloxyphenyl) - (3-fluoro-4-methoxyphenyl) methanol

A solution of n-butyllithium in hexane (1.54M, 6.79mL) was added dropwise to a THF solution (30mL) of 1-benzyloxy-2-bromobenzene (2.5g, 9.50mmol) at-78 ℃ in a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 3-fluoro-4-methoxybenzaldehyde (1.32g, 8.56mmol) in THF (8mL) at-78 ℃. After stirring at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (2.79g, 96%).

¹H-NMR(CDCl₃)δ：2.92(1H，d，J＝5.8Hz)、3.87(3H，s)、5.03(2H，s)、5.98(1H，d，J＝6.0Hz)、6.85-7.10(5H，m)、7.21-7.35(7H，m)

2) Synthesis of 2- (3-fluoro-4-methoxybenzyl) phenol

To a solution of (2-benzyloxyphenyl) - (3-fluoro-4-methoxyphenyl) methanol (1.50g, 4.43mmol) in methanol (29mL) was added a 20% palladium hydroxide catalyst (150mg), followed by 2N-HCl (2 mL). After stirring for 15 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (0.95g, 92%).

¹H-NMR(CDCl₃)δ：3.85(3H，s)、3.91(2H，s)、4.69(1H，br s)、6.77(1H，dd，J＝1.1，8.0Hz)、6.84-6.97(4H，m)、7.09-7.16(2H，m)

3) Synthesis of [2- (3-fluoro-4-methoxybenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

2, 3, 4, 6-tetra-O-benzyl-5 a-carbon-. alpha. -D-glucopyranose (500mg, 0.93mmol) and tributylphosphine (0.35mL, 1.39mmol) were added to a toluene solution (3mL) of 2- (3-fluoro-4-methoxybenzyl) phenol (323mg, 1.39mmol) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (TMAD, 242mg, 1.40mmol) at the same temperature. The reaction mixture was stirred for 40.5 hours while slowly warmed to room temperature. The reaction mixture was subjected to silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 6)). The obtained crude product was dissolved in a mixed solution (6mL) of methanol-THF (1: 2), and a 20% palladium hydroxide catalyst (65mg) was added thereto, followed by stirring under a hydrogen atmosphere for 2 hours, and then the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (10: 1)) to obtain the title compound (78mg, 21%).

¹H-NMR(CD₃OD)δ：0.85-1.05(1H，m)、1.40-1.65(1H，m)、1.95-2.15(1H，m)、3.35-3.60(2H，m)、3.60-4.00(3H，m)、3.81(3H，s)、4.05-4.25(1H，m)，6.70-7.20(7H，m)

MS(ESI⁺)：392[M]⁺

HPLC retention time: 10.7 minutes

Example 42

[4- (4-cyclopropyl-benzyl) pyridin-3-yl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 3- (2-trimethylsilylethoxymethyl) pyridine

Sodium hydride (3.85g, 96.3mmo1) was washed with hexane, and dimethoxyethane (90mL) was added. Under ice-cooling, 3-hydroxypyridine (4.97g, 52.3mmol) was added over 10 minutes. After stirring for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (10.0mL, 56.5mmol) was added over 25 minutes under ice-cooling. After stirring at room temperature for 14.5 hours, water was added to the reaction mixture under ice-cooling, the mixture was extracted with ether, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by flash column chromatography on silica gel (developing solution ═ hexane: ethyl acetate ═ 3: 1) to obtain the title compound (10.8g, 92%).

¹H-NMR(CDCl₃)δ：0.00(9H，s)、0.93-0.98(2H，m)、3.73-3.79(2H，m)、5.24(2H，s)、7.18-7.23(1H，m)、7.34-7.38(1H，m)、8.25(1H，dd、J＝4.7，1.4Hz)、8.40(1H，dd，J＝3.0，0.6Hz)

2) Synthesis of (4-cyclopropylphenyl) - [3- (2-trimethylsilylethoxymethyloxy) pyridin-4-yl ] methanol

A solution of tert-butyllithium in n-pentane (1.47M, 6.20mL) was added dropwise to a solution of 3- (2-trimethylsilylethoxymethyl) pyridine (1.77g, 7.85mmol) in dry THF (31mL) at-70 ℃ over 25 minutes in a stream of nitrogen. After stirring at-70 ℃ for 1 hour, a solution of 4-cyclopropylbenzaldehyde (1.49g, 10.19mmol) in ether (10mL) was added dropwise over 25 minutes. Stirring was carried out at-70 ℃ for 2 hours and at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added, extraction was performed with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (developing solution ═ n-hexane: ethyl acetate (2: 1)) to obtain the title compound (2.17g, 74%).

¹H-NMR(CDCl₃)δ：-0.04(9H，s)、0.61-0.66(2H，m)、0.84-0.96(4H，m)、1.79-1.90(1H，m)、3.48-3.59(2H，m)、5.13(2H，dd、J＝22.8，6.9Hz)、6.00(1H，s)、6.97-6.99(2H，m)、7.20-7.23(2H，m)、7.48(1H，d、J＝4.9Hz)、8.18(1H，d，J＝4.9Hz)、8.27(1H，s)

3) Synthesis of (4-cyclopropylphenyl) - [3- (2-trimethylsilylethoxymethyl) -pyridin-4-yl ] methanone

To a solution of (4-cyclopropylphenyl) - [3- (2-trimethylsilylethoxymethyl) pyridin-4-yl ] methanol (2.17g, 5.84mmol) in methylene chloride (31mL) was added Dess-Martin Periodinane (2.71g, 6.39mmol) in a nitrogen stream, and the mixture was stirred at room temperature for 1.5 hours. Then Dess-Martin Periodinane (0.27g, 0.64mmol) was added and stirred for 1.5 hours. The insoluble matter was filtered, and the filtrate was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 1)) to obtain the title compound (1.96g, 91%).

¹H-NMR(CDCl₃)δ：-0.04(9H，s)、0.76-0.90(4H，m)、1.05-1.12(2H，m)、1.92-1.98(1H，m)、3.56-3.62(2H，m)、5.17(2H，s)、7.09-7.13(2H，m)、7.19-7.21(1H，m)、7.67-7.71(2H，m)、8.40(1H，d，J＝4.67Hz)、8.65(1H，s)

4) Synthesis of (4-cyclopropylphenyl) - (3-hydroxypyridin-4-yl) methanone

To a solution of (4-cyclopropylphenyl) - [3- (2-trimethylsilylethoxymethyl) pyridin-4-yl ] methanone (1.96g, 5.30mmol) in THF (49mL) was added p-toluenesulfonic acid 1 hydrate (3.03g, 15.9mmol), and the mixture was stirred at 65 ℃ for 1 hour. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (developing solution ═ n-hexane: ethyl acetate (2: 3)) to obtain the title compound (1.10g, 87%).

¹H-NMR(CDCl₃)δ：0.80-0.86(2H，m)、1.09-1.16(2H，m)、1.97-2.03(1H，m)、7.18-7.22(2H，m)、7.42(1H，dd 、J＝5.2，0.6Hz)、7.63-7.68(2H，m)、8.24(1H，d，J＝5.2Hz)、8.59(1H，d、J＝0.6Hz)、11.15(1H，s)

5) Synthesis of (4-cyclopropylphenyl) - [3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridin-4-yl ] methanone

Diisopropyl azodicarboxylate (0.14mL, 0.72mmol) was slowly added dropwise to a mixture of (4-cyclopropylphenyl) - (3-hydroxypyridin-4-yl) methanone (0.18g, 0.74mmol), (1S, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexanol (0.20g, 0.37mmol), triphenylphosphine (0.19g, 0.74mmol) and toluene (1.3mL) under ice-cooling in a nitrogen stream. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (developing solution ═ n-hexane: ethyl acetate (2: 3)) to obtain the title compound (0.20g, 71%).

¹H-NMR(CDCl₃)δ：0.67-0.73(2H，m)、1.00-1.06(2H，m)、1.39-1.47(1H，m)、1.81-1.88(1H，m)、2.09-2.16(1H，m)、3.37-3.58(5H，m)、4.36-4.51(6H，m)、4.76-4.86(3H，m)、 6.98-7.07(4H，m)、7.13-7.35(19H，m)、7.62-7.66(2H，m)、8.34(1H，d，J＝4.9Hz)、8.54(1H，s)

6) Synthesis of (4-cyclopropylphenyl) - [3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridin-4-yl ] methanol

To a solution of (4-cyclopropylphenyl) - [3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridin-4-yl ] methanone (0.20g, 0.26mmol) in THF (1.37mL) -water (0.67mL) was added sodium borohydride (40mg, 1.06mmol) under ice-cooling, and the mixture was stirred at room temperature for 14.5 hours. THF was added to the reaction mixture, and concentrated hydrochloric acid (0.2mL) was added under ice-cooling, followed by stirring for 10 minutes. Saturated aqueous sodium carbonate solution was added and stirred at room temperature for 10 minutes. The organic layer was dried (anhydrous magnesium sulfate), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (3: 2)) to obtain the title compound (0.20g, 100%) as a diastereomer mixture.

¹H-NMR(CDCl₃)δ：0.47-0.53(1H，m)，0.58-0.63(1H，m)、0.80-0.92(2H，m)、1.09-1.27(2H，m)、1.68-1.84(2H，m)、3.32-3.64(5H，m)、4.34-4.53(4H，m)、4.70-4.88(5H，m)、5.84(0.5H，s)、5.96(0.5H，s)，6.85-6.97(3H，m)、7.05-7.35(21H，m)、7.43-7.48(1H，m)、8.20-8.24(2H，m)

MS(ESI⁺)：762[M+H]⁺

7) Synthesis of 4- [ chloro- (4-cyclopropylphenyl) methyl ] -3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridine

To a solution of (4-cyclopropylphenyl) - [3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridin-4-yl ] methanol (0.20g, 0.26mmol) in methylene chloride (3.0mL) was added thionyl chloride (0.05mL, 0.68mmol) in a nitrogen stream under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane, and after drying the organic layer (anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 1)) to obtain the title compound (0.20g, 100%) as a diastereomer mixture.

¹H-NMR(CDCl₃)δ：0.51-0.53(1H，m)，0.61-0.64(1H，m)、0.83-0.93 (2H，m)、1.10-1.18(1H，m)、1.66-1.77(3H，m)、2.15-2.27(1H，m)、3.30-3.66(5H，m)、4.38-4.55(4H，m)、4.83-4.91(4H，m)、6.23(0.5H，s)、6.39(0.5H，s)、6.85-6.96(3H，m)、7.11-7.33(21H，m)、7.54-7.58(1H，m)、8.26-8.42(2H，m)

MS(ESI⁺)：780[M+H]⁺

8) Synthesis of 4- (4-cyclopropylbenzyl) -3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridine

To a solution of 4- [ chloro- (4-cyclopropylphenyl) methyl ] -3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridine (0.22g, 0.28mmol) in dichloromethane (4.1mL) -acetic acid (12.4mL) was added zinc (0.14g, 2.14mmol) in a nitrogen stream, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium carbonate solution, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 1)) to obtain the title compound (0.14g, 67%).

¹H-NMR(CDCl₃)δ：0.57-0.62(2H，m)、0.86-0.92(2H，m)、1.51-1.59(1H，m)、1.70-1.85(2H，m)、2.08-2.15(1H，m)、3.44(1H，dd，J＝9.1，2.5Hz)、3.53-3.70(4H，m)、3.87(2H，d，J＝1.6Hz)、4.42-4.54(4H，m)、4.71(2H，dd，J＝17.6，10.7Hz)，4.83-4.93(3H，m)、6.90-7.34(25H，m)、8.11(1H，d、J＝4.7Hz)、8.35(1H，s)

9) Synthesis of [4- (4-cyclopropylbenzyl) pyridin-3-yl ] -5 a-carbon-beta-D-glucopyranoside

To a solution of 4- (4-cyclopropylbenzyl) -3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) pyridine (136mg, 0.18mmol) in methylene chloride (7.1mL) was added pentamethylene (0.40g, 2.70mmol) and a solution of boron trichloride in methylene chloride (1.0M, 1.00mL, 1.00mmol) in a nitrogen stream at-78 ℃ and the mixture was stirred at-78 ℃ for 3.5 hours. After methanol (1.7mL) was added, a methanol solution (1.0M, 4mL) of sodium methoxide was added, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (5: 1)) to obtain the title compound (66mg, 95%).

¹H-NMR(CD₃OD)δ：0.60-0.65(2H，m)、0.88-0.95(2H，m)、1.06-1.19(1H，m)、1.56-1.61(1H，m)、1.81-1.88(1H，m)、2.05-2.12(1H，m)、3.20-3.27(2H，m)、3.47-3.55(2H，m)、3.72(1H，dd，J＝10.7，3.8Hz)、3.90-4.03(2H，m)、4.28-4.36(1H，m)、6.97(2H，td、J＝8.2，1.9Hz)、7.07-7.10(3H，m)、8.00(1H，d，J＝4.7Hz)、8.30(1H，s)

MS(ESI⁺)：386[M+H]⁺

HPLC retention time: 8.40 minutes

Example 43

[2- (4-Carboxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

To a methanol-THF solution (10mL-5mL) of [2- (4-methoxycarbonylbenzyl) phenyl ] -5 a-carbon-. beta. -D-glucopyranoside (72.0mg, 0.1mmol) obtained in example 31 was added a 20% palladium hydroxide catalyst (7.2 mg). After stirring for 15 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure to give the title compound (38.2mg, 100%).

