WO2009096503A1

WO2009096503A1 - Benzyl phenyl glucopyranoside derivative

Info

Publication number: WO2009096503A1
Application number: PCT/JP2009/051532
Authority: WO
Inventors: Shigeo Yamanoi; Kazuki Mori; Mitsuhiro Iwamoto; Atsuko Nakashima; Takeshi Honda; Masanori Izumi; Tsuneaki Ogata; Ryo Okuyama
Original assignee: Daiichi Sankyo Company, Limited
Priority date: 2008-01-31
Filing date: 2009-01-30
Publication date: 2009-08-06
Also published as: TW200934503A

Abstract

Disclosed is a compound having a novel structure, few adverse side effects and an excellent inhibitory activity on human SGLT1 and/or SGLT2, or a hydrate of the compound. Also disclosed is a pharmaceutical composition for treating and/or preventing type-1 diabetes, type-2 diabetes, gestational diabetes, hyperglycemia induced by other factor, impaired glucose tolerance (IGT), diabetes-related diseases or diabetic complications, which comprises the compound or the hydrate as an active ingredient. Specifically disclosed is a compound represented by the formula shown below or a hydrate thereof.

Description

Benzylphenylglucopyranoside derivatives

The present invention relates to a compound having a human SGLT1 and / or SGLT2 activity inhibitory action.

Diabetes is a group of metabolic diseases characterized mainly by chronic hyperglycemia due to insufficient insulin action. For diabetes treatment, pharmacotherapy is given along with diet therapy and exercise therapy. Diabetes treatment drugs include biguanides and thiazolidinediones that improve insulin resistance, sulfonylureas and glinides that promote insulin secretion from pancreatic β cells. Systemic drugs, α-glucosidase inhibitors that inhibit sugar absorption, and the like are used. However, it has been reported that biguanides have lactic acidosis, thiazolidinedione has weight gain and edema, sulfonylureas and glinides have secondary effects due to hypoglycemia and long-term use, and α-glucosidase inhibitors have side effects such as diarrhea. Therefore, development of an antidiabetic drug having a new mechanism of action that solves such problems is desired.

In recent years, research and development of drugs with a new mechanism that increases glucose excretion in urine and lowers blood glucose levels by inhibiting glucose reabsorption in the kidney has been promoted (for example, Non-Patent Document 1) reference). This drug inhibits the reabsorption of sugar from raw urine by inhibiting sodium-dependent glucose transporter 2 (hereinafter referred to as SGLT2) present in the proximal tubule of the kidney It has been shown that blood glucose levels are reduced by suppressing and increasing the excretion of sugar outside the body (see, for example, Non-Patent Document 2). Against this background, compounds that inhibit human SGLT2 are expected to normalize blood glucose levels by increasing urinary glucose excretion and are associated with various types of diabetes associated with type 1 and type 2 diabetes and hyperglycemia It becomes an effective drug for diseases. In addition, anti-obesity effect is expected by reducing sugar accumulation in the body by increasing sugar excretion.

On the other hand, SGLT1, another subtype of SGLT (Sodium-dependent glucose cotransporter 1: hereinafter referred to as SGLT1), is expressed mainly in the small intestine and is a transporter that absorbs sugar (glucose, galactose) from food. (See Non-Patent Document 3, etc.) It is known that a sugar deficiency occurs in humans who are naturally deficient in SGLT1 (see, for example, Non-Patent Document 4). Based on these findings, it is considered that drugs that inhibit SGLT1 exhibit a postprandial hyperglycemic inhibitory action by inhibiting or delaying the absorption of sugar from the small intestine. In addition, an anti-obesity effect can be expected by suppressing the inflow of sugar into the body.

Based on the above, drugs that suppress human SGLT1 and / or SGLT2 activity are potent type 1 and type 2 diabetes mellitus drugs, anti-obesity drugs, high anti-obesity drugs that have both urinary glucose excretion-increasing activity and glucose absorption inhibition activity from the small intestine. It is expected to be an effective drug for various related diseases accompanying blood glucose.

It is known that O-aryl glucoside compounds have human SGLT2 inhibitory activity (see, for example, Patent Documents 1 to 5).
International Publication No. 01/68660 Pamphlet International Publication No. 02/28872 Pamphlet International Publication No. 02/44192 Pamphlet International Publication No. 02/64606 Pamphlet International Publication No. 08/016132 Pamphlet J. Clin. Invest., Vol. 79, pp. 1510-1515 (1987) J. Clin. Invest., Vol. 93, pp. 397-404 (1994) Am J Clin Nutr.Vol.59 (3 Suppl) pp.690S-698S (1994) Nature, Vol.350, pp.354-356 (1991)

However, none of the above Patent Documents 1 to 4 describes a compound having a substituent in the sugar moiety, and further describes or suggests that such a compound has a human SGLT1 inhibitory action. Absent. On the other hand, Patent Document 5 discloses a compound having a substituent in the sugar moiety and also describes that it has an SGLT1 inhibitory action. However, it is a patent document filed before the priority date of the present application and published after the priority date. is there.

Accordingly, the present invention provides a compound having a novel structure and excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects or a hydrate thereof, type 1 diabetes, type 2 diabetes containing them as active ingredients Gestational diabetes, hyperglycemia due to other factors, impaired glucose tolerance (IGT), diabetes related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver) Metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc. or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection) The object is to provide a pharmaceutical composition for treating and / or preventing ketosis and the like.

The present invention
(1) General formula (I):

(Wherein R ¹ is a hydrogen atom or a hydroxyl group,
R ² is a fluorine atom or a chlorine atom,
R ³ is a methyl group optionally substituted with a halogen atom, an ethyl group optionally substituted with a halogen atom, a cyclopropyl group, or a methoxy group optionally substituted with a halogen atom;
R ⁴ is a hydrogen atom or a methyl group,
n is 1 or 2,
m is 0 or 1;
(However, when R ¹ is a hydrogen atom, R ⁴ is a hydrogen atom, and when R ¹ is a hydroxyl group, R ⁴ is a methyl group.)
Or a hydrate thereof, represented by
(2) General formula (II):

[Wherein R ¹ is a hydrogen atom or a hydroxyl group;
R ² is a fluorine atom or a chlorine atom,
R ³ is a methyl group optionally substituted with a halogen atom, an ethyl group optionally substituted with a halogen atom, a cyclopropyl group, or a methoxy group optionally substituted with a halogen atom;
R ⁴ is a hydrogen atom or a methyl group,
n is 1 or 2,
m is 0 or 1;
However, when R ¹ is a hydrogen atom, R ⁴ is a hydrogen atom, and when R ¹ is a hydroxyl group, R ⁴ is a methyl group (provided that (I) R ¹ is a hydroxyl group and R ² is When it is a fluorine atom, m is 0 and n is 1, R ³ is not a methyl group, an ethyl group, a cyclopropyl group or a methoxy group;
(B) when R ¹ is a hydroxyl group, R ² is a chlorine atom, m is 0, and n is 1, R ³ is not a methoxy group, or
(C) When R ¹ is a hydrogen atom, R ² is a fluorine atom or a chlorine atom, m is 0, and n is 1, R ³ is not a methoxy group)]
Or a hydrate thereof, represented by
(3) The compound according to (2), wherein R ¹ is a hydroxyl group,
(4) The compound according to the above (2) or (3), wherein R ³ is a methyl group which may be substituted with a halogen atom or a methoxy group which may be substituted with a halogen atom,
(5) The compound according to any one of (2) to (4), wherein R ⁴ is a methyl group,
(6) The compound according to any one of (2) to (5) above, wherein n is 1.
(7) 3-chloro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-2- (4-Ethylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 2- [4- (difluoromethoxy) benzyl] -3-fluoro-5- (hydroxy Methyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco -Heptopyranoside, 3-fluoro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-2- ( 3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3- Luolo-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-2- (3-fluoro-4 -Methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-fluoro-2- (2-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) ) Phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-2- [4- (difluoromethoxy) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β -D-gluco-heptopyranoside, 3-fluoro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3- Fluoro-5-hydroxymethyl-2-[(4-trifluoromethoxy) benzyl] phenyl 7-deoxy-D-glycero-β-D -Gluco-heptopyranoside, 3-fluoro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside, 3-chloro-5-hydroxymethyl-2- (4-methylbenzyl) Phenyl 4-deoxy-β-D-glucopyranoside, 2- (4-ethylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside, 3-chloro-2- (4- Ethylbenzyl) -5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside, 2- (4-cyclopropylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D- Glucopyranoside, 3-fluoro-5-hydroxymethylphenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-2- (4-ethyl-3-fluorobenzyl) -5- (hydroxymethyl) Phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-fluoro B-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-5- (2-hydroxyethyl) -2 -(4-Methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy- D-glycero-β-D-gluco-heptopyranoside, 3-chloro-5- (hydroxymethyl) -2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero- β-D-gluco-heptopyranoside, 3-chloro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3- Chloro-2- (4-ethyl-2-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-fluoro-5- (H Roxymethyl) -2-[(4-trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-5- (hydroxymethyl) -2-[(4-trimethyl) Fluoromethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, 2- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5- (hydroxymethyl) phenyl 7 -Deoxy-D-glycero-β-D-gluco-heptopyranoside, 3-chloro-2- [4- (2,2-difluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- β-D-gluco-heptopyranoside, 3-fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside, and 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-g Co - Heputopiranoshido is selected from the group consisting of compounds or a hydrate thereof,
(8) A pharmaceutical composition comprising the compound according to any one of (1) to (7) or a hydrate thereof as an active ingredient,
(9) The pharmaceutical composition according to (8), which inhibits human SGLT1 and / or human SGLT2 activity,
(10) In the above (8) or (9) for the treatment or prevention of type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes related diseases or diabetic complications The pharmaceutical composition described,
(11) Diabetes-related diseases are obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, high uric acid The pharmaceutical composition according to (10), wherein the composition is diabetic or gout, or the diabetic complication is retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection or ketosis,
(12) Use of the compound according to any one of (1) to (7) or a hydrate thereof for producing a pharmaceutical composition,
(13) The use according to (12) above, wherein the pharmaceutical composition is a composition for inhibiting human SGLT1 and / or human SGLT2 activity,
(14) The pharmaceutical composition is a composition for treating or preventing type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes-related diseases or diabetic complications, The use according to (12) or (13),
(15) Diabetes-related diseases are obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, high uric acid The use according to (14) above, wherein the complication is retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection or ketosis.
(16) A method for inhibiting human SGLT1 and / or human SGLT2 activity, comprising administering to a mammal a therapeutically effective amount of the compound or hydrate thereof according to any one of (1) to (7) above ,
(17) A method for treating or preventing a disease, comprising administering to a mammal a therapeutically effective amount of the compound or hydrate thereof according to any one of (1) to (7) above,
(18) The method according to (17), wherein the disease is type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes-related diseases or diabetic complications,
(19) Diabetes-related diseases are obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, high uric acid Or the method according to (18) above, wherein the diabetic complication is retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection or ketosis, and
(20) The method according to any one of (17) to (19), wherein the mammal is a human,
I will provide a.

According to the present invention, it is possible to provide a compound or hydrate thereof having excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects. In addition, according to the present invention, these compounds or hydrates thereof are used as active ingredients, and type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes related diseases (for example, Obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or Pharmaceutical compositions for treating and / or preventing diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) can be provided.

In this specification, “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Table 1 shows preferred combinations of R ¹ , R ² , R ³ , R ⁴ , n and m in the general formula (I) or (II).

As used herein, “hydrate” refers to a pharmaceutically acceptable hydrate of the compound of the present invention. When the compound of the present invention is left in the air or recrystallized, it may absorb moisture and attach adsorbed water or become a hydrate. Such hydrates are also included in the “hydrate” in the present specification.

Since the compound of the present invention has an asymmetric carbon atom in the molecule, these isomers in which optical isomers exist, and mixtures of these isomers are all represented by a single formula, that is, the general formula (I) or It is represented by (II). Accordingly, the present invention includes all optical isomers and mixtures of optical isomers in an arbitrary ratio.

The compound (I) or (II) of the present invention can be produced, for example, according to Method A described later.

In method A and methods B to D described later, after completion of each reaction, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, after removing by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the organic layer containing the target compound is separated, After washing with water or the like and drying with anhydrous sodium sulfate or the like, the solvent is distilled off. If necessary, the obtained compound can be separated and purified by a conventional method such as silica gel column chromatography.

Further, in the method A and the later-described methods B to D, when the compound serving as a reaction substrate has a group that inhibits a desired reaction such as an amino group, a hydroxy group, or a carboxyl group, those compounds are appropriately selected as necessary. A protecting group may be introduced into the group and the introduced protecting group may be removed. The protecting group is not particularly limited as long as it is a commonly used protecting group.For example, T. H. Greene, P. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, ion1999, John Wiley & Sons, The protecting group described in Inc. etc. is mentioned. Such protecting group introduction reaction and removal reaction can be carried out according to a conventional method such as the method described in the above-mentioned literature.

(Wherein R ¹ , R ² , R ³ , R ⁴ , n and m are as defined above, and R ¹¹ , R ¹² and R ¹³ are the same or different and are a hydrogen atom or a protecting group.)

Step A1 is a step for producing compound (2), and is performed by reacting compound (1) with trichloroacetonitrile in the presence of a base in an inert solvent.

Examples of the inert solvent used in the above reaction include halogenated hydrocarbons and ethers, preferably halogenated hydrocarbons, more preferably methylene chloride.

Examples of the base used in the above reaction include organic amines, and preferably 1,8-diazabicyclo [5.4.0] -7-undecene.

The reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is usually -20 ° C to reflux temperature, preferably 0 ° C to room temperature.

The reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature, etc., but is usually 15 minutes to 48 hours, preferably 30 minutes to 5 hours.

Step A2 is a step for producing compound (I). After reacting compound (2) with compound (3) in the presence of a Lewis acid in an inert solvent, R ¹¹ , R ¹² and and removing the protecting group represented by R ^13.

Although the removal of the protecting group varies depending on the type, as described above, in general, methods well known in the art of organic synthetic chemistry, such as T. H. Greene, P. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, In 1999, it can be carried out according to conventional methods such as those described in John Wileyons & Sons, Inc.

Examples of the inert solvent used when the compound (2) is reacted with the compound (3) include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, and preferably halogens Hydrocarbon, more preferably methylene chloride.

Examples of the Lewis acid used in the above reaction include boron trifluoride-diethyl ether complex and trimethylsilyl trifluoromethanesulfonate, and boron trifluoride-diethyl ether complex is preferable.

The reaction temperature varies depending on the raw material compound, Lewis acid, inert solvent and the like, but is usually -30 ° C to reflux temperature, preferably 0 ° C to room temperature.

The reaction time varies depending on the raw material compound, Lewis acid, inert solvent, reaction temperature, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

Step A3 is a step for producing compound (4), and is performed by reacting compound (1) with hydrobromic acetic acid in an inert solvent.

Examples of the inert solvent used in the above reaction include halogenated hydrocarbons, and methylene chloride is preferable.

The reaction temperature varies depending on the raw material compound, the inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.

The reaction time varies depending on the raw material compound, inert solvent, reaction temperature, etc., but is usually 5 to 50 hours, preferably 15 to 35 hours.

Step A4 is a step of producing compound (I). After reacting compound (4) with compound (3) in the presence of silver carbonate in an inert solvent, R ¹¹ , R ¹² and and removing the protecting group represented by R ^13.

The removal of the protecting group may be performed in the same manner as in step A2.

Examples of the inert solvent used in the above reaction include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, etc., preferably halogenated hydrocarbons, more preferably methylene chloride. .

The reaction time varies depending on the raw material compound, inert solvent, reaction temperature and the like, but is usually 5 to 150 hours, preferably 10 to 50 hours.

Compound (1) which is a raw material compound of Method A can be produced by, for example, the following Method B, and Compound (3) can be produced by, for example, the following Method C or Method D.

(Wherein R ¹ , R ⁴ , R ¹¹ , R ¹² and R ¹³ are as defined above, and R ¹⁴ is a hydrogen atom or a protecting group.)

Step B1 is a step for producing compound (1) and is performed by removing the protecting group represented by R ¹⁴ .

For example, when the protecting group represented by R ¹⁴ is a benzoyl group, the reaction is performed by reacting hydrazine acetate in an inert solvent.

Examples of the inert solvent used in the above reaction include amides, and preferably dimethylformamide.

The reaction temperature varies depending on the raw material compound, inert solvent and the like, but is usually 0 to 50 ° C., preferably room temperature.

The reaction time varies depending on the raw material compound, inert solvent, reaction temperature, etc., but is usually 30 minutes to 35 hours, preferably 1 to 24 hours.

Step B2 is a step for producing compound (6), and is performed by acetylating R ¹⁴ in compound (5) in the presence of an acid catalyst in an inert solvent.

Examples of the inert solvent used in the above reaction include carboxylic acids and the like, and preferably acetic acid.

The acid catalyst used in the above reaction is preferably an inorganic acid, more preferably sulfuric acid.

The reaction temperature varies depending on the raw material compound, acid catalyst, inert solvent and the like, but is usually 0 to 50 ° C., preferably room temperature.

The reaction time varies depending on the raw material compound, acid catalyst, inert solvent, reaction temperature and the like, but is usually 3 to 48 hours, preferably 6 to 24 hours.

Step B3 is a step of producing compound (1), and is performed by reacting compound (6) with hydrazine acetate in an inert solvent. This step can be performed in the same manner as step B1.

Next, the method C will be described. Compound (14) in the following scheme is a compound in which n is 1 in compound (3).

(Wherein R ² , R ³ and m are as described above.)

Step C1 is a step for producing compound (9). In an inert solvent, compound (7) is reacted with compound (8) in the presence of a base, and a catalytic amount of trimethylsilylcyanide is added to react. Is done.

Examples of the inert solvent used in the above reaction include halogenated hydrocarbons, hydrocarbons, aromatic hydrocarbons, ethers, nitriles, etc., preferably nitriles, more preferably acetonitrile. is there.

Examples of the base used in the above reaction include organic amines, and preferably triethylamine.

The reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature to 60 ° C.

The reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature, etc., but is usually 10 minutes to 12 hours, preferably 2 to 4 hours.

Step C2 is a step of producing compound (10), and is performed by reacting compound (9) with a halogenating agent in an inert solvent.

Examples of the inert solvent used in the halogenation reaction that is the first stage of the above reaction include halogenated carbons, and preferably methylene chloride.

As the halogenating agent used in the above reaction, when R ² is fluorine, for example, dimethylaminosulfur trifluoride, 2,2-difluoro-1,3-dimethylimidazolidine, hydrogen fluoride-pyridine, etc. When R ² is chlorine, for example, oxalyl dichloride, thionyl chloride, phosphorus oxychloride and the like are preferable, and oxalyl dichloride is preferable.

The reaction temperature varies depending on the raw material compound, halogenating agent, inert solvent and the like, but is usually -30 to 100 ° C, preferably 0 ° C to room temperature.

The reaction time varies depending on the raw material compound, halogenating agent, inert solvent, reaction temperature, etc., but when R ² is fluorine, it is usually 30 minutes to 12 hours, preferably 3 hours, and R ² is chlorine. In this case, it is usually 30 minutes to 24 hours, preferably 1 to 3 hours.

Step C3 is a step of producing compound (11), and is performed by reacting compound (10) with an oxidizing agent in a basic solvent.

Examples of the basic solvent used in the above reaction include organic amines, and preferably N-methylmorpholine.

Examples of the oxidizing agent used in the above reaction include heavy metal salts such as permanganic acid and chromic acid, halogens such as bromine and iodine, and 2,3-dichloro-5,6-dicyano-p-benzoquinone. , Preferably halogen, more preferably iodine.

The reaction temperature varies depending on the raw material compound, basic solvent, type of oxidizing agent, etc., but is usually 0 to 100 ° C., preferably room temperature.

The reaction time varies depending on the raw material compound, basic solvent, oxidizing agent, reaction temperature, etc., but is usually 15 minutes to 12 hours, preferably 30 minutes to 2 hours.

Step C4 is a step for producing compound (12), and is performed by reacting compound (11) with a reducing agent in an inert solvent.

Examples of the inert solvent used in the above reaction include ethers and alcohols, preferably ethers, more preferably tetrahydrofuran.

Examples of the reducing agent used in the above reaction include alkali metal borohydrides such as sodium borohydride and lithium borohydride, aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum, hydrogen And a hydride reagent such as sodium telluride, preferably an aluminum hydride compound, more preferably lithium aluminum hydride.

The reaction temperature varies depending on the raw material compound, the reducing agent, the inert solvent and the like, but is usually -30 ° C to reflux temperature, preferably 0 ° C to room temperature.

The reaction time varies depending on the raw material compound, reducing agent, inert solvent, reaction temperature, etc., but is usually 10 minutes to 10 hours, preferably 30 minutes to 1 hour.

Step C5 is a step for producing compound (13), and is performed by reacting vinyl acetate with compound (12) in the presence of a bis (dibutyltin chloride) oxide catalyst in an inert solvent.

Examples of the inert solvent used in the above reaction include ethers, and tetrahydrofuran is preferable.

The reaction temperature varies depending on the raw material compound, the inert solvent and the like, but is usually 0 to 50 ° C., preferably room temperature to 35 ° C.

The reaction time varies depending on the raw material compound, inert solvent, reaction temperature and the like, but is usually 1 to 100 hours, preferably 24 to 48 hours.

Step C6 is a step for producing compound (14), and is performed by reacting compound (13) with a reducing agent in the presence of an acid or a Lewis acid in an inert solvent.

Examples of the acid or Lewis acid used in the above reaction include trifluoroacetic acid, boron trifluoride-diethyl ether complex, aluminum chloride, and the like, and preferably boron trifluoride-diethyl ether complex.

Examples of the reducing agent used in the above reaction include trialkylsilane, alkali metal borohydride, aluminum hydride compound, etc., preferably trialkylsilane, and more preferably triethylsilane.

The reaction temperature varies depending on the raw material compound, acid or Lewis acid, reducing agent, inert solvent, etc., but is usually −20 to 50 ° C., preferably 0 ° C. to room temperature.

The reaction time varies depending on the raw material compound, acid or Lewis acid, reducing agent, inert solvent, reaction temperature, etc., but is usually 30 minutes to 10 hours, preferably 1 to 2 hours.

Finally, the D method will be explained. Compound (22) in the following scheme is a compound in which n is 2 in compound (3).

(Wherein R ² , R ³ and m are as described above.)

Step D1 is a step of producing compound (15), and is performed by reacting compound (14) with a benzylating reagent in the presence of a base in an inert solvent.

Examples of the base used in the above reaction include inorganic bases, and potassium carbonate is preferable.

Examples of the benzylating reagent used in the above reaction include benzyl halide, benzyl arylsulfonate, benzyl alkylsulfonate, and the like, preferably benzyl halide, more preferably benzyl bromide.

The reaction temperature varies depending on the raw material compound, base, benzylating reagent, inert solvent, etc., but is usually 0 to 100 ° C., preferably room temperature.

The reaction time varies depending on the raw material compound, base, benzylating reagent, inert solvent, reaction temperature, etc., but is usually 30 minutes to 48 hours, preferably 2 to 4 hours.

Step D2 is a step of producing compound (16), and is performed by reacting compound (15) with a base in an inert solvent.

Examples of the inert solvent used in the above reaction include water and alcohols, preferably alcohols, more preferably methanol.

The reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.

The reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature and the like, but is usually 10 minutes to 24 hours, preferably 1 to 18 hours.

Step D3 is a step of producing compound (17), and is performed by reacting compound (16) with an oxidizing agent in an inert solvent.

Examples of the inert solvent used in the above reaction include hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, etc., preferably halogenated hydrocarbons, more preferably Chloroform.

The reaction temperature varies depending on the raw material compound, oxidizing agent, inert solvent and the like, but is usually 0 to 200 ° C., preferably the reflux temperature.

The reaction time varies depending on the raw material compound, oxidizing agent, inert solvent, reaction temperature, etc., but is usually 30 minutes to 48 hours, preferably 2 to 4 hours.

Step D4 is a step of producing compound (18), and is performed by reacting a phosphonium salt with a base in an inert solvent and further reacting with compound (17).

Examples of the phosphonium salt used in the above reaction include halogenated (methoxymethyl) triphenylphosphonium, and preferably (methoxymethyl) triphenylphosphonium chloride.

Examples of the base used in the above reaction include alkali metal bis (trimethylsilyl) amides and alkali metal dialkylamides, preferably alkali metal bis (trimethylsilyl) amide, more preferably lithium bis (trimethylsilyl) amide. It is.

The reaction temperature varies depending on the raw material compound, phosphonium salt, base, inert solvent and the like, but is usually -78 ° C to reflux temperature, preferably 0 ° C to room temperature.

The reaction time varies depending on the raw material compound, (methoxymethyl) phosphonium salt, base, inert solvent, reaction temperature, etc., but is usually 30 minutes to 24 hours, preferably 1 to 2 hours.

