WO2013151033A1 - C-glycoside derivative having a spiro ring - Google Patents

Abstract

A compound or pharmaceutically acceptable salt thereof represented by general formula (I) providing a compound or pharmaceutically acceptable salt thereof having a novel structure, low adverse effects, and excellent human SGLT1 and/or SGLT2 inhibiting activity and a pharmaceutical composition for treating and/or preventing diabetes and the like containing these as an active ingredient.

Description

C-glycoside derivatives with spiro ring

The present invention relates to a compound having an SGLT activity inhibitory action or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these as active ingredients.

Research and development of a drug with a new mechanism that increases glucose excretion in urine and lowers blood glucose level by inhibiting glucose reabsorption in the kidney (see Non-Patent Document 1, etc.). 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 to reduce blood glucose levels by suppressing and increasing sugar excretion outside the body (see Non-Patent Document 2, etc.). 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, an anti-obesity effect is expected by reducing excessive energy accumulation by increasing sugar excretion.

On the other hand, SGLT1, another subtype of SGLT (Sodium-dependent glucose cotransporter 1), is expressed in the small intestine and absorbs sugar (glucose, galactose, etc.) from food into the body. (See Non-Patent Document 3 etc.). It is known that a sugar deficiency occurs in humans who are naturally deficient in SGLT1 (see Non-patent Document 4). Based on these findings, drugs that inhibit SGLT1 are thought to exhibit postprandial hyperglycemia suppression and anti-obesity effects by inhibiting and delaying the absorption of sugar from the small intestine. Furthermore, a transient influx of sugar after meal promotes insulin secretion, and it can be expected to correct hyperinsulinemia by correcting this.

On the other hand, by inhibiting SGLT1, secretion of gastrointestinal hormones such as GLP-1 and PYY is promoted when sugar flows into the lower gastrointestinal tract. As a result, anti-obesity action, pancreatic protection action, anti-diabetic action, fatty liver improving action and the like can be expected.

From the above, a drug that suppresses human SGLT1 and / or SGLT2 activity has both an action of increasing urinary glucose excretion and an action of inhibiting sugar absorption from the small intestine, and such drugs include type 1 and type 2 diabetes, obesity, It is expected to be an effective drug for various related diseases accompanying hyperglycemia, hyperinsulinemia, fatty liver and the like. Examples of such drugs include compounds disclosed in Patent Documents 1 to 7, Non-Patent Document 5, and the like.

WO2006 / 011502 WO2006 / 080421 WO2008 / 013277 WO2007 / 140191 WO2008 / 083200 WO2008 / 016132 WO2009 / 096503

None of the above documents describes or suggests the specific structure of the compound of the present invention.

Accordingly, the present invention contains a compound or a pharmaceutically acceptable salt thereof having a novel structure, low side effects and excellent human SGLT1 and / or SGLT2 inhibitory activity, and an active ingredient thereof. Type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, impaired glucose tolerance (IGT), diabetes related diseases (obesity, hyperlipidemia, hypercholesterolemia, abnormal lipid metabolism) , Hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc. or diabetic complications (retinopathy, nephropathy, neuropathy, cataract, foot An object is to provide a pharmaceutical composition for treating and / or preventing gangrene, infection, ketosis and the like.

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

Wherein R ¹ is a methyl or ethyl group,
R ² is a chlorine atom, a bromine atom, a C1-C3 alkyl group or a hydroxy C1-C3 alkyl group,
Ring A may have one or two substituents selected from substituent group α, wherein:

A ring selected from the group consisting of
Substituent group α is a halogen atom, C1-C3 alkyl group, C1-C3 alkoxy group, hydroxy C1-C3 alkyl group, hydroxy C1-C3 alkoxy group or mono (C1-C3 alkyl) amino group)
Or a pharmaceutically acceptable salt thereof,
(2) The monovalent group of ring A may have one or two substituents selected from substituent group α, the following:

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is one group selected from the group consisting of:
(3) The monovalent group of ring A may have one or two substituents selected from substituent group α.

The compound or a pharmaceutically acceptable salt thereof according to the above (1),
(4) The compound according to any one of (1) to (3) above, wherein R ¹ is a methyl group, or a pharmaceutically acceptable salt thereof,
(5) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R ² is a methyl group, a chlorine atom or a hydroxymethyl group,
(6) The following:
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1 -Hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6- (2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6- (1-Benzofuran-5-ylmethyl) -5-chloro-6 '-[(1R) -1-hydroxyethyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6- (4-Ethylbenzyl) -6 '-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6- (4-Ethoxybenzyl) -6 '-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6- (2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (3,4-dihydro-2H-chromen-7-ylmethyl) -6 '-[(1R) -1-hydroxyethyl ] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran-3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1 -Hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [4- (3-hydroxypropyl) benzyl] -3' , 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [3- (3-hydroxypropyl) benzyl] -3' , 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6- [4- (2-hydroxyethoxy) benzyl] -6 '-[(1R) -1-hydroxyethyl] -5-methyl-3' , 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [4- (methylamino) benzyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -6 '-[(1R) -1-hydroxyethyl] -5-methyl-6- [4- (methylamino) benzyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- (1,2,3,4-tetrahydroquinoline-6- Ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (3,4-dihydro-2H-1,4-benzoxazin-7-ylmethyl) -6 '-[(1R)- 1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6-{[6- (methylamino) pyridin-3-yl] Methyl} -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [3- (methylamino) benzyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [3-methyl-4- (methylamino) benzyl]- 3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1H-indol-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl ] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1H-indol-5-ylmethyl) -6 '-[(1R) -1-hydroxyethyl ] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6-[(5-methoxypyridin-2-yl) methyl]- 3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol, and
(1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6-[(6-methoxypyridin-2-yl) methyl]- 3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof,
(7) A pharmaceutical composition comprising the compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient,
(8) The pharmaceutical composition according to the above (7) for treating type 1 diabetes, type 2 diabetes or obesity,
(9) Use of the compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition,
(10) A method for treating a disease, comprising administering the compound according to any one of (1) to (6) above or a pharmaceutically acceptable salt thereof to a mammal, and
(11) The method according to (10) above, wherein the mammal is human.
I will provide a.

According to the present invention, a compound or a pharmaceutically acceptable salt thereof having low side effects and having excellent human SGLT1 and / or SGLT2 inhibitory activity, and a pharmaceutical composition containing them as an active ingredient, Type 1 diabetes, Type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, IGT, diabetes related diseases (obesity, hyperlipidemia, hypercholesterolemia, lipid metabolism disorder, hypertension, fatty liver, metabolic syndrome, Treatment of edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or diabetic complications (retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) And / or can be prevented.

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

In this specification, the “C1-C3 alkyl group” means a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group.

In the present specification, the “hydroxy C1-C3 alkyl group” refers to a group in which one hydrogen atom of the “C1-C3 alkyl group” is substituted with a hydroxy group. Specific examples include hydroxymethyl group, hydroxyethyl group, 2-hydroxyethyl group, hydroxypropyl group and the like.

In the present specification, the “C1-C3 alkoxy group” means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a cyclopropyloxy group.

In the present specification, the “hydroxy C1-C3 alkoxy group” refers to a group in which one hydrogen atom of the “C1-C3 alkoxy group” is substituted with a hydroxy group. Specific examples include hydroxymethoxy group, hydroxyethoxy group, hydroxypropoxy group, hydroxycyclopropyl group and the like.

In this specification, “mono or di (C1-C3 alkyl) amino group” refers to a group in which one or two hydrogen atoms of an amino group are substituted with the above-mentioned “C1-C3 alkyl group”. Examples of the mono (C1-C3 alkyl) amino group include a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group. Examples of the di (C1-C3 alkyl) amino group include a dimethylamino group and a diethylamino group. N-ethyl-N-methylamino group, dipropylamino group and the like.

In the present specification, the “pharmaceutically acceptable salt” refers to a salt formed by reacting the compound of the present invention with an acid.

Salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate Methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonates such as ethanesulfonate; arylsulfonates such as benzenesulfonate, p-toluenesulfonate; acetate, malate, fumarate And organic acid salts such as acid salts, succinates, citrates, ascorbates, tartrate, oxalates and maleates.

The compound of the present invention may absorb water and become a hydrate when left in the air, for example, and such a hydrate is also included in the salt of the present invention.

Since the compound of the present invention may have an asymmetric carbon atom in its molecule, a stereoisomer exists. These stereoisomers and mixtures of stereoisomers are all represented by a single formula, that is, general formula (I). Accordingly, the present invention includes all of these stereoisomers and a mixture of these stereoisomers in an arbitrary ratio. The definition of stereoisomers is as shown in "1996 IUPAC, Pure and Applied" Chemistry 68, 2193-2222.

The present invention can also include a compound in which one or more atoms of the compound represented by the general formula (I) are substituted with an isotope of the atom. There are two types of isotopes: radioactive isotopes and stable isotopes. Examples of isotopes include hydrogen isotopes ( ² H and ³ H), carbon isotopes ( ¹¹ C, ¹³ C and ¹⁴ C ), Nitrogen isotopes ( ¹³ N and ¹⁵ N), oxygen isotopes ( ¹⁵ O, ¹⁷ O and ¹⁸ O), fluorine isotopes ( ¹⁸ F) and the like. Compositions containing isotope-labeled compounds are useful as therapeutic agents, prophylactic agents, research reagents, assay reagents, diagnostic agents, in vivo diagnostic imaging agents, and the like. All isotope-labeled compounds and mixtures of isotope-labeled compounds in any proportion are also encompassed by the invention. An isotope-labeled compound can be produced by a method known in the art (for example, using an isotope-labeled raw material instead of the raw material in the method for producing the compound of the present invention described later).

The present invention can also include a prodrug of the compound represented by the general formula (I). The prodrug is a derivative of the compound represented by the general formula (I) and refers to a compound that is converted in vivo to an enzyme or a chemical compound of the present invention.

Prodrugs include compounds in which the amino group in the molecule is acylated, alkylated or phosphorylated, compounds in which the hydroxy group in the molecule is acylated, alkylated or phosphorylated (for example, PovlP Krogsgaard- Larsen et al., “A Textbook of Drug Design and Development, 2nd edition, harwood academic publishers, 1996, pp. 351-385). Such a prodrug can be produced from the compound represented by the general formula (I) by a method known in the art.

R ¹ is preferably a methyl group.

R ² is preferably a chlorine atom, a methyl group or a hydroxymethyl group.

The monovalent group of ring A may preferably have one or two substituents selected from substituent group α, the following:

One group selected from the group consisting of, and more preferably, may have one substituent selected from the substituent group α.

It is.

The substituent group α is preferably a hydroxypropyl group, a hydroxyethoxy group, an ethyl group or a monomethylamino group.

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

In method A, the target compound of each reaction can be collected from the reaction mixture by using a method known in the art after completion of each reaction. For example, after neutralizing the reaction mixture as appropriate, or if insoluble matter is present in the reaction mixture, the insoluble matter is removed from the reaction mixture by filtration, and then water and an organic matter that is not miscible with water, such as ethyl acetate. A solvent is added to the reaction mixture, an organic layer containing the target compound is separated, washed with water and the like, dried over anhydrous sodium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained compound can be separated and purified by a method known in the art, for example, silica gel column chromatography.

Furthermore, in the method A, when the compound serving as a reaction substrate has a group that inhibits the target reaction such as an amino group, a hydroxyl group, or a carboxyl group, introduction and introduction of a protective group to those groups as necessary. Removal of the protecting group may be performed. The protecting group is not particularly limited as long as it is a commonly used protecting group, and is described in THGreene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. Groups. Such protective group introduction reaction and removal reaction can be carried out according to the methods described in the above-mentioned literature.

Wherein R ¹ , R ² and ring A are as defined above, X ¹ is a halogen atom or R ² , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ Are the same or different and each is a protecting group)

Step A1 is a step of producing compound (3) by adding (2) lithiated with alkyllithium (such as n-butyllithium) to (1) in an inert solvent.

Examples of the inert solvent include aromatic hydrocarbons, ethers, etc., preferably tetrahydrofuran (hereinafter sometimes referred to as “THF”) or a mixed solvent of toluene and THF in any ratio. . The mixing ratio of the solvent is preferably toluene: THF = 1: 1 to 2: 1 as a volume ratio.

The reaction temperature is -78 ° C to 0 ° C, although it varies depending on the raw material compound and inert solvent.

The reaction time varies depending on the starting compound, inert solvent, reaction temperature, etc., but the lithiation step is 15 minutes to 2 hours, the subsequent addition reaction is 1 hour to 3 hours, more preferably 20 minutes to 40 minutes, 1 Hours to 1 and a half hours.

Step A2 is a step for producing compound (4) by removing R ¹⁵ and R ¹⁶ in compound (3) in a mixed solvent of an inert solvent and an alcohol in the presence of an acid and cyclization.

Examples of the inert solvent include hydrocarbons and ethers, preferably THF. The alcohol is preferably methanol. The mixing ratio of the solvent is preferably an inert solvent: alcohols = about 1: about 1 in volume ratio.

Examples of the acid include hydrochloric acid, sulfuric acid, and sulfonic acids, and p-toluenesulfonic acid monohydrate is preferable.

The reaction temperature varies depending on the raw material compound, reaction solvent and the like, but is 40 ° C. to reflux temperature, preferably about 60 ° C.

The reaction time varies depending on the raw material compound, reaction solvent, reaction temperature, etc., but is 30 minutes to 6 hours, preferably 2 hours to 3 hours.

Step A3 is a step for producing compound (5) by introducing a protecting group into compound (4) in an inert solvent.

The protecting group is not particularly limited as long as it is a commonly used protecting group, and is preferably a methoxymethyl group.

The introduction of protecting groups varies depending on the type, but is described in methods known in the art, for example, THGreene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, 年 John Wiley & Sons, Inc. Can be done according to the method.

Step A4 is a step for producing compound (6) by condensing compound (5) and alkylboric acid (such as methylboric anhydride) in an inert solvent in the presence of a transition metal catalyst and a base.

Examples of the inert solvent include aromatic hydrocarbons, ethers, hydrous alcohols, and the like, preferably 1,4-dioxane.

Examples of the transition metal catalyst include a palladium complex, and tetrakis (triphenisphosphine) palladium (0) or palladium (II) acetate is preferable.

Examples of the base include inorganic bases, and although it varies depending on the raw material compound, potassium carbonate or sodium carbonate is preferred.

The reaction temperature varies depending on the raw material compound, reaction solvent, etc., but is 80 ° C. to reflux temperature, preferably 100 ° C. to 110 ° C.

The reaction time varies depending on the raw material compound, the reaction solvent, the reaction temperature, etc., but is 1 hour to 9 hours, more preferably 2 hours to 4 hours.

Step A5 is a step for producing compound (7) by removing R ¹⁷ in compound (6) in an inert solvent.

Examples of the inert solvent include alcohols and ethers, and a mixed solvent of methanol and 1,4-dioxane is preferable.

Protecting group can be introduced according to the same method as described above.

For example, when R ¹⁷ is a methoxymethyl group, it can be carried out by reacting a hydrogen chloride solution at room temperature in a mixed solvent of methanol and 1,4-dioxane.

Step A6 is a step of producing compound (8) by bromine substitution of the hydroxyl group of compound (7) in an inert solvent.

Examples of the brominating agent include carbon tetrabromide in the presence of triphenylphosphine, N-bromosuccinimide, etc., preferably carbon tetrabromide in the presence of triphenylphosphine.

Examples of the inert solvent include halogenated hydrocarbons, preferably methylene chloride.

Step A7 comprises condensing compound (9) by condensing compound (7) and arylboric acids (such as 1,4-benzodioxan-6-boric acid) in the presence of a transition metal catalyst and a base in an inert solvent. It is a manufacturing process.

Examples of the inert solvent include aromatic hydrocarbons, ethers, hydrous alcohols, and the like, and preferably a toluene-ethanol-water mixed solvent.

Examples of the transition metal catalyst include a palladium complex, and tetrakis (triphenisphosphine) palladium (0) is preferable.

Examples of the base include inorganic bases, and sodium carbonate is preferable.

The reaction temperature varies depending on the raw material compound, reaction solvent, etc., but is 80 ° C. to reflux temperature, preferably about 100 ° C.

The reaction time varies depending on the raw material compound, reaction solvent, reaction temperature, etc., but is 30 minutes to 9 hours, preferably 1 hour to 2 hours.

Step A8 is a step for producing compound (I) by removing R ¹¹ , R ¹² , R ¹³ and R ¹⁴ in compound (9) in an inert solvent.

The removal of the protecting group can be performed, for example, according to the method described in the literature shown in the step A3.

For example, when R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are benzyl groups, the protecting group is removed from compound (9) by the action of hydrogen in the presence of a palladium carbon catalyst in a mixed solvent of methanol and THF. can do. In this case, for example, by adding an additive such as 1,2-dichlorobenzene, the reaction can be accelerated and side reactions can be suppressed.

Compound (1) as a raw material of Method A can be produced, for example, by the following Method B, and Compound (2) can be produced, for example, by the following Method C, or can be produced according to the method described in WO2008 / 016132 and the like.

(Wherein R ¹ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as defined above, and R ¹⁸ is a protecting group.)

Step B1 is a step for producing compound (11) by introducing R ¹⁸ into compound (10).

Protecting group may be introduced in the same manner as in step A3.

Step B2 is a step for producing compound (12) by reacting compound (10) with trichloroacetonitrile in the presence of a base in an inert solvent.

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

Examples of the base 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 -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 15 minutes to 48 hours, preferably 30 minutes to 5 hours.

Step B3 is a step of producing compound (11) by reacting compound (12) with an alcohol in the presence of a Lewis acid in an inert solvent.

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

Examples of Lewis acids include boron trifluoride-diethyl ether complex and trimethylsilyl trifluoromethanesulfonate, and boron trifluoride-diethyl ether complex is preferred.

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

Step B4 is a step of producing compound (13) by removing the benzoyl group of compound (11).

Removal of the benzoyl group can be carried out according to a method known in the art, for example, the method described in THGreene, WPGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. .

Step B5 is a step for producing compound (14) by introducing R ¹¹ , R ¹² , R ¹³ and R ¹⁴ into compound (13).

Protecting group may be introduced in the same manner as in step A3.

For example, when R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are benzyl groups, compound (13) is reacted with benzyl bromide, benzyl chloride, etc. in the presence of a base in an inert solvent to give compound (13) A protecting group can be introduced into the.

Examples of the inert solvent include amides and ethers, preferably amides, more preferably N, N-dimethylformamide.

Examples of the base include sodium hydride and alkali hydroxides, preferably sodium hydride. Moreover, reaction can also be accelerated | stimulated by adding additives, such as a tetrabutyl ammonium iodide.

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

The reaction time varies depending on the raw material compound, inert solvent, base, reaction temperature, etc., but is 15 minutes to 48 hours, preferably 30 minutes to 12 hours.

Step B6 is a step for producing compound (15) by removing R ¹⁸ in compound (14).

The removal of the protecting group can be performed according to the method described above.

For example, when R ¹⁸ is an allyl group, the allyl group is isomerized in the presence of a base in an inert solvent, and then an oxidizing agent such as N-iodosuccinimide in the presence of water in an inert solvent. R ¹⁸ can be removed from compound (14) by reacting the compound with compound (14).

Step B7 is a step of producing compound (1) by reacting compound (12) with an oxidizing agent in an inert solvent.

Examples of the inert solvent include halogenated hydrocarbons, preferably methylene chloride.

Examples of the oxidizing agent include dimethyl sulfoxide, chromic acid, Dess-Martin Periodinane (hereinafter sometimes referred to as “DMP”), and preferably DMP.

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

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

(Wherein X ¹ , R ¹⁵ and R ¹⁶ are as defined above, and R ¹⁹ and R ²⁰ are the same or different and each is a protecting group)

Step C1 is a step of producing compound (17) by reacting compound (16) with a reducing agent in an inert solvent.

Examples of the inert solvent include ethers and alcohols, preferably ethers, more preferably THF.