¹H-NMR(CD₃OD)δ：0.86-1.00(1H，m)、1.51-1.58(1H，m)、2.01-2.11(1H，m)、3.16-3.34(2H，m)、3.43-3.50(2H，m)、3.67-3.73(1H，m)、3.95-4.88(3H，m)、6.87(1H，t，J＝13.5Hz)、7.03(1H，d，J＝7.4Hz)、7.12-7.21(2H，m)、7.30(2H，d，J＝8.1Hz)、7.88(2H，d，J＝8.1Hz)

MS(ESI⁺)：389[M+H]⁺

HPLC retention time: 10.6 minutes

Example 44

[2- (4-vinylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 2- (4-bromobenzyl) phenol

To a solution of 1-benzyloxy-2- (4-bromobenzyl) benzene (1.0g, 2.83mmol) in methylene chloride (30.0mL) was added dimethyl sulfide (1.83mL, 42.46mmol) and boron trifluoride diethyl etherate (0.9mL, 7.07mmol) under a nitrogen stream under ice cooling. The reaction mixture was stirred while slowly warmed to room temperature for 19 hours, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (527mg, 70.8%).

¹H-NMR(CDCl₃)δ：3.92(2H，s)、4.62(1H，s)、6.73-6.76(1H，m)、6.85-6.99(1H，m)、7.06-7.14(4H，m)、7.35-7.40(2H，m)

2) Synthesis of (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl trifluoromethanesulfonate

To a solution of (1S, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexanol (300mg, 0.557mmol) in methylene chloride (5.5mL) was added pyridine (205. mu.L, 2.53mmol), cooled to 0 ℃ and then trifluoromethanesulfonic anhydride (210. mu.L, 1.25mmol) was added. After stirring at the same temperature for 1 hour, a saturated aqueous sodium bicarbonate solution was added, and extraction was performed with dichloromethane. The combined organic layers were washed with a saturated aqueous potassium hydrogensulfate solution and a saturated brine, and dried over magnesium sulfate. The solvent was distilled off to obtain a crude product (380 mg).

¹H-NMR(CDCl₃)δ：1.83(1H，dd，J＝15.9，14.0Hz)、2.00-2.14(2H，m)、3.39(1H，dd，J＝9.2，2.3Hz)、3.50(1H，dd，J＝9.6，2.6Hz)、3.56(1H，dd，J＝10.2，9.3Hz)、3.75(1H，dd，J＝9.2，3.4Hz)、3.86(1H，dd，J＝9.5，9.3Hz)、4.40(2H、s)、4.50(1H，d，J＝10.8Hz)、4.62(1H，d，J＝11.4Hz)、4.79(1H，d，J＝10.7Hz)、4.82(1H，d，J＝11.5Hz)、4.89(1H，d，J＝10.7Hz)、4.92(1H，d，J＝10.7Hz)、5.33(1H，br)、7.15-7.30(20H，m)

3) Synthesis of [2- (4-bromobenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

A solution of 1-benzyloxy-2- (4-bromobenzyl) benzene (386mg, 1.46mmol) in DMF (1mL) was cooled in an ice bath under a nitrogen stream, and NaH (60%, 52mg) was added. After stirring at the same temperature for 10 minutes, the reaction mixture was added dropwise to a suspension of trifluoromethanesulfonic acid (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl ester (655mg, 0.97mmol) in DMF (2.5mL) at-40 ℃. Stirring at the same temperature for 2 minutes, at-40 ℃ to 0 ℃ for 30 minutes, further at 0 ℃ for 1 hour, and then adding saturated brine and water. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to crude purification by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain a crude product (200 mg). The resulting crude product was dissolved in dichloromethane (2.5mL) in a nitrogen stream. Dimethyl sulfide (0.6mL, 13.48mmol) and boron trifluoride diethyl etherate (284. mu.L, 2.2mmol) were added under ice cooling. The reaction mixture was stirred for 25 hours while slowly warmed to room temperature, and then water was added thereto under ice-cooling, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution: dichloromethane: methanol (10: 1)) to obtain the title compound (40.0mg, 42.9%).

¹H-NMR(CD₃OD)δ：0.85(1H，q，J＝13.2，J＝11.1Hz)、1.44-1.59(1H，m)、2.03-2.09(1H，m)、3.13(1H，d，J＝8.7Hz)、3.19(1H，d，J＝5.1Hz)、3.23-3.26(2H，m)、3.37-3.45(2H，m)、3.63-3.68(1H，dd，J＝10.6，3.9Hz)、3.81(1H，d，J＝14.4Hz)、4.10(1H，d，J＝14.4Hz)、4.09-4.18(1H，m)、6.79(1H，t，J＝7.5Hz)、6.96(1H，d，J＝9.0Hz)、7.03-7.13(4H，m)、7.27-7.32(2H，m)

4) Synthesis of 2- (4-vinylbenzyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

[2- (4-bromobenzyl) phenyl ] -5 a-carbon-. beta. -D-glucopyranoside (40mg, 0.094mmol) was dissolved in toluene (2mL) in a nitrogen stream, and tributylvinyltin (36mg, 0.11mmol), tetrakis (triphenylphosphine) palladium (0) (2.7mg), and 2, 6-di-tert-butyl-4-methylphenol (1.5mg, 0.007mmol) were added thereto and then refluxed at 110 ℃ for 15 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 10)) to obtain the title compound (9mg, 25.7%).

¹H-NMR(CD₃OD)δ：0.86(1H，q，J＝12.0，11.7)、1.42-1.55(1H，m)、1.96-2.03(1H，m)、3.10-3.19(2H，m)、3.22-3.25(2H，m)、3.36-3.44(2H，m)、3.63(1H，dd，J＝10.6，4.1Hz)、3.81-4.08(2H，m)、4.09-4.16(1H，m)、5.07(1H，dd，J＝11.0，1.2Hz)、5.63(1H，dd，J＝18.0，1.2Hz)、6.61(1H，dd，J＝18.0，11.0Hz)、6.78(1H，t，J＝7.3Hz)、7.03(1H，d，J＝6.3Hz)、7.02-7.24(6H，m)

MS(ESI⁺)：370[M]⁺

HPLC retention time: 11.8 minutes

Example 45

{2- [4- (2, 2-difluorovinyl) benzyl]Phenyl } -5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 1-diethoxymethyl-4- (2, 2-difluorovinyl) benzene to diisopropylamine (3.40mL, 24.2mmol) cooled in an ice bath in a nitrogen stream, a hexane solution of n-butyllithium (2.44M, 9.94mL) was added dropwise, followed by addition of THF (20 mL). The resulting solution was cooled to-78 ℃ and diethyl (difluoromethyl) phosphonate (3.62mL, 23.1mmol) was added dropwise thereto. After stirring at the same temperature for 5 minutes, terephthalaldehyde mono (diethyl) acetal (4.2mL, 21.0mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 50 minutes, at room temperature for 20 minutes, and at 70 ℃ to 75 ℃ for 34 hours. After cooling to room temperature, saturated aqueous ammonium chloride and water were added, followed by extraction with diethyl ether. The organic layer was washed with a saturated aqueous solution of ammonium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 20)) to obtain the title compound (1.10g, 22%).

¹H-NMR(CDCl₃)δ：1.24(6H，t，J＝7.1Hz)、3.45-3.68(4H，m)、5.27(1H，dd，J＝26.4，3.8Hz)、5.49(1H，s)、7.32(2H，d，J＝8.4Hz)、7.44(2H，d，J＝8.4Hz)

2) Synthesis of 4- (2, 2-difluorovinyl) benzaldehyde

To a solution of 1-diethoxymethyl-4- (2, 2-difluorovinyl) benzene (998.1mg, 4.12mmol) in diethyl ether (4mL) cooled in an ice bath was added 2M aqueous hydrochloric acid (2.5mL) under a nitrogen stream, and the reaction mixture was stirred at the same temperature for 3 minutes and at room temperature for 3.75 hours. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product.

¹H-NMR(CDCl₃)δ：5.37(1H，dd，J＝25.7，3.5Hz)、7.49(2H，d，J＝8.4Hz)、7.85(2H，d，J＝8.4Hz)、9.98(1H，s)

3) Synthesis of (2-benzyloxyphenyl) - [4- (2, 2-difluorovinyl) phenyl ] methanol

A solution of 2-benzyloxybromobenzene (1.63g, 6.18mmol) in THF (4mL) was cooled to-78 deg.C under a nitrogen stream, and a solution of n-butyllithium in hexane (2.44M, 2.66mL) was added dropwise. After stirring at the same temperature for 25 minutes, a solution of the crude 4- (2, 2-difluorovinyl) benzaldehyde obtained previously in THF (1mL) was added dropwise. After stirring at the same temperature for 1.25 hours, a saturated aqueous ammonium chloride solution and water were added. The organic layer was washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (1.17g, 81%).

¹H-NMR(CDCl₃)δ：2.94(1H，d，J＝6.1Hz)、4.98-5.04(2H，m)、5.26(1H，dd，J＝26.4，3.8Hz)、6.03(1H，d，J＝6.1Hz)、6.88-7.04(2H，m)、7.14-7.38(11H，m)

4) Synthesis of 1-benzyloxy-2- [4- (2, 2-difluorovinyl) benzyl ] benzene

A solution of (2-benzyloxyphenyl) - [4- (2, 2-difluorovinyl) phenyl ] methanol (1.14g, 3.24mmol) in dichloromethane (10mL) was cooled to-78 deg.C under a nitrogen stream, and triethylsilane (5.17mL, 32.35mmol) was added. Boron trifluoride diethyl etherate (0.49mL, 3.88mmol) was added dropwise over 5 minutes, and the reaction mixture was stirred at-78 ℃ for 5 minutes and then under ice-cooling for 10 minutes. Saturated aqueous sodium bicarbonate and water were added and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 30)) to obtain the title compound (984.5mg, 90%).

¹H-NMR(CDCl₃)δ：4.00(2H，s)、5.05(2H，s)、5.23(1H，dd，J＝26.2，3.8Hz)、6.85-6.95(2H，m)、7.05-7.40(11H，m)

5) Synthesis of 2- [4- (2, 2-difluorovinyl) benzyl ] phenol

A solution of 1-benzyloxy-2- [4- (2, 2-difluorovinyl) benzyl ] benzene (984.5mg, 2.93mmol) in dichloromethane (12mL) was cooled to-78 deg.C under a stream of nitrogen and a solution of boron tribromide-dimethyl sulfide in dichloromethane (1.0M, 7.32mL) was added dropwise. After stirring at the same temperature for 10 minutes and further stirring under ice-cooling for 2 hours, a solution of boron tribromide-dimethylsulfide in methylene chloride (4.39mL) was further added dropwise. After stirring at the same temperature for 3.5 hours, an aqueous sodium hydroxide solution and an aqueous sodium hydrogencarbonate solution were added. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 7)) to obtain the title compound (647.5mg, 90%).

¹H-NMR(CDCl₃)δ：3.98(2H，s)、4.62(1H，s)、5.24(1H，dd，J＝26.2，3.8Hz)、6.78(1H，d，J＝8.1Hz)、6.84-6.94(1H，m)、7.04-7.32(6H，m)

6) Synthesis of {2- [4- (2, 2-difluorovinyl) benzyl ] phenyl } -5 a-carbon-. beta. -D-glucopyranoside

A solution of 2- [4- (2, 2-difluorovinyl) benzyl ] phenol (80mg, 0.324mmol) in DMF (1mL) was cooled in an ice bath under a stream of nitrogen and NaH (60%, 13mg) was added thereto. After stirring at the same temperature for 10 minutes, the reaction mixture was added dropwise to a suspension of trifluoromethanesulfonic acid (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl ester (181mg, 0.270mmol) in DMF (2.5mL) at-40 ℃. Stirring at the same temperature for 2 minutes, at-40 ℃ to 0 ℃ for 30 minutes, further at 0 ℃ for 1 hour, and then adding saturated brine and water. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 7)) to obtain the intended product (180.7 mg). 65mg (0.0848mmol) of the product was mixed with pentamethylene (188mg, 1.27mmol) in a nitrogen stream and dissolved in dichloromethane (2.5 mL). After cooling to-78 deg.C, a solution of boron trichloride in methylene chloride (1.0M, 0.42mL) was added dropwise. After the reaction mixture was stirred at the same temperature for 2.25 hours, methanol (0.5mL) was added dropwise. After a methanol solution of sodium methoxide (1M, 1.26mL) was added dropwise at the same temperature, the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 10)) to give the title compound (22.1mg, 64%).

¹H-NMR(CD₃OD)δ：0.82-1.04(1H，m)、1.44-1.64(1H，m)、1.98-2.12(1H，m)、3.12-3.28(2H，m)、3.40-3.54(2H，m)、3.69(1H，dd，J＝10.7，4.0Hz)、3.89(1H，d，J＝14.8Hz)、4.02(1H，d，J＝14.8Hz)、4.10-4.26(1H，m)、5.40(1H，dd，J＝27.0，4.0Hz)、6.78-6.90(1H，m)、6.96-7.30(7H，m)

MS(ESI⁺)：406[M]⁺

HPLC retention time: 18.51 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Mobile phase: according to the formula from 10mM AcONH₄/H₂O(95％)+10mM AcONH₄MeOH (5%) to 10mM AcONH₄A concentration gradient of 20 min/MeOH (100%) was performed, then under the same conditions (10mM AcONH)₄MeOH (100%)) for 5 minutes.

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Detection conditions are as follows: plotting the total amount of the total band of 230 to 400nm

Examples 46 to 58

The procedure of the above examples was repeated using the corresponding starting materials and reagents to obtain the objective compound.