Step D5 is a step of producing compound (19), and is performed by hydrolyzing compound (18) in the presence of an acid catalyst in an inert solvent.

Examples of the inert solvent used in the above reaction include ethers, and preferably 1,4-dioxane.

Examples of the acid catalyst used in the above reaction include inorganic acids, aryl sulfonic acids, etc., preferably inorganic acids, more preferably hydrochloric acid.

The reaction temperature varies depending on the raw material compound, acid catalyst, inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.

The reaction time varies depending on the raw material compound, acid catalyst, inert solvent, reaction temperature, etc., but is usually 5 minutes to 10 hours, preferably 10 minutes to 1 hour.

Step D6 is a step of producing compound (20), and is performed by reacting compound (19) with a reducing agent in an inert solvent.

Examples of the inert solvent used in the above reaction include ethers and alcohols, preferably alcohols, more preferably methanol.

Examples of the reducing agent used in the above reaction include alkali metal borohydrides such as sodium borohydride and lithium borohydride, aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum, hydrogen And a hydride reagent such as sodium telluride, preferably an alkali metal borohydride, more preferably sodium borohydride.

Step D7 is a step for producing compound (21). When R ² is fluorine, it is carried out by catalytic reduction of compound (20) in the presence of hydrogen and a metal catalyst in an inert solvent. On the other hand, when R ² is chlorine, the reaction is carried out by reacting compound (20) with a Lewis acid in an inert solvent.

As the inert solvent used in the above reaction, when R ² is fluorine, examples thereof include ethers and alcohols, preferably alcohols, more preferably methanol, and R ² is chlorine. In the case, for example, nitriles and the like can be mentioned, and acetonitrile is preferable.

Examples of the metal catalyst used when R ² is fluorine include metal catalysts such as platinum, palladium, rhodium and nickel, preferably a palladium catalyst, and more preferably a palladium carbon catalyst.

Examples of the Lewis acid used in the above reaction when R ² is chlorine include trialkylsilyl halide, and trimethylsilyl iodide is preferable.

When R ² is fluorine, the reaction temperature varies depending on the raw material compound, metal catalyst, inert solvent, etc., but is usually 0 to 100 ° C., preferably room temperature, and when R ² is chlorine, the raw material Although it varies depending on the compound, Lewis acid, inert solvent and the like, it is usually 0 to 100 ° C., preferably 40 ° C.

The reaction time, when R ² is fluorine, the starting compound, a metal catalyst in an inert solvent, varying reaction temperature and the like, usually, 10 minutes to 24 hours, preferably 30 minutes to 2 hours, R ² When is chlorine, it varies depending on the raw material compound, Lewis acid, inert solvent, reaction temperature, etc., but is usually 30 minutes to 24 hours, preferably 1 to 3 hours.

Step D8 is a step for producing compound (22), and is performed by reacting compound (21) with vinyl acetate in the presence of a bis (dibutyltin chloride) oxide catalyst in an inert solvent. The method is carried out in the same manner as in the method of protecting the primary hydroxyl group of compound (12) in step C5 with an acetyl group.

The compounds of the present invention can be produced by using the above-mentioned methods, and examples described later from known compounds or methods well known in the art (for example, Chem. Ber, 71, 1938, 1843-1849, Carbohydr. Res. 1995). , 273,249-254, Bull.Chem.Soc.Jpn., 1982,55,938-942, Bull.Chem.Soc.Jpn., 1976,49,788-790, Org.Lett., 2003,5,3419-3421, Org. Biomol.Chem, 2003, 1,767-771, J. Chem. Soc., 1956, 2124-2126, WO 02/064606 pamphlet, Liebigs Ann. Chem, GE, 1992, 7, 747-758, etc.) Can be manufactured easily.

The compound of the present invention or a hydrate thereof exhibits excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects, type 1 diabetes, type 2 diabetes, gestational diabetes, other factors, hyperglycemia, glucose intolerance, Diabetes-related diseases (eg, obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia , Gout, etc.) or diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) are useful as an active ingredient of a pharmaceutical composition.

Such pharmaceutical compositions can be administered to mammals (eg, humans, horses, cows, pigs, preferably humans).

The administration form may be any of oral administration such as tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories.

These preparations include excipients (eg, lactose, corn starch, crystalline cellulose, D-mannitol, anhydrous calcium hydrogen phosphate, sucrose, etc.), disintegrants (eg, corn starch, carmellose calcium, low substituted hydroxypropyl) Cellulose, croscarmellose sodium, sodium carboxymethyl starch, etc.), binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, popidone, corn starch, methylcellulose, etc.), lubricants (eg, magnesium stearate, calcium stearate, talc) , Stearic acid, etc.), fluidizing agents (eg, light anhydrous silicic acid, talc, hydrous silicon dioxide, etc.), coating agents (eg, hydroxypropyl methylcellulose, hydride) (Xypropyl cellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, aminoalkyl methacrylate copolymer RS, etc.) Suspension agents (eg, sodium alginate, carmellose sodium, methylcellulose, polysorbate 80, etc.), emulsifiers (eg, glyceryl monostearate, sucrose fatty acid esters, etc.), stabilizers (eg, dibutylhydroxytoluene, tocopherol, Sulfites, etc.), preservatives (eg, paraoxybenzoates), isotonic agents (eg, salts) Sodium, glycerin), flavoring agent (e.g., sucrose, D- sorbitol, xylitol, licorice, saccharin sodium, aspartame, are prepared by methods well known in the art using additives such as stevia, etc.).

The amount of the compound of the present invention or hydrate thereof used varies depending on symptoms, age, etc., but in the case of oral administration, 1 to 2000 mg, preferably 10 to 400 mg per day, and in the case of intravenous administration, It is desirable to administer 0.1 to 500 mg per day, preferably 1 to 300 mg per day, one to several times per day depending on the symptoms.

Example 1 3-Chloro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No in Table 1) .12)

Example 1a) 4- (2-Fluoroethyl) benzoyl chloride 4- (2-fluoroethyl) benzoic acid (Bioorg. Med. Chem., 2005, 13, 77-78.) (1.8 g, 11 mmol) was salified The mixture was dissolved in methylene, added with oxalyl chloride (1.1 mL, 13 mmol) and N, N-dimethylformamide (0.1 mL, 1.3 mmol) under ice cooling, and stirred for 3 hours and a half while raising the temperature to room temperature. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude product (2.1 g) of the title compound as a colorless oil.

Example 1b Ethyl 4- [4- (2-fluoroethyl) benzoyl] -3-hydroxy-5-oxocyclohex-3-enecarboxylic acid 3-hydroxy-5-oxocyclohex-3-enecarboxylic acid Ethyl (EP1571148A1) (2.0 g, 11 mmol) and the crude product obtained in Example 1a (2.1 g, 11 mmol) were dissolved in acetonitrile (20 mL), and triethylamine (4.6 mL, 33 mmol) was added dropwise under ice cooling. . After 10 minutes, the completion of the reaction was confirmed. Trimethylsilyl cyanide (0.21 mL, 1.6 mmol) was added to this suspension, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (20 mL) and saturated brine (20 mL, twice). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (4.3 g) of the title compound.

Example 1c Ethyl 3-chloro-4- [4- (2-fluoroethyl) benzoyl] -5-oxocyclohex-3-enecarboxylate The crude product obtained in Example 1b (2.1 g, 6.5 mmol) was dissolved in methylene chloride (20 mL), and under ice cooling, 2-methyl-2-butene (2.8 mL, 26 mmol), oxalyl dichloride (0.83 mL, 9.8 mmol) and N, N-dimethylformamide (0.1 mL) , 0.13 mmol) was added successively, and the mixture was stirred for 2 hours while warming to room temperature. The reaction mixture was cooled to room temperature, diluted with methylene chloride (20 mL), and washed with saturated brine (20 mL, twice). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was concentrated under reduced pressure twice under azeotropy with toluene (10 mL) to obtain a crude product (2.2 g) of the title compound.

(Example 1d) Ethyl 3-chloro-4- [4- (2-fluoroethyl) benzoyl] -5-hydroxybenzoate The crude product obtained in Example 1c (2.2 g, 6.5 mmol) was converted to N-methyl. It melt | dissolved in the morpholine (26 mL), the anhydrous sodium sulfate (1.1g) and iodine (2.0g, 7.8mmol) were added, and it stirred at room temperature for 1 hour. The dark brown suspension was filtered through celite, diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (50 mL, 2 times), 30% aqueous sodium thiosulfate (20 mL), and saturated brine (20 mL). . The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product (2.2 g) of the title compound.

Example 1e 3-Chloro-2- {1- [4- (2-fluoroethyl) phenyl] -1-hydroxymethyl} -5- (hydroxymethyl) phenol The crude product obtained in Example 1d ( 2.2 g, 6.5 mmol) was dissolved in tetrahydrofuran (65 mL), the gas phase was replaced with nitrogen, and lithium aluminum hydride (1.0 g, 26 mmol) was added in small portions under ice cooling. The mixture was stirred for 1 hour while warming to room temperature, and water (1 mL) was added dropwise under ice cooling to stop the reaction. The mixture was diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (20 mL, twice) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 1: 1, V / V) to give the title compound. (1.0 g) was obtained.

(Example 1f) Acetic acid 3-chloro-4- {1- [4- (2-fluoroethyl) phenyl] -1-hydroxymethyl} -5-hydroxybenzyl Compound obtained in Example 1e (1.0 g, 3.2 mmol) was dissolved in a solution consisting of vinyl acetate (10 mL) and diisopropyl ether (10 mL), and porcine pancreatic lipase (1.0 g) was added. The suspension was stirred at 37 ° C. for 8 hours, filtered through celite and washed with ethyl acetate (2 × 5 mL). The obtained filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (1.1 g).

Example 1g Acetic acid 3-chloro-2- [4- (2-fluoroethyl) benzyl] -5-hydroxybenzyl The crude product (0.90 g, 2.5 mmol) obtained in Example 1f was converted to acetonitrile (10 mL). Then, triethylsilane (1.2 mL, 7.6 mmol) and boron trifluoride-diethyl ether complex (0.47 mL, 3.8 mmol) were added under ice cooling, and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 5: 1, V / V) to give the title compound. (0.76 g, including about 20% of raw material).

Example 1h 5-Acetoxymethyl-3-chloro-2- [4- (2-fluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) (1.1 g, 1.8 mmol) was dissolved in methylene chloride (10 mL). Under ice cooling, trichloroacetonitrile (0.50 mL, 5.41 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7.5 μL, 0.05 mmol) was added and stirred for 1 hour. The solution was diluted with methylene chloride (20 mL), and washed successively with saturated aqueous ammonium chloride (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Toluene (2 mL) was added and azeotropy was performed under reduced pressure to obtain the corresponding imidate crude product as a yellow amorphous product.

This imidate (1.36 g, 1.8 mmol) and the crude product obtained in Example 1g (0.66 g, 1.8 mmol) were dissolved in methylene chloride (5 mL). Under ice cooling, boron trifluoride-diethyl ether complex ( 0.11 mL, 0.90 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes. The mixture was quenched with triethylamine (0.14 mL, 1.0 mmol), diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous ammonium chloride (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound.

Example 1i 3-chloro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 1h The obtained crude product (1.8 mmol) was dissolved in a solution consisting of tetrahydrofuran (6 mL) and methanol (6 mL), 2M aqueous sodium hydroxide solution (6 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 30 min. Water (20 mL) was added to the mixture, followed by extraction with ethyl acetate (20 mL, 3 times), and the organic layer was washed twice with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (methylene chloride: methanol, 10: 1, V / V). The obtained solid was dissolved in ethyl acetate: diisopropyl ether: hexane (1: 1: 2, V / V) and then cooled to obtain a precipitate. The precipitate was collected to obtain the title compound (0.19 g) as a colorless solid.
¹ H NMR (500 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 6.4 Hz), 2.91 (2H, dt, J = 22.9, 6.6 Hz), 3.32-3.45 (4H, m), 4.04-4.06 (1H, m), 4.12 (1H, d, J = 14.6 Hz), 4.25 (1H, d, J = 14.6 Hz), 4.53 (2H, dt, J = 47.4, 6.6 Hz), 4.55 (2H, s) , 4.93 (1H, d, J = 6.8 Hz), 7.07 (2H, d, J = 7.8 Hz), 7.09 (1H, s), 7.12 (1H, s), 7.18 (2H, d, J = 8.3 Hz) ;
MS (FAB) m / z: 471 (M + H) ⁺ , 493 (M + Na) ^+.

(Example 2) 3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 13 in Table 1)

Example 2a (2-Chloro-4,6-dihydroxyphenyl) (4-ethylphenyl) methanone 1-Chloro-3,5-dimethoxybenzene (8.11 g, 47.0 mmol) was dissolved in toluene (40 mL), Aluminum chloride (6.26 g, 46.9 mmol) and 4-ethylbenzoyl chloride (6.89 mL, 47.0 mmol) were added, and the mixture was stirred at room temperature for 15 minutes, and then stirred at 85 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was added to 1N aqueous hydrochloric acid (300 mL) under ice cooling. After extraction with toluene (100 mL), the mixture was washed with saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was washed with hexane and filtered to give a crude solid product (10.3 g).

The obtained crude product (10.3 g) was dissolved in methylene chloride (100 mL) and cooled to −78 ° C., 1 mol / L boron tribromide methylene chloride solution (106 mL, 106 mmol) was added, and the mixture was stirred at room temperature for 16 hours. did. The reaction solution was added to ice (300 g) under ice cooling. After extraction with methylene chloride (100 mL, twice), the mixture was washed successively with water (200 mL) and saturated sodium bicarbonate solution (200 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was washed with methylene chloride / hexane and filtered to give a crude product of the title compound (7.53 g) as a solid.

Example 2b 5-chloro-2,2-dimethyl-4- (4-ethylphenyl) -4H-benzo [1,3] dioxin-7-ol The crude product obtained in Example 2a (1.59 g , 5.75 mmol) was dissolved in methanol (15 mL), sodium borohydride (326 mg, 8.62 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. After cooling to 0 ° C., saturated aqueous ammonium chloride solution (1 mL) was added, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed successively with saturated aqueous ammonium chloride (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product (1.17 g).

The crude product (1.17 g) was dissolved in acetone (25 mL), paratoluenesulfonic acid monohydrate (0.24 g, 1.26 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After filtration through celite, an appropriate amount of triethylamine was added, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 5: 1, V / V) to obtain the amorphous title compound (620 mg).

(Example 2c) Methyl 5-chloro-2,2-dimethyl-4- (4-ethylphenyl) -4H-benzo [1,3] dioxin-7-carboxylate The compound obtained in Example 2b (620 mg, 1.94 mmol) was dissolved in methylene chloride (10 mL), pyridine (0.235 mL, 2.91 mmol) was added, and after cooling to 0 ° C., trifluoromethanesulfonic anhydride (0.390 mL, 2.32 mmol) was added and stirred for 20 minutes. Further, methylene chloride (20 mL) was added and washed with water (20 mL, 3 times). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Toluene azeotropy was performed to obtain a crude product of triflate (790 mg).

The obtained crude product (790 mg) was dissolved in N, N-dimethylformaldehyde (8 mL), methanol (1.42 mL, 35.0 mmol), palladium acetate (39 mg, 0.17 mmol), 1,3-bis (diphenylphosphino) ) Propane (72 mg, 0.17 mmol) and triethylamine (4.86 mL, 35.0 mmol) were added, and the mixture was stirred at 55 ° C. for 3 hours under a carbon monoxide atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (60 mL) and washed successively with 1 mol / L hydrochloric acid aqueous solution (30 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 4: 1, V / V) gave the title compound (584 mg) as an oil.

Example 2d 3-chloro-2- [1- (4-ethylphenyl) -1-methoxymethyl] -5- (hydroxymethyl) phenol Lithium aluminum hydride (103 mg, 2.71 mmol) in tetrahydrofuran (3 mL) After dissolution, under ice cooling, a tetrahydrofuran solution (4 mL) in which the compound obtained in Example 2c (651 mg, 1.80 mmol) was dissolved was added. The reaction mixture was stirred at room temperature for 30 minutes, cooled to 0 ° C, water (0.1 mL), 5 mol / L aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. And left at room temperature for 14 hours. After filtration through celite, the solvent was removed under reduced pressure to obtain an oily crude alcohol product (470 mg).

The obtained crude product (470 mg) was dissolved in methanol (10 mL), paratoluenesulfonic acid monohydrate (130 mg, 0.68 mmol) and water (1 mL) were added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (20 mL), and washed successively with aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 3: 2, V / V) gave the title compound (401 mg) as an oil.

(Example 2e) Acetic acid 3-chloro-4- [1- (4-ethylphenyl) -1-methoxymethyl] -5-hydroxybenzyl Compound (401 mg, 1.31 mmol) obtained in Example 2d was added to tetrahydrofuran (4 mL). ), Vinyl acetate (4 mL) and bis (dibutyltin chloride) oxide (144 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 72 hours. The solvent was removed under reduced pressure, and finally purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the title compound (380 mg) as an oil.

(Example 2f) Acetic acid 3-chloro-4- (4-ethylbenzyl) -5-hydroxybenzyl The compound (380 mg, 1.09 mmol) obtained in Example 2e was dissolved in acetonitrile (8 mL) and cooled to 0 ° C. Thereafter, triethylsilane (0.520 mL, 3.26 mmol) and boron trifluoride-diethyl ether complex (0.210 mL, 1.67 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (40 mL) and washed successively with aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (40 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, the residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 2: 1, V / V) to obtain the title compound (293 mg) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.7 Hz), 2.11 (3H, s), 2.60 (2H, q, J = 7.7 Hz), 4.15 (2H, s), 5.00 (2H, s), 6.72 (1H, d, J = 1.6 Hz), 7.02 (1H, d, J = 1.6 Hz), 7.11 (2H, d, J = 8.0 Hz), 7.18 (2H, d, J = 8.0 Hz);
MS (EI) m / z: 318, 320 (M) ^+.

Example 2g 5-Acetoxymethyl-3-chloro-2- (4-ethylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β-D-gluco -Heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (722 mg, 1.18 mmol) was dissolved in methylene chloride (8 mL) and 0 After cooling to ° C., trichloroacetonitrile (0.597 mL, 5.91 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.018 mL, 0.12 mmol) were added, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with saturated aqueous ammonium chloride (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Toluene (2 mL) was added and azeotroped under reduced pressure to give the corresponding imidate as a yellow amorphous.

The compound (290 mg, 0.91 mmol) and imidate (890 mg, 1.18 mmol) obtained in Example 2f were dissolved in methylene chloride (8 mL), and molecular sieve 4A (manufactured by Nacalai Tesque, hereinafter referred to as MS4A) was added. Boron trifluoride-diethyl ether complex (0.148 mL, 1.18 mmol) was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 15 minutes and then at room temperature for 15 minutes. Saturated sodium bicarbonate (5 mL) was added to the reaction mixture, diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (850 mg) of the title compound.

(Example 2h) 3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Crude product obtained in Example 2g (850 mg) was dissolved in methanol / methylene chloride (16 mL / 4 mL), potassium carbonate (1.63 g, 11.8 mmol) was added, and the mixture was stirred overnight at room temperature. After filtering through Celite to remove excess potassium carbonate, an appropriate amount of acetic acid was added for neutralization, and methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed successively with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was solidified from hexane / ethyl acetate / methanol to give the title compound (196 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.17 (3H, t, J = 7.5 Hz), 1.21 (3H, d, J = 6.3 Hz), 2.56 (2H, q, J = 7.5 Hz), 3.36 -3.38 (2H, m), 3.44-3.46 (2H, m), 4.05 (1H, dd, J = 6.3, 3.5 Hz), 4.11 (1H, d, J = 14.5 Hz), 4.24 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.93 (1H, d, J = 7.8 Hz), 7.02 (2H, d, J = 8.2 Hz), 7.10 (1H, s), 7.12 (1H, s), 7.15 (2H, d, J = 8.2 Hz);
MS (FAB) m / z: 475 (M + Na) ^+.

Example 3 2- [4- (Difluoromethoxy) benzyl] -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 1 in Table 1) )

Example 3a) Ethyl 4- [4- (difluoromethoxy) benzoyl] -3-hydroxy-5-oxocyclohex-3-enecarboxylate ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate ( 2.0 g, 11 mmol) and 4- (difluoromethoxy) benzoyl chloride (J. Org. Chem. USSR, 1981, 1470-1475.) (2.3 g, 11 mmol) (2.3 g, 11 mmol) in the same manner as in Example 1b. Crude product (3.3 g) was obtained.

Example 3b Ethyl 4- [4- (difluoromethoxy) benzoyl] -3-fluoro-5-oxocyclohex-3-enecarboxylate Crude product obtained in Example 3a (1.6 g, 4.4 mmol) Was dissolved in methylene chloride (10 mL), diethylaminosulfur trifluoride (1.7 mL, 13 mmol) was added under ice cooling, and the mixture was stirred for 5 hours while warming to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL), and washed successively with saturated brine (10 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title compound. (1.5 g) was obtained.

Example 3c Ethyl 4- [4- (difluoromethoxy) benzoyl] -3-fluoro-5-hydroxybenzoate The compound obtained in Example 3b (1.2 g, 3.4 mmol) was converted to N-methylmorpholine (15 mL). Into the solution, anhydrous sodium sulfate (1.2 g) and iodine (0.97 g, 3.8 mmol) were added at room temperature, followed by stirring at room temperature for 1 hour. The dark brown suspension was filtered through celite, diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (50 mL, 2 times), 30% aqueous sodium thiosulfate (20 mL), and saturated brine (20 mL). . The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.2 g) of the title compound.

Example 3d Ethyl 4- {1- [4- (difluoromethoxy) phenyl] -1-hydroxymethyl} -3-fluoro-5-hydroxybenzoate The crude product obtained in Example 3c (1.5 g, 4.1 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (0.31 g, 8.2 mmol) was added under ice cooling. The mixture was stirred for 2 hours while warming to room temperature, and saturated aqueous ammonium chloride (1 mL) was added dropwise under ice cooling to stop the reaction. The mixture was diluted with ethyl acetate (50 mL), and washed successively with saturated sodium hydrogen carbonate (20 mL, twice) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title compound. (0.82 g) was obtained as a colorless solid.

(Example 3e) Ethyl 4- [4- (difluoromethoxy) benzyl] -3-fluoro-5-hydroxybenzoate The compound obtained in Example 3d (0.82 g, 2.3 mmol) was dissolved in ethanol (8 mL). The solution was stirred for 10 minutes while blowing nitrogen into the solution. To this solution, 2M hydrochloric acid (0.57 mL, 1.1 mmol) and 10% palladium carbon catalyst (containing water, 0.5 g) were added under a nitrogen stream, and the gas phase was replaced with hydrogen, followed by stirring at room temperature for 6 hours. The mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (0.76 g) as a colorless solid.

Example 3f 2- [4- (Difluoromethoxy) benzyl] -3-fluoro-5- (hydroxymethyl) phenol The crude product obtained in Example 3e (0.76 g, 2.2 mmol) was added to tetrahydrofuran (10 mL). After the gas phase was replaced with nitrogen, lithium aluminum hydride (0.25 g, 6.6 mmol) was added in small portions under ice cooling. The mixture was stirred for 1 hour while warming to room temperature, and water (1 mL) was added dropwise under ice cooling to stop the reaction. The mixture was diluted with ethyl acetate (30 mL), and washed successively with 2M hydrochloric acid (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.65 g) of the title compound as a colorless solid.

(Example 3g) Acetic acid 4- [4- (difluoromethoxy) benzyl] -3-fluoro-5-hydroxybenzyl The crude product obtained in Example 3f (0.65 g, 2.2 mmol) was added to vinyl acetate (5 mL) and Dissolved in a solution consisting of diisopropyl ether (5 mL), porcine pancreatic lipase (1.0 g) was added. The suspension was stirred at 37 ° C. for 8 hours and the suspension was filtered through celite and washed with ethyl acetate (5 mL, 2 ×). The obtained filtrate was concentrated under reduced pressure, and the residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 4: 1, V / V) to give the title compound (0.75 g, quant.) As a slightly yellow solid. Got as.
¹ H NMR (500 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.98 (2H, s), 5.00 (2H, s), 6.45 (1H, t, J = 74.2 Hz), 6.60 (1H, s ), 6.69 (1H, d, J = 9.3 Hz), 7.01 (2H, d, J = 7.3 Hz), 7.27 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 340 (M) ^+.

Example 3h 5-Acetoxymethyl-2- [4- (difluoromethoxy) benzyl] -3-fluorophenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β- D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.37 g, 0.60 mmol) in methylene chloride (4 mL) Dissolve and prepare an imidate in the same manner as Example 1h using trichloroacetonitrile (0.18 mL, 1.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2.7 μL, 0.018 mmol). . Similar to Example 1h using the obtained imidate (0.45 g, 0.60 mmol), the compound obtained in Example 3g (0.20 g, 0.60 mmol) and boron trifluoride-diethyl ether complex (37 μL, 0.30 mmol). By this method, a mixture containing the title compound was obtained.