Examples of the reducing agent include alkali metal borohydrides such as lithium borohydride, aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum, and hydride reagents such as sodium tellurium hydride. When R ¹⁹ and R ²⁰ are methyl groups, lithium borohydride is preferred.

The reaction temperature varies depending on the raw material compound, reducing agent, inert solvent, etc., but is -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 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

Step C2 is a step for producing compound (2) by introducing R ¹⁵ and R ¹⁶ into compound (17).

Protecting group may be introduced in the same manner as in step A3.

The compound of the present invention can also be produced from a known compound with reference to Examples described later or methods well known in the art.

Since the compound of the present invention or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, IGT, obesity, diabetes-related diseases (Hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or diabetes It can be used as an active ingredient of a pharmaceutical composition that can be used for the treatment and / or prevention of diseases (retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.).

The compound of the present invention or a pharmaceutically acceptable salt thereof can also be used in combination with other therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, therapeutic agents for hypertension and the like.

A pharmaceutical composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof is systemically or locally when administered to a mammal (human, horse, cow, pig, etc., preferably human). And can be administered orally or parenterally.

The pharmaceutical composition of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.

Examples of the form of an oral pharmaceutical composition include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like. The pharmaceutical composition in such a form comprises excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants that are usually used as additives. , Coloring agents, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffers, diluents, wetting agents, and the like may be appropriately selected as necessary and produced according to conventional methods.

Examples of pharmaceutical compositions for parenteral use include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, etc. Can be mentioned. The pharmaceutical composition in such a form comprises a stabilizer, preservative, solubilizer, moisturizer, preservative, antioxidant, flavoring agent, gelling agent, neutralizing agent, buffer, Isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc. are selected as necessary and manufactured according to conventional methods. Can be done.

The dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, etc. In the case of oral administration, it is 1 to several times a day, once per adult, as a compound. The amount is 1 to 2000 mg, preferably 1 to 400 mg, and in the case of parenteral administration, it is 0.01 to 500 mg, preferably 0.1 to 300 mg in terms of compound per adult once or several times a day. .

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the scope of the present invention is not limited thereto.

The following abbreviations may be used in the following reference examples and examples.
Bn: benzyl group
Bz: Benzoyl group
Tf: trifluoromethanesulfonyl group
Ac: Acetyl group
Me: Methyl group
Et: Ethyl group
Boc: tert-butoxycarbonyl group

(Reference Example 1) 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycero-D-gluco-heptopyranolactone

(Reference Example 1a) Allyl 2,3,4,6-tetra-O-benzoyl-7-deoxy-D-glycero-D-gluco-heptopyranoside

2,3,4,6-Tetra-O-benzoyl-7-deoxy-D-glycero-α, β-D-gluco-heptopyranose (WO2008 / 016132) (30.0 g, 49.1 mmol) in methylene chloride (100 mL) And trichloroacetonitrile (15.0 mL, 150 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.25 mL, 1.68 mmol) were added at 15 ° C. The reaction solution was stirred at 15 ° C. for 2 hours, diluted with methylene chloride (200 mL), and washed successively with water (50 mL) and a saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Toluene (30 mL) was added to the resulting residue, and the solvent was evaporated under reduced pressure.

Dissolve the resulting residue in methylene chloride (200 mL), add allyl alcohol (6.9 mL, 101 mmol) under ice-cooling, and then gradually drop borane trifluoride diethyl ether complex (1.9 mL, 15.0 mmol) dropwise. did. The reaction solution was stirred for 15 minutes under ice-cooling, and further stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was ice-cooled again, and triethylamine (2.8 mL, 20 mmol) was added to the reaction solution. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ice-cooled methylene chloride (100 mL) was added to the resulting residue, and the precipitate (ca. 5 g) was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 70: 30 (concentration gradient) V / V) to obtain the title compound (27.0 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (3H, d, J = 6.6 Hz), 4.10-4.13 (1H, m), 4.18-4.24 (1H, m), 4.36-4.41 (1H, m) , 4.87 (1H, d, J = 7.8Hz), 5.10-5.15 (1H, m), 5.19-5.24 (1H, m), 5.33-5.39 (1H, m), 5.54 (1H, dd, J = 9.8Hz , 8.2Hz), 5.59 (1H, t, J = 9.8Hz), 5.79-5.88 (1H, m), 5.89 (1H, t, J = 7.6Hz), 7.26-7.57 (12H, m), 7.81-7.84 (2H, m), 7.90-7.93 (2H, m), 7.95-7.98 (2H, m), 8.02-8.04 (2H, m).

(Reference Example 1b) Allyl 7-deoxy-D-glycero-D-gluco-heptopyranoside

The compound obtained in Reference Example 1a (27.0 g, 41.5 mmol) was dissolved in a mixed solvent of methylene chloride (84 mL) and methanol (336 mL), and potassium carbonate (47.0 g, 0.34 mol) was added at room temperature. . The reaction mixture was stirred for 4 hours and a half, filtered to remove insoluble matters, and acetic acid (30 mL) was added to the filtrate. The solvent was distilled off under reduced pressure, and the insoluble material was filtered off. Subsequently, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 99: 1 → 85: 15 (concentration gradient) V / V) to obtain the title compound (9.2 g).

(Reference Example 1c) Allyl 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycero-D-gluco-heptopyranoside

The compound (12.1 g, 51.6 mmol) obtained in Reference Example 1b was dissolved in N, N-dimethylformamide (250 mL), and sodium hydride (oil, 63% w / w, 8.3 g, 0.23) was cooled with ice. mol) was added slowly. Under ice-cooling, benzyl bromide (27.3 mL, 0.23 mol) was added dropwise to this reaction solution, tetrabutylammonium iodide (0.96 g, 2.6 mmol) was added, and the mixture was stirred for 9 hours while warming to room temperature. The reaction mixture was allowed to stand at room temperature overnight, neutralized with a saturated aqueous ammonium chloride solution (200 mL), and diluted with ethyl acetate (250 mL). This was washed successively with 10% w / v saline (200 mL, twice) and saturated brine (50 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, 99: 1 → 80: 20 (concentration gradient) V / V) to obtain the title compound (27.2 g).
¹ H NMR (500 MHz, CDCl ₃ ): δ1.15 (3H, d, J = 6.4 Hz), 3.39-3.47 (2H, m), 3.53 (1H, d, J = 9.8 Hz), 3.64-3.68 (1H , m), 3.83 (1H, dd, J = 12.9Hz, 6.6Hz), 4.10-4.17 (1H, m), 4.42-4.45 (2H, m), 4.56-4.59 (1H, m), 4.59 (2H, s), 4.72 (1H, d, J = 10.8Hz), 4.77 (1H, d, J = 10.7Hz), 4.82 (1H, d, J = 10.7Hz), 4.95 (1H, d, J = 11.2Hz) , 4.97 (1H, d, J = 11.2Hz), 5.21 (1H, d, J = 10.3Hz), 5.34 (1H, d, J = 17.1Hz), 5.91-6.01 (1H, m), 7.14-7.15 ( 2H, m), 7.26-7.36 (18H, m).

Reference Example 1d 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycero-D-gluco-heptopyranose

The compound obtained in Reference Example 1c (27.2 g, 45.6 mmol) was dissolved in N, N-dimethylformamide (150 mL), and potassium tert-butoxide (15.3 g, 137 mmol) was gradually added at room temperature. The reaction mixture was heated to 80 ° C. and stirred for 4 and a half hours. After completion of the reaction, the reaction solution was cooled to room temperature and diluted with ethyl acetate (200 mL). This was washed successively with a saturated aqueous ammonium chloride solution (100 mL, twice), 10% w / v saline (150 mL, twice) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The obtained residue was dissolved in THF (120 mL) and water (30 mL), and N-iodosuccinimide (11.3 g, 50.2 mmol) was gradually added thereto at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, ethyl acetate (100 mL) was added thereto, and the mixture was washed successively with 10% w / v aqueous sodium thiosulfate solution (50 mL, twice) and saturated brine (50 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, 98: 2 → 75: 25 (concentration gradient) V / V) to obtain the title compound (21.3 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.14 (3H, d, J = 6.7Hz), 3.43-3.58 (3H, m), 3.68 (1H, t, J = 9.0Hz), 3.80-3.86 (1H , m), 4.56-4.63 (5H, m), 4.74 (1H, d, J = 10.6Hz), 4.79 (1H, d, J = 10.9Hz), 4.83 (1H, d, J = 11.0Hz), 4.95 (1H, d, J = 10.5Hz), 4.98 (1H, d, J = 10.6Hz), 6.27-6.30 (0H, m), 7.13-7.20 (3H, m), 7.25-7.40 (17H, m).

(Reference Example 1e) 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycero-D-gluco-heptopyranolactone

The compound (25.2 g, 45.4 mmol) obtained in Reference Example 1d was dissolved in methylene chloride (150 mL), and DMP (25.0 g, 59.0 mmol) was gradually added thereto under ice cooling. The reaction solution was stirred for 2 hours while gradually warming to room temperature. After the reaction was completed, a saturated aqueous sodium hydrogen carbonate solution (100 mL) and a 10% w / v aqueous sodium thiosulfate solution (50 mL) were added. The reaction mixture was stirred at room temperature for 30 minutes, filtered to remove insoluble materials, and the filtrate was diluted with ethyl acetate (150 mL). This was washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL, 2 times) and saturated brine (50 mL, 2 times). 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, 98: 2 → 80: 20 (concentration gradient) V / V) to obtain the title compound (19.7 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.20 (3H, d, J = 6.2 Hz), 2.36 (1H, s), 3.84-3.90 (1H, m), 3.92-3.98 (2H, m), 4.14 (1H, d, J = 7.4Hz), 4.43 (1H, d, J = 11.4Hz), 4.50 (1H, d, J = 11.7Hz), 4.55-4.60 (3H, m), 4.72 (1H, d, J = 11.4Hz), 4.76 (1H, d, J = 11.4Hz), 4.95 (1H, d, J = 11.4Hz), 7.16-7.38 (20H, m).

Reference Example 2 2-Bromo-1,4-bis [(methoxymethoxy) methyl] benzene

THF (60 mL) was added to 2-bromoterephthalic acid (5.00 g, 20.4 mmol), and a THF solution of a borane tetrahydrofuran complex (1.0 M, 51.0 mL, 51.0 mmol) was gradually added dropwise thereto. This reaction solution was stirred at 40 ° C. for 1 hour and a half. After the reaction was completed, the reaction solution was ice-cooled, and water (100 mL) was gradually added. To this reaction solution was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 2 times). 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 diol (4.30 g).

This diol was dissolved in methylene chloride (100 mL), and diisopropylethylamine (52.0 mL, 0.31 mol) and chloromethyl methyl ether (15.5 mL, 0.20 mol) were added to the solution under ice cooling. The reaction solution was stirred for 5 hours while gradually warming to room temperature, allowed to stand overnight, then saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction solution, and the solvent was distilled off to about half amount under reduced pressure. The concentrate was diluted with ethyl acetate (50 mL), and washed successively with water (30 mL), saturated aqueous ammonium chloride solution (50 mL, twice) and saturated brine (50 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, 95: 5 → 65: 35 (concentration gradient) V / V) to obtain the title compound (5.5 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ3.42 (3H, s), 3.44 (3H, s), 4.57 (2H, s), 4.67 (2H, s), 4.71 (2H, s), 4.77 (2H , s), 7.31 (1H, dd, J = 7.8Hz, 1.5 Hz), 7.47 (1H, d, J = 7.8Hz), 7.59 (1H, d, J = 1.5Hz).

Reference Example 3 1-Bromo-4-fluoro-2,5-bis [(methoxymethoxy) methyl] benzene

Using 2-bromo-4-fluorobenzyl alcohol (2.0 g, 10 mmol) as a starting material, a diol (1.16 g) was obtained according to the method described in the literature (EP2048153 (A1)), and the title was obtained in the same manner as in Reference Example 2. Compound (1.5 g) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ3.42 (3H, s), 3.43 (3H, s), 4.62 (2H, s), 4.62 (2H, s), 4.72 (2H, s), 4.77 (2H , s), 7.25 (1H, d, J = 10.5Hz), 7.61 (1H, d, J = 6.7Hz).

Reference Example 4 1-Bromo-4-chloro-2,5-bis [(methoxymethoxy) methyl] benzene

THF (150 mL) was added to diethyl 2-bromo-5-chloroterephthalate (9.2 g, 30.0 mmol), and lithium borohydride (10.9 g, 0.45 mol) was gradually added thereto under ice cooling. The reaction solution was stirred for 9 hours while gradually warming to room temperature, and then allowed to stand overnight. After completion of the reaction, the reaction solution was ice-cooled, and saturated aqueous ammonium chloride solution (150 mL) was added dropwise. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL, 3 times) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The obtained residue was dissolved in methylene chloride (100 mL), and diisopropylethylamine (77.0 mL, 0.45 mol) and chloromethyl methyl ether (23.0 mL, 0.30 mol) were added thereto under ice cooling. The reaction mixture was stirred for 3 hours while gradually warming to room temperature, and then allowed to stand overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (150 mL) and washed successively with saturated aqueous ammonium chloride solution (50 mL, 3 times) and saturated brine (50 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, 98: 2 → 75: 25 (concentration gradient) V / V) to obtain the title compound (6.4 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ3.43 (3H, s), 3.44 (3H, s), 4.62 (2H, s), 4.65 (2H, s), 4.76 (2H, s), 4.77 (2H , s), 7.51 (1H, s), 7.70 (1H, s).

(Reference Example 5) 1,4-dibromo-2,5-bis [(methoxymethoxy) methyl] benzene

To 2,5-dibromoterephthalic acid (15.4 g, 47.5 mmol) was added THF (200 mL). Under ice cooling, a THF solution of borane tetrahydrofuran complex (0.95 M, 200 mL, 0.19 mol) was gradually added dropwise. . The reaction solution was stirred for 3 hours while gradually warming to room temperature, and then allowed to stand overnight. Further, this reaction solution was stirred at 60 ° C. for 2 hours. After completion of the reaction, the reaction mixture was ice-cooled, water (100 mL) and 1M hydrochloric acid (500 mL) were added, and the mixture was stirred at room temperature for 1 hr. The precipitate in this reaction solution was filtered, and the precipitate was successively rinsed with water (50 mL) and diethyl ether (50 mL). The precipitate was dried at 40 ° C. under reduced pressure to obtain a diol (15.4 g).

This diol was dissolved in methylene chloride (150 mL), and diisopropylethylamine (121 mL, 0.71 mol) and chloromethyl methyl ether (36.0 mL, 0.48 mol) were added to the solution under ice cooling. The reaction solution was stirred for 5 hours while gradually warming to room temperature, water (100 mL) was added to the reaction solution, and the solvent was distilled off to about half amount under reduced pressure. Dilute the concentrate with ethyl acetate (150 mL), 10% w / v brine (100 mL), saturated aqueous sodium carbonate (50 mL, 1 time), saturated aqueous ammonium chloride (50 mL, 2 times) and The extract was washed successively with saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A mixed solvent of hexane (300 mL) and ethyl acetate (6 mL) was added to the resulting residue to obtain the title compound (14.5 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ3.44 (6H, s), 4.62 (4H, s), 4.77 (4H, s), 7.68 (2H, s).

Reference Example 6 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

(Reference Example 6a) {(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy ) Ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methanol

The compound obtained in Reference Example 4 (14.0 g, 41.1 mmol) was dissolved in THF (200 mL), and in a nitrogen atmosphere, n-butyllithium in hexane solution (1.59 M, 25.8 mL, 41.1 mmol) Was added dropwise over 15 minutes. After completion of the dropwise addition, the reaction solution was stirred at −78 ° C. for 45 minutes, and a solution of the compound obtained in Reference Example 1 (20.6 g, 37.4 mmol) in THF (50 mL) was added dropwise, and the mixture was further stirred for 1 hour. After completion of the reaction, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction solution, and the temperature was raised to room temperature.The reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated brine (50 mL, 2 times). . The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The obtained crude product (33.3 g) was dissolved in a mixed solvent of methanol (80 mL) and THF (80 mL), and p-toluenesulfonic acid monohydrate (21.3 g, 112 mmol) was reacted at room temperature. Added to. The reaction mixture was stirred at 60 ° C. for 3 hours under a nitrogen atmosphere, cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution (80 mL) was added. The reaction solution was concentrated to about half amount under reduced pressure. The concentrate was diluted with ethyl acetate (100 mL) and washed successively with saturated aqueous sodium carbonate solution (50 mL) and saturated brine (50 mL, 2 times). 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 column chromatography (hexane: ethyl acetate, 98: 2 → 70: 30 (concentration gradient) V / V). Purification gave the title compound (17.2 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.10 (3H, d, J = 6.6 Hz), 3.60 (1H, dd, J = 10.1 Hz, 9.0 Hz), 3.77-3.80 (1H, m), 3.83 ( 1H, d, J = 9.8Hz), 4.16-4.22 (2H, m), 4.27 (1H, d, J = 11.4Hz), 4.56 (2H, dd, J = 17.2Hz, 12.5Hz), 4.61-4.72 ( 4H, m), 4.91 (1H, d, J = 10.9Hz), 4.91 (1H, d, J = 10.9Hz), 4.98 (1H, d, J = 10.9Hz), 5.18 (2H, s), 6.82 ( 2H, d, J = 8.2Hz), 7.11-7.20 (6H, m), 7.25-7.35 (14H, m).

(Reference Example 6b) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

The compound obtained in Reference Example 6a was dissolved in methylene chloride (170 mL), and carbon tetrabromide (11.9 g, 36 mmol) and triphenylphosphine (9.5 g, 36 mmol) were added under ice cooling. The reaction solution was stirred under a nitrogen atmosphere under ice cooling for 2 hours, then warmed to room temperature and washed with water (100 mL, twice). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 80: 20 (concentration gradient) V / V). Purification gave the title compound (14.1 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.10 (3H, d, J = 6.7 Hz), 3.60 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.81 (2H, m), 4.15- 4.21 (4H, m), 4.46 (1H, d, J = 10.2Hz), 4.54-4.57 (2H, m), 4.62 (1H, d, J = 11.3Hz), 4.67 (1H, d, J = 11.0Hz) ), 4.90 (1H, d, J = 11.0Hz), 4.91 (1H, d, J = 10.8 Hz), 4.98 (1H, d, J = 10.8 Hz), 5.15 (2H, s), 6.83 (2H, d , J = 6.7Hz), 7.11-7.19 (6H, m), 7.26-7.35 (14H, m).

(Reference Example 7) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

(Reference Example 7a) {(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy ) Ethyl] -5-bromo-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methanol

The compound obtained in Reference Example 5 (20.0 g, 52.1 mmol) was dissolved in a mixed solvent of THF (200 mL) and toluene (200 mL), and a hexane solution of n-butyllithium at -78 C in a nitrogen atmosphere ( 1.59 M, 32.5 mL, 52.1 mmol) was added dropwise over 15 minutes. After completion of the addition, the reaction solution was stirred at −78 ° C. for 1 hour, and a solution of the compound obtained in Reference Example 1 (25.0 g, 46.4 mmol) in toluene (100 mL) was added dropwise. Further, the reaction solution was stirred at -78 ° C for 1 hour and a half, then heated to 0 ° C and stirred for 5 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, diluted with ethyl acetate (100 mL), and washed with saturated brine (50 mL, 2 times). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The obtained crude product was dissolved in a mixed solvent of methanol (150 mL) and THF (150 mL), and p-toluenesulfonic acid monohydrate (27.0 g, 142 mmol) was added at room temperature. The reaction solution was stirred at 60 ° C. for 2.5 hours under a nitrogen atmosphere, and then allowed to stand at room temperature overnight. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution (80 mL) was added, and the mixture was concentrated under reduced pressure to about half. This was diluted with ethyl acetate (100 mL), and washed successively with saturated aqueous sodium carbonate solution (50 mL) and saturated brine (50 mL, 2 times). 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 column chromatography (hexane: ethyl acetate, 98: 2 → 70: 30 (concentration gradient) V / V). Purification gave the title compound (22.0 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.10 (3H, d, J = 6.7 Hz), 3.60 (1H, dd, J = 10.2 Hz, 9.4 Hz), 3.75-3.80 (1H, m), 3.82 ( 1H, d, J = 6.6Hz), 4.15-4.22 (2H, m), 4.27 (1H, d, J = 11.3Hz), 4.55-4.71 (6H, m), 4.90 (1H, d, J = 11.0Hz) ), 4.91 (1H, d, J = 10.7 Hz), 4.97 (1H, d, J = 10.7 Hz), 5.17 (2H, s), 6.81 (2H, d, J = 7.1 Hz), 7.11-7.20 (6H , m), 7.28-7.43 (14H, m);
MS (ESI) m / z: 751 (M + H) ⁺ .