Example 46

[2- (2, 3-dihydrobenzofuran-5-ylmethyl) phenyl ] -5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.93(1H，q，J＝13.2Hz，J＝11.4Hz)、1.49-1.58(1H，m)、2.01-2.07(1H，dt，J＝13.2，4.5Hz)、3.12(1H，t，J＝8.4Hz)、3.20(1H，d，J＝9.3Hz)、3.25(1H，d，J＝4.8Hz)、3.30-3.53(2H，m)、3.69(1H，dd，J＝6.6，4.2Hz)、3.85(1H，d，J＝15Hz)、3.91(1H，d，J＝15Hz)、4.13-4.21(1H，m)、4.47(2H，t，J＝8.7Hz)、6.59(1H，d，J＝8.4Hz)、6.83(1H，t，J＝7.2Hz)、6.89(1H，d，J＝8.1Hz)、6.99-7.15(4H，m)

MS(ESI⁺)：386[M]⁺

HPLC retention time: 10.5 minutes

Example 47

[2- (3-fluoro-4-methylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.99(1H，q，J＝12.6Hz)、1.48-1.59(1H，m)、2.04-2.10(1H，dt，J＝13.2，4.2Hz)、2.18(3H，s)、3.18-3.32(2H，m)、3.44-3.51(2H，m)、3.68(1H，dd，J＝6.9，3.9Hz)、3.89(1H，d，J＝15Hz)、3.97(1H，d，J＝15Hz)、4.14-4.22(1H，m)、6.81-6.90(3H，m)、7.00-7.17(4H，m)

MS(ESI⁺)：376.4[M]⁺

HPLC retention time: 11.7 minutes

Example 48

[2- (4-methoxy-3-methylbenzyl) phenyl]-5a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.94(1H，q，J＝12.9，11.7Hz)、1.47-1.57(1H，m)、2.01-2.08(1H，dt，J＝13.2，4.2Hz)、2.12(3H，s)、3.18-3.34(2H，m)、3.45-3.52(2H，m)、3.68(1H，dd，J＝6.6，4.2Hz)、3.75(3H，s)、 3.84(1H，d，J＝14.7Hz)、3.90(1H，d，J＝14.7Hz)、4.14-4.21(1H，m)、6.76(1H，d，J＝8.7Hz)、6.83(1H，t，J＝7.5Hz)、6.95-7.15(5H，m)

MS(ESI⁺)：389[M+H]⁺

HPLC retention time: 11.5 minutes

Example 49

[2- (4-pyrazol-1-ylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.95(1H，q，J＝12.9，11.4Hz)、1.49-1.59(1H，m)、2.02-2.09(1H，dt，J＝12.3，4.2Hz)、3.20(1H，d，J＝9.0Hz)、3.23(1H，d，J＝6.3Hz)、3.43-3.53(2H，m)、3.67(1H，dd，J＝6.6，4.2Hz)、3.98(1H，d，J＝14.7Hz)、4.07(1H，d，J＝15Hz)、4.16-4.24(1H，m)、6.49(1H，s)、6.87(1H，t，J＝7.5Hz)、7.05(1H，d，J＝8.1Hz)、7.14(2H，d，J＝7.5Hz)、7.35(2H，d，J＝8.4Hz)、7.56(2H，d，J＝8.4Hz)、7.68(1H，s)、8.12(1H，s)

MS(ESI⁺)：411[M+H]⁺

HPLC retention time: 10.5 minutes

Example 50

[2- (3-chloro-4-methoxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.94(1H，dd，J＝24.4，13.2Hz)、1.5-1.65(1H，m)、2.05(1H，dt，J＝13.5，4.1Hz)、3.18-3.35(2H，m)、3.43-3.55(2H，m)、3.70(1H，dd，J＝10.7，4.1Hz)、3.82(3H，s)、3.82(1H，d，J＝14.8Hz)、3.97(1H，d，J＝14.8Hz)、4.15-4.25(1H，m)、6.86(1H，td，J＝7.4，1.1Hz)、6.92(1H，d，J＝8.2Hz)、7.0-7.2(5H，m)

MS(ESI⁺)：409[M+H]⁺、431[M+Na]⁺

HPLC retention time: 11.25 minutes

Example 51

[2- (3, 4-methylenedioxybenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：1.01(1H，q，J＝12.7Hz)、1.45-1.64(1H，m)、2.04-2.13(1H，m)、3.19-3.35(4H，m)、3.46-3.54(2H，m)、3.69-3.74(1H，m)、3.89(2H，q，J＝16.1)，4.15-4.22(1H，m)、5.86(2H，s)，6.68(3H，s)、6.85(1H，t、J＝6.1Hz)、7.00-7.18(3H，m)

MS(ESI⁺)：389[M+H]⁺

HPLC retention time: 10.6 minutes

Example 52

[2- (4-Cyclobutylbenzyl) phenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.81-0.96(1H，m)、1.45-1.61(1H，m)、1.78-2.37(7H，m)、3.15-3.34(5H，m)、3.40-3.55(2H，m)、3.66-4.76(1H，m)、3.95(2H，q、J＝13.7Hz)、4.13-4.24(1H，m)、6.87(1H，t、J＝8.1Hz)、6.97-7.17(7H、m)

MS(ESI⁺)：425[M+Na]⁺

HPLC retention time: 13.6 minutes

Example 53

[2- (4-Acetylbenzyl) phenyl group]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.84-0.98(1H，m)、1.50-1.56(1H，m)、2.00-2.08(1H，m)、2.55(3H，s)、3.15-3.32(3H，m)、3.42-3.50(2H，m)、3.65-3.70(1H，m)、3.94-4.24(3H，m)、4.89(2H，s)、6.86(1H，t、J＝7.3Hz)、7.03(1H，d，J＝8.1Hz)、7.12-7.20(2H、m)、7.34(2H，d，J＝8.1Hz)、7.86(2H，d，J＝8.1Hz)

MS(ESI⁺)：386[M+1]⁺

HPLC retention time: 9.8 minutes

Example 54

[2- (4-methoxybenzyl) -5-methylphenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：0.92-1.06(1H，m)、1.51-1.66(1H，m)，2.08(1H，dt，J＝13.2，4.0Hz)、2.32(3H，s)、3.21-3.40(2H，m)、3.47-3.56(2H，m)、3.71-3.78(1H，m)、3.77(3H，s)、3.84(1H，d，J＝14.2Hz)，3.95(1H，d，J＝14.2Hz)、4.14-4.26(1H，m)、6.68-6.72(1H，m)、6.78-6.85(2H，m)、6.86-6.91(1H，m)、6.97(1H，d，J＝7.8Hz)、7.10-7.16(2H，m)

MS(ESI⁺)：388[M]⁺

HPLC retention time: 11.26 minutes

Example 55

[2- (4-ethylbenzyl) thiophen-3-yl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：1.20(1H，t，J＝7.6Hz)、1.40-1.80(1H，m)、2.04-2.09(1H，m)、2.59(2H，q，J＝7.58Hz)、3.19-3.55(5H，m)、3.88-3.96(1H，m)、3.99(2H，m)、6.89(2H，d，J＝5.4Hz)、7.06-7.15(5H，m)

MS(ESI⁺)：378[M]⁺

HPLC retention time: 11.9 minutes

Example 56

[ (benzothien-2-yl) methylphenyl]-5 a-carbon-beta-D-glucopyranoside

¹H-NMR(CD₃OD)δ：1.04(1H，m)、1.40-1.80(1H，m)、2.08-2.16(1H，m)、3.14-3.67(5H，m)、4.14(1H，d，J＝15.7Hz)、4.19-4.27(1H，m)、4.36(1H，d，J＝15.5Hz)、6.89(1H，dd、J＝8.1，6.6Hz)、7.02(1H，s)、7.07(1H，d，J＝8.1Hz)、7.17-7.28(4H，m)、7.63(1H，d，J＝7.6Hz)、7.71(1H，d，J＝7.6Hz)

MS(ESI⁺)：400[M]⁺

HPLC retention time: 12.0 minutes

Example 57

{2- [1- (4-Cyclopropylphenyl) ethyl]Phenyl } -5 a-carbon-beta-D-glucopyranoside

(isomer on the low polarity side separated by preparative TLC (developing solution: methanol: dichloromethane ═ 1: 10))

¹H-NMR(CD₃OD)δ：0.40(1H，dd，J＝9.3，9.0Hz)、0.56-0.66(2H，m)、0.84-0.96(2H，m)、1.36-1.54(1H，m)、1.52(3H，d，J＝6.6Hz)、1.76-1.88(2H，m)、3.04-3.12(1H，dd，J＝10.8，9.9Hz)、3.25(1H，t，J＝10.8Hz)、3.26-3.40(1H，m)、3.42(1H，t，J＝9.9Hz)、3.64(1H，dd，J＝10.4，4.8Hz)、4.08-4.22(1H，m)、4.50(1H，dd，J＝12.0，6.3Hz)、6.84-6.99(4H，m)、6.99-7.06(2H，m)、7.06-7.28(1H，m)、7.20-7.26(1H，m)

MS(ESI⁺)：399[M+H]⁺

HPLC retention time: 12.7 minutes

Example 58

{2- [1- (4-Cyclopropylphenyl) ethyl]Phenyl } -5 a-carbon-beta-D-glucopyranoside

(highly polar isomer separated by preparative TLC (developing solution: methanol: dichloromethane ═ 1: 10))

¹H-NMR(CD₃OD)δ：0.56-0.66(2H，m)、0.84-0.96(2H，m)、1.10(1H，dd，J＝9.6，9.0Hz)、1.44-1.64(1H，m)、1.53(3H，d，J＝6.6Hz)、1.76-1.88(1H，m)、2.13(1H，ddd，J＝12.2，4.5，3.3Hz)、3.20-3.28(2H，m)、3.44(1H，t，J＝10.5Hz)、3.53(1H，dd，J＝11.4，6.6Hz)、3.73(1H，dd，J＝11.4，2.4Hz)、4.06-4.22(1H，m)、4.50(1H，dd，J＝12.0，6.3Hz)、6.82-7.03(4H，m)、7.06-7.16(4H，m)

MS(ESI⁺)：399[M+H]⁺

HPLC retention time: 12.7 minutes

Example 59

[2- (4-Cyclopropylbenzyl) -5-methylthiophen-3-yl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of (4-cyclopropylphenyl) - (3-methoxy-5-methylthiophen-2-yl) methanone

To a THF solution (20mL) of (4-cyclopropylphenyl) - (3-methoxythiophen-2-yl) methanone (1.05g, 4.06mmol) synthesized in the same manner as in example 38 was added methyl iodide (2.53mL, 40.6mmol) under a nitrogen atmosphere. The solution was cooled to-78 ℃ and a solution of lithium diisopropylamide in heptane-THF-ethylbenzene (2.0M, 2.44mL, 4.88mmol) was added over 20 minutes. Stirred at the same temperature for 3 hours. To this solution was added a solution of lithium diisopropylamide in heptane-THF-ethylbenzene (2.0M, 2.44mL, 4.88mmol) over 20 minutes, stirred for 2 hours, and saturated ammonium chloride solution was added. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (589mg, 53%).

¹H-NMR(CDCl₃)δ：0.74-0.80(2H，m)、1.00-1.06(2H，m)、1.91-1.97(1H，m)、2.49(3H，s)、3.81(3H，s)、6.62(1H，s)、7.08(2H，d，J＝7.9Hz)、7.68(2H，d，J＝8.3Hz)

2) Synthesis of (4-cyclopropylphenyl) - (3-hydroxy-5-methylthiophen-2-yl) methanone

A solution of boron trichloride in methylene chloride (1.0M, 6.4mL, 6.4mmol) was added to a solution of (4-cyclopropylphenyl) - (3-methoxy-5-methylthiophen-2-yl) methanone (582mg, 2.14mmol) in methylene chloride (12mL) at-15 ℃ in a nitrogen stream, and the mixture was stirred for 1 hour. Water was added and extracted with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution: methanol: dichloromethane (1: 100)) to obtain the title compound (497mg, 90%).

¹H-NMR(CDCl₃)δ：0.76-0.82(2H，m)、1.03-1.10(2H，m)、1.93-1.98(1H，m)、2.49(3H，s)、6.57(1H，s)、7.15(2H，d，J＝8.4Hz)、7.85(2H，d，J＝8.4Hz)、12.80(1H，s)

3) Synthesis of (4-cyclopropylphenyl) - [ 5-methyl-3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) thiophen-2-yl ] methanone

Diisopropyl azodicarboxylate (0.27mL, 1.39mmol) was added dropwise to a mixture of (4-cyclopropylphenyl) - (3-hydroxy-5-methylthiophen-2-yl) methanone (360mg, 1.39mmol), (1S, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexanol (500mg, 0.93mmol), triphenylphosphine (365mg, 1.39mmol) and toluene (3.1mL) under a nitrogen stream under ice cooling. After stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (developing solution ═ n-hexane: ethyl acetate (4: 1)) to obtain the title compound (237mg, 33%).

¹H-NMR(CDCl₃)δ：0.70-0.73(2H，m)、0.99-1.02(2H，m)、1.35-1.50(1H，m)、1.64-1.72(1H，m)、1.87-1.94(1H，m)、2.07-2.14(1H，m)、2.44(3H，s)、3.36-3.56(5H，m)、4.07-4.13(1H，m)、4.33-4.88(8H，m)、6.61(1H，s)、7.01(2H，d，J＝7.9Hz)、7.05-7.35(22H，m)、7.62(2H，d，J＝8.2Hz)

4) Synthesis of 2- (4-cyclopropylbenzyl) -5-methyl-3- [ (1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyloxy ] thiophene

Under a nitrogen atmosphere, (4-cyclopropylphenyl) - [ 5-methyl-3- ((1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethylcyclohexyloxy) thiophen-2-yl ] methanone (237mg, 0.30mmol) was added to an acetonitrile (5mL) solution under ice-cooling, chlorotrimethylsilane (0.46mL, 3.65mmol), sodium cyanoborohydride (230mg, 3.65mmol) and stirred at 0 ℃ for 1 hour. Dichloromethane was added, and the mixture was filtered through celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain the title compound (135mg, 58%).

¹H-NMR(CDCl₃)δ：0.58-0.65(2H，m)、0.86-0.94(2H，m)、1.23-1.28(1H，m)、1.57-1.65(1H，m)、1.77-1.86(1H，m)、2.06-2.12(1H，m)、2.33(3H，s)、3.43-3.65(5H，m)、3.93(2H，s)、3.98-4.08(1H，m)、4.44(2H，s)、4.51(1H，d，J＝10.8Hz)、4.75-4.97(5H，m)、6.55(1H，s)、6.92(2H，d，J＝8.1Hz)、7.10(2H，d，J＝8.1Hz)、7.18-7.37(20H，m)

5) Synthesis of [2- (4-cyclopropylbenzyl) -5-methylthiophen-3-yl ] -5 a-carbon-beta-D-glucopyranoside

To a solution of 2- (4-cyclopropylbenzyl) -5-methyl-3- [ (1R, 2S, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethylcyclohexyloxy) ] thiophene (134mg, 0.18mmol) in methylene chloride (6mL) was added pentamethylene (390mg, 2.63mmol) and a solution of boron trichloride in methylene chloride (1.0M, 0.88mL, 0.88mmol) in a nitrogen stream at-78 ℃ and the mixture was stirred at-78 ℃ for 1 hour. Methanol was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane: methanol (20: 1)), to obtain the title compound (35mg, 49%).