Example 3i 2- [4- (Difluoromethoxy) benzyl] -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 3h The mixture (0.60 mmol) was dissolved in a solution consisting of tetrahydrofuran (2 mL) and methanol (2 mL), 2M aqueous sodium hydroxide solution (2 mL, 4 mmol) was added, and the mixture was stirred at room temperature for 30 min. Water (10 mL) was added to the mixture, followed by extraction with ethyl acetate (20 mL, 3 times), and the organic layer was washed twice with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (methylene chloride: methanol, 10: 1, V / V) to give the title compound. (0.11 g) was obtained as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.6 Hz), 3.36-3.51 (4H, m), 4.00 (1H, d, J = 15.1 Hz), 4.06-4.07 ( 1H, m), 4.08 (1H, d, J = 15.1 Hz), 4.55 (2H, s), 4.95 (1H, d, J = 7.4 Hz), 6.71 (1H, t, J = 74.5 Hz), 6.80 ( 1H, d, J = 9.8 Hz), 6.98 (2H, d, J = 8.6 Hz), 6.99 (1H, s), 7.32 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 497 (M + Na) ^+.

(Example 4) 3-chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 9 in Table 1)

Example 4a) Ethyl 3-hydroxy-4- (4-methylbenzoyl) -5-oxocyclohex-3-enecarboxylate Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (3.0 g, 16.3 mmol) was dissolved in acetonitrile (50 mL), triethylamine (6.8 mL, 48.8 mmol) and p-toluoyl chloride (2.26 mL, 17.1 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Further, trimethylsilylcyanide (260 μL, 1.95 mmol) was added and stirred at 60 ° C. for 2 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate (30 mL) and washed successively with 1M hydrochloric acid (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to obtain the title compound (3.47 g) as a brown oily substance.

(Example 4b) Ethyl 3-chloro-4- (4-methylbenzoyl) -5-oxocyclohex-3-enecarboxylate The compound obtained in Example 4a (1.0 g, 3.3 mmol) was dissolved in methylene chloride (10 mL). ) Oxalyl dichloride (300 μL, 3.5 mmol), 2-methyl-2-butene (1.4 mL, 13.2 mmol) and N, N-dimethylformamide (100 μL, 1.29 mmol) were added under ice-cooling at room temperature. For 2 hours. Distilled water (5 mL) was added to the reaction solution, diluted with methylene chloride (10 mL), and washed successively with distilled water (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Toluene (10 mL) was added to the residue, and the solvent was distilled off under reduced pressure twice. Thus, a crude product (1.2 g) of the title compound was obtained as a brown oily substance.

(Example 4c) Ethyl 3-chloro-5-hydroxy-4- (4-methylbenzoyl) benzoate To the crude product (1.2 g) obtained in Example 4b, N-methylmorpholine (10 mL) and iodine ( 1.68 g, 6.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After filtration through celite, the mixture was diluted with toluene (10 mL), and washed successively with aqueous sodium sulfite solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-3: 1, V / V) to give the title compound (0.77 g) as a yellow solid.

Example 4d Ethyl 3-chloro-5-hydroxy-4- [1-hydroxy-1- (4-methylphenyl) methyl] benzoate The compound obtained in Example 4c (0.77 g, 2.4 mmol) was dissolved in methanol. (6 mL) and tetrahydrofuran (1 mL) were dissolved in the solution. Under ice cooling, sodium borohydride (137 mg, 3.6 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Under ice cooling, a saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate (10 mL), and washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL), and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1 to 5: 1, V / V) to obtain the title compound (0.57 g) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.38 (3H, t, J = 7.3 Hz), 2.34 (3H, s), 2.97 (1H, brs), 4.36 (2H, q, J = 7.2 Hz), 6.47 (1H, s), 7.17 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.51 (1H, s), 7.56 (1H, s), 9.15 (1H, brs ) ..

Example 4e) Ethyl 5-chloro-2,2-dimethyl-4- (4-methylphenyl) -4H-benzo [1,3] dioxin-7-carboxylate The compound obtained in Example 4d (0.57 g 1.8 mmol) was dissolved in acetone (6 mL), boron trifluoride-diethyl ether complex (220 μL, 1.8 mmol) was added at −10 ° C., and the mixture was stirred for 3 hours while slowly warming to 0 ° C. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, diluted with ethyl acetate (20 mL), and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 10: 1, V / V) to obtain the title compound (0.65 g, quant.) As a colorless oily substance.

Example 4f 5-chloro-2,2-dimethyl-4- (4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethanol The compound obtained in Example 4e (0.65 g, 1.8 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (101 mg, 2.7 mmol) was added under ice cooling, followed by stirring at room temperature for 2 hours. Distilled water (5 mL) was added to the reaction mixture under ice cooling, diluted with ethyl acetate (10 mL), and washed successively with 2M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL), and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.55 g) of the title compound as a colorless solid.

(Example 4g) Acetic acid 5-chloro-2,2-dimethyl-4- (4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethyl The crude product (0.55) obtained in Example 4f g, 1.8 mmol) is dissolved in methylene chloride (7 mL), acetic anhydride (200 μL, 2.1 mmol), pyridine (350 μL, 3.5 mmol) and 4-dimethylaminopyridine (65 mg, 0.5 mmol) are added under ice-cooling, Stir at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and washed successively with 2M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.65 g) of the title compound as a colorless oil.

(Example 4h) 3-chloro-5-hydroxy-4- (4-methylbenzyl) benzyl acetate Acetic acid (0.65 g, 1.8 mmol) obtained in Example 4 g was dissolved in acetonitrile (7 mL) and iced. Under cooling, triethylsilane (850 μL, 5.3 mmol) and boron trifluoride-diethyl ether complex (340 μL, 2.7 mmol) were added, and the mixture was stirred at 0 ° C. for 1 hour. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 8: 1 to 6: 1 to 4: 1, V / V) to obtain the title compound (376 mg) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.12 (3H, s), 2.30 (3H, s), 4.14 (2H, s), 4.93 (1H, s), 5.00 (2H, s), 6.72 (1H , s), 7.02 (1H, s), 7.09 (2H, d, J = 7.8 Hz), 7.15 (2H, d, J = 7.8 Hz);
MS (EI) m / z: 304 (M) ^+.

Example 4i 5-Acetoxymethyl-3-chloro- (4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) (240 mg, 0.39 mmol) in methylene chloride (5 mL ), Trichloroacetonitrile (120 μL, 1.20 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol) were added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with methylene chloride (10 mL) and washed successively with saturated aqueous ammonium chloride (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a corresponding imidate crude product as a yellow amorphous product.

The obtained imidate was dissolved in methylene chloride (5 mL), and the compound obtained in Example 4h (100 mg, 0.33 mmol) and boron trifluoride-diethyl ether complex (50 μL, 0.39 mmol) were added under ice cooling. And stirred at 0 ° C. for 2 hours. Triethylamine (100 μL, 0.72 mmol) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (10 mL) and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (350 mg) of the title compound.

(Example 4j) 3-Chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside The crude product obtained in Example 4i (350 mg , 0.33 mmol) was dissolved in a solution consisting of tetrahydrofuran (1 mL) and methanol (4 mL), sodium carbonate (46 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in ethyl acetate (10 mL) and washed successively with saturated aqueous ammonium chloride (10 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 20: 1 to 15: 1 to 10: 1, V / V) to obtain the title compound (76 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.3 Hz), 2.25 (3H, s), 3.37-3.38 (2H, m), 3.43-3.45 (2H, m), 4.05 (1H, dd, J = 6.7 Hz, 3.5 Hz), 4.10 (1H, d, J = 14.4 Hz), 4.23 (1H, d, J = 14.4 Hz), 4.55 (2H, s), 4.92 (1H, d, J = 7.4 Hz), 7.00 (2H, d, J = 7.9 Hz), 7.09-7.12 (4H, m);
MS (FAB) m / z: 438 (M + Na) ^+.

(Example 5) 3-Fluoro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 7)

Example 5a) Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (0.35 g, 1.9 mmol) was dissolved in acetonitrile (4 mL), triethylamine (0.79 mL, 5.7 mmol), 3-fluoro-4-methylbenzoyl chloride (J. Med. Chem., 1997, 40, 2064-2084. ) (0.33 g, 1.9 mmol) and trimethylsilylcyanide (0.030 mL, 0.23 mmol) were used in the same manner as in Example 1b to obtain a crude product. The crude product was purified using silica gel flash column chromatography (methylene chloride: methanol, 10: 1, V / V) to obtain the title compound (0.61 g).

Example 5b Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-fluoro-5-oxocyclohex-3-enecarboxylate The compound obtained in Example 5a (0.61 g, 1.9 mmol) was obtained. The title compound (0.31 g) was obtained by dissolving in methylene chloride (8 mL) and using diethylaminosulfur trifluoride (0.75 mL, 5.7 mmol) in the same manner as Example 3b.

Example 5c Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-fluoro-5-hydroxybenzoate Dissolve the compound obtained in Example 5b (0.31 g, 0.96 mmol) in acetonitrile (3 mL). Then, ice cooling, triethylamine (0.40 mL, 2.9 mmol) and trimethylsilyl iodide (0.34 mL, 2.4 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with toluene (10 mL) under ice cooling, and washed twice with a phosphate buffer solution (pH 7, 5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with toluene (10 mL). To this solution, silica gel (manufactured by Kanto Chemical Co., Inc., silica gel 60 (spherical), 40 to 100 μm, 1 g) was added and stirred at room temperature for 1 hour. The mixture was filtered through celite, the solvent was distilled off under reduced pressure, ethanol (10 mL) and potassium carbonate (0.41 g, 3.0 mmol) were added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed successively with 1M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL), and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to obtain the title compound (0.17 g).

Example 5d 3-Fluoro-2- [1- (3-fluoro-4-methylphenyl) -1-hydroxymethyl] -5- (hydroxymethyl) phenol The compound obtained in Example 5c (0.17 g, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL), and the title compound (0.13 g) was obtained as a crude product in the same manner as in Example 1e using lithium aluminum hydride (60 mg, 1.6 mmol).

Example 5e) Acetic acid 3-fluoro-4- [1- (3-fluoro-4-methylphenyl) -1-hydroxymethyl] -5-hydroxybenzyl Crude product obtained in Example 5d (0.13 g, 0.46 mmol) was dissolved in a solution consisting of vinyl acetate (3 mL) and diisopropyl ether (3 mL), porcine pancreatic lipase (0.13 g) was added, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, V / V) to obtain the title compound (0.12 g).

Example 5f Acetic acid 3-fluoro-4- (3-fluoro-4-methylbenzyl) -5-hydroxybenzyl The compound (0.12 g, 0.37 mmol) obtained in Example 5e was dissolved in acetonitrile (3 mL). Triethylsilane (0.18 mL, 1.1 mmol) and boron trifluoride-diethyl ether complex (70 μL, 0.56 mmol) were added at −40 ° C., and the mixture was stirred for 1 hour while warming to room temperature. After completion of the reaction, triethylamine (0.15 mL, 1.1 mmol) was added to the reaction mixture under ice-cooling, diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous ammonium chloride (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, V / V) to give an oil Of the title compound (85 mg).
¹ H NMR (500 MHz, CDCl ₃ ): δ 2.12 (3H, s), 2.22 (3H, s), 3.96 (2H, s), 5.01 (2H, s), 6.61 (1H, s), 6.68 (1H , d, J = 9.8 Hz), 6.91-6.97 (2H, m), 7.07 (1H, m);
MS (EI) m / z: 306 (M) ^+.

Example 5g 5-acetoxymethyl-3-fluoro-2- (3-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.37 g, 0.60 mmol) in methylene chloride (4 mL) Prepared in the same manner as in Example 1h using trichloroacetonitrile (0.18 mL, 1.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2.7 μL, 0.018 mmol). did. Using this imidate (0.45 g, 0.60 mmol), the compound obtained in Example 5f (85 mg, 0.28 mmol) and boron trifluoride-diethyl ether complex (37 μL, 0.30 mmol), the same method as in Example 1h To give a mixture containing the title compound.

Example 5h 3-Fluoro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 5g The resulting mixture (0.28 mmol) was dissolved in a solution consisting of tetrahydrofuran (2 mL) and methanol (1 mL), 2M aqueous sodium hydroxide solution (2 mL, 4 mmol) was added, and the title compound (84 mg) was prepared in the same manner as in Example 3i. Obtained as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.20 (3H, d, J = 6.7 Hz), 2.17 (3H, s), 3.38-3.47 (4H, m), 3.97 (1H, d, J = 14 Hz), 4.03-4.05 (1H, m), 4.05 (1H, d, J = 14 Hz), 4.56 (2H, s), 4.95 (1H, d, J = 7.4 Hz), 6.80 (1H, d, J = 9.3 Hz), 6.91 (1H, d, J = 11 Hz), 6.96-7.06 (3H, m);
MS (FAB) m / z: 441 (M + H) ⁺ , 463 (M + Na) ^+.

(Example 6) 3-chloro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 17)

Example 6a 3-Fluoro-4-methylbenzoyl chloride 3-fluoro-4-methylbenzoic acid (880 mg, 5.71 mmol), oxalyl dichloride (0.50 mL, 5.71 mmol), catalytic amount of N, N-dimethylformamide A crude product of the title compound (950 mg) was obtained as a colorless oil in the same manner as in Example 1a using tetrahydrofuran and tetrahydrofuran (10 mL).

Example 6b Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (950 mg, 5.16 mmol), using the crude product obtained in Example 6a (950 mg, 11 mmol), acetonitrile (10 mL), triethylamine (2.27 mL, 1.63 mmol) and trimethylsilylcyanide (0.087 mL, 0.65 mmol). In the same manner as in Example 1b, a crude product (1.65 g) of the title compound was obtained.

Example 6c Ethyl 3-chloro-4- (3-fluoro-4-methylbenzoyl) -5-oxocyclohex-3-enecarboxylate Crude product obtained in Example 6b (1.65 g, 5.15 mmol ), Methylene chloride (20 mL), 2-methyl-2-butene (2.19 mL, 20.6 mmol), oxalyl dichloride (0.46 mL, 5.36 mmol) and a catalytic amount of N, N-dimethylformamide as in Example 1c. By the method, a crude product (1.75 g) of the title compound was obtained.

Example 6d Ethyl 3-chloro-4- (3-fluoro-4-methylbenzoyl) -5-hydroxybenzoate Crude product obtained in Example 6c (1.75 g, 5.15 mmol), N-methylmorpholine (20 mL), anhydrous sodium sulfate (14.6 g) and iodine (1.43 g, 5.63 mmol) were used in the same manner as in Example 1d to obtain a crude product of the title compound. Then, purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the amorphous title compound (1.28 g).

Example 6e) Ethyl 5-chloro-2,2-dimethyl-4- (3-fluoro-4-methylphenyl) -4H-benzo [1,3] dioxin-7-benzoate Obtained in Example 6d A crude diol product (1.28 g) was obtained in the same manner as in Example 2b using the compound (1.28 g, 3.80 mmol), methanol (12 mL) and sodium borohydride (290 mg, 7.67 mmol). Boron trifluoride-diethyl ether complex (0.475 mL, 3.78 mmol) cooled to −10 ° C. is dissolved in acetone (10 mL), and an acetone solution (15 mL) in which the diol crude product (1.28 g) is dissolved is slowly added. added. Thereafter, the temperature of the reaction solution was raised to 10 ° C. over 1 hour. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (30 mL) and saturated brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 5: 1, V / V) gave the title compound (964 mg) as an oil.

Example 6f 5-Chloro-2,2-dimethyl-4- (3-fluoro-4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethanol Compound obtained in Example 6e (960 mg, 2.53 mmol), lithium aluminum hydride (96 mg, 2.53 mmol) and tetrahydrofuran (5 mL) were used in the same manner as in Example 2d to obtain a crude product (860 mg) of the title compound as an amorphous product.

(Example 6g) Acetic acid 5-chloro-2,2-dimethyl-4- (3-fluoro-4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethyl Crude obtained in Example 6f The product (860 mg) was dissolved in pyridine (8.6 mL), acetic anhydride (2.2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. Methanol (2.2 mL) was added to the reaction solution, and the mixture was stirred for 15 minutes, then ethyl acetate (40 mL) was added, 30% aqueous citric acid solution (10 mL, twice), saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine ( 20 ml). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) gave the title compound (900 mg) as an oil.

(Example 6h) Acetic acid 3-chloro-4- (3-fluoro-4-methylbenzyl) -5-hydroxybenzyl Compound (900 mg, 2.38 mmol) obtained in Example 6f, acetonitrile (15 mL), triethylsilane ( 1.14 mL, 7.09 mmol) and boron fluoride-diethyl ether complex (0.450 mL, 3.58 mmol) were used in the same manner as in Example 2f to obtain the title compound (631 mg) as a colorless solid.
¹ H NMR (500 MHz, CDCl ₃ ): δ 2.11 (3H, s), 2.21 (3H, s), 4.12 (2H, s), 5.00 (2H, s), 5.28 (1H, brs), 6.71 (1H , s), 6.89 (1H, d, J = 10.8 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.01 (1H, s), 7.06 (1H, t, J = 8.0 Hz);
MS (FAB) m / z: 345 (M + Na) ⁺ .

Example 6i 5-Acetoxymethyl-3-chloro-2- (3-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (250 mg, 0.41 mmol), methylene chloride (4 mL), The imidate was prepared in the same manner as in Example 2g using trichloroacetonitrile (0.210 mL, 2.08 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol). Using the obtained imidate (309 mg), the compound obtained in Example 6h (100 mg, 0.41 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.051 mL, 0.41 mmol) In the same manner as in Example 2g, a crude product (280 mg) of the title compound was obtained.

Example 6j 3-chloro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 6i Using the crude product (280 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (566 mg, 4.10 mmol), the title compound (76 mg) was obtained as a colorless solid in the same manner as in Example 2h. However, solidification was performed from hexane / ethyl acetate.
¹ H NMR (500 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.3 Hz), 2.18 (3H, s), 3.35-3.41 (2H, m), 3.44-3.46 (2H, m), 4.03-4.08 (1H, m), 4.12 (1H, d, J = 15.0 Hz), 4.24 (1H, d, J = 15.0 Hz), 4.56 (2H, s), 4.94 (1H, d, J = 7.8 Hz ), 6.87 (1H, d, J = 11.2 Hz), 6.95 (1H, d, J = 7.9 Hz), 7.04 (1H, t, J = 7.9 Hz), 7.11 (1H, s), 7.14 (1H, s );
MS (FAB) m / z: 479 (M + Na) ^+.

Example 7 3-Fluoro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 8)

Example 7a 3,5-difluoro-4- [1- (3-fluoro-4-methoxyphenyl) -1-hydroxymethyl] benzonitrile Dissolve diisopropylamine (1.20 mL, 8.49 mmol) in tetrahydrofuran (7 mL) Then, n-butyllithium (2.60 mL, 7.19 mmol, 2.77 M n-hexane solution) was added dropwise under ice cooling. After stirring at the same temperature for 10 minutes, the mixture was cooled to −78 ° C., and a tetrahydrofuran solution (5 mL) in which 3,5-difluorobenzonitrile (1.00 g, 7.19 mmol) was dissolved was slowly added dropwise to the reaction solution. After stirring at the same temperature for 1 hour, a tetrahydrofuran solution (5 mL) in which 3-fluoro-4-methoxybenzaldehyde (1.11 g, 7.20 mmol) was dissolved was slowly added dropwise to the reaction solution, followed by stirring at the same temperature for 2 hours. After the temperature was raised to −20 ° C., 0.5M hydrochloric acid was added to the reaction solution to stop the reaction. The reaction mixture was diluted with ethyl acetate (60 mL), and washed successively with water (30 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 3: 1 to 2: 1, V / V). To give the oily title compound (1.59 g).

(Example 7b) 3,5-difluoro-4- (3-fluoro-4-methoxybenzyl) benzonitrile The compound (1.59 g, 5.42 mmol) obtained in Example 7a was dissolved in acetonitrile (16 mL), and iced. Under cooling, triethylsilane (2.6 mL, 16 mmol) and boron trifluoride-diethyl ether complex (1.0 mL, 7.9 mmol) were added. After stirring at room temperature for 2.5 hours, the reaction was stopped by adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution. The reaction mixture was diluted with ethyl acetate (60 mL), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 2: 1, V / V) to obtain the title compound (1.05 g) as a colorless solid.

Example 7c 3-Benzyloxy-5-fluoro-4- (3-fluoro-4-methoxybenzyl) benzonitrile The compound obtained in Example 7b (1.05 g, 3.79 mmol) and benzyl alcohol (0.53 g, 4.9 mmol) was dissolved in N, N-dimethylformamide (11 mL), and sodium hydride (63%, 0.22 g, 5.7 mmol) was added under ice cooling. After stirring at the same temperature for 2 hours, 2M hydrochloric acid was added dropwise to the reaction solution to stop the reaction. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 mL, twice), and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 4: 1 to 2: 1, V / V) to give a mixture containing the title compound (1.05 g) was obtained.

Example 7d 3-Benzyloxy-5-fluoro-4- (3-fluoro-4-methoxybenzyl) benzoic acid The mixture obtained in Example 7c (1.04 g, 2.85 mmol) was added to ethanol (14.5 mL). Dissolve and add 5M aqueous sodium hydroxide (2.9 mL, 15 mmol) at room temperature. The mixture was stirred for 2 hours under heating and refluxing conditions, then cooled to room temperature, and 2M hydrochloric acid (8 mL) was added to the reaction solution (pH = 1). The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain a mixture containing the title compound.

Example 7e) 3-Fluoro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzoic acid The mixture (2.85 mmol) obtained in Example 7d was taken from tetrahydrofuran (10 mL) and methanol (10 mL). The solution was dissolved in the solution, and nitrogen substitution was performed while stirring. A 10% palladium carbon catalyst (containing water, 0.20 g) was added to the reaction solution, and the gas phase was replaced with hydrogen, followed by stirring at room temperature for 40 minutes. The mixture was filtered through a membrane filter to remove the catalyst, and then the solvent was distilled off under reduced pressure to obtain a mixture (0.90 g) containing the title compound as a colorless solid.

Example 7f 3-Fluoro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenol Lithium aluminum hydride (0.27 g, 7.1 mmol) was suspended in tetrahydrofuran (2 mL) and iced. Under cooling, a tetrahydrofuran solution (28 mL) in which the mixture (0.90 g, 2.85 mmol) obtained in Example 7e was dissolved was added dropwise. After stirring at 50 ° C. for 2 hours, water and 2M hydrochloric acid were added dropwise to the reaction solution under ice cooling to stop the reaction. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated brine (20 mL, twice), and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified using silica gel flash chromatography (hexane: ethyl acetate, 1: 1, V / V) to obtain the title compound (0.61 g) as a colorless solid. .

(Example 7g) 3-fluoro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzyl acetate The compound (0.60 g, 2.14 mmol) obtained in Example 7f was dissolved in tetrahydrofuran (3 mL). , Vinyl acetate (3 mL) and bis (dibutyltin chloride) oxide (0.35 g, 0.63 mmol) were added, and the mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 2: 1 to 1: 1, V / V) to obtain the title compound (0.69 g) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.85 (3H, s), 3.93 (2H, s), 5.00 (2H, s), 5.17 (1H, d, J = 1.2 Hz ), 6.60 (1H, brs), 6.69 (1H, dd, J = 9.5 Hz, 1.4 Hz), 6.86 (1H, t, J = 8.6 Hz), 6.97-7.03 (2H, m);
MS (FAB) m / z: 322 (M) ⁺ .

Example 7h 5-Acetoxymethyl-3-fluoro-2- (3-fluoro-4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.68 g, 1.1 mmol), methylene chloride (14 mL) , Trichloroacetonitrile (0.34 mL, 3.4 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (15 μL, 0.10 mmol) were used to prepare an imidate in the same manner as Example 1h. Using the obtained imidate (1.1 mmol), the compound obtained in Example 7g (300 mg, 0.931 mmol), methylene chloride (5 mL) and boron trifluoride-diethyl ether complex (60 μL, 0.47 mmol), Example 1h A crude product of the title compound was obtained in the same manner as above.

Example 7i 3-Fluoro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 7h The crude product was dissolved in a solution consisting of tetrahydrofuran (2 mL) and methanol (6 mL), and a methanol solution (3 mL) in which sodium methoxide (28% methanol solution, 0.36 g, 1.9 mmol) was dissolved was added at room temperature. I left it all night. Under ice-cooling, 2M hydrochloric acid (0.95 mL, 1.9 mmol) and saturated brine were added to the reaction solution, followed by extraction with ethyl acetate (50 mL, twice), and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified using silica gel flash chromatography (methylene chloride: methanol, 9: 1 to 5: 1, V / V) to give the title compound (343 mg) as colorless. Obtained as a solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.6 Hz), 3.37-3.40 (2H, m), 3.44-3.51 (2H, m), 3.80 (3H, s), 3.94 (1H, d, J = 14.5 Hz), 3.99-4.08 (2H, m), 4.55 (2H, s), 4.95 (1H, d, J = 7.4 Hz), 6.80 (1H, dd, J = 10.4 Hz , 1.0 Hz), 6.91 (1H, t, J = 8.8 Hz), 6.98-7.03 (3H, m);
MS (FAB) m / z: 479 (M + Na) ^+.