(Reference Example 7b) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-bromo-6-[(methoxymethoxy) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

The compound (6.18 g, 8.22 mmol) obtained in Reference Example 7a was dissolved in methylene chloride (41 mL), and diisopropylethylamine (14.0 mL, 82.3 mmol) and chloromethyl methyl ether (4.37 mL, 57.5 mmol) were dissolved at room temperature. added. The reaction solution was stirred at room temperature for 2 hours and a half under a nitrogen atmosphere, then cooled with ice, water (10 mL) was added, and the solvent was removed to about half the amount under reduced pressure. The obtained residue was diluted with ethyl acetate (60 mL), and washed successively with saturated aqueous ammonium chloride solution (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 80: 20 (concentration gradient) V / V). Purification gave the title compound (4.63 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.11 (3H, d, J = 6.6 Hz), 3.39 (3H, s), 3.63 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.83 ( 1H, m), 3.86 (1H, d, J = 9.4Hz), 4.14-4.22 (3H, m), 4.53-4.69 (7H, m), 4.72 (2H, s), 4.90 (2H, d, J = 10.2 Hz), 4.97 (1H, d, J = 10.2 Hz), 5.18 (2H, brs), 6.67-6.82 (2H, m), 7.10-7.21 (5H, m), 7.28-7.34 (14H, m), 7.46 (1H, brs);
MS (FAB) m / z: 795 (M + H) ⁺ .

(Reference Example 7c) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6-[(methoxymethoxy) methyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Compound (4.63 g, 5.82 mmol) obtained in Reference Example 7b, methyl boric anhydride (2.44 mL, 17.46 mmol), potassium carbonate (2.41 g, 17.46 mmol) and tetrakis (triphenylphosphine) palladium (0) (672 1,4-Dioxane (30 mL) was added to a mixture of mg, 0.58 mmol) under a nitrogen atmosphere. The reaction solution was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere, and further allowed to stand overnight while cooling to room temperature. After completion of the reaction, the reaction mixture was ice-cooled, water (10 mL) was added thereto, and the mixture was diluted with ethyl acetate (60 mL). The reaction mixture was washed with saturated brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100 0 → 75: 25 (concentration gradient) V / V) to obtain the title compound (3.56 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.13 (3H, d, J = 7.0 Hz), 2.37 (3H, s), 3.37 (3H, s), 3.64 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.79-3.84 (1H, m), 3.88 (1H, d, J = 9.7Hz), 4.14 (2H, t, J = 9.9Hz), 4.21 (1H, dd, J = 10.2Hz, 1.2Hz) , 4.50-4.63 (5H, m), 4.66 (2H, s), 4.67-4.70 (1H, m), 4.87 (1H, d, J = 10.6Hz), 4.91 (1H, d, J = 11.0Hz), 4.96 (1H, d, J = 11.0Hz), 5.18 (2H, brs), 6.80 (2H, d, J = 6.7Hz), 7.08-7.21 (6H, m), 7.27-7.34 (14H, m);
MS (ESI) m / z: 731 (M + H) ⁺ .

(Reference Example 7d) {(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy ) Ethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methanol

The compound obtained in Reference Example 7c (3.56 g, 4.87 mmol) was dissolved in a mixed solvent of methanol (19 mL) and 1,4-dioxane (2 mL), and a 1,4-dioxane solution of hydrogen chloride at room temperature ( 4 M, 19 mL) was added slowly. This reaction solution was stirred at room temperature for 2.5 hours, and after the reaction was completed, the reaction solution was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution (50 mL) under ice cooling. The solvent was removed from the reaction solution under reduced pressure, and the resulting residue was diluted with ethyl acetate (50 mL) and washed twice with saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 60: 40 (concentration gradient) V / V). Purification gave the title compound (2.83 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.7 Hz), 2.36 (3H, s), 3.62 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.78-3.83 ( 1H, m), 3.86 (1H, d, J = 9.3Hz), 4.16-4.24 (3H, m), 4.52-4.63 (5H, m), 4.68 (1H, d, J = 11.0Hz), 4.89 (1H , d, J = 7.9Hz), 4.92 (1H, d, J = 10.7 Hz), 4.97 (1H, d, J = 10.7 Hz), 5.18 (2H, brs), 6.79-6.81 (2H, m), 7.07 -7.21 (7H, m), 7.26-7.35 (13H, m);
MS (FAB) m / z: 687 (M + H) ⁺ .

(Reference Example 7e) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

The compound (2.83 g, 4.12 mmol) obtained in Reference Example 7d was dissolved in methylene chloride (30 mL), and carbon tetrabromide (2.46 g, 7.42 mmol) and triphenylphosphine (1.95 g, 7.42 mmol) were cooled with ice. mmol) was added. The reaction solution was stirred for 10 minutes under ice cooling under a nitrogen atmosphere. After completion of the reaction, water (20 mL) and saturated brine (20 mL) were added to the reaction mixture, and the mixture was extracted twice with methylene chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 75: 25 (concentration gradient) V / V). Purification gave the title compound (2.52 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.6 Hz), 2.45 (3H, s), 3.61 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.83 ( 1H, m), 3.83 (1H, d, J = 9.4Hz), 4.12-4.19 (2H, m), 4.21 (1H, dd, J = 10.2Hz, 1.2Hz), 4.45 (1H, d, J = 10.2) Hz), 4.51 (1H, d, J = 10.1Hz), 4.54-4.61 (3H, m), 4.68 (1H, d, J = 10.9Hz), 4.88 (1H, d, J = 7.4Hz), 4.89 ( 1H, d, J = 10.7 Hz), 4.98 (1H, d, J = 10.7 Hz), 5.15 (2H, dd, J = 16.8 Hz, 13.0 Hz), 6.81-6.84 (2H, m), 7.08-7.21 ( 7H, m), 7.25-7.35 (13H, m);
MS (ESI) m / z: 749 (M + H) ⁺ .

(Reference Example 8) (1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-Tris (benzyloxy) -6 '-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound (623 mg, 2.04 mmol) obtained in Reference Example 2 and the compound (1.00 g, 1.86 mmol) obtained in Reference Example 1, the title compound (421 mg) was obtained in the same manner as in Reference Example 6. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.7 Hz), 3.62 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.88 (2H, m), 4.10- 4.26 (3H, m), 4.41-4.62 (5H, m), 4.68 (1H, d, J = 11.1 Hz), 4.90 (1H, d, J = 11.0 Hz), 4.91 (1H, d, J = 11.1 Hz) ), 4.98 (1H, d, J = 11.0 Hz), 5.17 (1H, d, J = 13.0 Hz), 5.21 (1H, d, J = 13.0 Hz), 6.80 (2H, d, J = 6.2 Hz), 7.09-7.43 (21H, m).

(Reference Example 9) (1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-Tris (benzyloxy-6 '-[(1R) -1- (benzyloxy) ethyl ] -6- (Bromomethyl) -5-fluoro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound (659 mg, 2.04 mmol) obtained in Reference Example 3 and the compound (1.00 g, 1.86 mmol) obtained in Reference Example 1, the title compound (173 mg) was obtained in the same manner as in Reference Example 6. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.10 (3H, d, J = 6.6Hz), 3.59 (1H, dd, J = 10.2Hz, 9.0Hz), 3.76-3.83 (2H, m), 4.13- 4.23 (3H, m), 4.39 (1H, d, J = 10.7 Hz), 4.48 (1H, d, J = 10.7 Hz), 4.52-4.69 (4H, m), 4.90 (2H, d, J = 11.3 Hz) ), 4.98 (1H, d, J = 10.6Hz), 5.15 (2H, s), 6.81-6.87 (2H, m), 6.94 (1H, d, J = 9.3Hz), 7.12-7.38 (19H, m) .

Reference Example 10 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-ethyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

(Reference Example 10a) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6-[(methoxymethoxy) methyl] -5-vinyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Compound (0.36 g, 0.46 mmol) obtained in Reference Example 7b, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.17 mL, 1.0 mmol), potassium carbonate (0.13 g, 0.94 mmol) and tetrakis (triphenylphosphine) palladium (0) (53 mg, 0.046 mmol) were used to give the title compound (0.30 g) in the same manner as in Reference Example 7c.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.7 Hz), 3.36 (3H, s), 3.63 (1H, dd, J = 10.0 Hz, 9.2 Hz), 3.80-3.82 ( 1H, m), 3.88 (1H, d, J = 9.4Hz), 4.10-4.20 (3H, m), 4.22 (1H, dd, J = 10.2Hz, 1.2Hz), 4.53-4.72 (9H, m), 4.89 (1H, d, J = 10.9Hz), 4.91 (1H, d, J = 11.0Hz), 4.97 (1H, d, J = 10.5Hz), 5.21 (1H, brs), 5.38 (1H, dd, J = 10.9Hz, 1.1Hz), 5.71 (1H, dd, J = 17.4Hz, 1.3Hz), 6.78-6.81 (2H, m), 7.00-7.21 (6H, m), 7.25-7.33 (14H, m);
MS (ESI) m / z: 743 (M + H) ⁺ .

(Reference Example 10b) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-ethyl-6-[(methoxymethoxy) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

The compound (0.30 g, 0.40 mmol) obtained in Reference Example 10a was dissolved in a mixed solvent of methanol (4 mL) and THF (2 mL), and palladium / fibroin catalyst (0.030 g) was added thereto under a nitrogen atmosphere. It was. This was stirred for 8 hours under a hydrogen atmosphere. The reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 70: 30 (concentration gradient) V / V) to obtain the title compound (0.25 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.13 (3H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.6 Hz), 2.73 (2H, q, J = 7.4 Hz), 3.37 ( 3H, s), 3.63 (1H, dd, J = 9.9Hz, 9.1Hz), 3.79-3.84 (1H, m), 3.88 (1H, d, J = 9.8Hz), 4.10-4.19 (2H, m), 4.22 (1H, dd, J = 10.2Hz, 1.2Hz), 4.52-4.72 (8H, m), 4.88 (1H, d, J = 11.0Hz), 4.91 (1H, d, J = 10.6Hz), 4.97 ( 1H, d, J = 10.6Hz), 5.16 (1H, d, J = 12.6Hz), 5.21 (1H, d, J = 12.1Hz), 6.75-6.77 (2H, m), 7.08-7.15 (4H, m ), 7.18-7.21 (2H, m), 7.27-7.35 (14H, m);
MS (ESI) m / z: 745 (M + H) ⁺ .

(Reference Example 10c) {(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy ) Ethyl] -5-ethyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methanol

Using the compound obtained in Reference Example 10b (0.66 g, 0.89 mmol), methanol (4 mL) and 1,4-dioxane solution of hydrogen chloride (4 M, 4 mL), the same as in Reference Example 7d Compound (0.56 g) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.4 Hz), 2.72 (2H, q, J = 7.4 Hz), 3.62 ( 1H, dd, J = 10.1Hz, 9.0Hz), 3.79-3.84 (1H, m), 3.87 (1H, d, J = 9.8Hz), 4.17-4.22 (2H, m), 4.24 (1H, dd, J = 10.3Hz, 1.3Hz), 4.53-4.70 (6H, m), 4.90 (1H, d, J = 11.0Hz), 4.92 (1H, d, J = 11.3Hz), 4.98 (1H, d, J = 10.5 Hz), 5.20 (2H, brs), 6.75-6.78 (2H, m), 7.08-7.21 (7H, m), 7.27-7.37 (13H, m).

(Reference Example 10d) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-ethyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound (0.25 g, 0.34 mmol) obtained in Reference Example 10c, the title compound (0.16 g) was obtained in the same manner as in Reference Example 7e.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.7 Hz), 1.31 (3H, t, J = 7.6 Hz), 2.81 (2H, q, J = 7.6 Hz), 3.61 ( 1H, dd, J = 10.2Hz, 9.0Hz), 3.81 (1H, dd, J = 6.7Hz, 1.2Hz), 3.84 (1H, d, J = 9.4Hz), 4.12-4.19 (2H, m), 4.22 (1H, dd, J = 10.3Hz, 1.4Hz), 4.48-4.62 (5H, m), 4.68 (1H, d, J = 11.3Hz), 4.90 (1H, d, J = 10.9Hz), 4.91 (1H , d, J = 11.0Hz), 4.99 (1H, d, J = 11.0Hz), 5.14 (1H, d, J = 12.5Hz), 5.19 (1H, d, J = 12.5Hz), 6.78-6.80 (2H , m), 7.09-7.21 (8H, m), 7.25-7.35 (12H, m);
MS (ESI) m / z: 763 (M + H) ⁺ .

(Reference Example 11) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-isopropenyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound (0.50 g, 0.63 mmol) obtained in Reference Example 7b and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.24 g, 1.2 mmol), The title compound (0.38 g) was obtained in the same manner as in Reference Example 7c to Reference Example 7e.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.6 Hz), 2.13 (3H, s), 3.61 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.81 (1H, dd, J = 6.7Hz, 1.2Hz), 3.86 (1H, d, J = 9.4Hz), 4.15-4.20 (2H, m), 4.23 (1H, dd, J = 10.4Hz, 1.4Hz), 4.52 (1H , d, J = 9.7Hz), 4.54-4.62 (4H, m), 4.67 (1H, d, J = 10.9Hz), 4.90 (1H, d, J = 10.9Hz), 4.91 (1H, d, J = 10.9Hz), 4.98-5.01 (2H, m), 5.12 (1H, d, J = 12.9Hz), 5.18 (1H, d, J = 13.3Hz), 5.32-5.33 (1H, m), 6.77-6.79 ( 2H, m), 7.03 (1H, s), 7.09-7.20 (6H, m), 7.25-7.37 (13H, m);
MS (ESI) m / z: 713 (M + H) ⁺ .

(Reference Example 12) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (bromomethyl) -5-cyclopropyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound (0.40 g, 0.50 mmol) obtained in Reference Example 7b and cyclopropylboronic acid (56 mg, 0.65 mmol), the title compound (0.35 g) was obtained in the same manner as in Reference Example 7c to Reference Example 7e. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.68-0.78 (2H, m), 1.06 (2H, dd, J = 8.6Hz, 1.1Hz), 1.11 (3H, d, J = 6.6Hz), 2.10- 2.17 (1H, m), 3.61 (1H, dd, J = 10.1Hz, 9.0Hz), 3.80 (1H, dd, J = 6.6Hz, 1.2Hz), 3.84 (1H, d, J = 9.3Hz), 4.10 -4.19 (2H, m), 4.21 (1H, dd, J = 10.6Hz, 1.1Hz), 4.54-4.58 (3H, m), 4.66-4.70 (3H, m), 4.89 (1H, d, J = 10.9 Hz), 4.91 (1H, d, J = 10.9Hz), 4.98 (1H, d, J = 10.9Hz), 5.11 (1H, d, J = 12.9Hz), 5.16 (1H, d, J = 12.9Hz) , 6.77-6.79 (2H, m), 6.94 (1H, s), 7.09-7.20 (6H, m), 7.28-7.35 (13H, m).

Reference Example 13 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Propyl] -6- (bromomethyl) -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

(Reference Example 13a) Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside uronic acid

Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (Heterocycles, 2007, vol. 73, 165-168) (9.0 g, 19 mmol) with ethyl acetate (45 mL) and water (17 mL) ), And sodium hydrogen carbonate (3.3 g, 39 mmol) and tetra n-butylammonium bromide (0.25 g, 0.78 mmol) were added at room temperature. The reaction mixture was ice-cooled, 2,2,6,6-tetramethylpiperidine 1-oxyl (60 mg, 0.38 mmol) was added, and a hypochlorous acid aqueous solution (37.5 mL) was added in small portions over 3 hours and a half. Added. The reaction solution was stirred for 2 hours while warming to room temperature. After completion of the reaction, 1M hydrochloric acid (100 mL) was added to acidify the reaction solution, followed by extraction with ethyl acetate (50 mL, 2 times). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The crude product of the title compound was used for the next step without purification.

(Reference Example 13b) (2S, 3S, 4S, 5R, 6S) -3,4,5-Tris (benzyloxy) -N, 6-dimethoxy-N-methyltetrahydro-2H-pyran-2-carboxamide

The compound (9.0 g) obtained in Reference Example 13a was dissolved in N, N-dimethylformamide (60 mL), and N, O-dimethylhydroxylamine monohydrochloride (2.8 g, 29 mmol), triethylamine (8.0 mL, 57 mmol), 1-hydroxybenzotriazole monohydrate (3.5 g, 23 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.4 g, 23 mmol) were added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with diethyl ether (60 mL, twice). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography (hexane: ethyl acetate, 90: 10 → 0: 100 (concentration gradient) V / V). To give the title compound (6.6 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.24 (3H, s), 3.43 (3H, s), 3.61 (1H, dd, J = 9.4 Hz, 3.5 Hz), 3.66 (3H, s), 3.94 ( 1H, t, J = 9.4Hz), 4.03 (1H, t, J = 9.4Hz), 4.59-4.69 (4H, m), 4.80-4.82 (2H, m), 4.84 (1H, d, J = 10.8 Hz ), 4.97 (1H, d, J = 10.8 Hz), 7.21-7.39 (15H, m).

(Reference Example 13c) Methyl 2,3,4-tri-O-benzyl-7,8-dideoxy-α-D-gluco-octopyranoside-6-urose

The compound (1.9 g, 3.6 mmol) obtained in Reference Example 13b was dissolved in THF (20 mL), and a THF solution of ethylmagnesium bromide (0.90 M, 5.2 mL, 4.7 mmol) at −78 ° C. under a nitrogen atmosphere. Was dripped. The reaction solution was stirred at −78 ° C. for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution (10 mL) was added. The reaction solution was extracted with ethyl acetate (50 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, 98: 2 → 75: 25 (concentration gradient) V / V) to obtain the title compound (1.2 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.03 (3H, t, J = 7.2 Hz), 2.55 (2H, dd, J = 14.5 Hz, 7.0 Hz), 3.40 (3H, s), 3.54 (1H, dd, J = 9.4Hz, 3.5Hz), 3.65 (1H, dd, J = 10.0Hz, 8.8Hz), 4.01 (1H, t, J = 9.4Hz), 4.15 (1H, d, J = 9.7Hz), 4.56-4.60 (2H, m), 4.65 (1H, d, J = 12.1Hz), 4.79 (1H, d, J = 2.7Hz), 4.81 (1H, d, J = 2.3Hz), 4.83 (1H, d , J = 10.5 Hz), 4.98 (1H, d, J = 10.5Hz), 7.20-7.40 (15H, m);
MS (ESI) m / z: 508 (M + NH ₄ ) ⁺ .