¹H-NMR(CD₃OD)δ：0.62-0.68(2H，m)、0.90-0.97(2H，m)、1.10-1.21(1H，m)、1.43-1.56(1H，m)、1.82-1.95(1H，m)、2.03-2.11(1H，m)、2.36(3H，s)、3.25-3.90(6H，m)、3.94(2H，m)、6.63(1H，m)、6.98(2H，d、J＝8.4Hz)、7.11(2H，d、J＝7.9Hz)

MS(ESI^-)：403[M-H]^-

Example 60

[2- (4-ethylbenzyl) -5-methylthiophen-3-yl]-5 a-carbon-beta-D-glucopyranoside

The procedure of example 59 was repeated using the corresponding starting materials and reagents to give the objective compound.

¹H-NMR(CD₃OD)δ：1.10-1.22(4H，m)、1.40-1.54(1H，m)、2.02-2.09(1H，m)、2.33(3H，s)、2.58(2H，d、J＝7.6Hz)3.22-3.25(2H，m)、 3.28-3.35(2H，m)、3.39-3.45(1H，m)、3.52(1H，dd、J＝10.7，6.2Hz)、3.71(1H，dd、J＝10.7，4.0Hz)、3.83-3.90(1H，m)、6.60(1H，s)、7.06(2H，d、J＝8.2Hz)、7.11(2H，d、J＝8.2Hz)

MS(ESI⁺)：393[M+H]⁺、415[M+Na]⁺

Example 61

[ 5-chloro-2- (4-cyclopropylbenzyl) thiophen-3-yl]-5 a-carbon-beta-D-glucopyranoside

1) Synthesis of 4-cyclopropyl-N-methoxy-N-methylbenzamide

An n-hexane solution of n-butyllithium (1.6M, 6.0mL, 9.59mmol) was added dropwise to a solution of 1-bromo-4-cyclopropylbenzene (1.8g, 9.13mmol) in anhydrous THF (30mL) at-78 ℃ for 15 minutes in a nitrogen stream. The solution was stirred at-78 ℃ for 10 minutes, and a solution of N, N '-dimethoxy-N, N' -dimethylurea (1.42g, 9.59mmol) in THF (5mL) was added dropwise. Stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added, extraction was performed with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ n-hexane: ethyl acetate (4: 1)) to obtain the title compound (875mg, 95%).

¹H-NMR(CDCl₃)δ：0.73-0.78(2H，m)、0.97-1.03(2H，m)、1.87-1.94(1H，m)、3.34(3H，s)、3.56(3H，s)、7.08(2H，d、J＝8.3Hz)、7.60(2H，d、J＝8.3Hz)

2) Synthesis of (5-chloro-3-methoxythiophen-2-yl) - (4-cyclopropylphenyl) methanone

A n-hexane solution of n-butyllithium (1.6M, 2.43mL, 3.88mmol) was added dropwise to a solution of 2-bromo-5-chloro-3-methoxythiophene (882mg, 3.88mmol) in anhydrous THF (15mL) synthesized according to the method described in the literature (J.or g.chem., 58, 4629-one 4633(1993)) at-78 ℃ under a nitrogen stream. The solution was stirred for 10 min at-78 ℃ and a solution of 4-cyclopropyl-N-methoxy-N-methylbenzamide (875mg, 4.26mmol) in THF (3mL) was added dropwise. The reaction was stirred at-78 ℃ for 30 minutes. Saturated aqueous ammonium chloride solution was added thereto, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ n-hexane: ethyl acetate (4: 1)) to obtain the title compound (714mg, 63%).

¹H-NMR(CDCl₃)δ：0.75-0.81(2H，m)、1.02-1.08(2H，m)、1.92-1.98 (1H，m)、3.80(3H，s)、6.78(1H，s)、7.10(2H，d、J＝8.3Hz)、7.68(2H，d、J＝8.3Hz)

3) Synthesis of [ 5-chloro-2- (4-cyclopropylbenzyl) thiophen-3-yl ] -5 a-carbon-beta-D-glucopyranoside

The procedure of example 59 was repeated using a reagent corresponding to the synthesized (5-chloro-3-methoxythiophen-2-yl) - (4-cyclopropyl-phenyl) methanone to obtain the objective compound.

¹H-NMR(CD₃OD)δ：0.63-0.66(2H，m)、0.88-0.93(2H，m)、1.15-1.21(1H，m)、1.61-1.67(1H，m)、1.82-1.87(1H，m)、1.99-2.03(1H，m)、3.22-3.57(4H，m)、3.70-3.74(1H，m)、3.87-3.91(1H，m)、3.92(2H，s)、6.86(1H，s)、6.97(2H，d、J＝8.1Hz)、7.09(2H，d、J＝8.1Hz)

MS(ESI⁺)：425[M+H]⁺

Example 62

(1R, 2S, 3R, 6R) -6- [2- (4-cyclopropylbenzyl) phenoxy]-4- (hydroxymethyl) cyclohex-4-ene-1, 2, 3-triol

1) Synthesis of 1- (4-cyclopropylphenyl) methyl-2- [ (1R, 4R, 5S, 6S) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-2-enyloxy ] benzene

2- (4-Cyclopropylbenzyl) phenol (31mg, 0.14mmol) and tributylphosphine (70. mu.L, 0.28mmol) were added to a toluene solution (300. mu.L) of (1S, 4R, 5S, 6S) -4, 5, 6-tris (benzyloxy) -3- (benzyloxymethyl) cyclohex-2-enol (51mg, 0.095mmol) described in the literature (J.Or g.chem., 63, 5668-5671(1998)) under ice-cooling in a nitrogen stream, followed by addition of tetramethylazodicarboxamide (48mg, 0.28mmol) at the same temperature. After stirring at the same temperature for 20 hours, hexane was added, the precipitate was removed by filtration, and the solvent of the filtrate was distilled off. The obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 5)) to obtain the title compound (44mg, 62%).

¹H-NMR(CDCl₃)δ：0.54(2H，m)、0.84(2H，m)、1.75(1H，m)、3.82-3.92(3H，m)、3.93(2H，s)、4.19(1H，d，J＝12.5Hz)、4.35(1H，br)、4.41(1H，d，J＝11.7Hz)、4.46(1H，d，J＝11.8Hz)、4.61(1H，d，J＝10.7Hz)、4.68(1H，d，J＝10.2Hz)、4.72(1H，d，J＝10.5Hz)、4.79(1H，d，J＝10.8Hz)、4.85(1H，d，J＝10.7Hz)、4.99(1H，d，J＝11.0Hz)、5.04(1H，br)、 5.65(1H，s)、6.8-7.4(28H，m)

2) Synthesis of (1R, 2S, 3R, 6R) -6- [2- (4-cyclopropylbenzyl) phenoxy ] -4- (hydroxymethyl) cyclohex-4-ene-1, 2, 3-triol

To a solution of 1- (4-cyclopropylphenyl) methyl-2- [ (1R, 4R, 5S, 6S) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-2-enyloxy ] benzene (12mg, 0.016mmol) and pentamethylene (24mg, 0.17mmol) in methylene chloride (300. mu.L) was added a 1.0M solution of boron trichloride in methylene chloride (160. mu.L, 0.16mmol) in a nitrogen stream at-78 ℃ and the mixture was stirred at the same temperature for 1.5 hours. After addition of methanol, the temperature was raised to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 8)) to obtain the title compound (4.1mg, 70%).

¹H-NMR(CD₃OD)δ：0.61(2H，m)、0.89(2H，m)、1.83(1H，m)、3.55(1H，dd，J＝10.5，7.8Hz)、3.72(1H，dd，J＝10.5，7.8Hz)、3.89(1H，d，J＝14.8Hz)、3.93(1H，d，J＝14.9Hz)、4.11(2H，brs)、4.15(1H，d，J＝7.8Hz)、4.80(1H，d，J＝7.6Hz)、5.60(1H，t，J＝1.5Hz)、6.84(1H，t，J＝7.3Hz)、6.93(2H，d，J＝8.1Hz)、7.06(1H，d，J＝8.2Hz)、6.97-7.18(3H，m)

MS(ESI⁺)：405[M+Na]⁺

HPLC retention time: 12.5 minutes

Example 63

(1R, 2S, 3R, 6R) -4-hydroxymethyl-6- [2- (4-methoxybenzyl) phenoxy]Cyclohex-4-ene-1, 2, 3-triol

1) Synthesis of 1- (4-methoxyphenyl) methyl-2- [ (1R, 4R, 5S, 6S) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-2-enyloxy ] benzene

2- (4-methoxybenzyl) phenol (299mg, 1.40mmol) and tributylphosphine (380. mu.L, 1.53mmol) were added to a toluene solution (3mL) of (1S, 3S, 4S, 5R, 6S) -4, 5, 6-tribenzyloxy-1- (benzyloxymethyl) cyclohexane-1, 3-diol (561mg, 1.01mmol) synthesized in the reference (Tetrahedron, 56, 7109) -7122(2000)) under a nitrogen stream under ice cooling, and then tetramethylazodicarboxamide (261mg, 1.52mmol) was added at the same temperature. After stirring at the same temperature for 20 hours, hexane was added, the precipitate was removed by filtration, and the solvent of the filtrate was distilled off. The obtained residue was purified by silica gel chromatography (developing solution ═ ethyl acetate: n-hexane (1: 7 → 1: 1)) to obtain the title compound (312mg, 42%).

¹H-NMR(CDCl₃)δ：3.64(3H，s)、3.80-3.95(3H，m)、3.92(2H，s)、4.19(1H，d，J＝13.6Hz)、4.36(1H，br)、4.41(1H，d，J＝11.9Hz)、4.46(1H，d，J＝11.8Hz)、4.64(1H，d，J＝11.0Hz)、4.69(1H，d，J＝10.8Hz)、4.71(1H，d，J＝10.8Hz)、4.79(1H，d，J＝10.8Hz)、4.85(1H，d，J＝11.0Hz)、4.99(1H，d，J＝11.0Hz)、5.05(1H，br)、5.67(1H，s)、6.71(2H，d，J＝8.7Hz)、6.80-7.40(26H，m)

MS(ESI⁺)：755[M+Na]⁺

2) Synthesis of (1R, 2S, 3R, 6R) -4-hydroxymethyl-6- [2- (4-methoxybenzyl) phenoxy ] cyclohex-4-ene-1, 2, 3-triol

To a solution of 1- (4-methoxyphenyl) methyl-2- [ (1R, 4R, 5S, 6S) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-2-enyloxy ] benzene (312mg, 0.426mmol) in methylene chloride (12mL) was added a 1.0M solution of boron trichloride in methylene chloride (6.0mL, 6.0mmol) in a nitrogen stream at-78 ℃ and the mixture was stirred at the same temperature for 1.5 hours. After addition of methanol, the temperature was raised to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ methanol: dichloromethane (1: 8)) to obtain the title compound (37.9mg, 24%).

¹H-NMR(CD₃OD)δ：3.56(1H，dd，J＝10.5，8.0Hz)、3.73(1H，m)、3.73(3H，s)、3.88(1H，d，J＝14.9Hz)、3.92(1H，d，J＝14.9Hz)、4.11(2H，brs)、4.16(1H，m)、4.81(1H，m)、5.61(1H，t，J＝1.7Hz)、6.77(2H，d，J＝8.7Hz)、6.84(1H，t，J＝7.3Hz)、6.99(1H，d，J＝8.1Hz)、7.04(1H，d，J＝7.5Hz)、7.10(2H，d，J＝8.9Hz)、7.13(1H，m)

MS(ESI⁺)：395[M+Na]⁺

HPLC retention time: 10.8 minutes

Example 64

(1R, 2S, 3S, 6R) -4- [3- (4-ethylbenzyl) phenyl]-6- (hydroxymethyl) cyclohex-4-ene-1, 2, 3-triol

1) Synthesis of 3- (4-ethylbenzyl) phenylboronic acid

A solution of 1-bromo-3- (4-ethylbenzyl) benzene (2.19g, 7.96mmol) in THF (20mL) was cooled to-78 ℃ in a nitrogen stream, and a hexane solution of n-butyllithium (2.44M, 3.42mL) was added dropwise and stirred at the same temperature for 20 minutes. Trimethyl borate (2.68mL, 23.87mmol) was added, followed by stirring at the same temperature for 5 minutes and at room temperature for 12.5 hours. After cooling in an ice bath, concentrated hydrochloric acid (10mL) was added dropwise and stirred at the same temperature for 1 hour. The mixture was extracted with diethyl ether, and the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and hexane-ethyl acetate (10: 1) (5mL) was added to the obtained white solid, followed by filtration and washing with hexane-ethyl acetate (10: 1). The obtained white powder was dried under reduced pressure to obtain the title compound (604.2mg, 32%).

¹H-NMR(CDCl₃)δ：1.22(3H，t，J＝7.6Hz)、2.62(2H，q，J＝7.6Hz)、4.07(2H，s)、7.10-7.20(4H，m)、7.36-7.44(2H，m)、8.00-8.10(2H，m)

2) Synthesis of (3R, 4R, 5S, 6R) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-1-enyl trifluoromethanesulfonate

Under a nitrogen stream, a hexane solution of n-butyllithium (322. mu.L, 0.787 mmol) was added dropwise to diisopropylamine (113. mu.L, 0.806mmol) cooled in an ice bath, followed by addition of THF (0.8 mL). The resulting solution was cooled to-78 deg.C, and a solution of (2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexanone (205.9mg, 0.384mmol) in THF (1mL) was added dropwise and stirred at the same temperature for 12 minutes. A solution of N- (5-chloro-2-pyridyl) triflimide (452mg, 1.15mmol) in THF (1.2mL) was added dropwise, and the reaction mixture was stirred at the same temperature for 2.5 hours. Saturated aqueous sodium bicarbonate and water were added to stop the reaction, and extracted with ether. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10 → 1: 8)) to obtain the title compound (161.4mg, 63%).