Example 8 3-Chloro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 19)

Example 8a) Ethyl 4- (3-fluoro-4-methoxybenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (800 mg, 4.34 mmol), 3-fluoro-4-methoxybenzoyl chloride (819 mg, 4.34 mmol), acetonitrile (14 mL), triethylamine (1.82 mL, 13.1 mmol) and trimethylsilylcyanide (0.070 mL, 0.52 mmol) In the same manner as in Example 1b, a crude product of the title compound (1.30 g) was obtained.

Example 8b Ethyl 3-chloro-4- (3-fluoro-4-methoxybenzoyl) -5-oxocyclohex-3-enecarboxylate The crude product obtained in Example 8a (1.30 g, 3.87 mmol ), Methylene chloride (18 mL), 2-methyl-2-butene (1.74 mL, 16.4 mmol), oxalyl dichloride (0.348 mL, 4.06 mmol) and a catalytic amount of N, N-dimethylformamide and In the same manner, a crude product (1.37 g) of the title compound was obtained.

Example 8c Ethyl 3-chloro-4- (3-fluoro-4-methoxybenzoyl) -5-hydroxybenzoate Crude product obtained in Example 8b (1.37 g, 3.86 mmol), N-methylmorpholine (15.6 mL), anhydrous sodium sulfate (11.0 g) and iodine (1.18 g, 4.65 mmol) were used to give a crude product of the title compound in the same manner as in Example 1d. Then, purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the amorphous title compound (672 mg).

Example 8d Ethyl 3-chloro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzoate Compound (670 mg, 1.90 mmol) obtained in Example 8c, methanol (8 mL) and hydrogenation 3-chloro-4- [1- (3-fluoro-4-methoxyphenyl) -1-hydroxymethyl] -5-hydroxybenzoate was prepared in the same manner as in Example 2b using sodium boron (144 mg, 3.81 mmol). Ethyl acid (670 mg) was obtained as a crude product and used in the next reaction without purification.

This crude product (670 mg, 1.89 mmol) was dissolved in acetonitrile (8 mL), triethylsilane (0.900 mL, 5.65 mmol) was added, and after cooling to 0 ° C., boron trifluoride-diethyl ether complex (0.356 mL, 2.87 mmol) was added. mmol) was further added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (40 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound and 3-chloro-4- [1- (3-fluoro-4-methoxyphenyl) -1-hydroxymethyl] -5- A mixture (525 mg) containing ethyl hydroxybenzoate was obtained.

Example 8e 3-chloro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzyl acetate Acetic acid mixture (525 mg), lithium aluminum hydride (118 mg, 3.11 mmol) and Tetrahydrofuran (8 mL) was used to obtain a mixture (333 mg) as amorphous by the same method as in Example 2d. Using the obtained mixture (333 mg), tetrahydrofuran (4 mL), vinyl acetate (4 mL) and bis (dibutyltin chloride) oxide (186 mg, 0.34 mmol), the title compound and acetic acid 3- A mixture (322 mg) containing chloro-4- [1- (3-fluoro-4-methoxyphenyl) -1-hydroxymethyl] -5-hydroxybenzyl was obtained.

Further, this mixture (322 mg) was dissolved in acetonitrile (4 mL), triethylsilane (0.430 mL, 2.70 mmol) was added, and after cooling to 0 ° C., boron trifluoride-diethyl ether complex (0.170 mL, 1.35 mmol) was added. And stirred at room temperature for 3 hours. Ethyl acetate (40 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and finally purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 2: 1, V / V) to give the title Compound (252 mg) was obtained as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.12 (3H, s), 3.85 (3H, s), 4.09 (2H, s), 5.00 (2H, s), 5.19 (1H, s), 6.72 (1H , d, J = 1.5 Hz), 6.86 (1H, t, J = 8.6 Hz), 6.98-7.02 (3H, m);
MS (FAB) m / z: 377 (M + K) ^+.

Example 8f 5-Acetoxymethyl-3-chloro-2- (3-fluoro-4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (328 mg, 0.54 mmol), methylene chloride (5 mL), The imidate was prepared in the same manner as Example 2g using trichloroacetonitrile (0.272 mL, 2.69 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7 μL, 0.05 mmol). Using the resulting imidate (406 mg), the compound obtained in Example 8e (140 mg, 0.41 mmol), methylene chloride (5 mL), MS4A and boron trifluoride-diethyl ether complex (0.068 mL, 0.54 mmol) In the same manner as in Example 2g, a crude product (540 mg) of the title compound was obtained.

Example 8g 3-chloro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 8f Using the crude product (540 mg), methanol / methylene chloride (10 mL / 5 mL) and potassium carbonate (570 mg, 4.12 mmol), the title compound (73 mg) was obtained as a colorless solid in the same manner as in Example 2h. However, solidification was performed from hexane / ethyl acetate / methanol.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.21 (3H, d, J = 6.2 Hz), 3.35-3.42 (2H, m), 3.45-3.47 (2H, m), 3.80 (3H, s), 4.06 (1H, dd, J = 6.5 Hz, 3.7 Hz), 4.09 (1H, d, J = 14.5 Hz), 4.20 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.95 (1H, d , J = 7.5 Hz), 6.89-7.02 (3H, m), 7.11 (1H, s), 7.13 (1H, s);
MS (FAB) m / z: 495 (M + Na) ^+.

Example 9 3-Fluoro-2- (2-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 8)

Example 9a 3,5-difluoro-4- [1- (2-fluoro-4-methoxyphenyl) -1-hydroxymethyl] benzonitrile diisopropylamine (1.20 mL, 8.49 mmol), n-butyllithium (2.60 mL, 7.19mmol, 2.77M n-hexane solution), 3,5-difluorobenzonitrile (1.00g, 7.19mmol), 2-fluoro-4-methoxybenzaldehyde (1.11g, 7.20mmol) and tetrahydrofuran (17mL) The title compound (1.66 g) was obtained as a pale yellow solid in the same manner as in Example 7a. The purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 4: 1 to 2: 1, V / V).

Example 9b 3,5-difluoro-4- (2-fluoro-4-methoxybenzyl) benzonitrile The compound obtained in Example 9a (1.66 g, 5.66 mmol), triethylsilane (2.7 mL, 17 mmol), The title compound (1.29 g) was obtained as a colorless solid in the same manner as in Example 7b using boron trifluoride-diethyl ether complex (1.1 mL, 8.7 mmol) and acetonitrile (17 mL). The purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 9: 1, V / V).

Example 9c 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methoxybenzyl) benzonitrile The compound obtained in Example 9b (1.28 g, 4.62 mmol), sodium hydride (63% 0.26 g, 6.8 mmol), benzyl alcohol (0.66 g, 6.1 mmol) and N, N-dimethylformamide (13 mL) were used to prepare a crude product of the title compound (0.95 g) in the same manner as in Example 7c. Obtained as a yellow solid.

Example 9d 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methoxybenzyl) benzoic acid Crude product obtained in Example 9c (0.95 g, 2.6 mmol), 5M sodium hydroxide A crude product (0.97 g) of the title compound was obtained as a pale yellow solid in the same manner as in Example 7d using an aqueous solution (2.6 mL, 13 mmol) and ethanol (13 mL).

Example 9e 3-Fluoro-4- (2-fluoro-4-methoxybenzyl) -5-hydroxybenzoic acid Crude product obtained in Example 9d (0.97 g, 2.5 mmol), 10% palladium on carbon catalyst (Water content, 0.20 g), tetrahydrofuran (10 mL), methanol (10 mL) and hydrogen were used in the same manner as in Example 7e to obtain a crude product (0.75 g) of the title compound as a pale yellow solid.

Example 9f 3-Fluoro-2- (2-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenol Crude product obtained in Example 9e (465 mg, 1.58 mmol), lithium aluminum hydride (0.12 g, 3.2 mmol) and tetrahydrofuran (12 mL) were used, and the title compound (0.37 g) was obtained as a colorless solid in the same manner as in Example 7f. The purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 1: 1 to 2: 3, V / V).

(Example 9g) Acetic acid 3-fluoro-4- (2-fluoro-4-methoxybenzyl) -5-hydroxybenzyl Compound (0.37 g, 1.32 mmol) obtained in Example 9f, bis (dibutyltin chloride) oxide (0.22 g, 0.40 mmol), vinyl acetate (2 mL) and tetrahydrofuran (2 mL) were used to give the title compound (0.39 g) as a pale yellow solid in the same manner as in Example 7 g. The purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 2: 1 to 3: 2, V / V).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.76 (3H, s), 3.93 (2H, s), 5.01 (2H, s), 5.20-5.21 (1H, m), 6.59 -6.64 (3H, m), 6.69 (1H, dd, J = 9.6 Hz, 1.3 Hz), 7.06 (1H, t, J = 8.8 Hz);
MS (FAB) m / z: 332 (M) ^+.

Example 9h 5-Acetoxymethyl-3-fluoro-2- (2-fluoro-4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.74 g, 1.2 mmol), methylene chloride (7.5 mL ), Trichloroacetonitrile (0.36 mL, 3.6 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (20 μL, 0.13 mmol) were prepared in the same manner as in Example 1h. Using the obtained imidate (1.2 mmol), the compound obtained in Example 9g (300 mg, 0.931 mmol), methylene chloride (7 mL) and boron trifluoride-diethyl ether complex (60 μL, 0.47 mmol), Example 1h A crude product of the title compound was obtained in the same manner as above.

(Example 9i) 3-fluoro-2- (2-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside

Using the crude product obtained in Example 9h, sodium methoxide (28% methanol solution, 0.36 g, 1.9 mmol), tetrahydrofuran (2 mL) and methanol (6 mL), the title compound ( 342 mg) was obtained as a colorless solid. The purification was performed using silica gel flash chromatography (methylene chloride: methanol, 7: 1 to 5: 1, V / V).
¹ H NMR (400 MHz, CD ₃ OD): δ 1.19 (3H, d, J = 6.3 Hz), 3.34-3.39 (2H, m), 3.42-3.48 (2H, m), 3.73 (3H, s), 3.97 (1H, d, J = 14.9 Hz), 4.01-4.07 (2H, m), 4.56 (2H, s), 4.93-4.95 (1H, m), 6.56 (1H, dd, J = 8.6 Hz, 2.4 Hz ), 6.60 (1H, dd, J = 11.8 Hz, 2.3 Hz), 6.80 (1H, d, J = 9.8 Hz), 6.99-7.03 (2H, m);
MS (FAB) m / z: 479 (M + Na) ^+.

(Example 10) 3-chloro-2- [4- (difluoromethoxy) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 10 in Table 1) )

Example 10a) Ethyl 3-chloro-4- [4- (difluoromethoxy) benzoyl] -5-oxocyclohex-3-enecarboxylate The compound obtained in Example 3b (1.7 g, 5.0 mmol) was salified. Dissolved in methylene (20 mL) and performed with 2-methyl-2-butene (2.2 mL, 20 mmol), oxalyl chloride (0.45 mL, 5.2 mmol) and N, N-dimethylformamide (0.1 mL, 0.13 mmol) A crude product of the title compound (1.8 g) was obtained in the same manner as in Example 1c.

Example 10b Ethyl 3-chloro-4- [4- (difluoromethoxy) benzoyl] -5-hydroxybenzoate The crude product obtained in Example 10a (1.8 g, 6.5 mmol) was converted to N-methylmorpholine ( 20 mL), and a crude product (1.9 g) of the title compound was obtained in the same manner as in Example 1d using anhydrous sodium sulfate (1.8 g) and iodine (1.5 g, 6.0 mmol).

Example 10c 3-Chloro-2- {1- [4- (difluoromethoxy) phenyl] -1-hydroxymethyl} -5- (hydroxymethyl) phenol The crude product obtained in Example 10b (1.8 g 4.9 mmol) was dissolved in tetrahydrofuran (55 mL), and the title compound (1.3 g) was obtained as a yellow solid in the same manner as in Example 1e using lithium aluminum hydride (0.57 g, 15 mmol).

(Example 10d) Acetic acid 3-chloro-4- {1- [4- (difluoromethoxy) phenyl] -1-hydroxymethyl} -5-hydroxybenzyl Compound obtained in Example 10c (1.3 g, 4.0 mmol) Is dissolved in a solution consisting of vinyl acetate (5 mL) and diisopropyl ether (5 mL), and the crude product obtained by the same method as in Example 1f is purified by silica gel flash chromatography using porcine pancreatic lipase (0.6 g). Purification using hexane: ethyl acetate, 4: 1, V / V) gave the title compound (0.99 g).

(Example 10e) Acetic acid 3-chloro-4- [4- (difluoromethoxy) benzyl] -5-hydroxybenzyl The compound (0.99 g, 2.56 mmol) obtained in Example 10d was dissolved in acetonitrile (10 mL). Using triethylsilane (1.3 mL, 7.9 mmol) and boron trifluoride-diethyl ether complex (0.49 mL, 3.9 mmol) in the same manner as in Example 1g, the title compound (0.58 g, but about 28% starting material) Obtained).

Example 10f 5-Acetoxymethyl-3-chloro-2- [4- (difluoromethoxy) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β- D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.61 g, 1.0 mmol) in methylene chloride (4 mL) Dissolve and prepare the imidate by the same method as Example 1h using trichloroacetonitrile (0.3 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4.3 μL, 0.03 mmol). did. This imidate (0.76 g, 1.0 mmol) and the compound obtained in Example 10e (0.20 g, substantial 0.40 mmol) were dissolved in methylene chloride (5 mL), and boron trifluoride-diethyl ether complex (63 μL, 0.50 mmol) Was used to obtain a mixture containing the title compound in the same manner as in Example 1h.

Example 10g 3-Chloro-2- [4- (difluoromethoxy) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 10f The mixture (0.40 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and the title compound (2) was added in a manner similar to Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). 32 mg) was obtained as a colorless solid.
¹ H NMR (500 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.4 Hz), 3.34-3.46 (4H, m), 4.15 (1H, d, J = 14.3 Hz), 4.25 (1H, d, J = 14.3 Hz), 4.55 (2H, s), 4.95 (1H, d, J = 7.3 Hz), 6.70 (1H, t, J = 74.4 Hz), 6.96 (2H, d, J = 8.6 Hz) , 7.10 (1H, s), 7.13 (1H, s), 7.29 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 491 (M + H) ⁺ , 513 (M + Na) ^+.

Example 11 3-Fluoro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No in Table 1) .2)

Example 11a) Ethyl 3-fluoro-4- [4- (2-fluoroethyl) benzoyl] -5-oxocyclohex-3-enecarboxylate The crude product obtained in Example 1b (2.0 g, 6.2 mmol) was dissolved in methylene chloride (18 mL), and the title compound (1.6 g) was obtained in the same manner as in Example 3b using diethylaminosulfur trifluoride (2.5 mL, 19 mmol).

Example 11b Ethyl 3-fluoro-4- [4- (2-fluoroethyl) benzoyl] -5-hydroxybenzoate The compound obtained in Example 11a (1.6 g, 4.9 mmol) was converted to N-methylmorpholine ( 16 mL) and the crude product (1.6 g) of the title compound was obtained in the same manner as in Example 3c using anhydrous sodium sulfate (1.6 g) and iodine (1.4 g, 5.4 mmol).

Example 11c Ethyl 3-fluoro-4- {1- [4- (2-fluoroethyl) phenyl] -1-hydroxymethyl} -5-hydroxybenzoate The crude product obtained in Example 11b (1.6 g, 4.9 mmol) was dissolved in ethanol (20 mL), and the title compound (0.83 g) was obtained as a colorless solid in the same manner as in Example 3d using sodium borohydride (0.37 g, 9.8 mmol).

Example 11d Ethyl 3-fluoro-4- [4- (2-fluoroethyl) benzyl] -5-hydroxybenzoate The compound (0.83 g, 2.5 mmol) obtained in Example 11c was added to ethanol (15 mL). Dissolved, and the crude product of the title compound was obtained in the same manner as in Example 3e using 10% hydrogen chloride methanol (0.5 mL, 2.5 mmol) and 10% palladium carbon catalyst (containing water, 0.5 g). The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 5: 1, V / V) to obtain the title compound (0.37 g) as a colorless solid.

(Example 11e) 3-Fluoro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenol The compound (0.37 g, 1.2 mmol) obtained in Example 11d was added to tetrahydrofuran (15 mL). The title compound (0.33 g) was obtained as a crude product in the same manner as in Example 3f using lithium aluminum hydride (0.13 g, 3.5 mmol).

Example 11f Acetic acid 3-fluoro-4- [4- (2-fluoroethyl) benzyl] -5-hydroxybenzyl The crude product obtained in Example 11e (0.33 g, 1.2 mmol) was converted into vinyl acetate (5 mL). ) And diisopropyl ether (5 mL), and using the porcine pancreatic lipase (1.0 g), the title compound (0.35 g) was obtained as a pale brown solid in the same manner as in Example 3 g.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11 (3H, s), 2.97 (2H, dt, J = 22.8, 6.5 Hz), 3.99 (2H, s), 4.60 (2H, dt, J = 46.9, 6.5 Hz), 5.01 (2H, s), 6.60 (1H, s), 6.69 (1H, d, J = 9.8 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz);
MS (FAB) m / z: 320 (M) ^+.

Example 11g 5-Acetoxymethyl-3-fluoro-2- [4- (2-fluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.61 g, 1.0 mmol) in methylene chloride (4 mL The imidate was prepared in the same manner as in Example 1h using trichloroacetonitrile (0.30 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4 μL, 0.03 mmol). did. Using this imidate (0.75 g, 1.0 mmol), the compound obtained in Example 11f (0.25 g, 0.78 mmol) and boron trifluoride-diethyl ether complex (39 μL, 0.39 mmol), the same method as in Example 1h Gave a mixture containing the title compound.

Example 11h 3-Fluoro-2- [4- (2-fluoroethyl) benzyl] -5-hydroxymethyl-phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 11g The title compound was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL) in the same manner as in Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). (0.21 g) was obtained as a colorless solid.
¹ H NMR (500 MHz, CD ₃ OD): δ 1.20 (3H, d, J = 6.4 Hz), 2.90 (2H, dt, J = 22.9, 6.6 Hz), 3.34-3.50 (4H, m), 3.97 ( 1H, d, J = 14.2 Hz), 4.05-4.06 (1H, m), 4.07 (1H, d, J = 7.8 Hz), 4.52 (2H, dt, J = 47.4, 6.6 Hz), 4.54 (2H, s ), 4.93 (1H, d, J = 7.4 Hz), 6.78 (1H, d, J = 9.8 Hz), 6.97 (1H, s), 7.08 (2H, d, J = 7.9 Hz), 7.21 (2H, d , J = 7.9 Hz);
MS (FAB) m / z: 493 (M + K) ^+.

Example 12 3-Fluoro-5-hydroxymethyl-2- (4-trifluoromethoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 3 in Table 1)

Example 12a) Ethyl 3-hydroxy-5-oxo-4- [4- (trifluoromethoxy) benzoyl] cyclohex-3-enecarboxylate ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate ( 1.3 g, 7.3 mmol) and 4- (trifluoromethoxy) benzoyl chloride (J. Med. Chem., 45 (14), 2002, 3112-3129.) (1.6 g, 7.3 mmol) In the same manner, a crude product (2.4 g) of the title compound was obtained.

Example 12b 3-Fluoro-5-oxo-4- [4- (trifluoromethoxy) benzoyl] cyclohex-3-enecarboxylic acid ethyl ester Crude product obtained in Example 12a (1.8 g, 5.4 mmol ) Was dissolved in methylene chloride (15 mL), and the title compound (1.5 g) was obtained as a yellow oil by the same method as Example 3b using diethylaminosulfur trifluoride (2.1 mL, 16 mmol).

Example 12c Ethyl 3-fluoro-5-hydroxy-4- [4- (trifluoromethoxy) benzoyl] benzoate The compound obtained in Example 12b (1.5 g, 4.5 mmol) was converted to N-methylmorpholine (18 mL). In the same manner as in Example 1d using anhydrous sodium sulfate (1.5 g) and iodine (1.3 g, 5.0 mmol), a crude product (1.5 g) of the title compound was obtained.

Example 12d) 3-Fluoro-5-hydroxy-4- {1-hydroxy-1- [4- (trifluoromethoxy) phenyl] methyl} ethyl benzoate The crude product obtained in Example 12c (1.5 g 4.5 mmol) was dissolved in ethanol (15 mL), and the title compound (1.0 g) was obtained in the same manner as in Example 3d using sodium borohydride (0.34 g, 9.0 mmol).

Example 12e) 3-Fluoro-5-hydroxymethyl-2- {1-hydroxy-1- [4- (trifluoromethoxy) phenyl] methyl} phenol The compound obtained in Example 12d (1.0 g, 3.0 mmol ) Was dissolved in tetrahydrofuran (20 mL), and the title compound (1.0 g) was obtained in the same manner as in Example 1e (but without purification) using lithium aluminum hydride (0.46 g, 12 mmol). Obtained as a crude product.

Example 12f 3-fluoro-5-hydroxy-4- {1-hydroxy-1- [4- (trifluoromethoxy) phenyl] methyl} benzyl acetate Acetic acid (1.0 g, 3.0 mmol) was dissolved in a solution consisting of vinyl acetate (5 mL) and diisopropyl ether (5 mL), and the crude product obtained in the same manner as in Example 1f was purified by silica gel flash using porcine pancreatic lipase (1.0 g). Purification using chromatography (hexane: ethyl acetate, 4: 1, V / V) gave the title compound (0.65 g).

(Example 12g) 3-fluoro-5-hydroxy-4- [4- (trifluoromethoxy) benzyl] benzyl acetate The compound (0.65 g, 1.7 mmol) obtained in Example 12f was dissolved in acetonitrile (10 mL). , Triethylsilane (0.83 mL, 5.2 mmol) and boron trifluoride-diethyl ether complex (0.33 mL, 2.6 mmol) were used in the same manner as in Example 1g to obtain the title compound (0.18 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11 (3H, s), 4.00 (2H, s), 5.01 (2H, s), 5.19 (1H, brs), 6.60 (1H, s), 6.70 (1H , dd, J = 9.6, 1.4 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz);
MS (FAB) m / z: 358 (M) ^+.

Example 12h 5-Acetoxymethyl-3-fluoro-2- [4- (trifluoromethoxy) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.61 g, 1.0 mmol) in methylene chloride (4 mL) The imidate was prepared in the same manner as Example 1h using trichloroacetonitrile (0.3 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4.3 μL, 0.03 mmol). did. This imidate (0.76 g, 1.0 mmol) and the compound obtained in Example 12g (0.18 g, 0.50 mmol) were dissolved in methylene chloride (5 mL), and boron trifluoride-diethyl ether complex (63 μL, 0.50 mmol) was dissolved. And a mixture containing the title compound was obtained in the same manner as in Example 1h.

Example 12i 3-Fluoro-5-hydroxymethyl-2- [4- (trifluoromethoxy) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Mixture obtained in Example 12h (0.50 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and the title compound (0.12 g) was prepared in the same manner as in Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). ) Was obtained as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 6.7 Hz), 3.36-3.51 (4H, m), 4.04 (1H, d, J = 14.2 Hz), 4.06-4.07 (1H , m), 4.11 (1H, d, J = 14.2 Hz), 4.55 (2H, s), 4.96 (1H, d, J = 7.5 Hz), 6.81 (1H, d, J = 10.2 Hz), 7.00 (1H , s), 7.11 (2H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 515 (M + Na) ^+.

(Example 13) 3-Fluoro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside (No. 25 in Table 1)

Example 13a) 5-Acetoxymethyl-3-fluoro-2- (4-methylbenzyl) phenyl 4-deoxy-2,3,6-tri-O-benzoyl-β-D-glucopyranoside 4-deoxy-2, 3,6-tri-4-O-benzoyl-D-glucopyranoside (Liebig Ann. Chem., 1992, 7, 747-758.) (200 mg, 0.42 mmol), trichloroacetonitrile (125 μL, 1.25 mmol), 1,8-diazabicyclo [5.4.0] -7-Undecene (6 μL, 0.04 mmol) and methylene chloride (5 mL) were used to prepare an imidate by the same method as in Example 4i, and 3-fluoro-4- (4-methylbenzyl) acetate was prepared. Example 4i using 5-hydroxybenzyl (WO2008 / 016132 (PCT / JP2007 / 65231)) (100 mg, 0.35 mmol), boron trifluoride-diethyl ether complex (44 μL, 0.35 mmol) and methylene chloride (5 mL) In the same manner as above, a crude product (285 mg) of the title compound was obtained.