(Reference Example 13d) Methyl 2,3,4-tri-O-benzyl-7,8-dideoxy-D-glycero-α-D-gluco-octopyranoside

The compound (1.2 g, 2.5 mmol) obtained in Reference Example 13c was dissolved in a mixed solvent of THF (3 mL) and ethanol (13 mL), and sodium borohydride (0.10 g, 2.6 mmol) was added. The reaction mixture was stirred for 16 hours while warming to room temperature. After the reaction was completed, a saturated aqueous ammonium chloride solution (10 mL) was added under ice cooling. The reaction solution was extracted with ethyl acetate (30 mL, twice), 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, 98: 2 → 60: 40 (concentration gradient) V / V) to obtain the title compound (1.1 g) (cf. Can. J Chem., 2001, 79, 238-255).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.93 (3H, t, J = 7.4 Hz), 1.37-1.44 (1H, m), 1.49-1.58 (1H, m), 2.50 (1H, d, J = 5.1Hz), 3.38 (3H, s), 3.47-3.51 (2H, m), 3.63-3.70 (2H, m), 4.02 (1H, t, J = 9.2Hz), 4.55 (1H, d, J = 3.5 Hz), 4.65 (1H, d, J = 11.0Hz), 4.66 (1H, d, J = 12.1Hz), 4.79 (1H, d, J = 12.1Hz), 4.80 (1H, d, J = 11.0Hz) , 4.98 (1H, d, J = 11.0Hz), 5.02 (1H, d, J = 10.9Hz), 7.25-7.38 (15H, m);
MS (ESI) m / z: 510 (M + NH ₄ ) ⁺ .

(Reference Example 13e) Methyl 2,3,4,6-tetra-O-benzyl-7,8-dideoxy-D-glycero-α-D-gluco-octopyranoside

The compound (1.1 g, 2.2 mmol) obtained in Reference Example 13d was dissolved in N, N-dimethylformamide (11 mL), and sodium hydride (oil, 55% w / w, 0.13 g, 3.0) was cooled with ice. mmol) and benzyl bromide (0.34 mL, 2.9 mmol) were added. The reaction mixture was stirred for 18 hours while raising the temperature to room temperature in a nitrogen atmosphere, ice-cooled again, and water (15 mL) was added. The reaction mixture was extracted with diethyl ether (30 mL, twice), and the organic layer was 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 obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 80: 20 (concentration gradient) V / V) to obtain the title compound (1.2 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.83 (3H, t, J = 7.5 Hz), 1.30-1.38 (1H, m), 1.58-1.68 (1H, m), 3.39 (3H, s), 3.42 (1H, dd, J = 10.2Hz, 9.0Hz), 3.47-3.51 (2H, m), 3.94-3.97 (1H, m), 4.03 (1H, t, J = 9.2Hz), 4.46 (1H, d, J = 11.3Hz), 4.59 (1H, d, J = 11.0Hz), 4.62 (1H, d, J = 3.5Hz), 4.68 (2H, d, J = 12.1Hz), 4.79 (1H, d, J = 12.1Hz), 4.82 (1H, d, J = 11.0Hz), 4.87 (1H, d, J = 10.9Hz), 5.01 (1H, d, J = 10.9Hz), 7.20-7.39 (20H, m)
MS (ESI) m / z: 600 (M + NH ₄ ) ⁺ .

Reference Example 13f 2,3,4,6-Tetra-O-benzyl-7,8-dideoxy-D-glycero-D-gluco-octopyranose

The compound (1.0 g, 1.7 mmol) obtained in Reference Example 13e was dissolved in acetic acid (32 mL), and an aqueous trifluoromethanesulfonic acid solution (2 M, 8 mL, 16 mmol) was added at room temperature. This reaction solution was heated at 80 ° C. for 6 hours under a nitrogen atmosphere. After completion of the reaction, triethylamine (3.0 mL) was added. The solvent of the reaction solution was evaporated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 60: 40 (concentration gradient) V / V) to obtain the title compound (0.6 g).
MS (ESI) m / z: 586 (M + NH ₄ ) ⁺ .

(Reference Example 13g) (3R, 4S, 5S, 6R) -3,4,5-Tris (benzyloxy) -6-[(1R) -1- (benzyloxy) propyl] tetrahydro-2H-pyran-2- on

The compound (0.60 g, 1.1 mmol) obtained in Reference Example 13f was dissolved in methylene chloride (6 mL), and DMP (0.61 g, 1.4 mmol) was added under ice cooling. The reaction solution was stirred for 2 hours while warming to room temperature. After completion of the reaction, a saturated aqueous sodium bicarbonate solution (2 mL) and a 10% w / v aqueous thiosulfate solution (2 mL) were added, and the mixture was further stirred for 1 hour. The reaction solution was extracted with diethyl ether (10 mL, twice), and the organic layer was 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 obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 75: 25 (concentration gradient) V / V) to obtain the title compound (0.58 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.94 (3H, t, J = 7.5 Hz), 1.47-1.54 (1H, m), 1.67-1.75 (1H, m), 3.63-3.67 (1H, m) , 3.94 (1H, dd, J = 7.8Hz, 5.8Hz), 4.00 (1H, t, J = 5.8Hz), 4.11 (1H, d, J = 7.4Hz), 4.48 (1H, d, J = 11.3Hz ), 4.52-4.60 (5H, m), 4.73 (1H, d, J = 11.8Hz), 4.75 (1H, d, J = 10.9Hz), 4.93 (1H, d, J = 11.3Hz), 7.21-7.36 (20H, m);
MS (ESI) m / z: 567 (M + H) ⁺ .

(Reference Example 13h) {(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy ) Propyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methanol

Compound (0.58 g, 1.1 mmol) obtained in Reference Example 13g, Compound (0.41 g, 1.2 mmol) obtained in Reference Example 4, hexane solution of n-butyllithium (1.63 M, 0.75 mL, 1.2 mmol), In the same manner as in Reference Example 6a, using THF (14 mL), p-toluenesulfonic acid monohydrate (0.63 g, 3.3 mmol), and a mixed solvent of methanol (3 mL) and THF (3 mL). A crude product of the title compound was obtained. The resulting crude product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 70: 30 (concentration gradient) V / V) to obtain the title compound (0.50 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.82 (3H, t, J = 7.2 Hz), 1.37-1.46 (1H, m), 1.60-1.68 (2H, m), 3.50 (1H, dd, J = 9.2Hz, 4.1Hz), 3.70 (1H, t, J = 9.5Hz), 3.83 (1H, d, J = 9.8Hz), 4.17-4.24 (2H, m), 4.27 (1H, d, J = 11.3Hz ), 4.47 (1H, d, J = 11.7Hz), 4.63-4.74 (5H, m), 4.92 (2H, d, J = 9.3Hz), 4.98 (1H, d, J = 10.9Hz), 5.15 (1H , d, J = 12.6Hz), 5.19 (1H, d, J = 12.6Hz), 6.82 (2H, d, J = 6.6Hz), 7.11-7.18 (3H, m), 7.24-7.34 (17H, m) ;
MS (ESI) m / z: 721 (M + H) ⁺ .

(Reference Example 13i) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Propyl] -6- (bromomethyl) -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound obtained in Reference Example 13h (0.50 g, 0.70 mmol), carbon tetrabromide (0.60 g, 1.8 mmol), triphenylphosphine (0.48 g, 36 mmol) and methylene chloride (7 mL), In the same manner as in Example 6b, a crude product of the title compound was obtained. The obtained crude product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 → 80: 20 (concentration gradient) V / V) to obtain the title compound (0.21 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.82 (3H, t, J = 7.4 Hz), 1.38-1.44 (1H, m), 1.60-1.68 (1H, m), 3.48-3.52 (1H, m) , 3.71 (1H, dd, J = 10.2Hz, 9.0Hz), 3.80 (1H, d, J = 9.8Hz), 4.15-4.23 (3H, m), 4.43 (1H, d, J = 10.2Hz), 4.50 (1H, d, J = 12.1Hz), 4.55 (1H, d, J = 10.6Hz), 4.62 (1H, d, J = 11.4Hz), 4.68 (1H, d, J = 11.7Hz), 4.73 (1H , d, J = 11.0Hz), 4.92 (1H, d, J = 11.0Hz), 4.98 (1H, d, J = 10.6Hz), 4.98 (1H, d, J = 10.6Hz), 5.14 (2H, brs ), 6.82-6.84 (2H, m), 7.10-7.18 (4H, m), 7.25-7.35 (16H, m);
MS (ESI) m / z: 783 (M + H) ⁺ .

(Reference Example 14) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) -2-methylpropyl] -6- (bromomethyl) -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Reference Example 14a 2-methyl-1-[(2S, 3S, 4S, 5R, 6S) -3,4,5-tris (benzyloxy) -6-methoxytetrahydro-2H-pyran-2-yl] propane -1-one

Using the compound obtained in Reference Example 13b (1.7 g, 3.3 mmol), isopropylmagnesium chloride in THF (2.0 M, 1.8 mL, 3.6 mmol) and THF (20 mL), the title compound was prepared in the same manner as in Reference Example 13c. (1.0 g) was obtained. The purification was performed by silica gel flash column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.07 (3H, d, J = 7.0 Hz), 1.12 (3H, d, J = 7.0 Hz), 2.82-2.89 (1H, m), 3.42 (3H, s ), 3.55 (1H, dd, J = 9.4Hz, 3.5Hz), 3.73 (1H, dd, J = 9.8Hz, 9.0Hz), 4.02 (1H, t, J = 9.4Hz), 4.34 (1H, d, J = 9.8Hz), 4.53 (1H, d, J = 10.6Hz), 4.59 (1H, d, J = 3.5Hz), 4.65 (1H, d, J = 12.1Hz), 4.80 (1H, d, J = 10.6Hz), 4.81 (1H, d, J = 12.1Hz), 4.82 (1H, d, J = 10.9Hz), 4.98 (1H, d, J = 10.9Hz), 7.18-7.20 (2H, m), 7.27 -7.37 (13H, m);
MS (ESI) m / z: 522 (M + NH ₄ ) ⁺ .

(Reference Example 14b) (1R) -2-methyl-1-[(2R, 3S, 4S, 5R, 6S) -3,4,5-tris (benzyloxy) -6-methoxytetrahydro-2H-pyran-2 -Il] propan-1-ol

Using the compound obtained in Reference Example 14a (0.95 g, 1.9 mmol), sodium borohydride (80 mg, 2.1 mmol) and a mixed solvent of ethanol (13 mL) and THF (3 mL), Reference Example 13d and In the same manner, the title compound (0.80 g) was obtained. The purification was performed by silica gel flash column chromatography (hexane: ethyl acetate, 95: 5 → 60: 40 (concentration gradient) V / V).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.89 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.8 Hz), 1.92-2.00 (1H, m), 3.00 (1H, d , J = 3.1Hz), 3.40 (3H, s), 3.50 (1H, dd, J = 9.6Hz, 3.7Hz), 3.53-3.54 (1H, m), 3.60 (1H, t, J = 9.2Hz), 3.68 (1H, dd, J = 9.3Hz, 6.2Hz), 4.04 (1H, dd, J = 9.6Hz, 8.8Hz), 4.53 (1H, d, J = 3.9Hz), 4.65 (1H, d, J = 12.1Hz), 4.70 (1H, d, J = 10.9Hz), 4.80 (1H, d, J = 10.2Hz), 4.80 (1H, d, J = 12.2Hz), 5.03 (1H, d, J = 10.9Hz) ), 5.05 (1H, d, J = 11.0Hz), 7.25-7.38 (15H, m);
MS (ESI) m / z: 524 (M + NH ₄ ) ⁺ .

(Reference Example 14c) (2R, 3S, 4S, 5R, 6S) -3,4,5-Tris (benzyloxy) -2-[(1R) -1- (benzyloxy) -2-methylpropyl] -6 -Methoxytetrahydro-2H-pyran

Compound (0.80 g, 1.6 mmol) obtained in Reference Example 14b, sodium hydride (oil,> 55%, 91 mg, 2.1 mmol), benzyl bromide (0.25 mL, 2.1 mmol) and N, N-dimethylformamide (8 mL) was used, and the title compound (0.87 g) was obtained in the same manner as in Reference Example 13e. The purification was performed by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 → 80: 20 (concentration gradient) V / V).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.90 (3H, d, J = 6.7 Hz), 0.99 (3H, d, J = 6.7 Hz), 2.00-2.08 (1H, m), 3.20 (1H, d , J = 9.0Hz), 3.38 (3H, s), 3.51 (1H, dd, J = 9.8Hz, 3.5Hz), 3.71 (1H, dd, J = 9.8Hz, 9.0Hz), 4.00 (1H, t, J = 9.4Hz), 4.03 (1H, t, J = 9.4Hz), 4.49 (1H, d, J = 11.4Hz), 4.63 (1H, d, J = 3.5Hz), 4.69 (1H, d, J = 12.1Hz), 4.74 (1H, d, J = 10.9Hz), 4.77 (1H, d, J = 11.4Hz), 4.80 (1H, d, J = 12.9Hz), 4.81 (1H, d, J = 10.6Hz) ), 4.86 (1H, d, J = 10.6Hz), 4.98 (1H, d, J = 10.5Hz), 7.25-7.40 (20H, m);
MS (ESI) m / z: 614 (M + NH ₄ ) ⁺ .

(Reference Example 14d) (3R, 4S, 5S, 6R) -3,4,5-Tris (benzyloxy) -6-[(1R) -1- (benzyloxy) -2-methylpropyl] tetrahydro-2H- Piran-2-ol

Using the compound obtained in Reference Example 14c (0.75 g, 1.3 mmol), trifluoromethanesulfonic acid aqueous solution (2 M, 5.2 mL, 10.4 mmol) and acetic acid (26 mL), the title compound ( 0.45 g) was obtained. The purification was performed by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 → 60: 40 (concentration gradient) V / V).
MS (ESI) m / z: 600 (M + NH ₄ ) ⁺ .

Reference Example 14e) (3R, 4S, 5S, 6R) -3,4,5-Tris (benzyloxy) -6-[(1R) -1- (benzyloxy) -2-methylpropyl] tetrahydro-2H- Piran-2-one

Using the compound (0.45 g, 0.78 mmol), DMP (0.43 g, 1.0 mmol) and methylene chloride (5 mL) obtained in Reference Example 14d, the title compound (0.44 g) was prepared in the same manner as in Reference Example 13g. Obtained. The purification was performed by silica gel flash column chromatography (hexane: ethyl acetate, 95: 5 → 30: 70 (concentration gradient) V / V).
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.95 (3H, d, J = 6.9 Hz), 1.07 (3H, d, J = 6.9 Hz), 1.85-1.94 (1H, m), 3.40 (1H, dd , J = 8.4Hz, 3.7Hz), 3.94 (1H, dd, J = 8.2Hz, 5.9Hz), 4.05-4.09 (2H, m), 4.41 (1H, d, J = 11.4Hz), 4.55 (1H, d, J = 11.7Hz), 4.55 (1H, d, J = 11.7Hz), 4.56 (1H, d, J = 11.3Hz), 4.62-4.67 (2H, m), 4.74 (1H, d, J = 11.4 Hz), 4.75 (1H, d, J = 11.0Hz), 4.89 (1H, d, J = 11.3Hz), 7.18-7.23 (4H, m), 7.27-7.33 (16H, m);
MS (ESI) m / z: 598 (M + NH ₄ ) ⁺ .

(Reference Example 14f) {(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy ) -2-Methylpropyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methanol

The compound obtained in Reference Example 14e (0.44 g, 0.76 mmol), the compound obtained in Reference Example 4 (0.29 g, 0.85 mmol), a hexane solution of n-butyllithium (1.63 M, 0.52 mL, 0.84 mmol), In the same manner as in Reference Example 6a, using THF (10 mL), p-toluenesulfonic acid monohydrate (0.44 g, 2.3 mmol), and a mixed solvent of methanol (2.5 mL) and THF (2.5 mL). A crude product of the title compound was obtained. The obtained crude product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 95: 5 → 30: 70 (concentration gradient) V / V) to obtain the title compound (0.38 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.91 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 2.01-2.08 (1H, m), 3.21 (1H, d , J = 9.8Hz), 3.83 (1H, d, J = 9.4Hz), 3.97 (1H, t, J = 9.5Hz), 4.20 (1H, t, J = 9.4Hz), 4.26 (1H, d, J = 11.8Hz), 4.31 (1H, d, J = 10.2Hz), 4.52 (1H, d, J = 12.1Hz), 4.63-4.67 (3H, m), 4.78 (1H, d, J = 12.1Hz), 4.84 (1H, d, J = 11.0Hz), 4.90 (1H, d, J = 10.5Hz), 4.94 (1H, d, J = 11.0Hz), 4.95 (1H, d, J = 11.0Hz), 5.16 ( 1H, d, J = 13.3Hz), 5.20 (1H, d, J = 12.9Hz), 6.81-6.83 (2H, m), 7.08-7.18 (4H, m), 7.26-7.39 (16H, m);
MS (ESI) m / z: 735 (M + H) ⁺ .

(Reference Example 14g) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) -2-methylpropyl] -6- (bromomethyl) -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Using the compound obtained in Reference Example 14f (0.37 g, 0.51 mmol), carbon tetrabromide (0.34 g, 1.0 mmol), triphenylphosphine (0.26 g, 0.99 mmol) and methylene chloride (5 mL), In the same manner as in Example 6b, a crude product of the title compound was obtained. The resulting crude product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 → 70: 30 (concentration gradient) V / V) to obtain the title compound (0.18 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ0.91 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.99-2.08 (1H, m), 3.20 (1H, d , J = 9.0Hz), 3.77 (1H, d, J = 9.4Hz), 3.98 (1H, t, J = 9.4Hz), 4.17 (1H, d, J = 9.4Hz), 4.19 (1H, d, J = 11.4Hz), 4.29 (1H, d, J = 9.7Hz), 4.39 (1H, d, J = 10.2Hz), 4.54 (1H, d, J = 10.2Hz), 4.57 (1H, d, J = 11.0) Hz), 4.62 (1H, d, J = 11.4Hz), 4.77 (1H, d, J = 12.1Hz), 4.85 (1H, d, J = 11.0Hz), 4.89 (1H, d, J = 10.6Hz) , 4.95 (1H, d, J = 10.6Hz), 4.96 (1H, d, J = 10.9Hz), 5.15 (2H, brs), 6.81-6.83 (2H, m), 6.99 (1H, s), 7.10- 7.18 (3H, m), 7.28-7.37 (16H, m);
MS (ESI) m / z: 797 (M + H) ⁺ .

Reference Example 15 5-Fluoro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1,4-benzodioxin

(Reference Example 15a) 3-Fluoro-4,5-dihydroxybenzaldehyde

3-Fluoro-4-hydroxy-5-methoxybenzaldehyde (2.0 g, 12 mmol) was dissolved in dichloromethane (36 mL) under a nitrogen atmosphere. This was cooled to −78 ° C., boron tribromide (17% w / v dichloromethane solution, about 1 mol / L) (36 mL, 36 mmol) was added, and the mixture was stirred at −78 ° C. for 1 hour, and then warmed to room temperature The temperature was raised, and the mixture was stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL, twice). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10 → 100: 0 (concentration gradient) V / V) to obtain the title compound (1.7 g).
¹ H NMR (400MHz, DMSO-d6): δ 7.16 (1H, dd, J = 2.0Hz, 1.2Hz), 7.24 (1H, dd, J = 10.6Hz, 2.0Hz), 9.72 (1H, d, J = 1.2Hz).

Reference Example 15b 8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde

The compound (1.7 g, 11 mmol) obtained in Reference Example 15a was dissolved in N, N-dimethylformamide (11 mL), potassium carbonate (4.6 g, 33 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 1,2-dibromoethane (1.1 mL, 13 mmol) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 15 hours. After cooling to room temperature, water (30 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.19 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.33-4.37 (2H, m), 4.39-4.43 (2H, m), 7.26-7.27 (1H, m), 7.24 (1H, d, J = 2.3Hz) , 9.80 (1H, d, J = 2.3Hz);
MS (CI) m / z: 183 (M + H) ⁺ .