¹H-NMR(CDCl₃)δ：2.60-2.70(1H，m)、3.40-3.58(2H，m)、3.70(1H，dd，J＝9.9，9.7Hz)、3.90(1H，dd，J＝9.7，7.1Hz)、4.32-4.54(4H，m)、4.70-4.94(5H，m)、5.76-5.83(1H，m)、7.10-7.40(20H，m)

3) Synthesis of 1- (4-ethylbenzyl) -3- [ (3R, 4R, 5S, 6S) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-1-enyl ] benzene

To trifluoromethanesulfonic acid (3R, 4R, 5S, 6R) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-1-enyl ester (656mg, 0.981mmol), K in a nitrogen stream₃PO₄(250mg, 1.18mmol), KBr (140mg, 1.18mmol), 3- (4-ethylbenzyl) phenylboronic acid (283mg, 1.18mmol) and Pd (PPh)₃)₄To the mixture (56.6mg, 0.049mmol) was added dioxane-water (10: 1) (12mL), and the reaction mixture was heated to 100 ℃ to 105 ℃ with stirring for 26 hours. After cooling to room temperature, saturated brine and water were added. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10 → 1: 8)) to obtain the title compound (510.0mg, 73%).

¹H-NMR(CDCl₃)δ：1.19(3H，t，J＝7.6Hz)、2.58(2H，q，J＝7.6Hz)、2.64-2.75(1H，m)、3.54(1H，dd，J＝8.9，5.9Hz)、3.64(1H，dd，J＝8.9，3.5Hz)、3.68-3.79(1H，m)、3.92(2H，s)、4.07(1H，dd，J＝9.7，7.3Hz)、4.31(1H，d，J＝10.6Hz)、4.45(2H，s)、4.48(1H，d，J＝10.6Hz)、4.54(1H，d，J＝10.9Hz)、4.79-5.00(4H，m)、5.85-5.92(1H，m)、6.73-6.82(2H，m)、6.98-7.42(26H，m)

4) Synthesis of (1R, 2S, 3S, 6R) -4- [3- (4-ethylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohex-4-ene-1, 2, 3-triol

Under a nitrogen stream, 1- (4-ethylbenzyl) -3- [ (3R, 4R, 5S, 6S) -4, 5, 6-tribenzyloxy-3- (benzyloxymethyl) cyclohex-1-enyl]A solution of benzene (494.5mg, 0.692mmol) and pentatoluene (1.05g, 7.06mmol) in dichloromethane (38mL) was cooled to-78 deg.C and BCl was added dropwise₃Dichloromethane (1.0M, 7.54 mL). The reaction mixture was stirred at the same temperature for 10 minutes, at-70 ℃ for 1.5 hours, and then methanol (20mL) was added. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to coarse purification by silica gel column chromatography (developing solution: methanol: dichloromethane (1: 20 → 1: 10)), and the product was usedTLC (developing solution methanol: dichloromethane (1: 10)) was purified to give the title compound (46.2mg, 19%).

¹H-NMR(CD₃OD)δ：1.19(3H，t，J＝7.6Hz)、2.27-2.44(1H，m)、2.58(2H，q，J＝7.6Hz)、3.44-3.68(3H，m)、3.76-3.94(3H，m)、4.45-4.57(1H，m)、5.74-5.84(1H，m)、6.95-7.25(8H，m)

MS(ESI⁺)：372[M+H₂O]⁺

HPLC retention time: 18.37 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 65

(1R, 2R, 3S, 4R, 5R) -1- [3- (4-ethylbenzyl) -4-methoxyphenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

1) Synthesis of (1R, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) -1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] cyclohexanol and (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) -1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] cyclohexanol

A hexane solution of n-butyllithium (2.70M, 1.03mL) was added dropwise under a nitrogen stream while cooling a solution of 4-bromo-2- (4-ethylbenzyl) -1-methoxybenzene (908mg, 2.98mmol) in THF (10mL) to-78 ℃. The reaction mixture was stirred at the same temperature for 10 minutes. To this solution was added dropwise a solution of (2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexanone (1.00g, 1.86mmol) in THF (2mL) and stirred at-78 ℃ for 30 minutes. Saturated aqueous ammonium chloride and water were added to stop the reaction. Extraction was performed with ethyl acetate, and the organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 5 → 1: 1)) to obtain (1R, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] cyclohexanol (0.32g, 23%) and (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] cyclohexanol (0.89g, 64%).

(1R) -isomer:¹H-NMR(CDCl₃)δ：1.17(3H，t，J＝7.6Hz)、1.80-2.00(2H，m)、2.20-2.36(1H，m)、2.55(2H，d，J＝7.6Hz)，2.91(1H，d， J＝2.0Hz)、3.35-3.42(1H，m)、3.65-4.05(10H，m)、4.41-4.45(3H，m)、4.59(1H，d，J＝10.7Hz)、4.81(1H，d，J＝10.7Hz)、4.87(1H，d，J＝10.7Hz)、4.90(1H，d，J＝10.7Hz)、6.78-6.84(3H，m)、6.99-7.20(6H，m)、7.20-7.40(18H，m)

(1S) -isomer:¹H-NMR(CDCl₃)δ：1.12(3H，t，J＝7.6Hz)、1.40-1.54(2H，m)

1.78-1.88(1H，m)，2.35(1H，dd，J＝3.3，13.7Hz)，2.43(1H，s)，2.47(2H，q，J＝7.6Hz)、3.34(1H，dd，J＝0.9，8.9Hz)，3.53-3.72(4H，m)、3.80(3H，s)，3.86-3.93(2H，m)，4.41(2H，s)、4.49(1H，d，J＝10.7Hz)、4.67-4.79(2H，m)，4.83(1H，d，J＝10.7Hz)、5.02(1H，d，J＝11.7Hz)、6.78(1H，d，J＝8.4Hz)，7.00(2H，d，J＝7.9Hz)、7.10(2H，d，J＝7.9Hz)、7.14-7.20(2H，m)，7.21-7.40(18H，m)，7.56-7.63(2H，m)

2) synthesis of (1R, 2R, 3S, 4R, 5R) -1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] -5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

To a solution of (1R, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) -1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] cyclohexanol (50.0mg, 0.067mmol) in THF (0.5mL) -methanol (2mL) was added 20% palladium hydroxide catalyst (10mg), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. After the catalyst was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 10)) to obtain the title compound (20mg, 74%).

¹H-NMR(CD₃OD)δ：1.22(3H，t，J＝7.6Hz)、1.65-1.84(2H，m)、2.01-2.14(1H，m)、2.60(2H，q，J＝7.6Hz)、3.39-3.46(1H，m)、3.62-3.75(4H，m)、3.82(3H，s)、3.94(2H，s)、6.94(1H，d，J＝8.4Hz)、7.06(2H，d，J＝8.2Hz)、7.13(2H，d，J＝8.2Hz)、7.30-7.38(2H，m)

MS(ESI⁺)：420[M+H₂O]⁺

HPLC retention time: 17.70 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 66

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-ethylbenzyl) -4-methoxyphenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

1) Synthesis of 2- (4-ethylbenzyl) -1-methoxy-4- [ (1S, 2S, 3R, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl ] benzene

A solution of (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [3- (4-ethylbenzyl) -4-methoxyphenyl ] cyclohexanol (124mg, 0.16mmol) obtained in example 65 in methylene chloride (2mL) was cooled to-5 ℃ and triethylsilane (0.39mL, 2.44mmol) was added. Trifluoroacetic acid (0.12mL, 1.6mmol) was added, and after stirring the reaction mixture at-5 ℃ for 1 hour, saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 9)) to obtain the title compound (10mg, 8%).

¹H-NMR(CDCl₃)δ：1.17(3H，t，J＝7.6Hz)、1.58-1.96(3H，m)、2.56(2H，q，J＝7.6Hz)、2.55-2.70(1H，m)，3.43-3.62(5H，m)、3.78-4.00(6H，m)，4.43(2H，s)、4.44(1H，d，J＝9.9Hz)、4.56(1H，d，J＝10.8Hz)、4.82-4.93(3H，m)、6.75-6.82(3H，m)、6.99-7.18(9H，m)、7.20-7.38(15H，m)

2) Synthesis of (1R, 2R, 3S, 4S, 6R) -4- [3- (4-ethylbenzyl) -4-methoxyphenyl ] -6- (hydroxymethyl) cyclohexan-1, 2, 3-triol

To a solution of 2- (4-ethylbenzyl) -1-methoxy-4- ((1S, 2S, 3R, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl) benzene (10mg, 0.013mmol) in THF (0.2mL) -methanol (1mL) was added 20% palladium hydroxide catalyst (10mg), and the mixture was stirred at room temperature for 13 hours under a hydrogen atmosphere. After the catalyst was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing solution: methanol: dichloromethane (1: 10)) to obtain the title compound (3.9mg, 75%).

¹H-NMR(CD₃OD)δ：1.23(3H，t，J＝7.4Hz)、1.34-1.48(1H，m)、1.60-1.76(1H，m)、1.83(1H，dt，J＝13.5，3.5Hz)，2.48-2.66(3H，m)、3.30-3.38(2H，m)，3.42-3.52(1H，m)、3.58-3.65(1H，m)、3.77(1H，d，J＝4.0Hz)、3.82(3H，s)、3.92(2H，s)、6.91(1H，d，J＝8.2Hz)、7.02-7.14(6H，m)

MS(ESI⁺)：406[M+H₂O]⁺

HPLC retention time: 12.53 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 67

(1R, 2R, 3S, 4R, 5R) -1- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

1) Synthesis of (3-bromo-4-ethoxyphenyl) - (4-ethylphenyl) methanol

THF (10mL) was added to magnesium (353mg, 14.5mmol), 1-bromo-4-ethylbenzene (2mL, 14.5mmol) was added dropwise, and the mixture was refluxed for 1 hour. The reaction solution was cooled to 0 ℃ and a solution of 3-bromo-4-ethoxybenzaldehyde (2.21g, 9.68mmol) in THF (5mL) was added, followed by stirring at the same temperature for 1.5 hours. Saturated aqueous ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ n-hexane → n-hexane: ethyl acetate (3: 1)) to obtain the title compound (2.83g, 88%).

¹H-NMR(CDCl₃)δ：1.22(3H，t，J＝7.6Hz)、1.45(3H，t，J＝7.0Hz)、 2.14(1H，d，J＝3.5Hz)、2.63(2H，q，J＝7.5Hz)、4.07(2H，q，J＝7.0Hz)、5.74(1H，d，J＝3.5Hz)、6.83(1H，d，J＝8.4Hz)、7.17(2H，d，J＝8.1Hz)、7.20-7.30(3H，m)、7.56(1H，d，J＝2.1Hz)

2) Synthesis of 2-bromo-1-ethoxy-4- (4-ethylbenzyl) benzene

To a solution of (3-bromo-4-ethoxyphenyl) - (4-ethylphenyl) methanol (2.83g, 8.44mmol) in methylene chloride (20mL) at 0 ℃ were added triethylsilane (2.7mL, 16.9mmol) and boron trifluoride-diethyl ether complex (1.2mL, 9.47mmol), and the mixture was stirred for 3 hours. After addition of methanol (50%) -water (4mL) extraction with dichloromethane was performed. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ n-hexane → n-hexane-ethyl acetate (4% (v/v))) to obtain the title compound (2.69g, 100%).

¹H-NMR(CDCl₃)δ：1.22(3H，t，J＝7.6Hz)、1.45(3H，t，J＝7.0Hz)、2.62(2H，q，J＝7.6Hz)、3.85(2H，s)、4.06(2H，q，J＝7.0Hz)、6.79(1H，d，J＝8.4Hz)、7.00-7.15(3H，m)、7.36(1H，d，J＝2.1Hz)

3) Synthesis of (1R, 2R, 3S, 4R, 5R) -, and (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] cyclohexanol

A solution of 2-bromo-1-ethoxy-4- (4-ethylbenzyl) benzene (1.18g, 3.70mmol) in THF (9mL) was added dropwise to a hexane solution of n-butyllithium (1.59M, 2.30mL, 3.66mmol) while cooling to-78 deg.C in a nitrogen stream. After the reaction mixture was stirred at the same temperature for 1 hour, a solution of (2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexanone (1.50g, 2.80mmol) in THF (4.5mL) was added dropwise and stirred at-78 ℃ for 10 minutes. Saturated aqueous ammonium chloride solution was added to stop the reaction. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain a (1R) isomer (884mg, 41%) and a (1S) isomer (740mg, 34%).