Example 13b 3-Fluoro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside Crude product obtained in Example 13a (285 mg, 0.35 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (48 mg, 0.35 mmol) were used in the same manner as in Example 4j to obtain the title compound (90 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.47 (1H, q, J = 11.8 Hz), 1.95-2.00 (1H, m), 2.25 (3H, s), 3.39 (1H, dd, J = 9.0 , 7.8 Hz), 3.57-3.59 (2H, m), 3.66-3.74 (2H, m), 3.94 (1H, d, J = 13.7 Hz), 4.06 (1H, d, J = 13.7 Hz), 4.55 (2H , s), 4.89 (1H, d, J = 7.4 Hz), 6.78 (1H, d, J = 9.8 Hz), 6.98 (1H, s), 7.00 (2H, d, J = 8.0 Hz), 7.14 (2H , d, J = 8.0 Hz);
MS (FAB) m / z: 393 (M + H) ⁺ , 415 (M + Na) ^+.

Example 14 3-Chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside (No. 26 in Table 1)

(Example 14a) 5-acetoxymethyl-3-chloro-2- (4-methylbenzyl) phenyl 4-deoxy-2,3,6-tri-O-benzoyl-β-D-glucopyranoside

4-deoxy-2,3,6-tri-4-O-benzoyl-D-glucopyranoside (188 mg, 0.39 mmol), trichloroacetonitrile (120 μL, 1.20 mmol), 1,8-diazabicyclo [5.4.0] -7- The imidate was prepared in the same manner as in Example 4i using undecene (6 μL, 0.04 mmol) and methylene chloride (5 mL). The compound obtained in Example 4h (100 mg, 0.33 mmol), boron trifluoride-diethyl A crude product (291 mg) of the title compound was obtained in the same manner as in Example 4i using an ether complex (41 μL, 0.33 mmol) and methylene chloride (5 mL).

Example 14b 3-Chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside Crude product obtained in Example 14a (291 mg, 0.33 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (46 mg, 0.33 mmol) were used in the same manner as in Example 4j to obtain the title compound (106 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.46 (1H, q, J = 11.8 Hz), 1.95-2.00 (1H, m), 2.25 (3H, s), 3.37 (1H, dd, J = 9.0 , 7.8 Hz), 3.57-3.59 (2H, m), 3.66-3.72 (2H, m), 4.09 (1H, d, J = 14.5 Hz), 4.24 (1H, d, J = 14.5 Hz), 4.55 (2H , s), 7.00 (2H, d, J = 7.8 Hz), 7.10 (2H, J = 7.8 Hz), 7.13 (2H, s);
MS (FAB) m / z: 431 (M + Na) ^+.

Example 15 2- (4-Ethylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside (No. 24 in Table 1)

Example 15a) 5-Acetoxymethyl-2- (4-ethylbenzyl) -3-fluorophenyl 4-deoxy-2,3,6-tri-O-benzoyl-β-D-glucopyranoside 4-deoxy-2, 3,6-tri-4-O-benzoyl-D-glucopyranoside (189 mg, 0.40 mmol), trichloroacetonitrile (120 μL, 1.20 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol) ) And methylene chloride (5 mL), and an imidate was prepared in the same manner as in Example 4i. 4- (4-Ethylbenzyl) -3-fluoro-5-hydroxybenzyl acetate (WO2008 / 016132 (PCT / JP2007 / 65231)) (100 mg, 0.33 mmol), boron trifluoride-diethyl ether complex (42 μL, 0.33 mmol) and methylene chloride (5 mL) were prepared in the same manner as in Example 4i by using a crude product of the title compound (323 mg )

Example 15b 2- (4-Ethylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside Crude product obtained in Example 15a (323 mg, 0.33 mmol) , Tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (46 mg, 0.33 mmol) were used in the same manner as in Example 4j to obtain the title compound (100 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.17 (3H, t, J = 7.6 Hz), 1.47 (1H, q, J = 11.7 Hz), 1.95-2.00 (1H, m), 2.56 (2H, q, J = 7.6 Hz), 3.40 (1H, dd, J = 9.0, 7.8 Hz), 3.57-3.59 (2H, m), 3.67-3.74 (2H, m), 3.95 (1H, d, J = 14.5 Hz ), 4.07 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.90 (1H, d, J = 7.5 Hz), 6.78 (1H, d, J = 9.7 Hz), 6.99 (1H, s ), 7.03 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz);
MS (FAB) m / z: 407 (M + H) ⁺ , 429 (M + Na) ^+.

Example 16 3-Chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside (No. 27 in Table 1)

Example 16a 5-Acetoxymethyl-3-chloro-2- (4-ethylbenzyl) phenyl 4-deoxy-2,3,6-tri-O-benzoyl-β-D-glucopyranoside 4-deoxy-2, 3,6-Tri-4-O-benzoyl-D-glucopyranoside (190 mg, 0.40 mmol), methylene chloride (4 mL), trichloroacetonitrile (0.200 mL, 1.98 mmol) and 1,8-diazabicyclo [5.4.0] -7 -Imidate was prepared in the same manner as Example 2g using undecene (6 μL, 0.04 mmol). Using the resulting imidate (248 mg), the compound obtained in Example 2f (100 mg, 0.31 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.050 mL, 0.40 mmol) In the same manner as in Example 2g, a crude product (270 mg) of the title compound was obtained.

Example 16b 3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside Crude product obtained in Example 16a (270 mg), methanol / The title compound (126 mg) was obtained as a colorless solid in the same manner as in Example 2h using methylene chloride (8 mL / 2 mL) and potassium carbonate (550 mg, 3.98 mmol). However, solidification was performed from hexane / ethyl acetate.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.18 (3H, t, J = 7.5 Hz), 1.46 (1H, q, J = 11.8 Hz), 1.95-2.00 (1H, m), 2.56 (2H, q, J = 7.5 Hz), 3.37 (1H, dd, J = 9.0, 7.8 Hz), 3.57-3.59 (2H, m), 3.66-3.72 (2H, m), 4.10 (1H, d, J = 14.5 Hz ), 4.25 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.89 (1H, d, J = 7.4 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.09 (1H, s ), 7.13 (1H, s), 7.15 (2H, d, J = 8.4 Hz);
MS (FAB) m / z: 445 (M + Na) ^+.

Example 17 2- (4-Cyclopropylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside (No. 23 in Table 1)

Example 17a 5-Acetoxymethyl-2- (4-cyclopropylbenzyl) -3-fluorophenyl 4-deoxy-2,3,6-tri-O-benzoyl-β-D-glucopyranoside 4-deoxy-2 , 3,6-Tri-4-O-benzoyl-D-glucopyranoside (192 mg, 0.40 mmol), trichloroacetonitrile (120 μL, 1.20 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol) and methylene chloride (5 mL) were used to prepare an imidate by the same method as in Example 4i, and 4- (4-cyclopropylbenzyl) -3-fluoro-5-hydroxybenzyl acetate (WO2008 / 016132 (PCT / JP2007 / 65231)) (100 mg, 0.32 mmol), boron trifluoride-diethyl ether complex (40 μL, 0.32 mmol) and methylene chloride (5 mL) were used in the same manner as in Example 4i to obtain a crude product of the title compound. (301 mg) was obtained.

Example 17b 2- (4-Cyclopropylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside The crude product obtained in Example 17a (301 mg, 0.32 mmol) ), Tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (44 mg, 0.32 mmol) were obtained in the same manner as in Example 4j to obtain the title compound (107 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 0.57-0.61 (2H, m), 0.85-0.90 (2H, m), 1.47 (1H, q, J = 11.8 Hz), 1.78-1.85 (1H, m ), 1.95-2.00 (1H, m), 3.39 (1H, dd, J = 9.0 Hz, 7.8 Hz), 3.57-3.59 (2H, m), 3.66-3.74 (2H, m), 3.93 (1H, d, J = 14.5 Hz), 4.05 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.89 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 10.2 Hz), 6.91 (2H, d, J = 8.0 Hz), 6.98 (1H, s), 7.14 (2H, d, J = 8.0 Hz);
MS (FAB) m / z: 419 (M + H) ⁺ , 441 (M + Na) ^+.

Example 18 3-Fluoro-5-hydroxymethyl-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (Table 1 No.4)

Example 18a 4- (2,2,2-trifluoroethyl) benzoyl chloride 4- (2,2,2-trifluoroethyl) benzoic acid (Liebigs Ann. Chem., 1983, 9, 1510-1523. ) (786 mg, 3.85 mmol), oxalyl dichloride (0.385 mL, 4.42 mmol), catalytic amounts of N, N-dimethylformamide and tetrahydrofuran (6 mL) in the same manner as in Example 1a to give a crude product of the title compound Product (857 mg) was obtained.

Example 18b Ethyl 3-hydroxy-5-oxo-4- [4- (2,2,2-trifluoroethyl) benzoyl] cyclohex-3-enecarboxylate 3-hydroxy-5-oxocyclohexa-3 -Ethylencarboxylate (709 mg, 3.85 mmol), crude product obtained in Example 18a (857 mg, 3.85 mmol), acetonitrile (10 mL), triethylamine (1.61 mL, 11.5 mmol) and trimethylsilylcyanide (0.062 mL, 0.46 mmol) was used in the same manner as in Example 1b to obtain a crude product of the title compound (1.42 g).

Example 18c Ethyl 3-fluoro-5-oxo-4- [4- (2,2,2-trifluoroethyl) benzoyl] cyclohex-3-enecarboxylate The crude product obtained in Example 18b ( 1.42 g, 3.61 mmol), methylene chloride (15 mL) and diethylaminosulfur trifluoride (1.51 mL, 11.5 mmol) were used to give the title compound (953 mg) as a white solid in the same manner as in Example 3b.

(Example 18d) 3-Fluoro-5-hydroxy-4- [4- (2,2,2-trifluoroethyl) benzoyl] ethyl benzoate

Using the compound obtained in Example 18c (953 mg, 2.56 mmol), N-methylmorpholine (12 mL), anhydrous sodium sulfate (7.27 g) and iodine (779 mg, 3.07 mmol), the title was prepared in the same manner as in Example 1d. A crude product of the compound was obtained. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to give the amorphous title compound (614 mg).

Example 18e) 3-Fluoro-5-hydroxymethyl-2- [1-hydroxy-1- {4- (2,2,2-trifluoroethyl) phenyl} methyl] phenol Compound obtained in Example 18d (610 mg, 1.65 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C., lithium aluminum hydride (187 mg, 4.93 mmol) was added, and the mixture was stirred at room temperature for 30 min. After cooling again to 0 ° C., water (0.19 mL), 5 mol / L aqueous sodium hydroxide solution (0.19 mL) and water (0.57 mL) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was washed successively with 2 mol / L hydrochloric acid (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product (540 mg) of the title compound.

Example 18f 3-Fluoro-5-hydroxymethyl-2- [1-methoxy-1- {4- (2,2,2-trifluoroethyl) phenyl} methyl] phenol Crude obtained in Example 18e The product (540 mg, 1.64 mmol) was dissolved in methanol (10 mL), paratoluenesulfonic acid monohydrate (157 mg, 0.83 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was cooled to room temperature, triethylamine was added, and the mixture was concentrated under reduced pressure. The residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 1: 4, V / V) to give the title compound (508 mg) as an oil.

Example 18g Acetic acid 3-fluoro-5-hydroxy-4- {1-methoxy-1- [4- (2,2,2-trifluoroethyl) phenyl] methyl} benzyl Compound obtained in Example 18f (508 mg, 1.48 mmol), tetrahydrofuran (5 mL), vinyl acetate (5 mL) and bis (dibutyltin chloride) oxide (325 mg, 0.59 mmol) were used in the same manner as in Example 2e to give the oily title compound (525 mg). Obtained.

(Example 18h) 3-Fluoro-5-hydroxy-4- [4- (2,2,2-trifluoroethyl) benzyl] benzyl acetate Acetic acid (525 mg, 1.36 mmol) obtained in Example 18g, acetonitrile ( 10 mL), triethylsilane (0.650 mL, 4.08 mmol) and boron trifluoride-diethyl ether complex (0.256 mL, 2.04 mmol) were used to give the title compound (363 mg) as a white solid in the same manner as in Example 2f. .
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.32 (2H, q, J = 10.8 Hz), 4.00 (2H, s), 5.01 (2H, s), 5.06 (1H, brs ), 6.61 (1H, s), 6.70 (1H, d, J = 9.4 Hz), 7.20 (2H, d, J = 7.8 Hz), 7.27 (2H, d, J = 7.8 Hz);
MS (FAB) m / z: 356 (M) ^+.

Example 18i 5-Acetoxymethyl-3-fluoro-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl -D-glycero-β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (267 mg, 0.44 mmol), The imidate was prepared in the same manner as in Example 2g using methylene chloride (5 mL), trichloroacetonitrile (0.221 mL, 2.19 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7 μL, 0.05 mmol). Prepared. Using the resulting imidate (330 mg), the compound obtained in Example 18h (120 mg, 0.34 mmol), methylene chloride (5 mL), MS4A and boron trifluoride-diethyl ether complex (0.055 mL, 0.44 mmol) In the same manner as in Example 2g, a crude product (460 mg) of the title compound was obtained.

Example 18j 3-Fluoro-5-hydroxymethyl-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Using the crude product obtained in 18i (460 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (604 mg, 4.34 mmol) in the same manner as in Example 2h, the title compound (58 mg) was obtained as a white solid. Obtained. However, solidification was performed from hexane / ethyl acetate / methanol.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 6.3 Hz), 3.34-3.49 (6H, m), 4.01 (1H, d, J = 14.5 Hz), 4.06 (1H, dd , J = 6.3 Hz, 3.7 Hz), 4.09 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.95 (1H, d, J = 7.5 Hz), 6.80 (1H, d, J = 9.8 Hz), 6.99 (1H, s), 7.17 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz);
MS (FAB) m / z: 529 (M + K) ^+.

Example 19 3-Chloro-2- (4-ethyl-3-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 18)

Example 19a Methyl 4-acetyl-3-fluorobenzoate 4-acetyl-3-fluorophenyl sulfonate (Org. Lett., 2002, 4 (26), 4717-4718.) (8.69 g, 30.4 mmol) in N, N-dimethylformaldehyde (120 mL), methanol (24.6 mL, 606 mmol), palladium acetate (682 mg, 3.03 mmol), 1,3-bis (diphenylphosphino) propane (1.25 g, 3.03 mmol) ) And triethylamine (84.0 mL, 606 mol) were added, and the mixture was stirred at room temperature for 16 hours under a carbon monoxide atmosphere. The solvent was removed to some extent under reduced pressure, ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with 1 mol / L aqueous hydrochloric acid solution (150 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the title compound (3.67 g) as a white solid.

Example 19b Methyl 3-fluoro-4- (1-hydroxyethyl) benzoate The compound obtained in Example 19a (3.67 g, 18.7 mmol) was dissolved in methanol (40 mL) and cooled to 0 ° C. Sodium borohydride (850 mg, 22.5 mmol) was added and stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution (2 mL) was added to the reaction solution, and the solvent was removed under reduced pressure. Ethyl acetate (50 mL) was added to the residue, and the mixture was washed successively with a saturated aqueous ammonium chloride solution (50 mL), a saturated aqueous sodium hydroxide solution (50 mL), and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Finally, purification using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 2, V / V) gave the title compound (3.59 g) as an oil.

Example 19c 4-Ethyl-3-fluorobenzoic acid The compound obtained in Example 19b (3.67 g, 18.7 mmol) was dissolved in methanol (35 mL), 2 mol / L hydrochloric acid (1.09 mL) and 10% wet Palladium / carbon (600 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite to remove palladium. Subsequently, a 5 mol / L aqueous sodium hydroxide solution (8 mL) and an appropriate amount of tetrahydrofuran were added to the reaction solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction solution to 0 ° C., an appropriate amount of 2 mol / L hydrochloric acid was added to adjust the pH to less than 3, and the solvent was removed under reduced pressure. Ethyl acetate (50 mL) was added to the residue and washed with saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was washed with hexane, and the solid obtained by filtration was dried under reduced pressure to obtain the title compound (2.98 g) as a white solid.

Example 19d 4-ethyl-3-fluorobenzoyl chloride The compound obtained in Example 19c (730 mg, 4.34 mmol), oxalyl dichloride (0.43 mL, 4.95 mmol), catalytic amounts of N, N-dimethylformamide and A crude product of the title compound (810 mg) was obtained as a colorless oil by a method similar to Example 1a using tetrahydrofuran (6 mL).

Example 19e Ethyl 4- (4-ethyl-3-fluorobenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (800 mg, 4.34 mmol), using the crude product obtained in Example 19d (810 mg, 4.34 mmol), acetonitrile (9 mL), triethylamine (1.82 mL, 13.1 mmol) and trimethylsilylcyanide (0.070 mL, 0.52 mmol). In the same manner as in Example 1b, a crude product (1.45 g) of the title compound was obtained.

Example 19f Ethyl 3-chloro-4- (4-ethyl-3-fluorobenzoyl) -5-oxocyclohex-3-enecarboxylate Crude product obtained in Example 19e (1.45 g, 4.34 mmol ), Methylene chloride (18 mL), 2-methyl-2-butene (1.84 mL, 17.3 mmol), oxalyl dichloride (0.39 mL, 4.55 mmol) and a catalytic amount of N, N-dimethylformamide and In the same manner, a crude product (1.52 g) of the title compound was obtained.

Example 19g Ethyl 3-chloro-4- (4-ethyl-3-fluorobenzoyl) -5-hydroxybenzoate Crude product obtained in Example 19f (1.52 g, 4.34 mmol), N-methylmorpholine (18 mL), anhydrous sodium sulfate (12.3 g) and iodine (1.32 g, 5.20 mmol) were used to give a crude product of the title compound in the same manner as in Example 1d. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to give the amorphous title compound (1.04 g).

Example 19h Ethyl 5-chloro-4- (4-ethyl-3-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-benzoate obtained in Example 19g A crude diol product (1.04 g) was obtained in the same manner as in Example 2b, using the compound (1.04 g, 2.96 mmol), methanol (12 mL) and sodium borohydride (220 mg, 5.82 mmol).

Using the boron trifluoride-diethyl ether complex (0.370 mL, 2.95 mmol), crude diol product (1.04 g, 2.95 mmol) and acetone (16 mL) in the same manner as in Example 6e, the oily title compound ( 730 mg) was obtained.

Example 19i 5-chloro-4- (4-ethyl-3-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ylmethanol Compound obtained in Example 19h (730 mg, 1.86 mmol), lithium aluminum hydride (71 mg, 1.87 mmol) and tetrahydrofuran (8 mL) were used in the same manner as in Example 2d to obtain a crude product of the title compound (664 mg) as an oil.

Example 19j Acetic acid 5-chloro-4- (4-ethyl-3-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ylmethyl Crude obtained in Example 19i Using the product (664 mg), pyridine (6.6 mL) and acetic anhydride (1.7 mL), the title compound (720 mg) was obtained in the same manner as in Example 6g.

(Example 19k) Acetic acid 3-chloro-4- (4-ethyl-3-fluorobenzyl) -5-hydroxybenzyl Compound (720 mg, 1.83 mmol) obtained in Example 19j, acetonitrile (12 mL), triethylsilane ( 0.880 mL, 5.47 mmol) and boron trifluoride-diethyl ether complex (0.350 mL, 2.79 mmol) were used in the same manner as in Example 2f to obtain the title compound (491 mg) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.19 (3H, t, J = 7.7 Hz), 2.12 (3H, s), 2.61 (2H, q, J = 7.7 Hz), 4.13 (2H, s), 5.00 (2H, s), 6.72 (1H, d, J = 1.5 Hz), 6.90 (1H, dd, J = 11.2 Hz, 1.8 Hz), 6.98 (1H, dd, J = 7.8 Hz, 1.8 Hz), 7.02 (1H, d, J = 1.5 Hz), 7.09 (1H, t, J = 7.8 Hz);
MS (FAB) m / z: 336 (M) ^+.

Example 19l 5-acetoxymethyl-3-chloro-2- (4-ethyl-3-fluorobenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) 318 mg, 0.52 mmol), methylene chloride (5 mL), trichloroacetonitrile (0.263 mL, 2.60 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7 μL, 0.05 mmol) as in Example 2g The imidate was prepared by the method. Performed using the obtained imidate (393 mg), the compound obtained in Example 19k (135 mg, 0.40 mmol), methylene chloride (5 mL), MS4A and boron trifluoride-diethyl ether complex (0.065 mL, 0.52 mmol). In the same manner as in Example 2g, a crude product (380 mg) of the title compound was obtained.

Example 19m 3-Chloro-2- (4-ethyl-3-fluorobenzyl) -5-hydroxymethylphenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Crude obtained in Example 19l The title compound (67 mg) was obtained as a white solid in the same manner as in Example 2h using the product (380 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (720 mg, 5.21 mmol). However, solidification was performed from hexane / ethyl acetate / methanol.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.16 (3H, t, J = 7.6 Hz), 1.20 (3H, d, J = 6.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.35 -3.42 (2H, m), 3.44-3.46 (2H, m), 4.06 (1H, dd, J = 6.6 Hz, 3.6 Hz), 4.12 (1H, d, J = 14.5 Hz), 4.24 (1H, d, J = 14.5 Hz), 4.56 (2H, s), 4.95 (1H, d, J = 7.5 Hz), 6.89 (1H, d, J = 1.2 Hz), 6.99 (1H, dd, J = 7.9 Hz, 1.6 Hz ), 7.06 (1H, t, J = 7.9 Hz), 7.11 (1H, d, J = 1.6 Hz), 7.14 (1H, d, J = 1.2 Hz);
MS (FAB) m / z: 509 (M + K) ^+.

Example 20 3-Fluoro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 6 in Table 1)

(Example 20a) 3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) benzyl alcohol Acetic acid 3-fluoro-5-hydroxy-4- (4-methoxybenzyl) benzyl (WO2008 / 016132 (PCT / JP2007 / 65231)) (1.0 g, 3.3 mmol) was dissolved in N, N-dimethylformamide (10 mL), and benzyl bromide (0.58 mL, 4.9 mmol) and potassium carbonate (2.3 g, 17 mmol) were added under ice cooling. It was. The suspension was stirred for 1 hour while warming to room temperature, methanol (1.0 mL) was added, and the mixture was further stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and washed successively with 10% brine (10 mL, 3 times) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.2 g) of the title compound.

(Example 20b) 3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) benzaldehyde The crude product obtained in Example 20a (1.2 g, 3.3 mmol) was dissolved in chloroform (12 mL). Manganese (4.3 mL, 50 mmol) was added, and the mixture was stirred with heating under reflux for 2.5 hours. The suspension was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (1.2 g) of the title compound.

(Example 20c) 1-benzyloxy-3-fluoro-2- (4-methoxybenzyl) -5- (2-methoxyvinyl) benzene (methoxymethyl) triphenylphosphonium chloride (3.4 g, 10 mmol) was added to tetrahydrofuran (8 mL). And stirred under ice cooling. Lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 10 mL, 10 mmol) was added dropwise to this suspension, and the mixture was stirred for 30 minutes while warming to room temperature. A tetrahydrofuran solution (8 mL) in which the crude product (1.2 g, 3.3 mmol) obtained in Example 20b was dissolved was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL, twice), and the organic layer was washed with saturated brine (10 mL, twice). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel flash chromatography (hexane: ethyl acetate, 10: 1, V / V) to give the title compound ( 0.92 g) was obtained.

Example 20d 3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) phenylacetaldehyde The compound obtained in Example 20c (0.92 g, 2.4 mmol) was dissolved in 1,4-dioxane (10 mL). Under ice-cooling, water (0.43 mL, 24 mmol) and 4M hydrogen chloride 1,4-dioxane solution (6.0 mL, 24 mmol) were added, and the mixture was stirred for 1 hour while warming to room temperature. The solution was diluted with ethyl acetate (50 mL), and washed successively with 10% brine (10 mL, twice), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.87 g) of the title compound.

(Example 20e) 2- [3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) phenyl] ethanol The crude product obtained in Example 20d (0.87 g, 2.4 mmol) was added to tetrahydrofuran (4 mL). And dissolved in a solution consisting of methanol (4 mL), and sodium borohydride (0.14 g, 3.6 mmol) was added under ice cooling. The reaction solution was stirred for 40 minutes while warming to room temperature, and saturated aqueous ammonium chloride solution (1 mL) was added dropwise under ice cooling to stop the reaction. The mixture was diluted with ethyl acetate (40 mL), and washed successively with saturated sodium hydrogen carbonate (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title compound. (0.57 g) was obtained.

(Example 20f) 3-Fluoro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenol The compound obtained in Example 20e (0.57 g, 1.6 mmol) was mixed with tetrahydrofuran (3 mL) and methanol ( 3 mL), and stirred for 10 minutes while blowing nitrogen into the solution. To this solution, 10% palladium carbon catalyst (containing water, 0.12 g) was added under a nitrogen stream, and the gas phase was replaced with hydrogen, followed by stirring at room temperature for 1 hour. The mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (0.44 g).