(Reference Example 15c) 8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-ol

m-Chloroperbenzoic acid (4.0 g, purity approx. 65% w / w, approx. 15 mmol) was dissolved in dichloromethane (36 mL), and potassium fluoride (1.4 g, 24 mmol) was added thereto. Stir for hours. To this reaction solution was added a solution of the compound (1.6 g, 8.8 mmol) obtained in Reference Example 15b in dichloromethane (50 mL), and the mixture was stirred at room temperature for 20 hours. Insoluble matters in the reaction solution were removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in THF (90 mL), 2M aqueous sodium hydroxide solution (45 mL, 90 mmol) was added, and the mixture was stirred at room temperature for 3 hr. To this reaction solution was added 2M hydrochloric acid (60 mL), and the mixture was extracted with ethyl acetate (200 mL, twice). The organic layer was washed successively with 5% w / v aqueous sodium thiosulfate solution (50 mL), 5% w / v aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10 → 100: 0 (concentration gradient) V / V) to obtain the title compound (0.26 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ4.23-4.30 (4H, m), 4.61 (1H, brs), 6.19 (1H, dd, J = 3.0 Hz, 2.0 Hz), 6.25 (1H, dd, J = 11.5Hz, 3.0Hz);
MS (CI) m / z: 171 (M + H) ⁺ .

(Reference Example 15d) 8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl trifluoromethanesulfonate

The compound (0.26 g, 1.6 mmol) obtained in Reference Example 15c was dissolved in dichloromethane (8 mL). To this, triethylamine (0.45 mL, 3.2 mmol) and trifluoromethanesulfonic anhydride (0.37 mL, 2.4 mmol) were added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, twice). The organic layer was washed successively with 0.5 M hydrochloric acid (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V) to obtain the title compound (0.40 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.34 (4H, s), 6.67 (1H, d, J = 3.1Hz), 6.69 (1H, dd, J = 11.7Hz, 3.1Hz);
MS (CI) m / z: 303 (M + H) ⁺ .

Reference Example 15e 5-fluoro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1,4-benzodioxin

The compound (0.40 g, 1.4 mmol) obtained in Reference Example 15d was dissolved in 1,4-dioxane (8 mL), bis (pinacolato) diboron (0.40 g, 1.5 mmol), potassium acetate (0.42 g, 4.2 mmol) ), 1,1'-bis (diphenylphosphino) ferrocene (24 mg, 0.042 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (35 mg, 0.042 mmol) ) And stirred at 80 ° C. for 22 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, twice). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V) to obtain the title compound (0.29 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32 (12H, s), 4.26-4.30 (2H, m), 4.31-4.36 (2H, m), 7.11-7.13 (2H, m);
MS (FAB) m / z: 281 (M + H) ⁺ .

Reference Example 16 6-Fluoro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1,4-benzodioxin

Reference Example 16a 6-Bromo-7-fluoro-2,3-dihydro-1,4-benzodioxin

4-Bromo-5-fluorobenzene-1,2-diol (0.50 g, 2.4 mmol), potassium carbonate (1.0 g, 7.2 mmol), 1,2-dibromoethane (0.23 mL, 2.6 mmol) and N, N- The title compound (0.20 g) was obtained in the same manner as in Reference Example 15b using dimethylformamide (2.4 mL).
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.19-4.28 (4H, m), 6.69 (1H, d, J = 8.9 Hz), 7.04 (1H, d, J = 6.7 Hz);
MS (CI) m / z: 233 (M + H) ⁺ .

Reference Example 16b 6-Fluoro-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1,4-benzodioxin

Compound obtained in Reference Example 16a (0.20 g, 0.86 mmol), bis (pinacolato) diboron (0.24 g, 0.95 mmol), potassium acetate (0.26 g, 2.6 mmol), 1,1′-bis (diphenylphosphino) Using ferrocene (15 mg, 0.026 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (21 mg, 0.026 mmol) and 1,4-dioxane (5 mL) In the same manner as in Reference Example 15e, the title compound (65 mg) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.34 (12H, s), 4.19-4.23 (2H, m), 4.25-4.29 (2H, m), 6.57 (1H, d, J = 9.8Hz), 7.21 (1H, d, J = 5.9Hz);
MS (FAB) m / z: 319 (M + K) ⁺ .

Reference Example 17 5-Fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1,4-benzodioxin

6-Bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin (1.0 g, 4.3 mmol), bis (pinacolato) diboron (1.2 g, 4.7 mmol) obtained according to the method described in WO2008 / 128942 , Potassium acetate (1.3 g, 13 mmol), 1,1'-bis (diphenylphosphino) ferrocene (72 mg, 0.13 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride The title compound (0.49 g) was obtained in the same manner as in Reference Example 15e using dichloromethane adduct (0.11 g, 0.13 mmol) and 1,4-dioxane (25 mL).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.35 (12H, s), 4.30 (4H, s), 6.66 (1H, dd, J = 8.2Hz, 1.4Hz), 7.18 (1H, dd, J = 8.2 Hz, 5.9Hz);
MS (CI) m / z: 281 (M + H) ⁺ .

Reference Example 18 5-Methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1,4-benzodioxin

6-Bromo-5-methyl-2,3-dihydro-1,4-benzodioxin (0.50 g, 2.2 mmol), bis (pinacolato) diboron (0.61 g, 2.4 mmol), potassium acetate (0.65 g, 6.6 mmol) , 1,1'-bis (diphenylphosphino) ferrocene (37 mg, 0.066 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (54 mg, 0.066 mmol) Using 1,4-dioxane (12 mL) and in the same manner as in Reference Example 15e, the title compound (0.22 g) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.33 (12H, s), 2.41 (3H, s), 4.22-4.30 (4H, m), 6.71 (1H, d, J = 8.3 Hz), 7.29 (1H , d, J = 8.3Hz);
MS (FAB) m / z: 299 (M + Na) ⁺ .

(Reference Example 19) 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-2H-1,5-benzodioxepin

Reference Example 19a 7-bromo-3,4-dihydro-2H-1,5-benzodioxepin

4-Bromocatechol (1.9 g, 10 mmol) was dissolved in acetonitrile (40 mL), and cesium carbonate (9.8 g, 30 mmol) was added thereto at room temperature, followed by stirring for 30 minutes. 1,3-Dibromopropane (1.0 mL, 10 mmol) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 14 hours under a nitrogen atmosphere. The reaction mixture is diluted with diethyl ether (40 mL), filtered to remove insolubles, and the filtrate is washed successively with water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 70: 30 (concentration gradient) V / V) to obtain the title compound (1.4 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ2.16-2.22 (2H, m), 4.18-4.23 (4H, m), 6.85 (1H, d, J = 8.6Hz), 7.03 (1H, dd, J = 8.4Hz, 2.5Hz), 7.13 (1H, d, J = 2.7Hz).

(Reference Example 19b) 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-2H-1,5-benzodioxepin

Compound (0.70 g, 3.1 mmol) obtained in Reference Example 19a, bis (pinacolato) diboron (0.87 g, 3.4 mmol), potassium acetate (0.92 g, 9.3 mmol), 1,1′-bis (diphenylphosphino) Using ferrocene (52 mg, 0.094 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (76 mg, 0.093 mmol) and 1,4-dioxane (20 mL) In the same manner as in Reference Example 15e, the title compound (0.61 g) was obtained.
¹ H NMR (400MHz, CDCl ₃ ): δ1.32 (12H, s), 2.16-2.22 (2H, m), 4.20 (2H, t, J = 5.6Hz), 4.25 (2H, t, J = 5.6Hz ), 6.96 (1H, d, J = 7.9Hz), 7.38 (1H, dd, J = 7.8Hz, 1.6Hz), 7.44 (1H, d, J = 1.6Hz).

Reference Example 20 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro [1,4] dioxino [2,3-b] Pyridine

7-bromo-2,3-dihydro [1,4] dioxino [2,3-b] pyridine (432 mg, 2.00 mmol), bis (pinacolato) diboron (609 mg, 2.40 mmol), potassium acetate (589 mg, 6.00 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (163 mg, 0.20 mmol) and 1,2-dimethoxyethane (10 mL), Reference Example 15e In the same manner as described above, the title compound (493 mg) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.34 (12H, s), 4.24-4.26 (2H, m), 4.45-4.47 (2H, m), 7.54 (1H, d, J = 1.6Hz), 8.19 (1H, d, J = 1.5Hz).

Reference Example 21 1-Benzyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,4-tetrahydroquinoline

Reference Example 21a 1-Benzyl-7-bromo-1,2,3,4-tetrahydroquinoline

7-Bromo-1,2,3,4-tetrahydroquinoline (1.00 g, 4.72 mmol) was dissolved in N, N-dimethylformamide (5 mL). Under ice cooling, tert-butoxypotassium (794 mg, 7.08 mmol) and benzyl bromide (0.84 mL, 7.08 mmol) were added, and the mixture was stirred for 2 hours while warming to room temperature. After completion of the reaction, water was added to the reaction solution and diluted with ethyl acetate (30 mL). This was washed successively with 10% w / v saline (10 mL, twice) and saturated brine (20 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, 97: 3 → 90: 10 (concentration gradient) V / V) to obtain the title compound (1.16 g).
¹ H NMR (500 MHz, CDCl ₃ ): δ1.95-2.00 (2H, m), 2.74 (2H, t, J = 6.1 Hz), 3.33 (2H, t, J = 5.6 Hz), 4.46 (2H, s ), 6.62 (1H, d, J = 1.9Hz), 6.67 (1H, dd, J = 7.8Hz, 2.0Hz), 6.81 (1H, d, J = 7.8Hz), 7.22-7.27 (3H, m), 7.32-7.35 (2H, m).

Reference Example 21b 1-Benzyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,4-tetrahydroquinoline

Compound (0.58 g, 1.9 mmol) obtained in Reference Example 21a, bis (pinacolato) diboron (584 mg, 2.30 mmol), potassium acetate (565 mg, 5.76 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride dichloromethane adduct (155 mg, 0.19 mmol) and 1,2-dimethoxyethane (10 mL) were used in the same manner as in Reference Example 15e to obtain the title compound (489 mg).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60 (12H, s), 2.40-2.46 (2H, m), 3.51 (2H, t, J = 6.3Hz), 4.04 (2H, t, J = 5.6Hz ), 5.67 (2H, brs), 8.74 (1H, d, J = 7.3Hz), 8.82 (1H, d, J = 7.3Hz), 8.88 (1H, s), 9.05-9.21 (5H, m).

Reference Example 22 7- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-4H-1,4-benzoxazine-4-carboxylic acid tert-butyl

(Reference Example 22a) 7-Bromo-3,4-dihydro-2H-1,4-benzoxazine

7-Bromo-2H-1,4-benzoxazin-3 (4H) -one (0.60 g, 2.6 mmol) was dissolved in THF (15 mL), and this was cooled to ice with a solution of borane tetrahydrofuran complex in THF (0.95 M , 4.2 mL, 4.9 mmol) was added dropwise. This reaction solution was stirred at room temperature for 30 minutes and at 70 ° C. for 1.5 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was ice-cooled, 1 M aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred for 1 hr. This was diluted with ethyl acetate (20 mL) and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 → 60: 40 (concentration gradient) V / V). Purification gave the title compound (0.57 g).
¹ H NMR (400MHz, CDCl ₃ ): δ3.41 (2H, t, J = 4.5Hz), 3.76 (1H, brs), 4.22-4.24 (2H, m), 6.46 (1H, d, J = 8.6Hz ), 6.85 (1H, dd, J = 8.4Hz, 2.2Hz), 6.92 (1H, d, J = 1.9Hz).

(Reference Example 22b) 7-bromo-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylic acid tert-butyl

The compound (0.57 g, 2.6 mmol) obtained in Reference Example 22a was dissolved in THF (7.8 mL), and this was dissolved in dibutyl dicarbonate (1.7 g, 7.8 mmol), N, N-dimethyl-4-aminopyridine at room temperature. (32 mg, 0.26 mmol) and triethylamine (1.08 mL, 7.8 mmol) were added. The reaction was stirred at room temperature for 30 minutes and at 70 ° C. for 8 hours. After completion of the reaction, the solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 → 70: 30 (concentration gradient) V / V), The title compound (0.70 g) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.54 (9H, s), 3.83-3.85 (2H, m), 4.22-4.25 (2H, m), 6.99 (1H, dd, J = 9.0Hz, 2.4Hz ), 7.03 (1H, d, J = 2.4Hz), 7.67 (1H, brs).

(Reference Example 22c) 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-4H-1,4-benzoxazine-4-carboxylic acid tert-butyl

Compound obtained in Example 22b (681 mg, 2.17 mmol), bis (pinacolato) diboron (660 mg, 2.60 mmol), potassium acetate (638 mg, 6.50 mmol), 1,1′-bis (diphenylphosphino) Ferrocene (120 mg, 0.22 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (177 mg, 0.22 mmo), and 1,4-dioxane (5 mL) The title compound (715 mg) was obtained in the same manner as in Reference Example 15e.
_{1H NMR (400MHz, CDCl 3)} : δ1.33 (12H, s), 1.54 (9H, s), 3.84-3.87 (2H, m), 4.22-4.24 (2H, m), 7.27-7.33 (2H, m ), 7.81 (1H, brs).

Reference Example 23 4-Benzyl-2-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-2H-1, 4-benzoxazine

(Reference Example 23a) 2- (5-Bromo-2-nitrophenoxy) propanoic acid ethyl

4-Bromo-2-fluoro-1-nitrobenzene (660 mg, 3.00 mmol) was dissolved in THF (6 ml), and sodium hydride (oily, 63% w / w, 137 mg, 3.60) was cooled with ice. mmol), and 15-crown-5 (0.03 mL). Ethyl lactate (0.36 mL, 3.15 mmol) was added to the reaction solution, and the mixture was stirred for 2 hours while warming to room temperature. After completion of the reaction, methanol (0.2 mL) was added to the reaction solution and diluted with ethyl acetate (30 mL). This was washed successively with 10% w / v brine (10 mL, twice) and saturated brine (20 mL), the organic layer was dried over anhydrous sodium sulfate, and the organic layer was filtered. The solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 → 80: 20 (gradient gradient) V / V) to give the title compound (681 mg )
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.27 (3H, t, J = 7.1 Hz), 1.70 (3H, d, J = 6.7 Hz), 4.25 (2H, q, J = 7.1 Hz), 4.83 ( 1H, q, J = 6.7 Hz), 7.12 (1H, d, J = 1.7 Hz), 7.23 (1H, dd, J = 8.6 Hz, 1.7 Hz), 7.75 (1H, d, J = 8.6 Hz).

(Reference Example 23b) 7-Bromo-2-methyl-2H-1,4-benzoxazine-3 (4H) -one

The compound (680 mg, 2.14 mmol) obtained in Reference Example 23a was dissolved in acetic acid (11 mL), and iron powder (1.2 kg, 21.4 mmol) was added thereto. The reaction was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate (20 mL). The reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was again diluted with ethyl acetate (20 mL), and this was sequentially washed with water (10 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated brine (20 mL). Dried over anhydrous sodium sulfate. The solvent of the organic layer was distilled off under reduced pressure, and the resulting residue (483 mg) was used in the next step without purification.

Reference Example 23c 7-Bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazine

The compound obtained in Reference Example 23b (483 mg, approximately 2.00 mmol) was dissolved in THF (4 mL), and a solution of borane tetrahydrofuran complex in THF (0.95 M, 6.32 mL, 6.00 mmol) was added dropwise thereto under ice cooling. did. The reaction was stirred at room temperature for 10 minutes and at 50 ° C. for 40 minutes under a nitrogen atmosphere. After completion of the reaction, the reaction solution was ice-cooled, and water (5 mL) was added dropwise thereto. The reaction solution was diluted with ethyl acetate (10 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated brine (20 mL) successively, and the organic layer was dried over anhydrous sulfuric acid. Dry with sodium. The solvent of the organic layer was distilled off under reduced pressure, and the resulting residue (462 mg) was used in the next step without purification.

Reference Example 23d 4-benzyl-7-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazine

Compound obtained in Reference Example 23c (462 mg, about 2.00 mmol), tert-butoxypotassium (337 mg, 3.00 mmol), benzyl bromide (0.36 mL, 3.00 mmol), and N, N-dimethylformamide (5 mL The title compound (340 mg) was obtained in the same manner as in Reference Example 21a.
¹ H NMR (500 MHz, CDCl ₃ ): δ1.34 (3H, d, J = 6.4 Hz), 3.10 (1H, dd, J = 11.7 Hz, 8.3 Hz), 3.25 (1H, dd, J = 11.7 Hz, 2.5Hz), 4.26-4.29 (1H, m), 4.41 (2H, brs), 6.49 (1H, d, J = 8.5 Hz), 6.85 (1H, dd, J = 8.5 Hz, 2.5Hz), 6.94 (1H , d, J = 2.5 Hz), 7.24-7.38 (5H, m).

(Reference Example 23e) 4-Benzyl-2-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-2H-1, 4-benzoxazine

Compound (340 mg, 1.07 mmol) obtained in Reference Example 23d, bis (pinacolato) diboron (326 mg, 1.28 mmol), potassium acetate (315 mg, 3.21 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride dichloromethane adduct (90 mg, 0.11 mmol) and 1,2-dimethoxyethane (5 mL) were used in the same manner as Reference Example 15e to obtain the title compound (252 mg). .
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.30 (12H, s), 1.33 (3H, d, J = 6.3Hz), 3.17 (1H, dd, J = 11.7Hz, 7.8Hz), 3.28 (1H, dd, J = 11.7Hz, 2.7Hz), 4.21-4.26 (1H, m), 4.48 (1H, d, J = 16.8Hz), 4.53 (1H, d, J = 16.8Hz), 6.67 (1H, d, J = 7.8Hz), 7.25-7.34 (7H, m).

Reference Example 24 4-Benzyl-2,2-dimethyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-2H- 1,4-benzoxazine

Using 4-bromo-2-fluoro-1-nitrobenzene (1.10 g, 5.00 mmol) and ethyl 2-hydroxyisobutyrate (0.75 mL, 5.50 mmol) as starting materials, the title compound (298 mg) was prepared in the same manner as in Reference Example 23. )
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.30 (3H, s), 1.31 (3H, s), 3.09 (2H, s), 4.52 (2H, s), 6.69 (1H, d, J = 7.8Hz ), 7.25-7.35 (7H, m).

Reference Example 25 4-Benzyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydrospiro [1,4-benzoxazine-2 , 1'-cyclopropane]

Using 4-bromo-2-fluoro-1-nitrobenzene (1.39 g, 6.00 mmol) and ethyl 1-hydroxycyclopropanecarboxylate (954 mg, 6.60 mmol) as raw materials in the same manner as in Reference Example 23, the title compound (626 mg) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.61-0.64 (2H, m), 1.01-1.04 (2H, m), 1.30 (12H, s), 3.34 (2H, s), 4.53 (2H, s) , 6.68 (1H, d, J = 8.2Hz), 7.20 (1H, d, J = 1.2Hz), 7.26-7.35 (6H, m).

Example 1 (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 1a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran- 1,2'-Pyran]

The compound (0.20 g, 0.26 mmol) obtained in Reference Example 6 was dissolved in a mixed solvent of toluene (1.1 mL) -ethanol (0.78 mL) -water (0.52 mL), Yl) boronic acid (54 mg, 0.30 mmol), sodium carbonate (56 mg, 0.53 mmol), and tetrakistriphenylphosphine palladium (0) (30 mg, 0.026 mmol). The reaction mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V) to obtain the title compound (0.19 g).

Example 1b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound (0.19 g, 0.23 mmol) obtained in Example 1a was dissolved in a mixed solvent of THF (8.0 mL) and methanol (4.0 mL), and 1,2-dichlorobenzene (0.13 mL, 1.2 mmol) was dissolved in the mixture. And 10% w / w palladium carbon (0.19 g) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering this reaction liquid, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 → 80: 20 (concentration gradient) V / V) to obtain the title compound (83 mg).
¹ H NMR (400 MHz, MeOH-d4): δ 1.13 (3H, d, J = 6.7 Hz), 3.39 (1H, dd, J = 10.2 Hz, 8.2 Hz), 3.69 (1H, d, J = 9.4 Hz) ), 3.73 (1H, dd, J = 9.4Hz, 8.2 Hz), 3.79 (1H, dd, J = 10.2Hz, 3.5Hz), 3.97-4.03 (3H, m), 4.19 (4H, s), 5.07 ( 1H, d, J = 12.9 Hz), 5.13 (1H, d, J = 12.9 Hz), 6.63-6.66 (2H, m), 6.72 (1H, dt, J = 8.8Hz, 1.0Hz), 7.21 (1H, s), 7.35 (1H, s);
MS (ESI) m / z: 465 (M + H) ⁺ .