(1R) isomers:¹H-NMR(CDCl₃)δ：1.23(3H，t，J＝7.6Hz)、1.37(3H，t，J＝7.0Hz)、1.70(1H，dd，J＝14.3，4.1Hz)、2.20-2.35(1H，m)、2.62(2H，q，J＝7.6Hz)、2.67-2.82(1H，m)、3.0-3.3(1H，br)、3.43(1H，dd，J＝8.8，2.0Hz)、3.71(1H，dd，J＝9.8，9.8Hz)、3.83(1H，dd， J＝8.9，4.0Hz)、3.86-4.10(3H，m)、3.91(2H，s)、4.44(2H，s)、4.48(1H，d，J＝10.3Hz)、4.58(1H，br)、4.63(1H，d，J＝10.3Hz)、4.85(1H，d，J＝11.0Hz)、4.88(1H，d，J＝11.0Hz)、4.95(1H，d，J＝10.8Hz)、6.75(1H，d，J＝8.4Hz)、6.79(2H，d，J＝7.0Hz)、7.00-7.40(24H，m)、7.53(1H，d，J＝2.0Hz)

(1S) isomer:¹H-NMR(CDCl₃)δ：1.12(3H，t，J＝7.6Hz)、1.30(3H，t，J＝7.2Hz)、1.40-1.55(1H，m)、1.76(1H，dd，J＝13.3，13.3Hz)、2.50(2H，q，J＝7.6Hz)、2.74(1H，dd，J＝13.7，3.2Hz)、3.38(1H，dd，J＝9.0，2.8Hz)、3.54(1H，dd，J＝9.0，5.3Hz)、3.64(1H，dd，J＝10.8，8.7Hz)、3.86(1H，dd，J＝9.5，9.5Hz)、3.89(2H，s)、4.0-4.1(2H，m)、4.39(2H，s)、4.53(1H，dd，J＝11.0Hz)、4.64-4.72(3H，m)、4.77(1H，d，J＝11.7Hz)、4.79(1H，d，J＝10.5Hz)、4.87(1H，d，J＝10.8Hz)、4.98(1H，d，J＝11.7Hz)、6.98-7.42(25H，m)、7.67(1H，d，J＝1.8Hz)

4) synthesis of (1R, 2R, 3S, 4R, 5R) -1- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] -5- (hydroxymethyl) cyclohexane-1, 2, 3, 4-tetraol

To a solution of (1R, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) -1- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] cyclohexanol (600mg, 0.772mmol) in THF (6mL) -methanol (3mL) was added 20% palladium hydroxide catalyst (60mg), and the mixture was stirred under a hydrogen atmosphere for 2.5 hours. After the catalyst was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ dichloromethane → dichloromethane methanol (12% (v/v))) to obtain the title compound (197mg, 61%).

¹H-NMR(CD₃OD)δ：1.18(3H，t，J＝7.6Hz)、1.43(3H，t，J＝7.0Hz)、1.60(1H，dd，J＝14.3，4.1Hz)、2.01(1H，m)、2.43(1H，dd，J＝14.0，13.0Hz)、2.57(2H，q，J＝7.5Hz)、3.39(1H，dd，J＝10.5，9.3Hz)、3.60-3.68(3H，m)、3.85(2H，s)、4.03(2H，m)、4.34(1H，d，J＝9.2Hz)、6.82(1H，d，J＝8.2Hz)、6.99(1H，dd，J＝8.4Hz、2.3Hz)、7.45(1H，d，J＝2.3Hz)

MS(ESI⁺)：434[M+H₂O]⁺

HPLC retention time: 18.71 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 68

(1R, 2R, 3S, 4S, 6R) -4- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

1) Synthesis of (1R, 2R, 3S, 4S, 6R) -4- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

To a solution of (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [ 2-ethoxy-5- (4-ethylbenzyl) phenyl ] cyclohexanol (402mg, 0.517mmol) obtained in example 67 in THF (4mL) -methanol (2mL) was added 20% palladium hydroxide catalyst (78mg), and the mixture was stirred under a hydrogen atmosphere for 19 hours. After the catalyst was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution: dichloromethane: methanol: 10: 1) to obtain the title compound (42mg, 20%).

¹H-NMR(CD₃OD)δ：1.18(3H，t，J＝7.6Hz)、1.25-1.50(1H，m)、1.38(3H，t，J＝7.0Hz)、1.62(1H，m)、1.78(1H，m)、2.57(2H，q，J＝7.6Hz)、2.95-3.15(1H，br)、3.25-3.33(2H，m)、3.54(1H，dd，J＝10.8，6.1Hz)、3.73(1H，dd，J＝10.8、3.8Hz)、3.65-3.85(1H，m)、3.83(2H，s)、4.00(2H，q，J＝7.0Hz)、6.81(1H，d，J＝8.4Hz)、6.94(1H，dd，J＝8.3、2.1Hz)、7.04(1H，d，J＝1.7Hz)、7.06(4H，s)

MS(ESI⁺)：401[M]⁺

HPLC retention time: 12.98 minutes

Examples 69 to 74

The procedure was carried out in the same manner as in example 67 or example 68 using the corresponding starting materials and reagents, respectively, to give the objective compound.

Example 69

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2, 4-dimethoxyphenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

¹H-NMR(CD₃OD)δ：1.17(3H，t，J＝7.6Hz)、1.61(1H，dd，J＝13.9，3.8Hz)、1.90-2.10(1H，m)、2.22(1H，dd，J＝13.9，13.2Hz)、2.55(2H，q，J＝7.6Hz)、3.32-3.42(1H，m)、3.58-3.70(3H，m)、3.76-3.88(2H，m)、3.80(3H，s)、3.84(3H，s)、4.19(1H，d，J＝9.1Hz)、6.58(1H，s)、7.00(2H，d，J＝8.2Hz)、7.06(2H，d，J＝8.2Hz)、7.35(1H，s)

MS(ESI⁺)：455[M+Na]⁺

HPLC retention time: 17.83 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 70

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2, 4-dimethoxyphenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

¹H-NMR(CD₃OD)δ：1.17(3H，t，J＝7.6Hz)、1.24-1.48(1H，m)、1.52-1.82(2H，m)、2.56(2H，d，J＝7.6Hz)、2.86-3.08(1H，m)、3.24-3.29(1H，m)、3.48-3.67(2H，m)、3.68-3.84(3H，m)、3.79(3H，s)、3.81(3H，s)、6.56(1H，s)、6.93(1H，s)、7.01(2H，d，J＝8.6Hz)、7.05(2H，d，J＝8.6Hz)

MS(ESI⁺)：416[M]⁺

HPLC retention time: 18.26 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 71

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-methylphenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

¹H-NMR(CD₃OD)δ：1.19(3H，t，J＝7.6Hz)、1.70(1H，m)、1.94(1H，m)、2.05(1H，m)、2.53(3H，s)、2.58(2H，q，J＝7.6Hz)、3.40(1H，d，J＝9.2Hz)、3.67(2H，d，J＝4.6Hz)、3.73(1H，d，J＝9.2Hz)、3.87(2H，s)、4.01(1H，d，J＝9.2Hz)、6.91(1H，dd，J＝7.6，1.5Hz)、7.01(1H，d，J＝7.6Hz)、7.07(4H，m)、7.42(1H，s)

MS(ESI⁺)：409[M+Na]⁺

Example 72

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-methylphenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

¹H-NMR(CD₃OD)δ：1.19(3H，t，J＝7.6Hz)、1.24-1.37(1H，m)、1.59-1.81(2H，m)、2.30(3H，s)、2.57(2H，q，J＝7.6Hz)、2.93(1H，m)、3.34(2H，m)、3.50-3.63(2H，m)、3.75(1H，dd，J＝10.7，4.2Hz)、3.86(2H，s)、6.87(1H，d，J＝7.6Hz)、7.03(1H，d，J＝7.6Hz、2.1Hz)、7.07(4H，s)、7.11(1H，s)

MS(ESI^-)：369[M-H]^-

Example 73

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-methoxyphenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

¹H-NMR(CD₃OD)δ：1.13(3H，t，J＝7.6Hz)、1.56(1H，dd，J＝14.1，3.9Hz)、1.94-2.04(1H，m)、2.24(1H，dd，J＝13.9，13.2Hz)、2.51(2H，q，J＝7.5Hz)、3.24-3.37(1H，m)、3.57-3.63(3H，m)、3.74(3H，s)、3.80-3.90(2H，m)、4.22(1H，d，J＝9.1Hz)、6.80(1H，d，J＝8.4Hz)、6.95-7.01(5H，m)、7.41(1H，d，J＝1.2Hz)

MS(ESI⁺)：425[M+Na]⁺

HPLC retention time: 11.69 minutes

Example 74

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-methoxyphenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

¹H-NMR(CD₃OD)δ：1.18(3H，t，J＝7.6Hz)、1.24-1.50(1H，m)、1.54-1.85(2H，m)、2.57(2H，d，J＝7.6Hz)、2.90-3.18(1H，m)、3.24-3.34(2H，m)、3.54(1H，dd，J＝10.7，5.9Hz)、3.60-3.78(2H，m)、3.76(3H，s)、3.83(2H，s)、6.82(1H，d，J＝8.4Hz)、6.96(1H，dd，J＝8.4，2.0Hz)、7.01-7.11(5H，m)

MS(ESI⁺)：404[M+H₂O]⁺

HPLC retention time: 12.33 minutes

Example 75

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-trifluoromethoxyphenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

The procedure of example 67 was repeated using the corresponding starting materials and reagents to give the objective compound.

¹H-NMR(CD₃OD)δ：1.17(3H，t，J＝7.6Hz)、1.73(1H，d，J＝10.1Hz)、2.00-2.12(2H，m)、2.58(2H，q，J＝7.5Hz)、3.35(1H，dd，J＝9.3，9.3Hz)、3.58-3.72(2H，m)、3.66(1H，dd，J＝9.2，9.2Hz)、3.93(2H，s)、3.99(1H，d，J＝8.9Hz)、7.09(4H，s)、7.13(2H，m)、7.69(1H，d，J＝1.4Hz)

MS(ESI⁺)：474[M+Na]⁺

HPLC retention time: 13.09 minutes

Examples 76 to 78

The procedure of example 68 was repeated except for using the corresponding starting materials and reagents to obtain the objective compound.

Example 76

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-isopropylbenzyl) -2-methoxyphenyl]-6- (hydroxymethyl)) Cyclohexane-1, 2, 3-triol

¹H-NMR(CD₃OD)δ：1.21(6H，d，J＝6.9Hz)、1.29-1.42(1H，m)、1.59-1.81(2H，m)、2.78-2.89(1H，m)、3.06-3.10(1H，m)、3.26-3.34(2H，m)、3.55(1H，dd，J＝10.7，6.0Hz)、3.62-3.85(5H，m)、3.84(2H，s)、6.82(1H，d，J＝8.5Hz)、6.96(1H，dd，J＝8.2，2.2Hz)、7.05-7.11(5H，m)

MS(ESI⁺)：400[M]⁺

HPLC retention time: 13.07 minutes

Example 77

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-ethylbenzyl) phenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

¹H-NMR(CD₃OD)δ：1.24(3H，t，J＝7.5Hz)、1.43-1.53(1H，m)、1.61-1.78(1H，m)、1.85(1H，dt，J＝13.4，3.7Hz)，2.56-2.68(3H，m)、3.29-3.40(2H，m)、3.50-3.66(2H，m)、3.80(1H，dd，J＝10.9，3.9Hz)、3.94(2H，s)、7.04-7.27(8H，m)

MS(ESI⁺)：357[M]⁺

HPLC retention time: 12.12 minutes

Example 78

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-hydroxybenzyl) phenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

¹H-NMR(CD₃OD)δ：1.43-1.52(1H，m)、1.64-1.78(1H，m)、1.85(1H，dt，J＝12.5，3.7Hz)、2.55-2.66(1H，m)、3.33-3.40(2H，m)、3.50-3.64(2H，m)、3.76-3.84(1H，m)、3.88(2H，s)、6.68-6.74(2H，m)、7.00-7.14(5H，m)、7.20-7.25(1H，m)

MS(ESI⁺)：362[M+H₂O]⁺

HPLC retention time: 13.70 minutes

Example 79

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-hydroxyphenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

(1R, 2R, 3S, 4S, 6R) -4- [5- (4-ethylbenzyl) -2-methoxyphenyl ] obtained in example 74 is placed in a nitrogen stream]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol (40mg, 0.1mmol) in dichloromethane (1mL) cooled to-78 deg.C and BBr added dropwise₃Dichloromethane (1.0M, 0.31 mL). Stirring at the same temperature for 10 minutes, further stirring under ice-cooling for 2 hours, and then dropwise adding BBr₃Dichloromethane (0.2 mL). After stirring at the same temperature for 3.5 hours, a solution of sodium hydroxide in methanol (0.93mL) was added. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (3.5mg, 9.1%).

¹H-NMR(CD₃OD)δ：0.87-0.98(1H，s)、1.19(3H，t，J＝7.8Hz)、1.39-1.52(1H，m)、1.59-1.66(1H，m)、1.78-1.83(1H，dt，J＝13.5，3.6Hz)、2.56(2H，q，J＝7.8，7.5Hz)、2.96-3.07(1H，m)、3.34(1H，s)、3.54-3.59(1H，m)、3.62-3.69(1H，m)、3.72(1H，dd，J＝6.6，3.9Hz)、3.80(2H，s)、6.68(1H，d，J＝8.4Hz)、6.80(1H，dd，J＝8.4，2.0Hz)、6.99(1H，s)、7.05(4H，s)

MS(ESI⁺)：372[M]⁺

HPLC retention time: 11.2 minutes

Example 80

(1R, 2R, 3S, 4S, 6R) -4- [3- (4-cyclopropylbenzyl) phenyl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

1)4- [3- ((3aS, 4S, 5aR, 9bR) -2, 2, 8, 8-tetramethyl-hexahydro [1, 3] dioxolyl [ dioxolo ] [4 ', 5': synthesis of 3, 4] benzo [1, 2-d ] [1, 3] dioxine [ dioxin ] -4-yl) benzyl ] phenol

To a solution of (1R, 2R, 3S, 4S, 6R) -4- [3- (4-hydroxybenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol (47mg, 0.136mmol) obtained in example 78 in N, N-dimethylformamide (1mL) at 0 ℃ was added 2, 2-dimethoxypropane (142mg, 1.36mmol), followed by p-toluenesulfonic acid hydrate (2 mg). The reaction mixture was stirred at room temperature for 30 minutes, and a saturated aqueous ammonium chloride solution was added thereto to stop the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (34mg, 59%).