(Example 20g) 2- [3-Fluoro-5-hydroxy-4- (4-methoxybenzyl) phenyl] ethyl acetate The crude product obtained in Example 20f (0.44 g, 1.6 mmol) was dissolved in collidine (5.0 mL). ), Acetyl chloride (0.11 mL, 1.6 mmol) was added at −20 ° C., and the mixture was stirred for 2 hours while raising the temperature to 0 ° C. Water (1 mL) was added to the reaction mixture, diluted with ethyl acetate (30 mL), and washed successively with 30% aqueous citric acid solution (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.51 g, including raw materials).

Example 20h 5- (2-acetoxyethyl) -3-fluoro-2- (4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (0.43 g, 0.71 mmol) in methylene chloride (4 mL) The imidate was prepared in the same manner as in Example 1h using trichloroacetonitrile (0.20 mL, 2.1 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (3 μL, 0.02 mmol). . Similar to Example 1h using this imidate (0.75 g, 1.0 mmol), the compound obtained in Example 11f (0.51 g, 1.6 mmol) and boron trifluoride-diethyl ether complex (0.05 mL, 0.4 mmol). By the method, a mixture containing the title compound was obtained.

Example 20i) 3-Fluoro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Mixture obtained in Example 20h (1.6 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and the title compound (64 mg) was prepared in the same manner as in Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). Was obtained as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.7 Hz), 2.77 (2H, t, J = 6.8 Hz), 3.35-3.51 (4H, m), 3.72 (3H, s), 3.75 (2H, t, J = 6.8 Hz), 3.91 (1H, d, J = 14.7 Hz), 4.00 (1H, d, J = 14.7 Hz), 4.05-4.07 (1H, m), 4.93 ( 1H, d, J = 7.4 Hz), 6.67 (1H, d, J = 9.4 Hz), 6.75 (2H, d, J = 8.8 Hz), 6.88 (1H, s), 7.19 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 475 (M + Na) ^+.

(Example 21) 3-chloro-5- (2-hydroxyethyl) -2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 15 in Table 1)

Example 21a Acetic acid 3-benzyloxy-5-chloro-4- (4-methylbenzyl) benzyl Compound (500 mg, 3.3 mmol) obtained in Example 4h was dissolved in N, N-dimethylformamide (10 mL). Benzyl bromide (430 μL, 3.6 mmol) and potassium carbonate (680 mg, 4.9 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with distilled water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.13 g) of the title compound as a yellow oily substance.

Example 21b 3-Benzyloxy-5-chloro-4- (4-methylbenzyl) benzyl alcohol The crude product obtained in Example 21a (1.13 g, 2.9 mmol) was dissolved in methanol (12 mL). 1M aqueous potassium hydroxide solution (3.3 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate (10 mL), and washed successively with distilled water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.91 g) of the title compound as a yellow oily substance.

Example 21c 3-Benzyloxy-5-chloro-4- (4-methylbenzyl) benzaldehyde The crude product (0.91 g, 2.6 mmol) obtained in Example 21b was dissolved in chloroform (10 mL) Manganese (2.85 g, 32.8 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. After filtration through celite, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.68 g) as a brown solid.

(Example 21d) 1-benzyloxy-3-chloro-5- (2-methoxyvinyl) -2- (4-methylbenzyl) benzene (methoxymethyl) triphenylphosphonium chloride (2.0 g, 5.4 mmol) in toluene ( 5 mL) was added, and the solvent was distilled off under reduced pressure. To the residue were added tetrahydrofuran (4 mL) and lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 5.9 mL, 5.9 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Further, a tetrahydrofuran solution (6 mL) in which the crude product obtained in Example 21c (0.68 g, 1.9 mmol) was dissolved was added dropwise to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL) and washed successively with distilled water (10 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 5: 1, V / V) to obtain the title compound (0.95 g, quant.) As a yellow solid.

Example 21e 3-Benzyloxy-5-chloro-4- (4-methylbenzyl) phenylacetaldehyde The compound obtained in Example 21d (0.95 g, 1.9 mmol) was dissolved in 1,4-dioxane (5 mL). Distilled water (350 μL) and 4N hydrochloric acid 1,4-dioxane solution (5 mL) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate (10 mL) and washed successively with distilled water (5 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 10: 1 to 4: 1, V / V) to obtain the title compound (0.48 g) as a yellow oily substance.

(Example 21f) 2- [3-Benzyloxy-5-chloro-4- (4-methylbenzyl) phenyl] ethanol The compound (0.48 g, 1.3 mmol) obtained in Example 21e was dissolved in methanol (5 mL). Under ice cooling, sodium borohydride (60 mg, 1.6 mmol) was added, and the mixture was stirred at 0 ° C. for 30 min. Under ice cooling, add saturated aqueous ammonium chloride solution (5 mL) to the reaction mixture, dilute with ethyl acetate (10 mL), and add saturated aqueous ammonium chloride solution (10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and saturated brine (10 mL). Washed sequentially. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.41 g) of the title compound as a colorless solid.

(Example 21g) 3-Chloro-5- (2-hydroxyethyl) -2- (4-methylbenzyl) phenol The crude product (0.41 g, 1.1 mmol) obtained in Example 21f was added to acetonitrile (5 mL). After dissolution, trimethylsilyl iodide (320 μL, 2.2 mmol) was added, and the mixture was stirred at 40 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (15 mL) and washed successively with 2M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-3: 1-2: 1, V / V) to obtain the title compound (122 mg) as a colorless solid.

(Example 21h) 2-{[3-Chloro-5-hydroxy-4- (4-methylbenzyl)] phenyl} ethyl acetate The compound (122 mg, 0.4 mmol) obtained in Example 21 g was added to tetrahydrofuran (2 mL). Dissolved, vinyl acetate (2 mL, 21.6 mmol) and bis (dibutyltin chloride) oxide (24 mg, 0.04 mmol) were added and stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1, V / V) to give the title compound (111 mg) as a colorless solid. It was.

Example 21i 5- (2-acetoxyethyl) -3-chloro-2- (4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (255 mg, 0.42 mmol), trichloroacetonitrile (125 μL, 1.25 mmol), 1 , 8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i, and the compound obtained in Example 21h (111 mg, 0.35 mmol), boron trifluoride-diethyl ether complex (44 μL, 0.35 mmol) and methylene chloride (5 mL) were used in the same manner as in Example 4i to obtain a crude product of the title compound (391 mg). It was.

Example 21j 3-Chloro-5- (2-hydroxyethyl) -2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Compound obtained in Example 21i (391 mg, 0.35 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (48 mg, 0.35 mmol) were used in the same manner as in Example 4j to obtain the title compound (104 mg) as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.2 Hz), 2.25 (3H, s), 2.77 (2H, t, J = 6.9 Hz), 3.35-3.36 (2H, m), 3.43-3.45 (2H, m), 3.76 (2H, t, J = 6.9 Hz), 4.03-4.05 (1H, m), 4.08 (1H, d, J = 14.9 Hz), 4.21 (1H, d , J = 14.9 Hz), 4.91 (1H, d, J = 7.4 Hz), 6.99 (2H, s), 7.02 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz);
MS (FAB) m / z: 453 (M + H) ⁺ , 475 (M + Na) ^+.

(Example 22) 3-chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 16 in Table 1)

Example 22a 3-Chloro-4- (4-methoxybenzyl) -5- (methoxymethoxy) benzyl alcohol Acetic acid 3-chloro-5-hydroxy-4- (4-methoxybenzyl) benzyl (WO2008 / 016132 (PCT / JP2007 / 65231)) (500 mg, 1.6 mmol) dissolved in N, N-dimethylformamide (5 mL), and ice-cooled, chloromethyl methyl ether (180 μL, 2.4 mmol) and calcium carbonate (1.08 g, 7.8 mmol) And stirred at room temperature for 4 hours. Methanol (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate (10 mL) and washed successively with distilled water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (511 mg) of the title compound as a colorless solid.

Example 22b 3-Chloro-4- (4-methoxybenzyl) -5- (methoxymethoxy) benzaldehyde The crude product obtained in Example 22a (511 mg, 1.6 mmol), chloroform (10 mL) and manganese dioxide ( 1.36 g (15.6 mmol) was used in the same manner as in Example 21c to obtain a crude product of the title compound (480 mg) as a pale yellow oily substance.

Example 22c 1-chloro-2- (4-methoxybenzyl) -3-methoxymethoxy-5- (2-methoxyvinyl) benzene Crude product obtained in Example 22b (480 mg, 1.5 mmol), chloride (Methylmethoxy) triphenylphosphonium (1.60 g, 4.8 mmol), lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 4.7 mL, 4.7 mmol) and tetrahydrofuran (8 mL) were used in the same manner as in Example 21d. The compound (810 mg, quant.) Was obtained as a yellow oil. The purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 15: 1 to 10: 1, V / V).

(Example 22d) 3-chloro-5-hydroxy-4- (4-methoxybenzyl) phenylacetaldehyde The compound obtained in Example 22c (810 mg, 1.5 mmol), 1,4-dioxane solution (4 mL) in 4N hydrochloric acid, The title compound (210 mg) was obtained as a yellow oil in the same manner as in Example 21e using distilled water (280 μL) and 1,4-dioxane (4 mL). The purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 8: 1 to 6: 1 to 4: 1, V / V).

Example 22e) 3-Chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenol The compound obtained in Example 22d (210 mg, 0.72 mmol), sodium borohydride (33 mg, 0.87) mmol) and methanol (2.5 mL) were used to give the title compound (157 mg) as a colorless oil in the same manner as in Example 21f.

Example 22f 2-{[3-Chloro-5-hydroxy-4- (4-methoxybenzyl)] phenyl} ethyl acetate The compound obtained in Example 22e (157 mg, 0.54 mmol), vinyl acetate (2 mL, 21.61 mmol), bis (dibutyltin chloride) oxide (38 mg, 0.07 mmol) and tetrahydrofuran (2 mL) were used in the same manner as in Example 21h to obtain the title compound (218 mg) as a colorless solid. The purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1 to 3: 1, V / V).

Example 22g 5-Acetoxymethyl-3-chloro-2- (4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β-D-gluco -Heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (220 mg, 0.36 mmol), trichloroacetonitrile (110 μL, 1.10 mmol), 1,8-diazabicyclo [5.4.0] -7-Undecene (6 μL, 0.04 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i, and the compound (100 mg, 0.30) obtained in Example 22f was prepared. mmol), boron trifluoride-diethyl ether complex (38 μL, 0.40 mmol) and methylene chloride (5 mL) were obtained in the same manner as in Example 4i to obtain a crude product (320 mg) of the title compound.

Example 22h 3-Chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Crude obtained in Example 22g Using the product (320 mg, 0.30 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (41 mg, 0.30 mmol), the title compound (81 mg) was obtained as a colorless solid in the same manner as in Example 4j. .
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.6 Hz), 2.76 (2H, t, J = 6.6 Hz), 3.35-3.38 (2H, m), 3.44-3.49 ( 2H, m), 3.72 (3H, s), 3.75 (2H, t, J = 6.6 Hz), 4.03-4.09 (1H, m), 4.06 (1H, d, J = 14.5 Hz), 4.18 (1H, d , J = 14.5 Hz), 4.93 (1H, d, J = 4.3 Hz), 6.75 (2H, d, J = 9.0 Hz), 6.98 (1H, d, J = 1.6 Hz), 7.03 (1H, d, J = 1.6 Hz), 7.18 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 469 (M + H) ⁺ , 491 (M + Na) ^+.

Example 23 3-Chloro-2- [4- (2,2,2-trifluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 14 in Table 1)

Example 23a) Ethyl 3-chloro-5-oxo-4- [4- (2,2,2-trifluoroethyl) benzoyl] cyclohex-3-enecarboxylate The crude product obtained in Example 18b ( 1.34 g, 3.61 mmol), methylene chloride (15 mL), 2-methyl-2-butene (1.54 mL, 14.5 mmol), oxalyl dichloride (0.32 mL, 3.73 mmol) and a catalytic amount of N, N-dimethylformamide In the same manner as in Example 1c, a crude product (1.40 g) of the title compound was obtained.

Example 23b Ethyl 3-chloro-5-hydroxy-4- [4- (2,2,2-trifluoroethyl) benzoyl] benzoate Crude product obtained in Example 23a (1.40 g, 3.60 mmol ), N-methylmorpholine (16 mL), anhydrous sodium sulfate (10.3 g) and iodine (1.10 g, 4.33 mmol) were used to give a crude product of the title compound in the same manner as in Example 1d. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to give the amorphous title compound (1.02 g).

Example 23c 3-Chloro-5-hydroxymethyl-2- [1-hydroxy-1- {4- (2,2,2-trifluoroethyl) phenyl} methyl] phenol Compound obtained in Example 23b (1.02 g, 2.64 mmol), tetrahydrofuran (30 mL) and lithium aluminum hydride (300 mg, 7.91 mmol) were used in the same manner as in Example 18e to obtain a crude product (866 mg) of the title compound.

Example 23d 3-chloro-5-hydroxymethyl-2- [1-methoxy-1- {4- (2,2,2-trifluoroethyl) phenyl} methyl] phenol Crude obtained in Example 23c Using the product (866 mg, 2.50 mmol), methanol (16 mL) and paratoluenesulfonic acid monohydrate (238 mg, 1.25 mmol), the title compound (654 mg) as an oil was obtained in the same manner as in Example 18f. .

Example 23e Acetic acid 3-chloro-4- [1-methoxy-1- {4- (2,2,2-trifluoroethyl) phenyl} methyl] -5-hydroxybenzyl Compound obtained in Example 23d (654 mg, 1.81 mmol), tetrahydrofuran (6 mL), vinyl acetate (6 mL) and bis (dibutyltin chloride) oxide (302 mg, 0.55 mmol) were used in the same manner as in Example 2e to give the oily title compound (703 mg). Obtained.

(Example 23f) Acetic acid 3-chloro-4- [4- (2,2,2-trifluoroethyl) benzyl] -5-hydroxybenzyl Compound obtained in Example 23e (703 mg, 1.75 mmol), acetonitrile ( 15 mL), triethylsilane (0.834 mL, 5.24 mmol) and boron trifluoride-diethyl ether complex (0.329 mL, 2.62 mmol) were used to give the title compound (306 mg) as a white solid in the same manner as in Example 2f. .

Example 23g 5-Acetoxymethyl-3-chloro-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl -D-glycero-β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (213 mg, 0.35 mmol), The imidate was prepared in the same manner as in Example 2g using methylene chloride (4 mL), trichloroacetonitrile (0.176 mL, 1.74 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (5 μL, 0.03 mmol). Prepared. Using the resulting imidate (263 mg), the compound obtained in Example 23f (105 mg, 0.23 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.044 mL, 0.34 mmol) In the same manner as in Example 2g, a crude product (280 mg) of the title compound was obtained.

Example 23h 3-Chloro-5-hydroxymethyl-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside The title compound (84 mg) was obtained as a white solid in the same manner as in Example 2h using 23 g of the crude product (280 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (480 mg, 3.47 mmol). Obtained. However, solidification was performed from hexane / ethyl acetate.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.20 (3H, d, J = 6.4 Hz), 3.34-3.46 (6H, m), 4.06 (1H, dd, J = 6.4 Hz, 3.7 Hz), 4.17 (1H, d, J = 14.5 Hz), 4.28 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.95 (1H, d, J = 7.8 Hz), 7.11 (1H, s), 7.13 (1H, s), 7.16 (2H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.3 Hz);
MS (FAB) m / z: 545 (M + K) ^+.

(Example 24) 3-chloro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 17)

Example 24a) 2-Fluoro-4-methylbenzoyl chloride 2-fluoro-4-methylbenzoic acid (500 mg, 3.24 mmol), oxalyl dichloride (0.31 mL, 3.57 mmol) and a catalytic amount of N, N-dimethylformamide , Tetrahydrofuran (10 mL) was used to give a crude product of the title compound (560 mg) as a colorless oil in the same manner as in Example 1a.

Example 24b (2-chloro-6-hydroxy-4-methoxyphenyl) (2-fluoro-4-methylphenyl) methanone 1-chloro-3,5-dimethoxybenzene (560 mg, 3.24 mmol), toluene (3 mL ), Aluminum chloride (480 mg, 3.60 mmol) and the crude product obtained in Example 24a (560 mg, 3.24 mmol) using the same method as in Example 2a to obtain the crude product of the title compound (630 mg). Obtained as a solid.

Example 24c (2-Chloro-4,6-dihydroxyphenyl) (2-fluoro-4-methylphenyl) methanone The crude product obtained in Example 24b (510 mg, 1.73 mmol) was converted to 1,2-dichloroethane. (5 mL), aluminum chloride (460 mg, 3.45 mmol) was added, and the mixture was stirred at 80 ° C. for 1.5 hr. The reaction mixture was cooled to 0 ° C., added with an appropriate amount of ice, stirred for 5 minutes, extracted with ethyl acetate (40 mL), and washed with 2 mol / L hydrochloric acid (10 mL) and saturated sodium hydrogen carbonate solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was washed with methylene chloride / hexane, and after filtration, a crude product of the title compound (366 mg) was obtained as a solid.

Example 24d 5-chloro-4- (2-fluoro-4-methylphenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ol Crude product obtained in Example 24c The product (366 mg, 1.30 mmol), methanol (5 mL) and sodium borohydride (123 mg, 3.25 mmol) were used in the same manner as in Example 2b to obtain a crude triol product (360 mg).

Using the crude product (360 mg), acetone (5 mL) and boron trifluoride-diethyl ether complex (0.160 mL, 1.27 mmol), the title compound (310 mg) was obtained as an amorphous form by the same method as in Example 6e.

Example 24e) Methyl 5-chloro-4- (2-fluoro-4-methylphenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-carboxylate obtained in Example 24d Using the compound (310 mg, 0.96 mmol), methylene chloride (6 mL), pyridine (0.120 mL, 1.49 mmol) and trifluoromethanesulfonic anhydride (0.190 mL, 1.13 mmol), the triflate form was prepared in the same manner as in Example 2c. Crude product (437 mg) was obtained.

The obtained crude product (437 mg, 0.96 mmol), N, N-dimethylformaldehyde (4 mL), methanol (0.780 mL, 19.2 mmol), palladium acetate (22 mg, 0.10 mmol), 1,3-bis (diphenylphosphino) The amorphous title compound (261 mg) was obtained in the same manner as in Example 2c using propane (40 mg, 0.10 mmol), triethylamine (2.66 mL, 19.2 mmol) and carbon monoxide.

(Example 24f) 5-chloro-4- (2-fluoro-4-methylphenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ylmethanol

Using the compound obtained in Example 24e (261 mg, 0.72 mmol), lithium aluminum hydride (41 mg, 1.08 mmol) and tetrahydrofuran (4 mL) in the same manner as in Example 2d, crude product of the title compound (241 mg) Was obtained as amorphous.

Example 24g 3-Chloro-2-{[1- (2-fluoro-4-methylphenyl) -1-methoxy] methyl} -5- (hydroxymethyl) phenol Crude product obtained in Example 24f (241 mg, 0.72 mmol) was dissolved in methanol (5 mL), paratoluenesulfonic acid monohydrate (68 mg, 0.36 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. Triethylamine was added to the reaction solution, and the solvent was removed under reduced pressure. Finally, purification using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 3: 2, V / V) gave the title compound (210 mg) as an oil.

(Example 24h) 3-Chloro-4-{[1- (2-fluoro-4-methylphenyl) -1-methoxy] methyl} -5-hydroxybenzyl acetate Compound (210 mg, 0.68) obtained in Example 24g mmol), tetrahydrofuran (2 mL), vinyl acetate (2 mL) and bis (dibutyltin chloride) oxide (112 mg, 0.20 mmol) were used in the same manner as in Example 2e to obtain the amorphous title compound (238 mg). It was.

(Example 24i) Acetic acid 3-chloro-4- (2-fluoro-4-methylbenzyl) -5-hydroxybenzyl Compound (238 mg, 0.67 mmol) obtained in Example 24h, acetonitrile (5 mL), triethylsilane ( 0.322 mL, 2.01 mmol) and boron trifluoride-diethyl ether complex (0.127 mL, 1.01 mmol) were used in the same manner as in Example 2f to obtain the title compound (96 mg) as a white solid.

Example 24j 5-Acetoxymethyl-3-chloro-2- (2-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (236 mg, 0.39 mmol), methylene chloride (4 mL), The imidate was prepared in the same manner as Example 2g using trichloroacetonitrile (0.195 mL, 1.93 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol). Using the resulting imidate (292 mg), the compound obtained in Example 24i (96 mg, 0.30 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.049 mL, 0.39 mmol) In the same manner as in Example 2g, a crude product (435 mg) of the title compound was obtained.

Example 24k 3-Chloro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 24j Using the same crude product (435 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (534 mg, 3.89 mmol) as in Example 2h, the title compound (86 mg) was obtained as a white solid. However, solidification was performed from hexane / ethyl acetate / methanol.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.20 (3H, d, J = 6.4 Hz), 2.27 (3H, s), 3.34-3.43 (4H, m), 4.05 (1H, dd, J = 6.4 Hz, 3.6 Hz), 4.15 (1H, d, J = 15.4 Hz), 4.23 (1H, d, J = 15.4 Hz), 4.58 (2H, s), 4.93 (1H, d, J = 7.4 Hz), 6.75 -6.76 (2H, m), 6.85 (1H, d, J = 11.3 Hz), 7.13 (1H, s), 7.15 (1H, s);
MS (FAB) m / z: 495 (M + K) ^+.

(Example 25) 3-Chloro-2- (4-ethyl-2-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 18)

Example 25a (2-chloro-6-hydroxy-4-methoxyphenyl) (4-ethyl-2-fluorophenyl) methanone 1-chloro-3,5-dimethoxybenzene (855 mg, 4.95 mmol), toluene (5 mL ), Aluminum chloride (727 mg, 5.45 mmol) and 4-ethyl-2-fluorobenzoyl chloride (US2006 / 20146A1) (918 mg, 4.92 mmol) in the same manner as in Example 2a, the crude product (1.02 g) was obtained as a solid.

Example 25b (2-Chloro-4,6-dihydroxyphenyl) (4-ethyl-2-fluorophenyl) methanone Crude product obtained in Example 25a (1.02 g, 3.30 mmol), 1,2- A crude product of the title compound (824 mg) was obtained as a solid in the same manner as in Example 24c using dichloroethane (10 mL) and aluminum chloride (880 mg, 6.60 mmol).

Example 25c 5-Chloro-2,2-dimethyl-4- (4-ethyl-2-fluorophenyl) -4H-benzo [1,3] dioxin-7-ol Crude product obtained in Example 25b Product (815 mg, 2.77 mmol), methanol (10 mL) and sodium borohydride (262 mg, 6.93 mmol) were obtained in the same manner as in Example 2b to obtain a crude triol product (564 mg).

Using the crude product (564 mg), acetone (6 mL) and boron trifluoride-diethyl ether complex (0.300 mL, 2.39 mmol), the title compound (515 mg) was obtained as an amorphous form in the same manner as in Example 6e.

Example 25d) 5-Chloro-2,2-dimethyl-4- (4-ethyl-2-fluorophenyl) -4H-benzo [1,3] dioxin-7-carboxylate methyl obtained in Example 25c Using the compound (515 mg, 1.53 mmol), methylene chloride (10 mL), pyridine (0.185 mL, 2.29 mmol) and trifluoromethanesulfonic anhydride (0.308 mL, 1.83 mmol) in the same manner as in Example 2c, Crude product (717 mg) was obtained.

The obtained crude product (717 mg, 1.53 mmol), N, N-dimethylformaldehyde (6.4 mL), methanol (1.24 mL, 30.5 mmol), palladium acetate (34 mg, 0.15 mmol), 1,3-bis (diphenylphosphine) Fino) propane (63 mg, 0.15 mmol), triethylamine (4.24 mL, 30.6 mmol) and carbon monoxide were used in the same manner as in Example 2c to obtain the title compound (465 mg) as a white solid.

(Example 25e) 5-chloro-4- (4-ethyl-2-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ylmethanol

Using the compound obtained in Example 25d (465 mg, 1.23 mmol), lithium aluminum hydride (70 mg, 1.84 mmol) and tetrahydrofuran (7 mL) in the same manner as in Example 2d, the crude product of the title compound (432 mg) Was obtained as amorphous.

Example 25f 3-Chloro-2- [1- (4-ethyl-2-fluorophenyl) -1-methoxymethyl] -5- (hydroxymethyl) phenol The crude product obtained in Example 25e (430 mg 1.23 mmol), methanol (10 mL), and paratoluenesulfonic acid monohydrate (116 mg, 0.61 mmol) were used to give the title compound (377 mg) as an oil in the same manner as in Example 24g.