(Example 2) (1S, 3'R, 4'S, 5'S, 6'R) -6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R)- 1-hydroxyethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 2a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran- 1,2'-Pyran]

Compound (266 mg, 0.36 mmol) obtained in Reference Example 7, (1,4-benzodioxan-6-yl) boronic acid (77 mg, 0.43 mmol), tetrakistriphenylphosphine palladium (0) (41 mg, 0.036 mmol) and sodium carbonate (75 mg, 0.71 mmol) were dissolved in a mixed solvent of toluene (2 mL) -ethanol (1.5 mL) -water (0.35 mL), and this was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. did. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 97: 3-75: 25 (concentration gradient) V / V) to give the title object compound (202 mg, 71% yield). Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.13 (3H, d, J = 6.7 Hz), 2.28 (3H, s), 3.63 (1H, dd, J = 10.0, 9.2 Hz), 3.76-3.93 (4H , m), 4.04-4.26 (7H, m), 4.45-4.72 (4H, m), 4.83-4.97 (3H, m), 5.14 (1H, d, J = 12.3 Hz), 5.19 (1H, d, J = 12.3 Hz), 6.47 (1H, dd, J = 8.2, 2.0 Hz), 6.56-6.66 (2H, m), 6.81 (2H, dd, J = 8.0, 1.4 Hz), 7.00-7.35 (20H, m) ;
MS (TOF MS ES +) m / z: 805 (M + H) ⁺ .

Example 2b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[(1R)- 1-hydroxyethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 2a (202 mg, 0.25 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (3 mL), and 1,2-dichlorobenzene (0.14 mL, 1.25 mmol) was dissolved therein. 10% w / w palladium / carbon (200 mg) was added, and this was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 97: 3-85: 15 (concentration gradient) V / V) to give the title object compound (97 mg, yield 87%). Obtained.
¹ H NMR (400MHz, CD ₃ OD): 1.14 (3H, d, J = 6.3 Hz), 2.22 (3H, s), 3.36-3.44 (1H, m), 3.70-3.76 (2H, m), 3.77- 3.84 (1H, m), 3.90 (2H, s), 3.95-4.06 (1H, m), 4.18 (4H, s), 5.05 (1H, d, J = 12.1 Hz), 5.13 (1 H, d, J = 12.1 Hz), 6.51-6.61 (2H, m), 6.69 (1H, d, J = 8.2 Hz), 7.08 (2H, s);
MS (TOF MS ES +) m / z: 445 (M + H) ⁺ .

Example 3 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (1-Benzofuran-5-ylmethyl) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 3a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (1-benzofuran-5-ylmethyl) -3 ′, 4 ′, 5′-tris (benzyloxy) -6 ′ -[(1R) -1- (benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Compound obtained in Reference Example 6 (0.20 g, 0.26 mmol), benzofuran-5-boronic acid (50 mg, 0.31 mmol), tetrakis (triphenylphosphine) palladium (0) (30 mg, 0.026 mmol), and carbonic acid Sodium (55 mg, 0.52 mmol) was dissolved in a mixed solvent of toluene (2 mL) -ethanol (1.5 mL) -water (0.3 mL) and stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 80: 20 (concentration gradient) V / V) to obtain the title object compound (0.18 g, yield 85%).

Example 3b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (1-benzofuran-5-ylmethyl) -5-chloro-6 ′-[(1R) -1-hydroxyethyl- 3 ', 4', 5 ', 6'-Tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 3a (0.18 g, 0.22 mmol) and 1,2-dichlorobenzene (0.12 mL, 1.1 mmol) were dissolved in a mixed solvent of THF (5 mL) -methanol (2.5 mL), 10 % W / w palladium carbon (0.18 g) was added, and the mixture was stirred at room temperature for 1 hour 30 minutes in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 100: 0 → 85: 15 (concentration gradient) V / V) to obtain the title object compound as a mixture (92 mg) with a by-product. It was.

Example 3c (1S, 3′R, 4 ′S, 5′R, 6′R) -6 ′-[(1R) -1- (acetyloxy) ethyl] -6- (1-benzofuran-5-ylmethyl ) -5-Chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triyl triacetate

The compound obtained in Example 3b (92 mg, 0.21 mmol) was dissolved in ethyl acetate (2 mL), pyridine (0.20 mL, 2.5 mmol), acetic anhydride (0.24 mL, 2.5 mmol), and 4-dimethylamino. Pyridine (3 mg, 0.021 mmol) was added and stirred at room temperature for 17 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with 1 M hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 70: 30 (concentration gradient) V / V) to obtain the title object compound (90 mg, yield 70%).

Example 3d (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (1-benzofuran-5-ylmethyl) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound (90 mg, 0.15 mmol) obtained in Example 3c was dissolved in a mixed solvent of 2-propanol (3 mL) -THF (1 mL) -water (1 mL), and 5 M aqueous sodium hydroxide solution (0.18 mL, 0.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours and 15 minutes. The reaction mixture was neutralized with 1 M hydrochloric acid (0.88 mL, 0.88 mmol) under ice-cooling, saturated brine (5 mL) was added, and the mixture was extracted with methylene chloride (30 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 (methylene chloride: methanol, 100: 0 → 85: 15 (concentration gradient) V / V) to give the title object compound (66 mg, 98% yield). Obtained.
¹ H NMR (400 MHz, MeOH-d4): δ1.11 (3H, d, J = 6.3 Hz), 3.37 (1H, dd, J = 10.2 Hz, 8.6 Hz), 3.67 (1H, d, J = 9.4 Hz) ), 3.73 (1H, dd, J = 9.4 Hz, 8.6 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.5Hz), 3.95-4.03 (1H, m), 4.23 (2H, s), 5.08 ( 1H, d, J = 12.9Hz), 5.14 (1H, d, J = 12.9Hz), 6.75 (1H, d, J = 2.3 Hz), 7.16 (1H, dd, J = 8.6Hz, 1.9Hz), 7.24 (1H, s), 7.37-7.41 (3H, m), 7.71 (1H, d, J = 2.3Hz);
MS (ESI) m / z: 447 (M + H) ⁺ .

Example 4 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (4-Ethylbenzyl) -6 ′-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 4a) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-bromo-6- (bromoethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

The compound obtained in Reference Example 7a (600 mg, 0.80 mmol) was dissolved in methylene chloride (8 mL), and to this was added triphenylphosphine (419 mg, 1.60 mmol) and carbon tetrabromide (529 mg) under ice cooling. , 1.60 mmol), and stirred for 10 minutes under ice-cooling. The reaction solution was purified using silica gel flash column chromatography (hexane: ethyl acetate, 97: 3-85: 15, V / V) to obtain the title object compound (608 mg, yield 94%).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.10 (3H, d, J = 6.7 Hz), 3.59 (1H, dd, J = 10.2, 9.0 Hz), 3.76-3.82 (2H, m), 4.14-4.23 (3H, m), 4.42-4.70 (6H, m), 4.86-5.01 (3H, m), 5.14 (2H, s), 6.79-6.85 (2H, m), 7.09-7.36 (19H, m), 7.45 (1H, s);
MS (TOF MS ES +) m / z: 813 (M + H) ⁺ .

Example 4b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-bromo-6- (4-ethylbenzyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

The compound obtained in Example 4a (400 mg, 0.49 mmol), 4-ethylphenylboronic acid (74 mg, 0.49 mmol), tetrakistriphenylphosphine palladium (0) (57 mg, 0.049 mmol), and sodium carbonate ( 104 mg, 0.98 mmol) was dissolved in a mixed solvent of toluene (2 mL) -ethanol (1.5 mL) -water (0.49 mL), and the mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL, twice). The organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 95: 5-85: 15 (concentration gradient) V / V) to give the title object compound (326 mg, yield 79%). Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.08 (3H, d, J = 6.7 Hz), 1.16 (3H, t, J = 7.6 Hz), 2.55 (2H, q, J = 7.6 Hz), 3.53- 3.61 (1H, m), 3.69-3.81 (2H, m), 3.99-4.20 (5H, m), 4.47-4.68 (4H, m), 4.83-4.95 (3H, m), 5.10-5.21 (2H, m ), 6.77 (2H, d, J = 7.0 Hz), 6.97 (1H, s), 7.00 (4H, s), 7.12-7.35 (18H, m), 7.48 (1H, s);
MS (TOF MS ES +) m / z: 839 (M + H) ⁺ .

(Example 4c) Methyl (1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-Tris (benzyloxy) -6 '-[(1R) -1- (benzyloxy ) Ethyl] -6- (4-ethylbenzyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -5-carboxylate

The compound (326 mg, 0.39 mmol) obtained in Example 4b was dissolved in a mixed solvent of N, N-dimethylformamide (2 mL) and methanol (2 mL), and this was dissolved in 1,3-bis (diphenylphosphino). ) Propane (32 mg, 0.078 mmol), N, N-diisopropylethylamine (0.27 mL, 1.55 mmol), and palladium acetate (17 mg, 0.078 mmol) were added, and the mixture was stirred at 80 ° C. for 16 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 95: 5-80: 20 (concentration gradient) V / V) to give the title object compound (276 mg, yield 87%). Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.09 (3H, d, J = 6.7 Hz), 1.13 (3H, t, J = 7.6 Hz), 2.53 (2H, q, J = 7.6 Hz), 3.54- 3.62 (1H, m), 3.73-3.80 (2H, m), 3.84 (3H, s), 3.97-4.69 (9H, m), 4.84-4.95 (3H, m), 5.20 (2H, s), 6.75 ( 2H, d, J = 7.0 Hz), 6.96 (4H, s), 7.03-7.35 (19H, m), 7.79 (1H, s);
MS (TOF MS ES +) m / z: 819 (M + H) ⁺ .

(Example 4d) Methyl (1S, 3'R, 4'S, 5'S, 6'R) -6- (4-Ethylbenzyl) -3 ', 4', 5'-trihydroxy-6 '-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -5-carboxylate

The compound obtained in Example 4c (132 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (3 mL), and to this, 1,2-dichlorobenzene (90 μL, 0.81 mmol), and 10% w / w palladium / carbon (130 mg) was added, and the mixture was stirred at room temperature for 1 hr in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 97: 3-90: 10 (concentration gradient) V / V) to give the title object compound (66 mg, 89% yield). Obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ1.12 (3H, d, J = 6.3 Hz), 1.18 (3H, t, J = 7.6 Hz), 2.57 (2H, q, J = 7.6 Hz), 3.35 -3.43 (1H, m), 3.68-3.85 (6H, m), 3.96-4.06 (1H, m), 4.30 (1H, d, J = 15.3 Hz), 4.37 (1H, d, J = 15.3 Hz), 5.12 (1H, d, J = 12.7 Hz), 5.18 (1H, d, J = 12.7 Hz), 7.01 (2H, d, J = 8.0 Hz), 7.06 (2H, d, J = 8.0 Hz), 7.27 ( 1H, s), 7.75 (1H, s);
MS (TOF MS ES +) m / z: 459 (M + H) ⁺ .

Example 4e) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (4-ethylbenzyl) -6 ′-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound (66 mg, 0.14 mmol) obtained in Example 4d was dissolved in THF (3.5 mL), and 1 M lithium aluminum hydride THF solution (0.86 mL, 0.86 mmol) was added to this at 0 ° C. under a nitrogen atmosphere. The mixture was further stirred at room temperature for 1 hour. Under ice-cooling, 1 M hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride: methanol (10: 1, V / V, 20 mL, twice). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 95: 5-85: 15 (concentration gradient) V / V) to give the title object compound (41 mg, 66% yield). Obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ1.13 (3H, d, J = 6.7 Hz), 1.19 (3H, t, J = 7.6 Hz), 2.59 (2H, q, J = 7.6 Hz), 3.39 (1H, dd, J = 10.0, 8.4 Hz), 3.69-3.84 (3H, m), 3.96-4.07 (3H, m), 4.58 (2H, s), 5.10 (1H, d, J = 12.5 Hz), 5.17 (1H, d, J = 12.5 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.12 (1H, s), 7.38 (1H, s);
MS (TOF MS ES +) m / z: 431 (M + H) ⁺ .

Example 5 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (4-Ethoxybenzyl) -6 ′-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Using the compound (0.33 g, 0.40 mmol) obtained in Example 4a and (4-ethoxyphenyl) boronic acid (66 mg, 0.40 mmol) as raw materials, the title compound (65 mg) was prepared in the same manner as in Example 4. Obtained.
¹ H NMR (400 MHz, MeOH-d4): δ1.13 (3H, d, J = 6.6 Hz), 1.35 (3H, t, J = 7.1 Hz), 3.38-3.42 (1H, m), 3.71 (1H, d, J = 9.4Hz), 3.75 (1H, d, J = 8.6Hz), 3.80 (1H, dd, J = 10.2Hz, 3.5Hz), 3.96-4.01 (5H, m), 4.59 (2H, s) , 5.09 (1H, d, J = 12.9 Hz), 5.17 (1H, d, J = 12.9 Hz), 6.80 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.11 (1H, s), 7.38 (1H, s);
MS (TOF MS ES +) m / z: 447 (M + H) ⁺ .

Example 6 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[(1R)- 1-hydroxyethyl] -5- (hydroxymethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5 '-Triol

Using the compound (0.40 g, 0.49 mmol) obtained in Example 4a and (1,4-benzodioxan-6-yl) boronic acid (97 mg, 0.54 mmol) as raw materials, the title was obtained in the same manner as in Example 4. Compound (75 mg) was obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ1.14 (3H, d, J = 6.7 Hz), 3.36-3.44 (1H, m), 3.69-3.84 (3H, m), 3.96 (2H, s), 3.97-4.04 (1H, m), 4.17 (4H, s), 4.55 (1H, d, J = 13.7 Hz), 4.59 (1H, d, J = 13.7 Hz), 5.10 (1H, d, J = 12.1 Hz) ), 5.17 (1H, d, J = 12.1 Hz), 6.55-6.62 (2H, m), 6.70 (1H, d, J = 8.2 Hz), 7.11 (1H, s), 7.37 (1H, s);
MS (TOF MS ES +) m / z: 461 (M + H) ⁺ .

Example 7 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6- (3,4-dihydro-2H-chromen-7-ylmethyl) -6 ′-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran-3', 4 ', 5'-triol

Example 7a 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-4H-chromen-4-one

7-bromochroman-4-one (1.13 g, 5.00 mmol), bis (pinacolato) diborane (1.52 g, 6.00 mmol), potassium acetate (1.47 g, 15.0 mmol), and [1,1'-bis (diphenylphosphino) ) Ferrocene] Palladium (II) dichloride dichloromethane adduct (0.41 g, 0.50 mmol) was dissolved in ethylene glycol dimethyl ether (25 mL) and stirred at 90 ° C for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL) was added and filtered, and the filtrate was poured into saturated aqueous sodium hydrogen carbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 75: 25 (concentration gradient) V / V) to obtain the title object compound (0.93 g, yield 68%).

Example 7b 7-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl) -2, 3-Dihydro-4H-chromen-4-one

The compound obtained in Reference Example 6 (0.53 g, 0.69 mmol), the compound obtained in Example 7a (0.23 g, 0.83 mmol), tetrakis (triphenylphosphine) palladium (0) (80 mg, 0.069 mmol), And sodium carbonate (0.15 g, 1.4 mmol) was dissolved in a mixed solvent of toluene (6 mL) -ethanol (4 mL) -water (0.7 mL) and stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 70: 30 (concentration gradient) V / V) to give the title compound (0.42 g, 73% yield). Obtained.

Example 7c 7-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ′, 4 ′, 5 ′, 6′-tetrahydro-3H-spiro [2-benzofuran-1,2′-pyran] -6-yl} methyl) -3, 4-Dihydro-2H-chromen-4-ol

The compound obtained in Example 7b (0.25 mg, 0.30 mmol) was dissolved in a mixed solvent of methanol (3 mL) -THF (1 mL), and sodium borohydride (18 mg, 0.45 mmol) under ice cooling. ) Was added and stirred for 30 minutes. To this reaction solution was added a saturated aqueous ammonium chloride solution (5 mL) under ice-cooling, followed by extraction with ethyl acetate (40 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title target compound as a crude product (0.25 g).

Example 7d 7-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ′, 4 ′, 5 ′, 6′-tetrahydro-3H-spiro [2-benzofuran-1,2′-pyran] -6-yl} methyl) -3, 4-Dihydro-2H-chromen-4-yl acetate

The compound obtained in Example 7c (0.25 g, 0.30 mmol) was dissolved in ethyl acetate (3 mL), and pyridine (73 μL, 0.90 mmol), acetic anhydride (66 μL, 0.69 mmol), and 4- Dimethylaminopyridine (4 mg, 0.030 mmol) was added and stirred at room temperature for 19 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with 1 M hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 70: 30 (concentration gradient) V / V) to obtain the title compound (0.23 g, yield 88%). Obtained.

Example 7e (1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-Tris (benzyloxy) -6 '-[(1R) -1- (benzyloxy) Ethyl] -5-chloro-6- (3,4-dihydro-2H-chromen-7-ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2 '-Pyran]

The compound obtained in Example 7d (0.18 g, 0.21 mmol) was dissolved in methylene chloride (4 mL) and cooled to -78 ° C. Triethylsilane (0.34 mL, 2.1 mL) and boron trifluoride ethyl ether complex (0.12 mL, 0.95 mmol) were added thereto and stirred for 2 hours. A saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 → 75: 25 (concentration gradient) V / V) to give the title compound (0.14 g, yield 81%). Obtained.

Example 7f (1S, 3'R, 4'S, 5'S, 6'R) -5-chloro-6- (3,4-dihydro-2H-chromen-7-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 7e (0.18 g, 0.34 mmol) and 1,2-dichlorobenzene (0.19 mL, 1.7 mmol) were dissolved in a mixed solvent of THF (4 mL) -methanol (2 mL). 10% palladium carbon (0.18 g) was added thereto, and the mixture was stirred at room temperature for 1 hour 30 minutes in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 100: 0 → 85: 15 (concentration gradient) V / V) to give the title object compound (0.10 g, yield 63%). Obtained.
¹ H NMR (400MHz, MeOH-d4): δ1.13 (3H, d, J = 6.6Hz), 1.91-1.99 (2H, m), 2.73 (2H, t, J = 6.5Hz), 3.39 (1H, dd, J = 10.2Hz, 8.6Hz), 3.69 (1H, d, J = 9.3Hz), 3.74 (1H, dd, J = 9.3 Hz, 8.6 Hz), 3.80 (1H, dd, J = 10.2Hz, 3.5 Hz), 3.96-4.05 (3H, m), 4.11 (2H, t, J = 5.1Hz), 5.07 (1H, d, J = 12.9Hz), 5.14 (1H, d, J = 12.9Hz), 6.53 ( 1H, d, J = 1.9 Hz), 6.65 (1H, dd, J = 7.8Hz, 1.9Hz), 6.92 (1H, d, J = 7.8Hz), 7.21 (1H, s), 7.36 (1H, s) ;
MS (ESI) m / z: 463 (M + H) ⁺ .