¹H-NMR(CDCl₃)δ：1.11-1.24(1H，m)、1.42(6H，s)，1.46(3H，s)，1.53(3H，s)，1.73(1H，dt，J＝13.7，3.9Hz)、1.80-1.93(1H，m)，2.94(1H，dt，J＝4.0，11.0Hz)、3.59-3.92(7H，m)、4.85(1H，s)、6.71-6.76(2H，m)、7.00-7.08(5H，m)、7.19-7.23(1H，m)

2) Trifluoromethanesulfonic acid 4- [3- ((3aS, 4S, 5aR, 9bR) -2, 2, 8, 8-tetramethyl-hexahydro- [1, 3] dioxolyl [4 ', 5': synthesis of 3, 4] benzo [1, 2-d ] [1, 3] dioxin-4-yl) benzyl ] phenyl ester

4- [3- ((3aS, 4S, 5aR, 9aR, 9bR) -2, 2, 8, 8-tetramethyl-hexahydro- [1, 3] dioxolyl [4 ', 5': 3, 4] benzo [1, 2-d ] [1, 3] dioxin-4-yl) benzyl ] phenol (34mg, 0.08mmol) was dissolved in dichloromethane (0.8mL) and stirred under ice-cooling. Pyridine (15mg, 0.19mmol), 2- [ N, N-bis (trifluoromethanesulfonyl) amino ] pyridine (34mg, 0.096mmol) and N, N-dimethylaminopyridine (1mg) were added thereto, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture to stop the reaction. The mixture was extracted with dichloromethane, and the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (37mg, 83%).

¹H-NMR(CDCl₃)δ：1.11-1.24(1H，m)、1.42(6H，s)，1.43(3H，s)，1.53(3H，s)，1.74(1H，dt，J＝13.7，3.9Hz)、1.80-1.93(1H，m)，2.96(1H，dt，J＝11.1，3.6Hz)、3.59-3.92(5H，m)、3.98(2H，s)、7.00-7.03(2H，m)、7.10-7.35(6H，m)

3) (3aS, 4S, 5aR, 9bR) -4- [3- (4-cyclopropylbenzyl) phenyl ] -2, 2, 8, 8-tetramethyl-hexahydro [1, 3] dioxolyl [4 ', 5': synthesis of 3, 4] benzo [1, 2-d ] [1, 3] dioxine

To trifluoromethanesulfonic acid 4- [3- ((3aS, 4S, 5aR, 9aR, 9bR) -2, 2, 8, 8-tetramethyl-hexahydro [1, 3] in a nitrogen atmosphere]Dioxolyl [4 ', 5': 3,4]Benzo [1, 2-d ] s][1，3]Dioxin-4-yl) benzyl]Phenyl ester (38mg, 0.068mmol), K₃PO₄(65mg, 0.31mmol), sodium bromide (7mg, 0.068mmol), cyclopropylboronic acid (9mg, 0.10mmol) and Pd (PPh)₃)₄To a mixture (8.0mg, 0.007mmol) was added toluene (0.5mL) -water (0.017mL), and the reaction mixture was heated and stirred at 100 ℃ for 6 hours. After cooling to room temperature, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the title compound (10mg, 33%).

¹H-NMR(CDCl₃)δ：0.62-0.68(2H，m)，0.89-0.96(2H，m)，1.10-1.24(1H，m)、1.42(3H，s)，1.43(3H，s)，1.46(3H，s)，1.54(3H，s)，1.74(1H，dt，J＝13.7，3.9Hz)、1.80-1.93(2H，m)，2.94(1H，dt，J＝10.9，3.6Hz)、3.59-3.96(8H，m)、6.96-7.07(7H，m)、7.16-7.25(1H，m)

4) Synthesis of (1R, 2R, 3S, 4S, 6R) -4- [3- (4-cyclopropylbenzyl) phenyl ] -6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

Reacting (3aS, 4S, 5aR, 9aR, 9bR) -4- [3- (4-cyclopropylbenzyl) phenyl ] -2, 2, 8, 8-tetramethyl-hexahydro [1, 3] dioxolyl [4 ', 5': a solution of 3, 4] benzo [1, 2-d ] [1, 3] dioxane (10mg, 0.022mmol) in dioxane (0.2mL) was cooled to 0 deg.C and 2N aqueous hydrochloric acid (0.2mL) was added dropwise. After the reaction mixture was stirred at the same temperature for 3 hours, a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (developing solution ═ methanol: dichloromethane (1: 10)) to give the title compound (4.5mg, 51%).

¹H-NMR(CD₃OD)δ：0.63-0.68(2H，m)、0.91-0.98(2H，m)、1.42-1.52(1H，m)、1.62-1.78(1H，m)、1.80-1.94(2H，m)、2.54-2.66(1H，m)、3.33-3.40(2H，m)、3.50-3.68(2H，m)、3.79(1H，dd，J＝10.9，3.9Hz)、3.93(2H，s)、6.85-7.16(7H，m)、7.21-7.26(1H，m)

MS(ESI⁺)：386[M+H₂O]⁺

HPLC retention time: 18.49 minutes

< conditions for HPLC measurement >

Column: YMC-Pack ODS-A6.0X 150mm, 5 μm

Flow rate: 1.5 mL/min

Column temperature: at room temperature

Example 81

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-fluorophenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

1) Synthesis of (1R, 2R, 3S, 4R, 5R) -and (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [5- (4-ethylbenzyl) -2-fluorophenyl ] cyclohexanol

To a solution of 2-bromo-4- (4-ethylbenzyl) -1-fluorobenzene (0.263g, 0.900mmol) in diethyl ether (3.0mL) at-78 deg.C in a nitrogen stream was added dropwise a solution of n-butyllithium in hexane (2.44M, 0.368mL) and stirred at the same temperature for 2 hours. A THF solution (1.5mL) of 2, 3, 4-tribenzyloxy-5-methylcyclohexanone (0.483g, 0.900mmol) was added and stirred for 2 hours. Saturated aqueous ammonium chloride was added to terminate the reaction, and extracted with ether. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 4)) to obtain the (1R) isomer (0.117g, 17.3%) and the (1S) isomer (0.311g, 46.1%) of the title compound.

(1R) isomers:¹H-NMR(CDCl₃)δ：1.15-1.32(3H，m)、1.81-1.92(1H，br)、2.20-2.38(2H，br)、2.62(2H，q，J＝9.8Hz)、3.07(1H，br)、3.40-3.55(1H，m)、3.66-3.80(2H，m)、3.84-4.06(4H，m)、4.28(1H，d，J＝12.3Hz)、4.45(2H，s)、4.58(2H，t，J＝12.1Hz)、4.80-4.96(3H，m)、6.76-6.84(2H，m)、6.86-7.00(1H，m)、7.02-7.44(23H，m)、7.52-7.60(1H，m)

(1S) isomer:¹H-NMR(CDCl₃)δ：1.13(3H，t，J＝1.5Hz)、1.34-1.55(1H，br)、 1.84(1H，t，J＝2.4Hz)2.50(2H，q，J＝1.5Hz)2.75(1H，dd，J＝2.4，0.9Hz)、2.93(1H，d，J＝0.9Hz)、3.37(1H，dd，J＝10.5，6.6Hz)、3.57-3.78(3H，m)、3.86-4.06(3H，m)、4.40-5.00(8H，m)、6.80-7.60(26H，m)、7.72-7.84(1H，m)

2) synthesis of (1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-fluorophenyl ] -5- (hydroxymethyl) cyclohexane-1, 2, 3, 4-tetraol

To a mixed solution (20mL) of (1R, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [5- (4-ethylbenzyl) -2-fluorophenyl ] cyclohexanol (271mg, 0.361mmol) in methanol-THF (1: 1) was added 20% palladium hydroxide catalyst (40 mg). After stirring for 30 minutes under hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ methanol: dichloromethane (1: 10)) to obtain the title compound (44.6mg, 31.6%).

¹H-NMR(CD₃OD)δ：1.18(3H，t，J＝7.2Hz)、1.15-1.26(1H，m)、1.48(1H，dd，J＝13.5，13.2Hz)、2.57(2H，q，J＝7.8Hz)、2.73(1H，dd，J＝13.5，3.0Hz)、3.30-3.80(1H，m)、3.50(1H，dd，J＝9.9，5.7Hz)、3.53-3.66(2H，m)、3.83-3.92(3H，m)、6.94(1H，dd，J＝12.3，8.1Hz)、7.00-7.25(5H，m)、7.95(1H，dd，J＝7.8，1.8Hz)

MS(ESI⁺)：413[M+Na]⁺

HPLC retention time: 10.9 minutes

Example 82

(1S, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-fluorophenyl]-5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol

To a mixed solution (1.4mL) of (1S, 2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [5- (4-ethylbenzyl) -2-fluorophenyl ] cyclohexanol (33mg, 0.044mmol) obtained in example 81 in methanol-THF (1: 1) was added 20% palladium hydroxide catalyst (7.5 mg). After stirring for 2.5 hours under a hydrogen atmosphere, the catalyst was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ methanol: dichloromethane (1: 10)) to obtain the title compound (17.5mg, 100%).

¹H-NMR(CD₃OD)δ：1.18(3H，t，J＝7.5Hz)、1.70-1.79(1H，m)、 1.98-2.11(2H，m)、2.57(2H，q，J＝7.8Hz)、3.32-3.45(1H，m)、3.60-3.71(3H，m)、3.90(2H，s)、3.94(1H，d，J＝9.0Hz)、6.91(1H，dd，J＝12.3，8.1Hz)、7.02-7.12(5H，m)、7.53(1H，dd，J＝7.8、2.4Hz)

MS(ESI⁺)：413[M+Na]⁺

HPLC retention time: 11.7 minutes

Example 83

(1R, 2R, 3S, 4R, 5R) -5-hydroxymethyl-1- [3- (4-methoxybenzyl) phenyl]Cyclohexan-1, 2, 3, 4-tetrols

The procedure of example 81 was repeated using the corresponding starting materials and reagents to give the objective compound.

¹H-NMR(CD₃OD)δ：1.62-1.80(2H，m)、1.94-2.10(1H，m)、3.40(1H，dd，J＝10.5，8.7Hz)、3.62-3.72(4H，m)、3.73(3H，s)、3.89(2H，s)、6.70-6.82(2H，m)、7.00-7.03(2H，m)、7.06-7.12(2H，m)、7.22(1H，t，J＝7.8Hz)、7.27-7.32(1H，m)、7.34-7.37(1H，m)

MS(ESI⁺)：375[M+H]⁺

HPLC retention time: 9.53 minutes

Example 84

(1S, 2R, 3S, 4R, 5R) -5-hydroxymethyl-1- [3- (4-methoxybenzyl) phenyl]Cyclohexan-1, 2, 3, 4-tetrols

¹H-NMR(CD₃OD)δ：1.28-1.44(1H，m)、1.56(1H，t，J＝13.2Hz)、2.35(1H，dt，J＝13.5，3.0Hz)、3.45(1H，dd，J＝11.1，6.0Hz)、3.60-3.70(3H，m)、3.73(3H，s)、3.89(2H，s)、6.77-6.82(2H，m)、7.00-7.05(1H，m)、7.06-7.13(2H，m)、7.20(1H，t，J＝7.8Hz)、7.60-7.65(1H，m)、7.68-7.70(1H，m)

MS(ESI⁺)：397[M+Na]⁺

HPLC retention time: 14.6 minutes

Example 85

(1R, 2R, 3S, 4S, 6R) -4- [1- (4-ethylbenzyl) -1H-indol-3-yl]-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol

1) Synthesis of 1- (4-ethylbenzyl) -1H-indole

To a solution of indole (4.0g, 34.1mmol) in ethanol (200mL) was added potassium hydroxide (2.40g, 42.6mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in acetone (200mL), and 1-chloromethyl-4-ethylbenzene (5.28g, 34.1mmol) was added. The reaction mixture was stirred at room temperature for one day and night, and then filtered through celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 500)) to obtain the title compound (3.8g, 47%).

¹H-NMR(CDCl₃)δ：1.19(3H，t，J＝7.6Hz)、2.60(2H，q，J＝7.6Hz)、5.27(2H，s)、6.53(1H，dd，J＝3.1，0.7Hz)、7.03(2H，d，J＝7.6Hz)、7.07-7.22(5H，m)、7.29(1H，d，J＝8.0Hz)、7.64(1H，d，J＝6.8Hz)

2) Synthesis of 3-bromo-1- (4-ethylbenzyl) -1H-indole

To a solution of bromine (0.46mL, 8.93mmol) in DMF (20mL) at room temperature was added dropwise a solution of 1- (4-ethylbenzyl) -1H-indole (2.0g, 8.50mmol) in DMF (20 mL). The reaction mixture was stirred for 2 hours and poured into an ice-cold aqueous solution of sodium metabisulfite. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. Recrystallization from ethyl acetate and n-hexane gave the title compound (1.68g, 63%).

¹H-NMR(CDCl₃)δ：1.20(3H，t，J＝7.6Hz)、2.61(2H，q，J＝7.6Hz)、5.23(2H，s)、7.05(2H，dd，J＝8.0Hz)、7.11-7.22(5H，m)、7.30(1H，dd，J＝6.5，1.9Hz)、7.57(1H，dd，J＝6.5，1.9Hz)

3) Synthesis of (2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [1- (4-ethylbenzyl) -1H-indol-3-yl ] cyclohexanol

A solution of 3-bromo-1- (4-ethylbenzyl) -1H-indole (427mg, 1.36mmol) in THF (8mL) was cooled to-78 deg.C under a nitrogen stream, and a solution of n-butyllithium in hexane (1.6M, 0.89mL, 1.43mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 5 minutes. To this solution was added dropwise a solution of (2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexanone (875mg, 1.63mmol) in THF (5.6mL) and the mixture was stirred at-78 ℃ for 2 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction. Extraction was performed with ethyl acetate, and the organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 10)) to obtain low-polar isomers (354mg, 34%) and high-polar isomers (115mg, 11%) of the title compound.