(Example 25g) Acetic acid 3-chloro-4- [1- (4-ethyl-2-fluorophenyl) -1-methoxymethyl] -5-hydroxybenzyl Compound obtained in Example 25f (377 mg, 1.16 mmol) , Tetrahydrofuran (4 mL), vinyl acetate (4 mL) and bis (dibutyltin chloride) oxide (192 mg, 0.35 mmol) were used in the same manner as in Example 2e to obtain the oily title compound (414 mg).

(Example 25h) Acetic acid 3-chloro-4- (4-ethyl-2-fluorobenzyl) -5-hydroxybenzyl Compound (414 mg, 1.13 mmol) obtained in Example 25 g, acetonitrile (8 mL), triethylsilane ( 0.539 mL, 3.38 mmol) and boron trifluoride-diethyl ether complex (0.213 mL, 1.70 mmol) were used in the same manner as in Example 2f to obtain the title compound (271 mg) as a white solid.

Example 25i) 5-Acetoxymethyl-3-chloro-2- (4-ethyl-2-fluorobenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (236 mg, 0.39 mmol), methylene chloride (4 mL), The imidate was prepared in the same manner as Example 2g using trichloroacetonitrile (0.195 mL, 1.93 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 μL, 0.04 mmol). Using the resulting imidate (292 mg), the compound obtained in Example 25h (100 mg, 0.30 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.049 mL, 0.39 mmol) In the same manner as in Example 2g, a crude product (409 mg) of the title compound was obtained.

Example 25j 3-Chloro-2- (4-ethyl-2-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 25i Using the same crude product (409 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (534 mg, 3.89 mmol), the title compound (52 mg) was obtained as a white solid in the same manner as in Example 2h. However, solidification was performed from hexane / ethyl acetate / methanol.
¹ H NMR (400MHz, CD ₃ OD): δ 1.17-1.20 (6H, m), 2.58 (2H, q, J = 7.6 Hz), 3.34-3.43 (4H, m), 4.05 (1H, dd, J = 6.4 Hz, 3.7 Hz), 4.15 (1H, d, J = 15.2 Hz), 4.24 (1H, d, J = 15.2 Hz), 4.57 (2H, s), 4.93 (1H, d, J = 7.4 Hz), 6.77-6.79 (2H, m), 6.87 (1H, d, J = 11.3 Hz), 7.13 (1H, s), 7.15 (1H, s);
MS (FAB) m / z: 509 (M + K) ^+.

Example 26 3-Fluoro-2- (4-trifluoromethyl) benzyl-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 5 in Table 1)

Example 26a Ethyl 3-hydroxy-5-oxo-4- [4- (trifluoromethyl) benzoyl] cyclohex-3-enecarboxylate ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate ( 1.0 g, 5.4 mmol), 4-trifluoromethylbenzoic acid chloride (1.16 g, 5.6 mmol), triethylamine (2.3 mL, 16.5 mmol), trimethylsilylcyanide (90 μL, 0.67 mmol) and acetonitrile (15 mL) In the same manner as in Example 4a, a crude product of the title compound (2.25 g) was obtained as a pale yellow solid.

Example 26b Ethyl 3-fluoro-5-oxo-4- [4- (trifluoromethyl) benzoyl] cyclohex-3-enecarboxylate Crude product obtained in Example 26a (2.25 g, 5.4 mmol) Was dissolved in methylene chloride (20 mL), diethylaminosulfur trifluoride (2.2 mL, 16.7 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. Distilled water (5 mL) was added dropwise to the reaction solution, diluted with methylene chloride (10 mL), and washed successively with distilled water (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1-5: 1-4: 1, V / V) to give the title compound (1.31 g) as a yellow solid.

Example 26c Ethyl 3-fluoro-5-hydroxy-4- [4- (trifluoromethyl) benzoyl] benzoate Compound obtained in Example 26b (1.31 g, 3.7 mmol), triethylamine (1.5 mL, 10.8 mmol), acetonitrile (13 mL) and trimethylsilane iodide (1.3 mL, 9.1 mmol) were used in the same manner as in Example 5c to obtain a silyl enol ether as an oily crude product. Further, according to the same method as in Example 5c, the obtained oily crude product was sequentially treated with toluene (13 mL), silica gel SK-85 (5.2 g), potassium carbonate (506 mg, 3.7 mmol) and ethanol (13 mL). Purification using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1, V / V) gave the title compound (0.82 g) as a pale yellow solid.

Example 26d 3-Fluoro-5-hydroxymethyl-2- {1-hydroxy-1- [4- (trifluoromethyl) phenyl] methyl} phenol The compound obtained in Example 26c (0.82 g, 2.3 mmol ) Was dissolved in tetrahydrofuran (12 mL), lithium aluminum hydride (0.26 g, 6.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Under ice-cooling, 2M hydrochloric acid (5mL) was added to the reaction mixture, diluted with ethyl acetate (20mL), washed successively with 2M hydrochloric acid (10mL), saturated aqueous sodium bicarbonate (10mL) and saturated brine (5mL). A crude product (0.66 g) of the title compound was obtained as a brown oil.

Example 26e) 3-Fluoro-5-hydroxymethyl-2- {1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl} phenol The crude product obtained in Example 26d (0.66 g, 2.1 mmol) was dissolved in methanol (10 mL), paratoluenesulfonic acid monohydrate (0.2 g, 1.1 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hr. Triethylamine (290 μL, 2.1 mmol) was added to the reaction solution under ice cooling. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate (20 mL) and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.74 g) of the title compound as a yellow oily substance.

Example 26f Acetic acid 3-fluoro-5-hydroxy-4- {1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl} benzyl Crude product obtained in Example 26e (0.74 g, 2.1 mol) was dissolved in diisopropyl ether (4 mL), vinyl acetate (4 mL, 43.2 mmol) and porcine pancreatic lipase (0.37 g) were added, and the mixture was stirred at 35 ° C. for 24 hours. After filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-2: 1, V / V) to give the title compound (0.43 g) as a pale yellow oil. .

Example 26h 3-Fluoro-5-hydroxy-4- [4- (trifluoromethyl) benzyl] benzyl acetate The compound (0.43 g, 1.2 mmol) obtained in Example 26g was dissolved in acetonitrile (5 mL). Under ice cooling, triethylsilane (550 μL, 3.5 mmol) and boron trifluoride-diethyl ether complex (440 μL, 3.5 mmol) were added, and the mixture was stirred at 50 ° C. for 4 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction solution, diluted with ethyl acetate (20 mL), and washed successively with a saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1-5: 1-4: 1, V / V) to obtain the title compound (0.14 g) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.12 (3H, s), 4.05 (2H, s), 5.01 (2H, s), 5.13 (1H, brs), 6.61 (1H, s), 6.71 (1H , d, J = 9.8 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.0 Hz);
MS (FAB) m / z: 342 (M) ⁺ .

Example 26i) 5-Acetoxymethyl-3-fluoro- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β-D -Gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (275 mg, 0.45 mmol), trichloroacetonitrile (135 μL, 1.35 mmol), 1,8 -Imidabicyclo [5.4.0] -7-undecene (7 μL, 0.05 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i. The compound (0.14 g) obtained in Example 26h 0.41 mmol), boron trifluoride-diethyl ether complex (51 μL, 0.41 mmol) and methylene chloride (5 mL) were obtained in the same manner as in Example 4i to obtain a crude product (339 mg) of the title compound.

Example 26j 3-Fluoro-5-hydroxymethyl-2- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Crude obtained in Example 26i Using the product (339 mg, 0.36 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (56 mg, 0.41 mmol), the title compound (100 mg) was obtained as a colorless solid in the same manner as in Example 4j. .
¹ H NMR (500 MHz, CD ₃ OD): δ 1.19 (3H, d, J = 6.4 Hz), 3.33-3.40 (2H, m), 3.43-3.49 (2H, m), 4.03-4.07 (1H, m ), 4.10 (1H, d, J = 14.6 Hz), 4.16 (1H, d, J = 14.6 Hz), 4.55 (2H, s), 4.95 (1H, d, J = 7.3 Hz), 6.81 (1H, d , J = 10.3 Hz), 7.00 (1H, s), 7.46 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz);
MS (FAB) m / z: 477 (M + H) ⁺ , 499 (M + Na) ^+.

Example 27 3-Chloro-2- (4-trifluoromethyl) benzyl-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. 11 in Table 1)

Example 27a Ethyl 3-chloro-5-oxo-4- [4- (trifluoromethyl) benzoyl] cyclohex-3-enecarboxylate Crude product obtained in Example 26a (2.25 g, 5.4 mmol) Example 4b, oxalyl dichloride (500 μL, 3.8 mmol), 2-methyl-2-butene (2.3 mL, 21.7 mmol), N, N-dimethylformamide (100 μL, 1.29 mmol) and methylene chloride (20 mL). In the same manner as above, a crude product (2.5 g) of the title compound was obtained as a brown oily substance.

Example 27b Ethyl 3-chloro-5-hydroxy-4- [4- (trifluoromethyl) benzoyl] benzoate Crude product obtained in Example 27a (2.5 g), N-methylmorpholine (10 mL) The title compound (1.66 g) was obtained as a brown solid in the same manner as in Example 4c, using iodine and iodine (1.65 g, 6.5 mmol). However, purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-3: 1, V / V).

Example 27c 3-Chloro-5-hydroxymethyl-2- {1-hydroxy-1- [4- (trifluoromethyl) phenyl] methyl} phenol The compound obtained in Example 27b (1.66 g, 4.5 mmol) ), Lithium aluminum hydride (0.51 g, 13.4 mmol) and tetrahydrofuran (17 mL) were obtained in the same manner as in Example 26d to obtain a crude product of the title compound (1.44 g) as a colorless solid.

Example 27d 3-chloro-5-hydroxymethyl-2- {1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl} phenol The crude product obtained in Example 27c (1.44 g, 4.3 mmol), paratoluenesulfonic acid monohydrate (0.41 g, 2.2 mmol) and methanol (15 mL) were used in the same manner as in Example 26e to obtain a crude product of the title compound. The product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1-3: 1-2: 1, V / V) to give the title compound (0.31 g) as a colorless oil.

(Example 27e) 3-chloro-5-hydroxy-4- {1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl} benzyl acetate Acetic acid (0.31 g, 0.89 mmol) obtained in Example 27d ), Vinyl acetate (3 mL, 32.4 mmol), porcine pancreatic lipase (0.16 g) and diisopropyl ether (3 mL) were used to give the title compound (0.33 g) as a yellow oil in the same manner as in Example 26f. . The purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1-5: 1-4: 1, V / V).

(Example 27f) Acetic acid 3-chloro-5-hydroxy-2- [4- (trifluoromethyl) benzyl] benzyl Compound obtained in Example 27e (0.33 g, 0.85 mmol), triethylsilane (400 μL, 2.5 mmol) ), Boron trifluoride-diethyl ether complex (320 μL, 2.5 mmol) and acetonitrile (3 mL) by a method similar to that in Example 26h, 3-chloro-5-hydroxymethyl-2- [4- (tri Fluoromethyl) benzyl] phenol (100 mg) was obtained. Using this compound, vinyl acetate (2 mL, 21.6 mmol), bis (dibutyltin chloride) oxide (16 mg, 0.03 mmol) and tetrahydrofuran (2 mL), the title compound (95 mg) was purified in the same manner as in Example 21h. Obtained as a solid. The purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1 to 5: 1, V / V).
¹ H NMR (500 MHz, CDCl ₃ ): δ 2.12 (3H, s), 4.21 (2H, s), 5.00 (2H, s), 5.09 (1H, s), 6.72 (1H, s), 7.02 (1H , s), 7.37 (2H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.0 Hz);
MS (FAB) m / z: 358 (M) ^+.

Example 27g 5-Acetoxymethyl-3-chloro-2- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (194 mg, 0.32 mmol), trichloroacetonitrile (95 μL, 0.95 mmol), 1 , 8-diazabicyclo [5.4.0] -7-undecene (5 μL, 0.03 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i, and the compound obtained in Example 27f ( 95 mg, 0.26 mmol), boron trifluoride-diethyl ether complex (33 μL, 0.26 mmol) and methylene chloride (5 mL) were used in the same manner as in Example 4i to obtain a crude product of the title compound (313 mg). .

Example 27h 3-Chloro-5-hydroxymethyl-2- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Crude obtained in Example 27g Using the product (313 mg, 0.26 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (36 mg, 0.26 mmol), the title compound (84 mg) was obtained as a colorless solid in the same manner as in Example 4j. .
¹ H NMR (400 MHz, CD ₃ OD): δ 1.20 (3H, d, J = 6.7 Hz), 3.34-3.46 (4H, m), 4.03-4.09 (1H, m), 4.26 (1H, d, J = 14.8 Hz), 4.35 (1H, d, J = 14.8 Hz), 4.56 (2H, s), 4.96 (1H, d, J = 7.5 Hz), 7.13 (1H, s), 7.16 (1H, s), 7.44 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz);
MS (FAB) m / z: 493 (M + H) ⁺ , 515 (M + Na) ^+.

Example 28 2- [4- (2,2-Difluoroethyl) benzyl] -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (Table 1) No.20)

Example 28a Methyl 4- (2,2-difluoroacetyl) benzoate Methyl 4-acetylbenzoate (1.0 g, 5.6 mmol) was dissolved in a solution consisting of benzene (28 mL) and hexane (56 mL), and morpholine ( Using a hexane solution (15 mL) in which 2.3 mL, 26 mmol) and titanium trichloride (0.42 mL, 3.9 mmol) are dissolved, the literature is known (J. Org. Chem., 2005, 70 (14), 5763.) The method yielded the corresponding crude enamine product as a yellow oil. This enamine was not purified but was dissolved in acetonitrile (120 mL) and MS4A (10 g) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octanebis (tetrafluoroborate) ( The crude product (1.2 g) of the title compound was obtained according to the above document using Selectfluor (3.9 g, 11 mmol) purchased from Aldrich.

Example 28b Methyl 4- (2,2-difluoro-1-hydroxyethyl) benzoate The crude product obtained in Example 28a (1.2 g, 5.6 mmol) was obtained from methanol (5 mL) and tetrahydrofuran (5 mL). The resulting solution was dissolved in sodium borohydride (0.32 g, 8.4 mmol) under ice cooling. The reaction mixture was stirred for 2 hours while warming to room temperature, and saturated aqueous ammonium chloride solution (1 mL) was added dropwise under ice cooling to stop the reaction. The mixture was diluted with ethyl acetate (50 mL), and washed successively with saturated sodium hydrogen carbonate (20 mL, twice) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title compound. (0.74 g) was obtained as a colorless solid.

Example 28c Methyl 4- (2,2-difluoroethyl) benzoate The compound synthesized in Example 28b (0.69 g, 3.2 mmol) was dissolved in tetrahydrofuran (10 mL), and thiocarbonyldiimidazole (0.86 g) was dissolved at room temperature. 4.8 mmol), and the mixture was stirred for 1 hour while heating under reflux. The mixture was cooled, diluted with ethyl acetate (50 mL), and washed successively with 1M hydrochloric acid (5 mL), saturated sodium bicarbonate (10 mL), and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of xanthate. This crude product was dissolved in toluene (10 mL) without purification, and after degassing, tributyltin hydride (1.2 mL, 4.6 mmol) and azobisisobutyronitrile (0.10 g, 0.61 mmol) were added under a nitrogen stream It was. The mixture was stirred at 90 ° C. for 2 hours, and the reaction solution was directly purified using silica gel flash chromatography (hexane: ethyl acetate, 10: 1, V / V) to obtain the title compound (0.54 g) as a colorless solid. It was.

Example 28d 4- (2,2-difluoroethyl) benzoic acid The compound obtained in Example 28c (0.53 g, 2.6 mmol) was dissolved in 1,4-dioxane (3.4 mL), and 2M water at room temperature. An aqueous sodium oxide solution (3.4 mL, 6.8 mmol) was added, and the mixture was stirred at 35 ° C. for 1 hour. The reaction mixture was poured into 1M hydrochloric acid (20 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated brine (10 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.48 g) as a colorless solid.

(Example 28e) 4- (2,2-difluoroethyl) benzoyl chloride The crude product (0.48 g, 2.6 mmol) obtained in Example 28d was dissolved in methylene chloride, and oxalyl chloride (1.1 mL) was cooled with ice. 13 mmol) and N, N-dimethylformamide (0.1 mL, 1.3 mmol) were added, and the mixture was stirred for 3 and a half hours while warming to room temperature. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude product (0.53 g) of the title compound as a colorless oil.

Example 28f Ethyl 4- [4- (2,2-difluoroethyl) benzoyl] -3-hydroxy-5-oxocyclohex-3-enecarboxylate 3-hydroxy-5-oxocyclohex-3-ene Using the ethyl carboxylate (EP1571148A1) (0.48 g, 2.6 mmol) and the crude product obtained in Example 28e (0.53 g, 2.6 mmol) in the same manner as in Example 1b, the crude product of the title compound (0.92 g) was obtained.

Example 28g Ethyl 4- [4- (2,2-difluoroethyl) benzoyl] -3-fluoro-5-oxocyclohex-3-enecarboxylate The crude product obtained in Example 28f (0.95 g 2.7 mmol) was dissolved in methylene chloride (10 mL), and the title compound (0.47 g) was obtained in the same manner as in Example 3b using diethylaminosulfur trifluoride (1.1 mL, 8.1 mmol).

Example 28h Ethyl 4- [4- (2,2-difluoroethyl) benzoyl] -3-fluoro-5-hydroxybenzoate The compound obtained in Example 28g (0.47 g, 1.3 mmol) was converted to N-methyl. It was dissolved in morpholine (6 mL), and a crude product (0.46 g) of the title compound was obtained in the same manner as in Example 3c using anhydrous sodium sulfate (0.47 g) and iodine (0.40 g, 1.6 mmol).

Example 28i Ethyl 4- {1- [4- (2,2-difluoroethyl) phenyl] -1-hydroxymethyl} -3-fluoro-5-hydroxybenzoate Crude product obtained in Example 28h (0.46 g, 1.3 mmol) was dissolved in a solution of tetrahydrofuran (3 mL) and methanol (2 mL), and the title compound (0.33 g) was prepared in the same manner as in Example 3d using sodium borohydride (98 mg, 2.6 mmol). ) Was obtained as a colorless solid.

Example 28j Ethyl 4- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5-hydroxybenzoate The compound obtained in Example 28i (0.33 g, 0.93 mmol) was added to ethanol (10 mL). In the same manner as in Example 3e using 10% methanolic hydrogen chloride (0.33 mL, 0.93 mmol) and 10% palladium on carbon catalyst (containing water, 0.5 g), the crude product of the title compound (0.31 g) Got.

Example 28k 2- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5- (hydroxymethyl) phenol The crude product obtained in Example 28j (0.31 g, 0.93 mmol) The product was dissolved in tetrahydrofuran (10 mL), and the crude product (0.31 g) of the title compound was obtained as a colorless solid in the same manner as in Example 3f using lithium aluminum hydride (0.14 g, 3.7 mmol).

(Example 28l) Acetic acid 4- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5-hydroxybenzyl The crude product obtained in Example 28k (0.31 g, 0.93 mmol) was converted into vinyl acetate. (3 mL) and diisopropyl ether (3 mL) were dissolved in the solution, and the title compound (0.30 g) was obtained as a pale brown solid by the same method as Example 3 g using porcine pancreatic lipase (1.0 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.09 (2H, dt, J = 17.4, 4.3 Hz), 3.99 (2H, s), 5.01 (2H, s), 5.88 (1H , tt, J = 56.7, 4.1 Hz), 6.60 (1H, s), 6.70 (1H, d, J = 9.4 Hz), 7.16 (2H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.8 Hz).

Example 28m 5-Acetoxymethyl-3-fluoro-2- [4- (2,2-difluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D- Glycero-β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231 )) (0.61 g, 1.0 mmol) dissolved in methylene chloride (4 mL) and trichloroacetonitrile (0.30 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4 μL, 0.03 mmol) The imidate was prepared in the same manner as in Example 1h. Using this imidate (0.75 g, 1.0 mmol), the compound obtained in Example 28l (0.30 g, 0.89 mmol) and boron trifluoride-diethyl ether complex (56 μL, 0.44 mmol), the same method as in Example 1h Gave a mixture containing the title compound.

Example 28n 3-Fluoro-2- [4- (2,2-difluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside Example 28m The mixture obtained in step (0.89 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol) was used in the same manner as in Example 3i. The title compound (0.12 g) was obtained as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.3 Hz), 3.05 (2H, dt, J = 17.5, 4.6 Hz), 3.33-3.50 (4H, m), 3.99 ( 1H, d, J = 14.5 Hz), 4.03-4.08 (1H, m), 4.08 (1H, d, J = 14.5 Hz), 4.55 (2H, s), 4.94 (1H, d, J = 7.5 Hz), 5.92 (1H, tt, J = 56.8, 4.6 Hz), 6.79 (1H, d, J = 10.1 Hz), 6.99 (1H, s), 7.12 (2H, d, J = 8.2 Hz), 7.25 (2H, d , J = 8.2 Hz);
MS (FAB) m / z: 495 (M + Na) ^+.

Example 29 3-Chloro-2- [4- (2,2-difluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (Table 1) No.21)

Example 29a) Ethyl 3-chloro-4- [4- (2,2-difluoroethyl) benzoyl] -5-oxocyclohex-3-enecarboxylate The crude product obtained in Example 28f (0.92 g , 2.6 mmol) in methylene chloride (10 mL), 2-methyl-2-butene (1.1 mL, 10 mmol), oxalyl dichloride (0.23 mL, 2.7 mmol) and N, N-dimethylformamide (0.05 mL, 0.07). The crude product (0.96 g) of the title compound was obtained in the same manner as in Example 1b.

Example 29b Ethyl 3-chloro-4- [4- (2,2-difluoroethyl) benzoyl] -5-hydroxybenzoate The crude product obtained in Example 29a (0.96 g, 2.6 mmol) was converted to N -Dissolved in methylmorpholine (12 mL), and obtained the crude product (0.96 g) of the title compound in the same manner as in Example 3c using anhydrous sodium sulfate (0.96 g) and iodine (0.79 g, 3.1 mmol). .

Example 29c 3-Chloro-2- {1- [4- (2,2-difluoroethyl) phenyl] -1-hydroxymethyl} -5- (hydroxymethyl) phenol Crude product obtained in Example 29b The product (0.96 g, 2.6 mmol) was dissolved in tetrahydrofuran (30 mL) and the title compound (0.85 g) was obtained as a crude product in the same manner as in Example 1e using lithium aluminum hydride (0.38 g, 10 mmol). Obtained.

Example 29d Acetic acid 3-chloro-4- {1- [4- (2,2-difluoroethyl) phenyl] -1-hydroxymethyl} -5-hydroxybenzyl Crude product obtained in Example 29c ( 0.85 g, 2.6 mmol) was dissolved in a solution consisting of vinyl acetate (5 mL) and diisopropyl ether (5 mL), and the title compound (0.51 g) was purified by the same method as Example 3 g using porcine pancreatic lipase (2.0 g). Obtained as a solid.

(Example 29e) 3-chloro-4- [4- (2,2-difluoroethyl) benzyl] -5-hydroxybenzyl acetate Acetic acid (10 mL) was prepared from the compound (0.40 g, 1.1 mmol) obtained in Example 29d. And triethylsilane (0.53 mL, 3.3 mmol) and boron trifluoride-diethyl ether complex (0.28 mL, 2.2 mmol) were used in the same manner as in Example 5f (but no purification was performed). To give a mixture containing the title compound.

Dissolve the resulting mixture in methanol (2.5 mL), add p-toluenesulfonic acid monohydrate (72 mg, 0.38 mmol), stir at 50 ° C. for 1.5 hours, dilute with ethyl acetate (20 mL), and then The mixture was washed successively with aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 98: 2, V / V) to give the title compound Was obtained as a colorless solid (0.16 g).

This deacetylated product was dissolved in vinyl acetate (5 mL) and diisopropyl ether (5 mL), and the title compound (0.13 g) was obtained as a colorless solid by the same method as Example 3 g using porcine pancreatic lipase (2.0 g). .
¹ H NMR (500 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.09 (2H, dt, J = 17.4, 4.6 Hz), 4.15 (2H, s), 5.00 (2H, s), 5.05 (1H , s), 5.88 (1H, tt, J = 56.7, 4.6 Hz), 6.72 (1H, d, J = 1.5 Hz), 7.02 (1H, d, J = 1.5 Hz), 7.15 (2H, d, J = 8.3 Hz), 7.23 (2H, d, J = 8.3 Hz);
MS (FAB) m / z: 354 (M) ^+.