Example 8 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 8a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran- 1,2'-Pyran]

Compound obtained in Example 4a (0.40 g, 0.49 mmol), (1,4-benzodioxan-6-yl) boronic acid (0.11 g, 0.61 mmol), sodium carbonate (0.10 g, 0.94 mmol), tetrakistri Using a mixed solvent of phenylphosphine palladium (0) (57 mg, 0.049 mmol) and toluene (4 mL) -ethanol (3 mL) -water (1 mL) in the same manner as in Example 1a, the title compound (0.21 )

Example 8b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 8a (100 mg, 0.11 mmol) and pentamethylbenzene (179 mg, 1.21 mmol) were dissolved in methylene chloride (5 mL). A solution of boron fluoride in methylene chloride (1.0 M, 1.10 mL, 1.10 mmol) was added. The reaction mixture was stirred at -78 ° C for 40 minutes, and methanol (1 mL) was added. The reaction mixture was warmed to room temperature, the solvent was distilled off under reduced pressure, water (3 mL) and saturated brine (3 mL) were added to the resulting residue, and methylene chloride and 2-propanol (3: 1) were added. ) Was extracted twice with a mixed solvent. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 100: 0 → 80: 20 (concentration gradient) V / V) to give the title object compound (20 mg, yield 36%). Obtained.
¹ H NMR (400 MHz, MeOH-d4): δ1.13 (3H, d, J = 6.7 Hz), 3.38 (1H, dd, J = 10.1 Hz, 8.6 Hz), 3.68 (1H, d, J = 9.4 Hz) ), 3.74 (1H, dd, J = 9.4 Hz, 8.6Hz), 3.80 (1H, dd, J = 10.1 Hz, 3.3Hz), 3.97-4.08 (3H, m), 4.19 (4H, s), 5.07 ( 1H, d, J = 13.0 Hz), 5.14 (1H, d, J = 13.0 Hz), 6.62-6.67 (2H, m), 6.72 (1H, d, J = 7.8 Hz), 7.20 (1H, s), 7.55 (1H, s);
MS (ESI) m / z: 509 (M + H) ⁺ .

Example 9 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [4- (3-hydroxypropyl) Benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

(Example 9a) Ethyl 3- [4-({(1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-Tris (benzyloxy) -6 '-[(1R ) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl ) Phenyl] propanoate

The compound (0.39 g, 0.50 mmol) obtained in Reference Example 6 was dissolved in a mixed solvent of toluene (2.0 mL) -ethanol (1.5 mL) -water (1.0 mL), and then [4- (3-ethoxy- 3-oxopropyl) phenyl] boronic acid (0.13 g, 0.59 mmol), sodium carbonate (0.11 g, 1.0 mmol), and tetrakistriphenylphosphine palladium (0) (58 mg, 0.050 mmol) were added, and under nitrogen atmosphere, The mixture was stirred at 100 ° C. for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V) to obtain the title compound (0.35 g).

Example 9b 3- [4-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl) Phenyl] propan-1-ol

The compound (0.17 g, 0.20 mmol) obtained in Example 9a was dissolved in THF (2.0 mL) under a nitrogen atmosphere. This was cooled to 0 ° C., lithium aluminum hydride (12 mg, 0.32 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. To this reaction solution were added waterpox (15 μL), 5 μM aqueous sodium hydroxide solution (15 μL) and waterpox (45 μL). After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 10: 90 → 0: 100 (concentration gradient V / V)) to obtain the title compound (0.15 g).

Example 9c (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [4- (3-hydroxypropyl) Benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound (0.15 g, 0.18 mmol) obtained in Example 9b was dissolved in a mixed solvent of THF (6.7 mL) and methanol (3.3 mL), and 1,2-dichlorobenzene (0.11 mL, 0.98 mmol) was dissolved in the mixture. 10% w / w palladium carbon (0.15 g) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 → 80: 20 (concentration gradient) V / V) to obtain the title compound (68 mg, 81%).
¹ H NMR (400MHz, MeOH-d4): δ1.12 (3H, d, J = 6.6Hz), 1.75-1.85 (2H, m), 2.58-2.68 (2H, m), 3.35-3.42 (1H, m ), 3.54 (1H, t, J = 6.4 Hz), 3.67 (1H, d, J = 9.6 Hz), 3.73 (1H, dd, J = 9.6 Hz, 8.6 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.2 Hz), 3.97-4.03 (1H, m), 4.06-4.14 (2H, m), 5.07 (1H, d, J = 12.7Hz), 5.14 (1H, d, J = 12.7 Hz), 7.11 ( 4H, s), 7.22 (1H, s), 7.36 (1H, s);
MS (ESI) m / z: 465 (M + H) ⁺ .

Example 10 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [3- (3-hydroxypropyl) Benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Using the compound obtained in Reference Example 6 (0.40 g, 0.52 mmol) and [3- (3-methoxy-3-oxopropyl) phenyl] boronic acid (0.13 g) as raw materials, the title was obtained in the same manner as in Example 9. Compound (77 mg) was obtained.
¹ H NMR (400 MHz, MeOH-d4): δ1.12 (3H, d, J = 6.6 Hz), 1.75-1.84 (2H, m), 2.63 (2H, t, J = 7.6 Hz), 3.37 (1H, dd, J = 10.2 Hz, 8.6 Hz), 3.54 (2H, t, J = 6.5 Hz), 3.68 (1H, d, J = 9.3 Hz), 3.74 (1H, dd, J = 9.3 Hz, 8.6 Hz), 3.79 (1H, dd, J = 10.2Hz, 3.5Hz), 3.97-4.05 (1H, m), 4.09 (1H, d, J = 15.4 Hz), 4.14 (1H, d, J = 15.4 Hz), 5.07 ( 1H, d, J = 13.1 Hz), 5.14 (1H, d, J = 13.1 Hz), 6.98-7.08 (3H, m), 7.18 (1H, t, J = 7.4 Hz), 7.21 (1H, s), 7.37 (1H, s);
MS (ESI) m / z: 465 (M + H) ⁺ .

Example 11 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- [4- (2-hydroxyethoxy) benzyl] -6 ′-[(1R) -1-hydroxyethyl] -5 -Methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 11a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- {4- [2- (methoxymethoxy) ethoxy] benzyl} -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2' -Piran]

The compound (0.28 g, 0.38 mmol) obtained in Reference Example 7 was dissolved in a mixed solvent of toluene (1.6 mL) -ethanol (1.2 mL) -water (0.8 mL), and 2- {4- [2- (Methoxymethoxy) ethoxy] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 g, 0.42 mmol), sodium carbonate (81 mg, 0.76 mmol), and tetrakistriphenylphosphine Palladium (0) (44 mg, 0.038 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V) to obtain the title compound (0.28 g).

Example 11b 2- [4-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) ethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl) Phenoxy] ethanol

The compound obtained in Example 11a (0.28 g, 0.38 mmol) was dissolved in methanol (2.0 mL), 4 M dioxane solution (2.0 mL, 8.0 mmol) was added thereto, and the mixture was stirred at room temperature for 室温 40 minutes. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2 × 2). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10 → 0: 100 (concentration gradient) V / V) to obtain the title compound (0.22 g).

Example 11c (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- [4- (2-hydroxyethoxy) benzyl] -6 ′-[(1R) -1-hydroxyethyl] -5 -Methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 11b (0.22 g, 0.17 mmol) was dissolved in a mixed solvent of THF (10 mL) and methanol (5.0 mL), and 1,2-dichlorobenzene (0.16 mL, 1.4 mmol) was dissolved therein. 10% w / w palladium carbon (0.22 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 → 80: 20 (concentration gradient) V / V) to obtain the title compound (0.11 g).
¹ H NMR (400 MHz, MeOH-d4): δ1.14 (3H, d, J = 6.6 Hz), 3.42 (3H, s), 3.39 (1H, dd, J = 10.2 Hz, 8.4 Hz), 3.71 (1H , d, J = 9.2 Hz), 3.75 (1H, dd, J = 9.2 Hz, 8.4 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.2 Hz), 3.83-3.86 (2H, m), 3.96 ( 2H, s), 3.98-4.02 (3H, m), 5.07 (1H, d, J = 12.1 Hz), 5.13 (1H, d, J = 12.1 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.6Hz), 7.09 (2H, s);
MS (FAB) m / z: 447 (M + H) ⁺ .

Example 12 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [4- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

(Example 12a) tert-butyl methyl [4-({(1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-tris (benzyloxy) -6 '-[( 1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} Methyl) phenyl] carbamate

The compound obtained in Reference Example 6 (300 mg, 0.39 mmol), N-Boc-N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (156 mg, 0.47 mmol), tetrakistriphenylphosphine palladium (0) (45 mg, 0.039 mmol), and sodium carbonate (83 mg, 0.78 mmol) in toluene (2 mL) -ethanol (1.5 mL) -water ( 0.39 mL) was dissolved in a mixed solvent and stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 97: 3-75: 25 (concentration gradient) V / V) to give the title object compound (254 mg, 73% yield). Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.07 (3H, d, J = 6.7 Hz), 1.41 (9H, s), 3.14 (3H, s), 3.56 (1H, dd, J = 10.2, 9.4 Hz ), 3.72-3.81 (2H, m), 4.02-4.22 (5H, m), 4.49-4.67 (4H, m), 4.85-4.96 (3H, m), 5.16 (2H, s), 6.73-6.79 (2H , m), 6.99-7.36 (24H, m);
MS (FAB) m / z: 896 (M + H) ⁺ .

Example 12b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [4- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 12a (123 mg, 0.14 mmol) was dissolved in a mixed solvent of THF (5 mL) and methanol (2.5 mL), to which 1,2-dichlorobenzene (77 μL, 0.69 mmol), and 10% w / w palladium / carbon (120 mg) was added, and this was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (2 mL), 4N hydrochloric acid dioxane solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, saturated sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform: 2-propanol (3: 1, V / V, 20 mL, twice). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification using silica gel flash column chromatography (methylene chloride: methanol, 95: 5-88: 12 (concentration gradient) V / V) gave the title object compound (52 mg, yield 87%).
¹ H NMR (400MHz, CD ₃ OD): 1.12 (3H, d, J = 6.3 Hz), 2.73 (3H, s), 3.36-3.42 (1H, m), 3.61-3.85 (3H, m), 3.92- 4.07 (3H, m), 5.05 (1H, d, J = 12.9 Hz), 5.12 (1H, d, J = 12.9 Hz), 6.58 (2H, d, J = 8.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.15 (1H, s), 7.33 (1H, s);
MS (TOF MS ES +) m / z: 436 (M + H) ⁺ .

Example 13 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6 ′-[(1R) -1-hydroxyethyl] -5-methyl-6- [4- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

(Example 13a) tert-butyl methyl [4-({(1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-tris (benzyloxy) -6 '-[( 1R) -1- (Benzyloxy) ethyl] -5-methyl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-3H-spiro [2-benzofuran-1,2′-pyran] -6-yl} Methyl) phenyl] carbamate

Compound (251 mg, 0.34 mmol) obtained in Reference Example 7, N-Boc-N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (134 mg, 0.40 mmol), tetrakistriphenylphosphine palladium (0) (39 mg, 0.034 mmol), and sodium carbonate (71 mg, 0.67 mmol) were added to toluene (2 mL) -ethanol (1.5 mL) -water ( 0.33 mL) was dissolved in a mixed solvent and stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 97: 3-75: 25 (concentration gradient) V / V) to give the title object compound (212 mg, yield 72%). Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.11 (3H, d, J = 6.7 Hz), 1.41 (9H, s), 2.25 (3H, s), 3.15 (3H, s), 3.60 (1H, dd , J = 10.2 Hz, 9.0 Hz), 3.76-3.84 (2H, m), 3.89-4.01 (2H, m), 4.08-4.25 (3H, m), 4.47-4.70 (4H, m), 4.84-4.97 ( 3H, m), 5.16 (1H, d, J = 12.5 Hz), 5.21 (1H, d, J = 12.5 Hz), 6.77-6.82 (2H, m), 6.92-7.35 (24H, m);
MS (FAB) m / z: 876 (M + H) ⁺ .

Example 13b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6 ′-[(1R) -1-hydroxyethyl] -5-methyl-6- [4- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 13a (212 mg, 0.24 mmol) was dissolved in a mixed solvent of THF (5 mL) and methanol (2.5 mL), and to this, 1,2-dichlorobenzene (136 μL, 1.21 mmol), and 10% w / w palladium / carbon (200 mg) was added, and this was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure.

The obtained residue was dissolved in methanol (2 mL), 4N hydrochloric acid dioxane solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, saturated sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform: 2-propanol (3: 1, V / V, 20 mL, twice). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 97: 3-85: 15 (concentration gradient) V / V) to give the title object compound (73 mg, 73% yield). Obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ 1.14 (3H, d, J = 6.3 Hz), 2.23 (3H, s), 2.73 (3H, s), 3.39 (1H, dd, J = 10.2, 8.2 Hz), 3.67-3.83 (3H, m), 3.88 (2H, s), 3.95-4.04 (1H, m), 5.05 (1H, d, J = 12.1 Hz), 5.12 (1H, d, J = 12.1 Hz ), 6.56 (2H, d, J = 8.6 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.06 (2H, s);
MS (TOF MS ES +) m / z: 416 (M + H) ⁺ .

Example 14 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6- (1,2,3,4- Tetrahydroquinolin-6-ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Starting from the compound obtained in Reference Example 6 (200 mg, 0.26 mmol) and 1- (tert-butoxycarbonyl) -1,2,3,4-tetrahydro-6-quinolinylboronic acid (86 mg, 0.31 mmol) Using the same method as in Example 12, the title compound (71 mg) was obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ1.12 (3H, d, J = 6.7 Hz), 1.84-1.92 (2H, m), 2.68 (2H, t, J = 6.5 Hz), 3.20 (2H, t, J = 5.5 Hz), 3.37 (1H, dd, J = 10.2, 8.6 Hz), 3.64-3.81 (3H, m), 3.88-4.04 (3H, m), 5.06 (1H, d, J = 12.9 Hz ), 5.12 (1H, d, J = 12.9 Hz), 6.45 (1H, d, J = 7.8 Hz), 6.71-6.77 (2H, m), 7.15 (1H, s), 7.33 (1H, s);
MS (TOF MS ES +) m / z: 462 (M + H) ⁺ .

Example 15 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6- (3,4-dihydro-2H-1,4-benzoxazin-7-ylmethyl) -6′- [(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'- Triol

The compound obtained in Reference Example 6 (200 mg, 0.26 mmol), and 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro- The title compound (68 mg) was obtained in the same manner as in Example 12 using tert-butyl 4H-1,4-benzoxazine-4-carboxylate (113 mg, 0.31 mmol) as a starting material.
¹ H NMR (400 MHz, MeOH-d4): δ1.13 (3H, d, J = 6.7 Hz), 3.27-3.41 (3H, m), 3.67-3.76 (2H, m), 3.79 (1H, dd, J = 10.1Hz, 3.5Hz), 3.95 (2H, d, J = 3.5Hz), 4.00 (1H, dd, J = 6.2Hz, 3.5Hz), 4.14-4.16 (2H, m), 5.06 (1H, d, J = 12.9Hz), 5.13 (1H, d, J = 12.9 Hz), 6.51-6.51 (1H, m), 6.55-6.55 (2H, m), 7.18 (1H, s), 7.34 (1H, s);
MS (TOF MS ES +) m / z: 464 (M + H) ⁺ .

Example 16 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6-{[6- (methylamino) pyridine -3-yl] methyl} -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Using the compound obtained in Reference Example 6 (200 mg, 0.26 mmol) and 6- (Boc-methylamino) pyridine-3-boronic acid (104 mg, 0.31 mmol) as raw materials, the same method as in Example 12 was performed. Used to give the title compound (49 mg).
¹ H NMR (400 MHz, MeOH-d4): δ 1.13 (3H, d, J = 6.6 Hz), 2.83 (3H, s), 3.39 (1H, dd, J = 10.1 Hz, 8.2 Hz), 3.69-3.77 (2H, m), 3.80 (1H, dd, J = 10.0Hz, 3.3Hz), 3.97 (2H, s), 3.98-4.03 (1H, m), 5.07 (1H, d, J = 12.9Hz), 5.13 (1H, d, J = 12.9Hz), 6.45 (1H, d, J = 8.6Hz), 7.25 (1H, s), 7.30 (1H, dd, J = 8.7Hz, 2.3Hz), 7.36 (1H, s ), 7.82 (1H, d, J = 2.4Hz);
MS (TOF MS ES +) m / z: 437 (M + H) ⁺ .

Example 17 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [3- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

(Example 17a) tert-butyl [3-({(1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-tris (benzyloxy) -6 '-[(1R ) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl ) Phenyl] carbamate

The compound (400 mg, 0.52 mmol) obtained in Reference Example 6, tert-butyl [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamate ( 198 mg, 0.62 mmol), tetrakistriphenylphosphine palladium (0) (60 (mg, 0.052 mmol), sodium carbonate (110 mg, 1.04 mmol), and toluene (2 mL) -ethanol (1.5 mL) -water (0.39 mL) ) Was used to obtain the title compound (213 mg, 46% yield) in the same manner as in Example 12a.

(Example 17b) tert-butyl methyl [3-({(1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5'-tris (benzyloxy) -6 '-[( 1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} Methyl) phenyl] carbamate

The compound (183 mg, 0.21 mmol) obtained in Example 17a was dissolved in N, N-dimethylformamide (5 mL), and sodium hydride (oil, 63% w / w, 24 mg) was cooled with ice. Then, the mixture was stirred for 30 minutes while warming to room temperature. Methyl iodide (78 μL, 1.3 μmmol) was added to the reaction solution under ice cooling, and the mixture was stirred for 1 hour and a half while warming to room temperature. After completion of the reaction, saturated aqueous ammonium chloride solution (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL, twice). The organic layer was washed with 10% w / v brine (10 mL, 3 times), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 97: 3-80: 20 (concentration gradient) V / V) to obtain the title object compound (158 mg, 73% yield). Obtained.

Example 17c) N-methyl-3-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-tris (benzyloxy) -6 ′-[(1R ) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl Aniline

The compound obtained in Example 17b (158 mg, 0.18 mmol) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (0.7 mL) was gradually added thereto under ice cooling. The reaction solution was stirred for 1 hour while warming to room temperature, and then the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate (10 mL), and this was 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 resulting residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 100: 0-80: 20 (concentration gradient) V / V) to obtain the title compound (130 mg, yield 91%). Obtained.

Example 17d (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [3- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound obtained in Example 17c (130 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and to this, 1,2-dichlorobenzene (130 μL, 1.16 mmol), and 10% w / w palladium / carbon (195 mg) was added, and this was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 95: 5-80: 20 (concentration gradient) V / V) to give the title object compound (49 mg, yield 70%). Obtained.
¹ H NMR (400 MHz, MeOH-d4): δ1.12 (3H, d, J = 6.7 Hz), 2.72 (3H, s), 3.37 (1H, dd, J = 10.2 Hz, 8.7 Hz), 3.67 (1H , d, J = 9.4Hz), 3.73 (1H, dd, J = 9.4 Hz, 8.7Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.6Hz), 3.96-4.09 (3H, m), 5.07 ( 1H, d, J = 12.9Hz), 5.13 (1H, d, J = 12.9Hz), 6.46-6.52 (3H, m), 7.04 (1H, t, J = 8.0Hz), 7.20 (1H, s), 7.35 (1H, s);
MS (ESI) m / z: 434 (MH) ^- .

Example 18 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [3-methyl-4- (methyl Amino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound (400 mg, 0.52 mmol) obtained in Reference Example 6 and tert-butyl [2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl] ) Phenyl] carbamate (207 mg, 0.62 mmol) was used as a starting material in the same manner as in Example 17 to obtain the title compound (179 mg).
¹ H NMR (400 MHz, MeOH-d4): δ1.13 (3H, d, J = 6.6 Hz), 2.41 (3H, s), 3.03 (3H, s), 3.38 (1H, dd, J = 10.2 Hz, 8.2Hz), 3.71 (1H, d, J = 9.7Hz), 3.76 (1H, dd, J = 9.7 Hz, 8.2 Hz), 3.81 (1H, dd, J = 10.2Hz, 3.5Hz), 3.99-4.06 ( 1H, m), 4.16 (1H, d, J = 15.3Hz), 4.20 (1H, d, J = 15.3Hz), 5.09 (1H, d, J = 12.9Hz), 5.15 (1H, d, J = 12.9 Hz), 7.21-7.28 (2H, m), 7.29-7.35 (2H, m), 7.39 (1H, s);
MS (ESI) m / z: 450 (M + H) ⁺ .