Low polar isomer:¹H-NMR(CDCl₃)δ：1.18(3H，t，J＝7.2Hz)、1.93(2H，m)、2.40(1H，m)、2.61(2H，q，J＝7.2Hz)、3.40-5.22(15H，m)、7.02-7.40(28H，m)、7.93(1H，d，J＝8.0Hz)

highly polar isomers:¹H-NMR(CDCl₃)δ：1.18(3H，t，J＝7.6Hz)、2.40(1H，m)、2.38(2H，m)、2.58(2H，q，J＝7.6Hz)、3.41-5.24(15H，m)、6.83(1H，d，J＝8.0Hz)、7.03-7.34(27H，m)、7.75(1H，d，J＝7.6Hz)

4) synthesis of 1- (4-ethylbenzyl) -3- [ (1S, 2S, 3R, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl ] -1H-indole

Triethylsilane (0.21mL, 1.22mmol) was added dropwise to a solution of (2R, 3S, 4R, 5R) -2, 3, 4-tribenzyloxy-5-benzyloxymethyl-1- [1- (4-ethylbenzyl) -1H-indol-3-yl ] cyclohexanol (469mg, 0.61mmol) in dichloromethane (6mL) at 0 ℃ under a nitrogen stream. Boron trifluoride etherate (0.093mL, 0.73mmol) was added dropwise over 5 minutes, and the reaction mixture was stirred at 0 ℃ for 2 hours. Saturated aqueous sodium bicarbonate was added and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solution ═ ethyl acetate: n-hexane (1: 15)) to obtain the title compound (232mg, 51%).

¹H-NMR(CDCl₃)δ：1.17(3H，t，J＝7.6Hz)、1.87(2H，m)、2.27(1H，m)、2.58(2H，q，J＝7.6Hz)、3.36(1H，dd，J＝9.0，1.7Hz)、3.59-3.70(2H，m)、3.88-4.00(2H，m)、4.12(1H，t，J＝8.6Hz)、4.38(2H，s)、4.47(1H，d，J＝11.4Hz)、4.54(1H，d，J＝2.7Hz)、4.58(1H，d，J＝3.1Hz)、4.80(1H，d，J＝10.7Hz)、4.89(1H，d，J＝10.7Hz)、4.98(1H，d，J＝10.7Hz)、5.25(2H，d，J＝4.9Hz)、6.97(2H，d，J＝8.4Hz)、7.05(2H，d，J＝8.0Hz)、7.08-7.35(24H，m)、7.62(1H，d，J＝7.2Hz)

5) Synthesis of 4- [1- (4-ethylbenzyl) -1H-indol-3-yl ] -6- (hydroxymethyl) cyclohexan-1, 2, 3-triol

Dimethyl sulfide (0.72mL) and boron trifluoride diethyl etherate (0.36mL, 2.8mmol) were added to 1- (4-ethylbenzyl) -3- [ (1S, 2S, 3R, 4R, 5R) -2, 3, 4-tribenzyloxy-5- (benzyloxymethyl) cyclohexyl ] -1H-indole (213mg, 0.28mmol) in dichloromethane (4.7mL) under a nitrogen stream under ice cooling. After stirring at room temperature for 64 hours, water was added under ice-cooling, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution: dichloromethane: methanol (50: 1)) to obtain the title compound (45mg, 41%).

¹H-NMR(CD₃OD)δ：1.17(3H，t，J＝7.6Hz)、1.66(1H，m)、1.79(1H，m)、2.16(1H，m)、2.58(2H，q，J＝7.6Hz)、3.33(1H，m)、3.57(1H，dd，J＝10.7，6.1Hz)、3.69(1H，dd，J＝10.7，4.2Hz)、3.76-3.88(3H，m)、5.29(2H，s)、6.98-7.11(6H，m)、7.24(1H，d，J＝8.0Hz)、7.30(1H，s)、7.62(1H，d，J＝7.6Hz)

MS(ESI⁺)：396[M+H]⁺

The structural formulae of the compounds of the above examples are shown in tables 1 to 10.

[ Table 1]

[ Table 2]

[ Table 3]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

[ Table 10]

Test example 1

Human Na ^± Test for confirming Activity inhibition of glucose Co-transporter (SGLT1 and SGLT2)

1) Preparation of human SGLT1 expression vector

A cDNA library derived from human small intestine (Clontech) was used as a template, and human SGLT1cDNA was amplified by PCR with KOD + DNA polymerase (Toyobo Co., Ltd.) using a synthetic DNA primer. Subsequently, the amplified fragment was cloned into pcRII-Topo vector using Topo TA Cloning Dual Promoter kit (Invitrogen), introduced into E.coli competent cells (Invitrogen, TOP10), and the cloned product showing ampicillin [ アンピシリン ampicillin ] resistance was grown in LB medium containing ampicillin (50 mg/L). The plasmid was purified from the grown Escherichia coli by a conventional method (see Maniatis et al, Molecular Cloning). This plasmid was used as a template, and human SGLT1cDNA (a fragment in which an Eco RI recognition site was added upstream and a Hind III recognition site was added downstream) was amplified by PCR using a synthetic DNA primer to which a restriction enzyme recognition site was introduced and KOD + DNA polymerase. The amplified fragment was digested with Eco RI and Hind III, and the digested fragment was ligated to the same recognition site of expression vector pcDNA3.1(-) (manufactured by Invitrogen) using Rapid DNA Ligation kit (manufactured by Roche Diagnostics). The joined expression vector was introduced into E.coli living cells (DH 5. alpha. manufactured by Invitrogen corporation), and the cells were grown in LB medium containing ampicillin to obtain a human SGLT1 expression vector by a conventional method.

2) Preparation of human SGLT2 expression vector

A human kidney-derived cDNA library (Clontech) was used as a template, and human SGLT2 cDNA was amplified by PCR with KOD + DNA polymerase using a synthetic DNA primer. Subsequently, the amplified fragment was cloned into pcRII-Topo vector using Topo TA Cloning Dual Promoter kit, introduced into E.coli viable cells (TOP10), and the ampicillin-resistant clone product was grown in LB medium containing ampicillin (50 mg/L). The plasmid was purified from the proliferated Escherichia coli by a conventional method. This plasmid was used as a template, and human SGLT2 cDNA (a fragment in which Xho I recognition site was added upstream and Hind III recognition site was added downstream) was amplified by PCR using KOD + DNA polymerase using synthetic DNA primers to which restriction enzyme recognition sites were introduced. The amplified fragment was digested with Xho I and HindIII, and the digested fragment was ligated to the same recognition site of the expression vector pcDNA3.1(-) using Rapid DNA Ligation kit. The joined expression vector was introduced into E.coli competent cells (DH 5. alpha.), propagated in LB medium containing ampicillin, and the human SGLT2 expression vector was obtained by a conventional method.

3) Preparation of human SGLT1 stably expressing [ stable expression ] cell and human SGLT2 stably expressing cell

Human SGLT1 expression vector or human SGLT2 expression vector digested with restriction enzyme PvuI was introduced into CHO-K1 cells using FuGENE (manufactured by Roche Diagnostics Co.). After gene transfer, the cells were cultured in DMEM medium (Gibco) containing penicillin (50U/mL, SIGMA), streptomycin (50mg/L, SIGMA), Geneticin (200mg/L, ナカライテスク) and 20% fetal calf serum at 37 ℃ under 5% CO₂The resultant was cultured in the presence for about 3 weeks to obtain a Geneticin-resistant clone product. Cells capable of stably expressing human SGLT1 or human SGLT2 were selected and obtained from these clone products using the activity of uptake of a sodium-dependent sugar (methyl-. alpha. -D-glucopyranoside) as an index.

4) Measurement of Activity for inhibiting uptake of methyl-alpha-D-glucopyranoside

The CHO cells stably expressed by human SGLT1 or the CHO cells stably expressed by human SGLT2 are inoculated on a 96-well plate according to the density of 30000-40000 cells/well and cultured for 4-6 days. Next, the medium was removed from these culture plates, and 150. mu.L of a buffer for pretreatment (containing 140mM choline chloride, 2mM potassium chloride, and calcium chloride) was added to each 1 well1mM magnesium chloride, 1mM 2- [4- (2-hydroxyethyl) -1-piperazinyl]Ethanesulfonic acid 10mM, tris (hydroxymethyl) aminomethane buffer pH7.4), and left to stand at 37 ℃ for 20 minutes. After removing the buffer for pretreatment, 50. mu.L of the buffer for pretreatment was added to 1 well, and the mixture was allowed to stand at 37 ℃ for 20 minutes. Buffer solution (containing 140mM of sodium chloride, 2mM of potassium chloride, 1mM of calcium chloride, 1mM of magnesium chloride, 1mM of methyl-alpha-D-glucopyranoside, and 1mM of [4- (2-hydroxyethyl) -1-piperazinyl)]10mM ethanesulfonic acid and 100mL of tris (hydroxymethyl) aminomethane buffer solution pH7.4), 6.3mL of methyl-. alpha. -D- (U-¹⁴C) Glucopyranoside (200 mCi/L, manufactured by Amersham Pharmacia Biotech) was mixed to prepare an uptake buffer, and a solution obtained by dissolving a test compound in the uptake buffer was used as an inhibitory activity measurement buffer. As a control, an uptake buffer containing no test compound was used. Further, in order to measure the basal uptake in the absence of the test compound and sodium, a buffer for basal uptake containing 140mM choline chloride instead of sodium chloride was prepared in the same manner and used for the measurement. The buffer for pretreatment was removed from the wells of the culture plate, 35. mu.L of the buffer for measuring inhibitory activity was added to each 1 well, and the mixture was allowed to stand at 37 ℃ for 45 minutes. The inhibitory activity assay buffer was removed and 300. mu.L of each washing buffer (containing 140mM choline chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10mM methyl-alpha-D-glucopyranoside, 2- [4- (2-hydroxyethyl) -1-piperazinyl) was added to each 1 well]Ethanesulfonic acid 10mM, tris (hydroxymethyl) aminomethane buffer pH7.4) and removed very quickly. This washing was further carried out 1 time, and 30mL of a cell lysate (sodium hydroxide 1M, sodium lauryl sulfate 0.1%) was added to each 1 well to render the cells soluble. To this was added 2M hydrochloric acid (15. mu.L), and 40. mu.L of the solution was transferred to a Luma-plate (manufactured by Packard Co., Ltd.) and left overnight at room temperature, whereby the solvent was evaporated. The radioactivity of the samples on the plates was measured by Topcount (Packard Co.). The concentration of the test compound (IC) at which the intake amount is 50% inhibited was calculated from the concentration-inhibition curve using calculation software (ELfit ver.3) with the value obtained by subtracting the basic intake amount from the control intake amount as 100%₅₀Value). The results show that the hair isThe clear compounds showed significant SGLT2 inhibition. IC for inhibition of SGLT2 by representative compounds of the invention₅₀The values are shown in the table.

[ Table 11]

TABLE 11

Test compounds	IC₅₀Value (nM)	Test compounds	IC₅₀Value (nM)
				Example 1	61	Example 59	8.9
Example 2	111	Example 62	7.1
				Example 8	7	Example 64	6.6
Example 11	14	Example 68	18
				Example 12	18	Example 69	5.1
Example 25	31	Example 70	7.4
				Example 42	7.7	Example 73	11
Example 44	16	Example 74	14
				Example 55	17

The present invention provides a cyclohexane compound or a pharmaceutically acceptable salt thereof which exhibits an excellent inhibitory activity against SGLT 2. The compound of the present invention is useful as a prophylactic or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications.

Claims

1. A compound represented by the formula (I):

in the formula (I), the compound is shown in the specification,

n is 0, or n is 1, A is-O-;

R⁶and R⁷Each independently is a hydrogen atom;

m is 1;

q is selected from Q represented by the following formula¹～Q⁵A substituted 6-membered carbocyclic ring of (a):

R¹、R²、R³and R⁴Each independently is a hydroxyl group;

R⁵selected from a hydrogen atom or a hydroxyl group;

Ar¹is phenylene, thienylene or pyridylene, which groups may be substituted by more than 1 Rb;

Ar²is phenyl which may be substituted by more than 1 Rb;

each Rb is independently selected from halogen atom, C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, and C₁-C₆An alkenyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein, in Ar¹Up, substituent- (CR)⁶R⁷)_m-Ar²To the ring atom adjacent to the ring atom to which substituent A is bonded.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, in Ar¹Up, substituent- (CR)⁶R⁷)_m-Ar²To the 2 nd ring atom away from the ring atom to which Q is bonded.

6. A compound selected from the group consisting of:

[2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclopentylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-chlorobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

(2-benzylphenyl) -5 a-carbon- β -D-glucopyranoside;

[2- (4-isopropylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclopropylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-n-propylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methylsulfanylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 3-fluoro-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -4-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -4-methoxyphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -6-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -4-fluorophenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-fluorobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 5-fluoro-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-fluorobenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3, 4-dimethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 5-methoxy-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-tert-butylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[ 3-methoxy-2- (4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -3-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-fluoro-4-methoxybenzyl) phenyl ] -5 a-carbon- α -D-glucopyranoside;

[4- (4-cyclopropylbenzyl) pyridin-3-yl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-vinylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-fluoro-4-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxy-3-methylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (3-chloro-4-methoxybenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-cyclobutylbenzyl) phenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-methoxybenzyl) -5-methylphenyl ] -5 a-carbon- β -D-glucopyranoside;

[2- (4-ethylbenzyl) thiophen-3-yl ] -5 a-carbon- β -D-glucopyranoside;

(1R, 2R, 3S, 4R, 5R) -1- [5- (4-ethylbenzyl) -2-methoxyphenyl ] -5- (hydroxymethyl) cyclohexan-1, 2, 3, 4-tetraol;

(1R, 2R, 3S, 4R, 5R) -5-hydroxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexa-1, 2, 3, 4-tetraol; and

(1S, 2R, 3S, 4R, 5R) -5-hydroxymethyl-1- [3- (4-methoxybenzyl) phenyl ] cyclohexa-1, 2, 3, 4-tetraol.

7. The use of a compound as claimed in any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis or treatment of diabetes, diabetic complications due to hyperglycemia, or obesity.

8. The use of claim 7, wherein the diabetes is type 1 diabetes or type 2 diabetes.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 for preventing or treating diabetes, diabetic complications due to hyperglycemia, or obesity.