Example 29f 5-Acetoxymethyl-3-chloro-2- [4- (2,2-difluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D- Glycero-β-D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231 )) (0.37 g, 0.60 mmol) dissolved in methylene chloride (4 mL) and trichloroacetonitrile (0.18 mL, 1.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 μL, 0.02 mmol) The imidate was prepared in the same manner as in Example 1h. Using this imidate (0.45 g, 0.60 mmol), the compound obtained in Example 29e (0.13 g, 0.36 mmol) and boron trifluoride-diethyl ether complex (46 μL, 0.37 mmol), the same method as in Example 1h Gave a mixture containing the title compound.

Example 29g 3-chloro-2- [4- (2,2-difluoroethyl) benzyl] -5-hydroxymethyl-phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D -Glycero-β-D-gluco-heptopyranoside The mixture (0.37 mmol) obtained in Example 29f was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol) was used. In the same manner as in Example 3i, the title compound (0.12 g) was obtained as a colorless solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.21 (3H, d, J = 6.3 Hz), 3.05 (2H, dt, J = 17.5, 4.6 Hz), 3.34-3.46 (4H, m), 4.03- 4.09 (1H, m), 4.14 (1H, d, J = 14.7 Hz), 4.27 (1H, d, J = 14.7 Hz), 4.55 (2H, s), 4.94 (1H, d, J = 7.5 Hz), 5.93 (1H, tt, J = 56.7, 4.7 Hz), 7.10-7.13 (4H, m), 7.22 (2H, d, J = 8.2 Hz);
MS (FAB) m / z: 511 (M + Na) ^+.

Example 30 3-Fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) 7)

Example 30a 3,5-difluoro-4- [1- (2-fluoro-4-methylphenyl) -1-hydroxymethyl] benzonitrile diisopropylamine (1.12 mL, 7.92 mmol), n-butyllithium (2.59 mL, 7.17 mmol, 2.77 M n-hexane solution), 3,5-difluorobenzonitrile (1.00 g, 7.19 mmol), 2-fluoro-4-methylbenzaldehyde (1.00 g, 7.24 mmol) and tetrahydrofuran (20 mL) The title compound (1.44 g) was obtained as a pale yellow solid in the same manner as in Example 7a.

Example 30b 3,5-Difluoro-4- (2-fluoro-4-methylbenzyl) benzonitrile Sodium borohydride (1.69 g, 44.7 mmol) was dissolved in trifluoroacetic acid (30 mL) and brought to 0 ° C. After cooling, a methylene chloride solution (7 mL) in which the compound obtained in Example 30a (1.24 g, 4.47 mmol) was dissolved was added. Thereafter, the reaction solution was stirred at room temperature for 30 hours. However, during that time, sodium borohydride (2.00 g, 52.9 mmol) and trifluoroacetic acid (20 mL) were added in several portions until the reaction was completed. Subsequently, the reaction solution was added to a 10% aqueous sodium hydroxide solution (300 mL) cooled to 0 ° C. The mixture was extracted with diethyl ether (300 mL), and washed successively with water (100 mL), saturated aqueous ammonium chloride (100 mL), and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 10: 1, V / V). The title compound (756 mg) was obtained as a white solid.

Example 30c 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methylbenzyl) benzonitrile The compound obtained in Example 30b (756 mg, 2.89 mmol), sodium hydride (63%, 165 mg, 4.33 mmol), benzyl alcohol (387 mg, 3.58 mmol) and N, N-dimethylformamide (10 mL) were used in the same manner as in Example 7c to obtain the title compound (768 mg) as a white solid. The purification was performed using silica gel flash chromatography (hexane: ethyl acetate 19: 1 to 10: 1, V / V).

Example 30d 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methylbenzyl) benzoic acid The compound obtained in Example 30c (768 mg, 2.20 mmol), 5M aqueous sodium hydroxide solution (2.2 mL, 11.0 mmol) and ethanol (10 mL) were used in the same manner as in Example 7d to obtain a crude product (740 mg) of the title compound.

Example 30e 3-Fluoro-4- (2-fluoro-4-methylbenzyl) -5-hydroxybenzoic acid Crude product obtained in Example 30d (740 mg, 2.01 mmol), 10% palladium on carbon catalyst ( A crude product (553 mg) of the title compound was obtained in the same manner as in Example 7e using water (150 mg), tetrahydrofuran (7 mL), methanol (7 mL) and hydrogen.

Example 30f 3-Fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenol Crude product obtained in Example 30e (553 mg, 1.99 mmol), lithium aluminum hydride (188 mg, 4.95 mmol) and tetrahydrofuran (20 mL) were used to give a crude product of the title compound (498 mg) in the same manner as in Example 7f.

(Example 30g) 3-fluoro-4- (2-fluoro-4-methylbenzyl) -5-hydroxybenzyl acetate Acetic product (498 mg, 1.88 mmol) obtained in Example 30f, bis (dibutyltin chloride) The title compound (522 mg) was obtained in the same manner as in Example 7g using oxide (312 mg, 0.56 mmol), vinyl acetate (5 mL) and tetrahydrofuran (5 mL).
¹ H NMR (500 MHz, CDCl ₃ ): δ 2.11 (3H, s), 2.29 (3H, s), 3.96 (2H, s), 5.00 (2H, s), 5.22 (1H, d, J = 3.9 Hz ), 6.63 (1H, s), 6.68 (1H, d, J = 9.2 Hz), 6.83-6.87 (2H, m), 7.03 (1H, t, J = 7.9 Hz);
MS (EI) m / z: 306 (M) ^+.

Example 30h 5-Acetoxymethyl-3-fluoro-2- (2-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) 311 mg, 0.51 mmol), methylene chloride (6 mL), trichloroacetonitrile (0.257 mL, 2.56 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (8 μL, 0.05 mmol) as in Example 1h The imidate was prepared by the method.

Same as Example 1h, using the compound obtained in Example 30g (122 mg, 0.40 mmol), imidate (0.51 mmol), methylene chloride (6 mL) and boron trifluoride-diethyl ether complex (0.064 mL, 0.51 mmol). In this way, a crude product of the title compound was obtained.

Example 30i 3-Fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 30h Using the crude product, methanol / methylene chloride (10 mL / 2.5 mL) and potassium carbonate (700 mg, 5.06 mmol), a crude product of the title compound was obtained in the same manner as in Example 2h. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 1: 1 to methylene chloride: methanol, 10: 1, V / V) to give the title compound (87 mg).
¹ H NMR (400 MHz, CD ₃ OD): δ 1.19 (3H, d, J = 6.6 Hz), 2.27 (3H, s), 3.33-3.38 (2H, m), 3.43-3.45 (2H, m), 3.98-4.05 (3H, m), 4.57 (2H, s), 4.93 (1H, d, J = 7.4 Hz), 6.78-6.84 (3H, m), 6.95 (1H, t, J = 7.8 Hz), 7.00 (1H, s);
MS (FAB) m / z: 479 (M + K) ^+.

Example 31 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside (No. in Table 1) twenty two)

Example 31a (4-Ethyl-2-fluorophenyl) methanol 4-ethyl-2-fluorobenzoyl chloride (US2006 / 20146 A1) (200 mg, 1.19 mmol), lithium aluminum hydride (90 mg, 2.37 mmol) and tetrahydrofuran (20 mL) was used to give a crude product of the title compound (194 mg) in the same manner as in Example 2d.

Example 31b 4-Ethyl-2-fluorobenzaldehyde The crude product obtained in Example 31a (194 mg) was dissolved in methylene chloride (10 mL), and cooled with ice, pyridinium chlorochromate (540 mg, 2.51 mmol). And stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, the solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 9: 1, V / V) to give the oily title compound ( 158 mg) was obtained.

Example 31c 3,5-difluoro-4- [1- (4-ethyl-2-fluorophenyl) -1-hydroxymethyl] benzonitrile diisopropylamine (0.85 mL, 6.01 mmol), n-butyllithium (1.97 mL, 5.46 mmol, 2.77 M n-hexane solution), 3,5-difluorobenzonitrile (759 mg, 5.46 mmol), the compound obtained in Example 31b (830 mg, 5.45 mmol) and tetrahydrofuran (12 mL) In the same manner as in Example 7a, the oily title compound (1.49 g) was obtained.

Example 31d 3,5-Difluoro-4- (4-ethyl-2-fluorobenzyl) benzonitrile Sodium borohydride (1.94 g, 51.2 mmol) was dissolved in trifluoroacetic acid (35 mL) and brought to 0 ° C. After cooling, a methylene chloride solution (7 mL) in which the compound obtained in Example 31c (1.49 g, 5.12 mmol) was dissolved was added. Then, it stirred at room temperature for 30 hours. However, during that time, sodium borohydride (1.94 g, 51.2 mmol) and trifluoroacetic acid (20 mL) were added in several portions until the reaction was completed. Subsequently, the reaction solution was added to a 10% aqueous sodium hydroxide solution (330 mL) cooled to 0 ° C. The mixture was extracted with diethyl ether (300 mL), and washed successively with water (100 mL), saturated aqueous ammonium chloride (100 mL), and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 10: 1, V / V). The title compound (947 mg) was obtained as a white solid.

Example 31e 3-Benzyloxy-4- (4-ethyl-2-fluorobenzyl) -5-fluorobenzonitrile The compound obtained in Example 31d (940 mg, 3.41 mmol), sodium hydride (63%, 195 mg, 5.12 mmol), benzyl alcohol (0.46 mL, 4.47 mmol) and N, N-dimethylformamide (12 mL) were used in the same manner as in Example 7c to obtain the title compound (1.11 g) as a white solid. The purification was performed using silica gel flash chromatography (hexane: ethyl acetate 19: 1 to 10: 1, V / V).

Example 31f 3-Benzyloxy-4- (4-ethyl-2-fluorobenzyl) -5-fluorobenzoic acid The compound obtained in Example 31e (1.11 g, 3.05 mmol), 5M aqueous sodium hydroxide solution ( The crude product (1.01 g) of the title compound was obtained in the same manner as in Example 7d using 3.37 mL, 16.8 mmol) and ethanol (10 mL).

Example 31g 4- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5-hydroxybenzoic acid Crude product obtained in Example 31f (1.01 g, 2.64 mmol), 10% palladium on carbon catalyst (Water content, 300 mg), tetrahydrofuran (10 mL), methanol (10 mL) and hydrogen were used in the same manner as in Example 7e to obtain a crude product of the title compound (806 mg).

Example 31h 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenol Crude product obtained in Example 31g (806 mg, 2.76 mmol), lithium aluminum hydride (342 mg, 9.0 mmol) and tetrahydrofuran (10 mL) were used in the same manner as in Example 7f to obtain a crude product (827 mg) of the title compound.

(Example 31i) 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5-hydroxybenzyl acetate The crude product obtained in Example 31h (827 mg, 2.97 mmol), bis (dibutyltin chloride) The title compound (871 mg) was obtained in the same manner as in Example 7g using oxide (164 mg, 0.30 mmol), vinyl acetate (10 mL) and tetrahydrofuran (10 mL).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.6 Hz), 2.11 (3H, s), 2.60 (2H, q, J = 7.4 Hz), 3.97 (2H, s), 5.01 (2H, s), 5.38 (1H, brs), 6.64 (1H, s), 6.69 (1H, d, J = 9.4 Hz), 6.88-6.90 (2H, m), 7.06 (1H, t, J = 8.0 Hz).

Example 31j 5-Acetoxymethyl-2- (4-ethyl-2-fluorobenzyl) -3-fluorophenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-β -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-α, β-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) 2.5 g, 4.08 mmol), methylene chloride (20 mL), trichloroacetonitrile (1.2 mL, 12.2 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (61 μL, 0.41 mmol) and Example 1h In the same manner, imidate was prepared.

As in Example 1h, using the compound obtained in Example 31i (870 mg, 2.7 mmol), imidate (4.1 mmol), methylene chloride (30 mL) and boron trifluoride-diethyl ether complex (0.38 mL, 3.0 mmol). In this way, a crude product of the title compound was obtained.

Example 31k 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside obtained in Example 31j Using the crude product, methanol / methylene chloride (16 mL / 4 mL) and sodium methoxide (162.1 mg, 3.0 mmol), a crude product of the title compound was obtained in the same manner as in Example 2h. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 1: 1 to methylene chloride: methanol, 10: 1, V / V) to give the title compound (829.5 mg). .
¹ H NMR (400 MHz, CD ₃ OD): δ 1.18 (3H, t, J = 7.5 Hz), 1.19 (3H, d, J = 6.6 Hz), 2.58 (2H, q, J = 7.4 Hz), 3.33 -3.36 (2H, m), 3.43-3.45 (2H, m), 3.99-4.09 (2H, m), 4.57 (2H, s), 4.93-4.95 (1H, m), 6.79-6.87 (3H, m) , 6.97 (1H, d, J = 7.8 Hz), 7.00 (1H, s);
MS (FAB) m / z: 477 (M + Na) ^+.

(Test Example 1) Measurement of SGLT1 inhibitory activity using human SGLT1-expressing cells 1) Preparation of animal cell expression vector for human SGLT1 cDNA Human SGLT1 cDNA clone (Origene Clone Number: TC119918; GenBank accession number: NM_000343) Amplification was performed using PCR as a template. As a sense oligonucleotide primer for PCR
5'-ttaagcttaccatggacagtagcacctggagccc-3 '(Primer 1: SEQ ID NO: 1 in the sequence listing),
As an antisense oligonucleotide primer,
5'-ttctcgagtcaggcaaaatatgcatggcaa-3 '(Primer 2: SEQ ID NO: 2 in the sequence listing)
Was used. After agarose electrophoresis of the PCR reaction product, the target DNA fragment is recovered from a single band corresponding to 2013 bases, cleaved with restriction enzymes HindIII and XhoI, and then placed on the HindIII / XhoI site of the vector pCMV-Script (Stratagene). The SGLT1 expression plasmid pCMV-SGLT1 was introduced. A HindIII / XhoI fragment was excised from pCMV-SGLT1 and introduced into the BamHI / XhoI site of pENTR1A (Gateway, Invitrogen) to create pENTR-SGLT1. SGLT1-expressing retroviral vector pLPCX-SGLT1 was prepared using the retroviral vector pLPCX (Clontech) into which Gateway Vector Conversion System Cassette A (Invitrogen) was introduced as the destination plasmid.

2) Establishment of human SGLT1-expressing cells The retrovirus pLPCX-SGLT1 obtained in 1) was transfected into integrin αvβ3-expressing HEK-293 cells, followed by antibiotic G418 (trade name: Geneticin, manufactured by Invitrogen), puromycin ( The cells were treated with Clontech), and stable expression cells HEK-SGLT1 of the target vector having resistance were obtained. Culture and maintenance of stably expressing cells were performed using DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin, 3 mM KGT-1075, 10% FBS.

3) Measurement of SGLT1 inhibitory activity HEK-SGLT1 cells were suspended in DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin and 10% FBS at a density of 10 ⁶ cells / ml, and a 96-well culture plate coated with type I collagen ( 100 μl was seeded in each well of Corning). On the next day, change the medium to a sugar uptake buffer (10 mM HEPES (pH 7.5), 5 mM Tris-HCl (pH 7.5), 140 mM NaCl, 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ ), 1 mM [ ¹⁴ C] -α Incubate with -methyl-D-glucopyranoside (0.1m Ci) and evaluation compound for 30 minutes at 37 ° C, then wash buffer (10mM HEPES (pH7.5), 5mM Tris-HCl (pH7.5), 140mM Choline Chloride, 2mM KCl , 1 mM CaCl ₂ , 1 mM MgCl ₂ ). Add 100 μl of liquid scintillation cocktail (trade name: Supermix, manufactured by Perkin Elmer) to each well of a 96-well plate, stir for 10 minutes, and then radiate with micro β (produced by PerkinElmer), a type of liquid scintillation counter. Activity was measured. The value obtained by subtracting from each measured value with the radioactivity in the presence of an excessive amount of SGLT1 inhibitor as the background is the sugar uptake activity, and the control sugar uptake activity obtained without using the test compound and the test compound at a certain concentration are used. The inhibition rate (%) was determined from the sugar uptake activity at the time of the test, and the concentration of the test compound inhibiting the sugar uptake activity by 50% was examined. The results are shown in Table 2. From the results shown below, the compound of the present invention showed excellent SGLT1 inhibitory activity.

(Test Example 2) Measurement of SGLT2 inhibitory activity using human SGLT2-expressing cells 1) Preparation of human SGLT2 cDNA into animal cell expression vector cDNA clone of human SGLT2 (Origene Clone Number: TC303267; GenBank accession number: NM_003041) Was amplified using the PCR method. As a sense oligonucleotide primer for PCR
5'-ttaagcttaccatggaggagcacacagaggcagg-3 '(Primer 3: SEQ ID NO: 3 in the sequence listing),
As an antisense oligonucleotide primer,
5'-ttctcgagttaggcatagaagccccagagg-3 '(Primer 4: SEQ ID NO: 4 in the sequence listing)
Was used. After agarose electrophoresis of the PCR reaction product, the target DNA fragment is recovered from a single band corresponding to 2037 bases, cleaved with restriction enzymes HindIII and XhoI, and then placed on the HindIII / XhoI site of the vector pCMV-Script (Stratagene). Introduced. This was designated as SGLT2 expression plasmid pCMV-SGLT2. A HindIII / XhoI fragment was excised from pCMV-SGLT2 and introduced into the BamHI / XhoI site of pENTR1A (Gateway, Invitrogen) to create pENTR-SGLT2. SGLT2-expressing retrovirus vector pLPCX-SGLT2 was prepared using the retrovirus vector pLPCX (Clontech) into which Gateway Vector Conversion System Cassette A (Invitrogen) was introduced as a destination plasmid.

2) Establishment of human SGLT2-expressing cells The retrovirus pLPCX-SGLT2 obtained in 1) was transfected into integrin αvβ3-expressing HEK-293 cells, followed by antibiotic G418 (trade name: Geneticin, manufactured by Invitrogen), puromycin ( The cells were treated with Clontech), and stable expression cells HEK-SGLT2 of the target vector having resistance were obtained. Culture and maintenance of stably expressing cells were performed using DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin, 3 mM KGT-1075, 10% FBS.

3) Measurement of SGLT2 inhibitory activity HEK-SGLT2 cells were suspended in DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin and 10% FBS at a density of 10 ⁶ cells / ml, and a 96-well culture plate coated with type I collagen ( 100 μl was seeded in each well of Corning). On the next day, change the medium to a sugar uptake buffer (10 mM HEPES (pH 7.5), 5 mM Tris-HCl (pH 7.5), 140 mM NaCl, 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ ), 1 mM [ ¹⁴ C] -α Incubate with -methyl-D-glucopyranoside (0.1m Ci) and evaluation compound for 30 minutes at 37 ° C, then wash buffer (10mM HEPES (pH7.5), 5mM Tris-HCl (pH7.5), 140mM Choline Chloride, 2mM KCl , 1 mM CaCl ₂ , 1 mM MgCl ₂ ). Add 100 μl of liquid scintillation cocktail (trade name: Supermix, manufactured by Perkin Elmer) to each well of a 96-well plate, stir for 10 minutes, and then radiate with micro β (manufactured by Perkin Elmer), a type of liquid scintillation counter. Activity was measured. The value obtained by subtracting from each measured value with the radioactivity in the presence of an excessive amount of SGLT2 inhibitory compound as the background is the sugar uptake activity, and the control sugar uptake activity obtained without using the test compound and the test compound at a certain concentration are used. The inhibition rate (%) was determined from the sugar uptake activity at the time of the test, and the concentration of the test compound that inhibits the sugar uptake activity by 50% was examined. The results are shown in Table 3. From the results shown below, the compound of the present invention showed excellent SGLT2 inhibitory activity.

(Test Example 3) In vivo test Each test compound is suspended or dissolved in a solvent (0.5% methylcellulose solution) to a dose of 10 mL / kg, and multiple doses (preferably in the range of 0.03 to 10 mg / kg). (Included) is orally administered to C57BL / 6NCrlCrlj mice (7-10 weeks old, male) fasted overnight. In the control group, the solvent is orally administered at 10 mL / kg. 10 minutes after administration, glucose is orally administered at 2 g / 10 mL / kg. The blood glucose level was measured over time (before glucose administration, 20, 40, 60, 120 minutes after administration), the area under the curve of the blood glucose level was calculated, and the rate of decrease in the area under the blood glucose level curve for each group from the control group The efficacy of each test compound in the living body is evaluated by obtaining a 50% effective dose ED50 by using as an index.

(Formulation example) Tablet After mixing 5 g of the compound of the example, lactose 90 g, corn starch 34 g, crystalline cellulose 20 g and magnesium stearate 1 g with a blender, the tablet is obtained by tableting with a tableting machine.

The compound of the present invention or a hydrate thereof exhibits excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects, type 1 diabetes, type 2 diabetes, gestational diabetes, other factors, hyperglycemia, glucose intolerance ( impaired glucose tolerance (IGT), diabetes related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteries Sclerosis, hyperuricemia, gout, etc.) or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) It is useful as a pharmaceutical composition for the prevention or treatment of mammals (eg, humans, horses, cows or pigs, preferably humans).

SEQ ID NO: 1: PCR sense primer for human SGLT1 SEQ ID NO: 2: PCR antisense primer for human SGLT1 SEQ ID NO: 3: PCR sense primer for human SGLT2 SEQ ID NO: 4: PCR antisense primer for human SGLT2

Claims

Formula (I):

(Wherein R 1 is a hydrogen atom or a hydroxyl group,
R 2 is a fluorine atom or a chlorine atom,
R 3 is a methyl group optionally substituted with a halogen atom, an ethyl group optionally substituted with a halogen atom, a cyclopropyl group, or a methoxy group optionally substituted with a halogen atom;
R 4 is a hydrogen atom or a methyl group,
n is 1 or 2,
m is 0 or 1;
(However, when R 1 is a hydrogen atom, R 4 is a hydrogen atom, and when R 1 is a hydroxyl group, R 4 is a methyl group.)
Or a hydrate thereof.
General formula (II):

[Wherein R 1 is a hydrogen atom or a hydroxyl group;
R 2 is a fluorine atom or a chlorine atom,
R 3 is a methyl group optionally substituted with a halogen atom, an ethyl group optionally substituted with a halogen atom, a cyclopropyl group, or a methoxy group optionally substituted with a halogen atom;
R 4 is a hydrogen atom or a methyl group,
n is 1 or 2,
m is 0 or 1;
However, when R 1 is a hydrogen atom, R 4 is a hydrogen atom, and when R 1 is a hydroxyl group, R 4 is a methyl group (provided that (I) R 1 is a hydroxyl group and R 2 is When it is a fluorine atom, m is 0 and n is 1, R 3 is not a methyl group, an ethyl group, a cyclopropyl group or a methoxy group;
(B) when R 1 is a hydroxyl group, R 2 is a chlorine atom, m is 0, and n is 1, R 3 is not a methoxy group, or
(C) When R 1 is a hydrogen atom, R 2 is a fluorine atom or a chlorine atom, m is 0, and n is 1, R 3 is not a methoxy group)]
Or a hydrate thereof.
The compound according to claim 2, wherein R 1 is a hydroxyl group.
The compound according to claim 2 or 3, wherein R 3 is a methyl group which may be substituted with a halogen atom or a methoxy group which may be substituted with a halogen atom.
The compound according to any one of claims 2 to 4, wherein R 4 is a methyl group.
The compound according to any one of claims 2 to 5, wherein n is 1.
3-chloro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
2- [4- (difluoromethoxy) benzyl] -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-2- (2-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- [4- (difluoromethoxy) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-5-hydroxymethyl-2-[(4-trifluoromethoxy) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside;
3-chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy-β-D-glucopyranoside;
2- (4-ethylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside;
3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside;
2- (4-cyclopropylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy-β-D-glucopyranoside;
3-fluoro-5-hydroxymethyl-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- (4-ethyl-3-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-5- (2-hydroxyethyl) -2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-5- (hydroxymethyl) -2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- (4-ethyl-2-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-5- (hydroxymethyl) -2-[(4-trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-5- (hydroxymethyl) -2-[(4-trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
2- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-chloro-2- [4- (2,2-difluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside;
3-fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside; and
A compound selected from the group consisting of 2- (4-ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero-β-D-gluco-heptopyranoside or water thereof Japanese products.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a hydrate thereof as an active ingredient.
The pharmaceutical composition according to claim 8, which inhibits human SGLT1 and / or human SGLT2 activity.
The pharmaceutical composition according to claim 8 or 9, for the treatment or prevention of type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes-related diseases or diabetic complications.
Diabetes-related diseases are obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia or 11. The pharmaceutical composition according to claim 10, wherein the composition is gout or the diabetic complication is retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection or ketosis.
Use of the compound or hydrate thereof according to any one of claims 1 to 7 for producing a pharmaceutical composition.
A method for inhibiting human SGLT1 and / or human SGLT2 activity, comprising administering to a mammal a therapeutically effective amount of the compound or hydrate thereof according to any one of claims 1 to 7.
A method for treating or preventing a disease, comprising administering to a mammal a therapeutically effective amount of the compound or hydrate thereof according to any one of claims 1 to 7.
15. The method according to claim 14, wherein the mammal is a human.