Example 19 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6- (2,3-dihydro-1H-indol-6-ylmethyl) -6 ′-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 19a) 6-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl) -1H- Indole

Compound (0.20 例 g, 0.26 mmol) obtained in Reference Example 6, 1H-indol-6-ylboronic acid (51 mg, 0.31 mmol), sodium carbonate (56 mg, 0.41 mmol), tetrakistriphenylphosphine palladium (0) The title compound (0.18 g) was obtained in the same manner as in Example 1a, using a mixed solvent of (30 mg, 0.026 mmol) and water (0.52 mL) -ethanol (0.78 mL) -toluene (1.1 mL).

Example 19b 6-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl) indoline

The compound obtained in Example 19a (0.18 g, 0.22 mmol) was dissolved in acetic acid (1.1 mL). This was cooled to 10 ° C, sodium cyanoborohydride (44 mg, 0.70 mmol) was added thereto, and the mixture was stirred at 10 ° C for 30 minutes. To this reaction solution was added chickenpox (20 mL), neutralized with potassium carbonate, and extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 → 50: 50 (concentration gradient) V / V) to obtain the title compound (0.14 g).

Example 19c (1S, 3'R, 4'S, 5'S, 6'R) -5-chloro-6- (2,3-dihydro-1H-indol-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Compound obtained in Example 19b (0.14 g, 0.18 mmol), 1,2-dichlorobenzene (0.10 mL, 0.89 mmol), 10% w / w palladium on carbon (0.14 g), and THF (6.0 mL) and methanol The title compound (54 mg) was obtained in the same manner as in Example 1b using a mixed solvent of (3.0 mL).
¹ H NMR (400MHz, CDCl ₃ ): δ2.94 (2H, t, J = 8.2Hz), 2.95 (3H, d, J = 8.2Hz), 3.38 (1H, dd, J = 10.2Hz, 8.7Hz) , 3.44 (2H, t, J = 8.2Hz), 3.67 (1H, d, J = 9.4Hz), 3.73 (1H, dd, J = 9.4Hz, 8.2 Hz), 3.79 (1H, dd, J = 10.2Hz , 3.5Hz), 3.96-4.01 (1H, m), 4.02 (2H, s), 5.06 (1H, d, J = 13.0Hz), 5.13 (1H, d, J = 13.0Hz), 6.54-6.56 (2H , m), 6.99 (1H, d, J = 6.7Hz), 7.19 (1H, s), 7.34 (1H, s);
MS (ESI) m / z: 448 (M + H) ⁺ .

Example 20 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6- (2,3-dihydro-1H-indol-5-ylmethyl) -6 ′-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

The compound (0.25 g, 0.32 mmol) obtained in Reference Example 6 and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (92 mg , 0.38 mmol) was used as a starting material in the same manner as in Example 19 to obtain the title compound (54 mg).
¹ H NMR (400 MHz, CD ₃ OD): δ1.12 (3H, d, J = 6.3 Hz), 2.93 (2H, t, J = 8.4 Hz), 3.36-3.46 (3H, m), 3.64-3.82 ( 3H, m), 3.94-4.07 (3H, m), 5.06 (1H, d, J = 12.9 Hz), 5.12 (1H, d, J = 12.9 Hz), 6.61 (1H, d, J = 7.8 Hz), 6.81-6.87 (1H, m), 6.94 (1H, s), 7.17 (1H, s), 7.33 (1H, s);
MS (TOF MS ES +) m / z: 448 (M + H) ⁺ .

Example 21 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6-[(5-methoxypyridine-2- Yl) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 21a) 5-Methoxy-2-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-tris (benzyloxy) -6 ′-[(1R ) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl Pyridine

In a nitrogen atmosphere, THF (2 mL) was added to zinc powder (65 mg, 0.99 mmol). Dibromoethane (9 μL, 0.074 μmmol) was added to this suspension, and the mixture was stirred at 70 ° C. for 1 minute. After cooling to room temperature, chlorotrimethylsilane (20 μL, 0.16 mmol) was added and stirred at room temperature for 10 minutes. To this suspension was added a THF (5 mL) solution of the compound obtained in Reference Example 6 (0.39 g, 0.50 mmol), and the mixture was stirred at room temperature for 30 minutes. Subsequently, this reaction solution was prepared in advance with tri (2-furyl) phosphine (28 mg, 0.12 mmol), tris (dibenzylideneacetone) dipalladium (0) (14 mg, 0.015 mmol), and THF (2 mL). To the mixture. Further, a THF (0.5 mL) solution of 2-bromo-5-methoxypyridine (0.12 g, こ の 0.64 mmol) was added to the reaction solution, and the mixture was stirred at 80 C for 2 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10 → 100: 0 (concentration gradient) V / V) to obtain the title compound (0.25 g).

Example 21b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6-[(5-methoxypyridine-2- Yl) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Compound obtained in Example 21a (0.13 g, 0.16 mmol), 1,2-dichlorobenzene (92 μL, 0.82 mmol), 10% w / w palladium on carbon (65 mg), THF (4.0 mL), methanol ( 2.0 mL) and in the same manner as in Example 1b, the title compound (58 mg) was obtained.
¹ H NMR (500 MHz, CDCl ₃ ): δ1.13 (3H, d, J = 6.3 Hz), 3.39 (1H, dd, J = 10.2 Hz, 8.3 Hz), 3.71 (1H, d, J = 9.5 Hz) , 3.75 (1H, dd, J = 9.5Hz, 8.3Hz), 3.80 (1H, dd, J = 10.2Hz, 3.4Hz), 3.84 (3H, s), 3.98-4.02 (1H, m), 4.24 (2H , s), 5.07 (1H, d, J = 13.2Hz), 5.14 (1H, d, J = 13.2Hz), 7.16 (1H, d, J = 8.3Hz), 7.28 (1H, s), 7.33 (1H , d, J = 2.9Hz), 7.37 (1H, s), 8.12 (1H, d, J = 2.9Hz);
MS (ESI) m / z: 438 (M + H) ⁺ .

Example 22 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6 ′-[(1R) -1-hydroxyethyl] -6-[(6-methoxypyridine-2- Yl) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Example 22a) 2-Methoxy-6-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-tris (benzyloxy) -6 ′-[(1R ) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl Pyridine

In a nitrogen atmosphere, THF (2 mL) was added to zinc powder (65 mg, 0.99 mmol). Dibromoethane (9 μL, 0.074 μmmol) was added to this suspension, and the mixture was stirred at 70 ° C. for 1 minute. This was cooled to room temperature, chlorotrimethylsilane (20 μL, 0.16 mmol) was added, and the mixture was further stirred at room temperature for 10 minutes. To this suspension was added a THF (5 mL) solution of the compound obtained in Reference Example 6 (0.39 g, 0.50 mmol), and the mixture was stirred at room temperature for 30 minutes. Subsequently, the reaction solution was prepared in advance with tri (2-furyl) phosphine (28 mg, 0.12 mmol), tris (dibenzylideneacetone) dipalladium (0) (14 mg, 0.015 mmol), and THF (2 mL). To the mixture. Further, 2-bromo-6-methoxypyridine (0.12 g, 0.64 mmol) in THF (0.5 mL) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10 → 100: 0 (concentration gradient) V / V) to obtain the title compound (0.25 g).

Example 22b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6-[(6-methoxypyridine-2- Yl) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol

Compound obtained in Example 22a (0.26 g, 0.33 mmol), 1,2-dichlorobenzene (0.19 mL, 1.7 mmol), 10% w / w palladium on carbon (0.26 g), and THF (6.0 mL) and methanol The title compound (30 mg) was obtained in the same manner as in Example 00 using a mixed solvent of (3.0 mL).
¹ H NMR (400 MHz, CDCl ₃ ): δ1.12 (3H, d, J = 6.6 Hz), 3.38 (1H, dd, J = 10.2 Hz, 8.2 Hz), 3.71 (1H, d, J = 9.4 Hz) , 3.75 (1H, dd, J = 9.4Hz, 8.2Hz), 3.80 (1H, dd, J = 10.2Hz, 3.5Hz), 3.86 (3H, s), 3.97-4.05 (1H, m), 4.16 (1H , d, J = 15.2Hz), 4.22 (1H, d, J = 15.2Hz), 5.08 (1H, d, J = 12.9Hz), 5.14 (1H, d, J = 12.9Hz), 6.59 (1H, d , J = 8.2Hz), 6.72 (1H, d, J = 7.5Hz), 7.37 (2H, s), 7.53 (1H, dd, J = 8.2Hz, 7.5Hz);
MS (FAB) m / z: 438 (M + H) ⁺ .

Example 23 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6- (3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl) -6′- [(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'- Triol

Example 23a 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-1,4-benzoxazin-3 (4H) -one

6-bromo-2H-1,4-benzoxazin-3 (4H) -one (1.14 g, 5.00 mmol), bis (pinacolato) diboron (1.52 g, 6.00 mmol), potassium acetate (1.47 g, 15.0 mmol), [ 1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (408 mg, 0.50 mmol) and 1,2-dimethoxyethane (25 mL), and in the same manner as in Reference Example 15e The title compound (1.30 g) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.34 (3H, s), 4.65 (2H, s), 6.98 (1H, d, J = 7.9 Hz), 7.22 (1H, d, J = 1.5 Hz), 7.46 (1H, dd, J = 7.9 Hz, 1.5 Hz), 7.78 (1H, brs).

Example 23b 6-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl} methyl) -2H- 1,4-benzoxazine-3 (4H) -one

The compound obtained in Reference Example 6 (770 mg, 1.00 mmol), the compound obtained in Example 23a (330 mg, 1.20 mmol), sodium carbonate (212 mg, 2.00 mmol), tetrakistriphenylphosphine palladium (0) The title compound (660 mg) was obtained in the same manner as in Example 1 using a mixed solvent of (116 mg, 0.10 mg) and toluene (15 mL) -ethanol (11 mL) -water (2 mL). .

Example 23c 6-({(1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ′, 4 ′, 5 ′, 6′-tetrahydro-3H-spiro [2-benzofuran-1,2′-pyran] -6-yl} methyl) -3, 4-dihydro-2H-1,4-benzoxazine

The compound obtained in Example 23b (510 mg, 0.61 mmol) was dissolved in THF (12 mL), and a solution of lithium aluminum hydride in THF (1.0 M, 2.14 mL, 2.14 mL) at -78 ° C under a nitrogen atmosphere. mmol) was added dropwise. The reaction mixture was stirred for 2 hours while gradually warming to room temperature, further stirred for 1 hour at 50 ° C., and then allowed to stand overnight. The reaction mixture was ice-cooled, and water (1 mL), 10% w / v Rochelle salt aqueous solution (2 mL), 1 M sodium hydroxide (2 mL), and diethyl ether (30 mL) were added. Stir for hours. The reaction mixture was washed with saturated brine (10 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 90: 10 → 60: 40 (concentration gradient) V / V) to obtain the title compound (250 mg).

Example 23d) (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6- (3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl) -6′- [(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'- Triol

The compound obtained in Example 23c (130 mg, 0.16 mmol), 10% w / w palladium on carbon (130 mg), 1,2-dichlorobenzene (0.09 mL, 0.8 mmol), and THF (4.0 mL) and methanol The title compound (70 mg) was obtained in the same manner as in Example 1b using a mixed solvent of (2.0 mL).
¹ H NMR (400MHz, MeOH-d4): δ1.13 (3H, d, J = 6.2Hz), 3.34-3.43 (3H, m), 3.68 (1H, d, J = 9.8Hz), 3.70-3.76 ( 1H, m), 3.79 (1H, dd, J = 10.1Hz, 3.5Hz), 3.96-4.03 (3H, m), 4.18-4.23 (2H, m), 5.06 (1H, d, J = 12.8 Hz), 5.13 (1H, d, J = 12.8 Hz), 6.57-6.62 (2H, m), 6.67 (1H, d, J = 8.6Hz), 7.21 (1H, s), 7.35 (1H, s);
MS (ESI) m / z: 464 (M + H) ⁺ .

Example 24 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-Chloro-6- (4-ethylbenzyl) -6 ′-[(1R) -1-hydroxyethyl] -3 ′ , 4 ', 5', 6'-Tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol

Example 24a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-chloro-6- (4-ethylbenzyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]

Compound (0.63 g, 0.82 mmol) obtained in Reference Example 6, 4-ethylphenylboronic acid (0.14 g, 0.90 mmol), sodium carbonate (0.18 g, 1.70 mmol), tetrakistriphenylphosphine palladium (0) (95 mg, 0.082 mmol) and a mixed solvent of toluene (3.4 mL) -ethanol (2.5 mL) -water (1.7 mL) were used to obtain the title compound (0.55 g) in the same manner as in Example 1a.

Example 24b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6- (4-ethylbenzyl) -6 ′-[(1R) -1-hydroxyethyl] -3 ′ , 4 ', 5', 6'-Tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol

Compound obtained in Example 24a (0.25 g, 0.32 mmol), 1,2-dichlorobenzene (0.18 mL, 1.6 mmol), 10% w / w palladium on carbon (0.25 g), and THF (12 mL) and methanol The title compound (0.13 g) was obtained in the same manner as in Example 1b using a mixed solvent of (6.0 mL).
¹ H NMR (400 MHz, MeOH-d4): δ1.12 (3H, d, J = 6.7 Hz), 1.20 (3H, t, J = 7.6 Hz), 2.59 (2H, q, J = 7.6 Hz), 3.37 (1H, dd, J = 10.1 Hz, 8.4 Hz), 3.67 (1H, d, J = 9.4 Hz), 3.73 (1H, dd, J = 9.4 Hz, 8.4 Hz), 3.79 (1H, dd, J = 10.1 Hz, 3.5 Hz), 3.97-4.03 (1H, m), 4.05-4.13 (2H, m), 5.07 (1H, d, J = 13.3Hz), 5.13 (1H, d, J = 13.3Hz), 7.10 ( 4H, s), 7.21 (1H, s), 7.36 (1H, s);
MS (FAB) m / z: 435 (M + H) ⁺ .

(Examples 25 to 63)
The compounds of Examples 25 to 63 were obtained with reference to the above Reference Examples and Examples.

(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 was performed using DMEM medium containing 250 μg / ml G418, 1 μg / ml puromycin, 3 μM KGT-1075, and 10% FBS.

3) Measurement of SGLT1 inhibitory activity HEK-SGLT1 cells were suspended in DMEM medium containing 250 μg / ml G418, 1 μg / 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 that inhibits the sugar uptake activity by 50% was examined. The results are shown in Table 11.

(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 was performed using DMEM medium containing 250 μg / ml G418, 1 μg / ml puromycin, 3 μM KGT-1075, and 10% FBS.

3) Measurement of SGLT2 inhibitory activity HEK-SGLT2 cells were suspended in DMEM medium containing 250 μg / ml G418, 1 μg / 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 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 11.

(Test Example 3) Urinary glucose excretion test SGLT2 inhibitory activity in vivo is examined using as an index the excretion of urinary glucose, which occurs mainly as a result of inhibiting SGLT2. Each test compound is suspended or dissolved in a solvent (such as 0.5% methylcellulose solution or a solution of propylene glycol and Tween 80 mixed at a ratio of 4: 1) to a dosage of 1 to 10 mL / kg, and multiple doses (preferably 0.03-10mg / kg) is orally administered to various animals (mouse, rat, dog, monkey, etc.). The same amount of solvent is orally administered to the control group. By collecting urine over time and calculating urinary glucose excretion from urine volume and glucose concentration, the SGLT2 inhibitory activity in vivo of each test compound is evaluated.

(Test Example 4) Antihyperglycemic test after glucose load or postprandial Evaluate the inhibitory effect of each test compound on hyperglycemia after glucose load or postprandial, and detect the total increase in blood glucose suppression based on SGLT1 and SGLT2 inhibition can do. Furthermore, SGLT1-specific inhibitory activity can be evaluated by examining the blood glucose elevation-inhibiting effect of the test compound in the presence of a selective SGLT2 inhibitor (such as dapagliflozin). Mice, rats, dogs and monkeys are preferred as animals used in the test.

For example, dapagliflozin was suspended in a solvent (0.5% methylcellulose solution) to a dose of 1-10 mL / kg and orally administered to C57BL / 6NCrlCrlj mice (7-10 weeks old, male) fasted overnight. To do. Furthermore, each test compound is suspended or dissolved in a solvent (such as a 0.5% methylcellulose solution or a solution prepared by mixing propylene glycol and Tween 80 at a ratio of 4: 1) to a dose of 1 to 10 mL / kg, and multiple doses ( Preferably, it is orally administered (within a range of 0.03 to 10 mg / kg). The same amount of solvent is orally administered to the control group. After a certain period of time (for example, after 30 minutes), a certain amount of glucose (eg 2 g / 10 mL / kg) is orally administered. Further, the blood glucose level is measured at a certain time (for example, after 30 minutes). Using the rate of decrease from the increase in blood glucose in the control group as an index, the SGLT1 inhibitory activity in vivo of each test compound in mice is evaluated.

(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.

Since the compound of the present invention exhibits excellent human SGLT1 and / or SGLT2 inhibitory activity, type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, IGT, diabetes related diseases (obesity, hyperlipidemia) , Hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout), or diabetic complications (retina) , Nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) are useful as an active ingredient of a pharmaceutical composition for treating or preventing.

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 (11)

1. Formula (I):
   

   

   
   Wherein R ¹ is a methyl or ethyl group,
   R ² is a chlorine atom, a bromine atom, a C1-C3 alkyl group or a hydroxy C1-C3 alkyl group,
   Ring A may have one or two substituents selected from substituent group α, wherein:
   

   

   
   A ring selected from the group consisting of
   Substituent group α is a halogen atom, C1-C3 alkyl group, C1-C3 alkoxy group, hydroxy C1-C3 alkyl group, hydroxy C1-C3 alkoxy group or mono (C1-C3 alkyl) amino group)
   Or a pharmaceutically acceptable salt thereof.
2. The monovalent group of ring A may have one or two substituents selected from substituent group α, the following:
   

   

   The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is one group selected from the group consisting of:
3. The monovalent group of ring A may have one substituent selected from substituent group α,
   

   

   
   The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ¹ is a methyl group.
5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ² is a methyl group, a chlorine atom or a hydroxymethyl group.
6. Less than:
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1 -Hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6- (2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6- (1-Benzofuran-5-ylmethyl) -5-chloro-6 '-[(1R) -1-hydroxyethyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6- (4-Ethylbenzyl) -6 '-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6- (4-Ethoxybenzyl) -6 '-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6- (2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -5- (hydroxymethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (3,4-dihydro-2H-chromen-7-ylmethyl) -6 '-[(1R) -1-hydroxyethyl ] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran-3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 '-[(1R) -1 -Hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [4- (3-hydroxypropyl) benzyl] -3' , 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [3- (3-hydroxypropyl) benzyl] -3' , 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6- [4- (2-hydroxyethoxy) benzyl] -6 '-[(1R) -1-hydroxyethyl] -5-methyl-3' , 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [4- (methylamino) benzyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -6 '-[(1R) -1-hydroxyethyl] -5-methyl-6- [4- (methylamino) benzyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- (1,2,3,4-tetrahydroquinoline-6- Ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (3,4-dihydro-2H-1,4-benzoxazin-7-ylmethyl) -6 '-[(1R)- 1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6-{[6- (methylamino) pyridin-3-yl] Methyl} -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [3- (methylamino) benzyl] -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6- [3-methyl-4- (methylamino) benzyl]- 3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1H-indol-6-ylmethyl) -6 '-[(1R) -1-hydroxyethyl ] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6- (2,3-dihydro-1H-indol-5-ylmethyl) -6 '-[(1R) -1-hydroxyethyl ] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6-[(5-methoxypyridin-2-yl) methyl]- 3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol, and
   (1S, 3'R, 4'S, 5'S, 6'R) -5-Chloro-6 '-[(1R) -1-hydroxyethyl] -6-[(6-methoxypyridin-2-yl) methyl]- 3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol,
   A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition according to claim 7, for treating type 1 diabetes, type 2 diabetes or obesity.
9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition.
10. A method for treating a disease, comprising administering the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof to a mammal.
11. The method according to claim 10, wherein the mammal is a human.