JP2017105748A - Method for producing 1,5-anhydro-1-substituted phenyl-d-glucitol compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel method for producing 1,5-anhydro-1-substituted phenyl-D-glucitol compounds useful as medicines having the action of inhibiting sodium-dependent glucose cotransporters 1.SOLUTION: The present invention provides a method for producing 1,5-anhydro-1-substituted phenyl-D-glucitol compounds represented by formula (XI), wherein, compounds represented by formula (II) are converted through a plurality of steps to produce the compounds represented by formula (XI).SELECTED DRAWING: None

Description

The present invention relates to sodium-dependent glucose cotransporter 1 (sodium-dependent glucose
The present invention relates to a 1,5-anhydro-1-substituted phenyl-D-glucitol compound useful as a pharmaceutical having inhibitory activity (hereinafter referred to as cotransporter 1, hereinafter referred to as SGLT1), and a method for producing an intermediate thereof. More specifically, (1S) -1,5-anhydro-1- {5-[(4-{(1E) -4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl) -1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl } -D-glucitol and its production intermediate (1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl ] 2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol.

  SGLT1 is expressed in small intestinal mucosal epithelium, renal proximal tubule, skeletal muscle, myocardium, trachea and brain, and is an active transporting sugar transporter involved in absorption and uptake of sugar into cells. SGLT1 is particularly abundant in the small intestine and is involved in the absorption of glucose and galactose produced by digestion of carbohydrates taken in the diet into cells. Since the compound that inhibits the function of SGLT1 expressed in the small intestine suppresses the absorption of sugar, pharmaceutical development has been carried out as being useful as a therapeutic agent for diabetes (Patent Documents 1 to 3). Patent Document 4 discloses that a compound that inhibits SGLT1 is useful for the prevention or treatment of constipation.

(1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2- described in Patent Documents 1 to 4 The method for producing methoxy-4- (propan-2-yl) phenyl} -D-glucitol (hereinafter referred to as compound (I)) comprises an ultra-low temperature (−80 to −70 ° C.) reaction step and silica gel column chromatography purification. It was not a manufacturing method suitable for industrial mass production, including processes.
For example, scheme 1 shows a method for producing compound (I) disclosed in Patent Document 4.
Scheme 1

In addition, (1S) -1,5-anhydro-1- {5-[(4-{(1E) -4-[(1-{[2- (dimethylamino) ethyl) described in Patent Documents 1 to 4 is used. Amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy-4- ( The method for producing propan-2-yl) phenyl} -D-glucitol (hereinafter referred to as compound (XI)) also includes a silica gel column chromatography purification step and cannot be said to be a production method suitable for industrial mass production. It was.
For example, scheme 2 shows a method for producing compound (XI) disclosed in Patent Document 2 and Patent Document 4. Although compound (XI) is an amorphous compound, an ethanol solvate of compound (XI) can be obtained as crystals. The ethanol solvate of compound (XI) can be easily changed to other crystal forms (A form, B form, C form, dihydrate; Patent Document 2).
Scheme 2

International Publication No. 2010/095768 Pamphlet International Publication No. 2012/023598 Pamphlet JP 2012-62308 A International Publication No. 2014/119787 Pamphlet International Publication No. 2012/140120 Pamphlet

Organic Letters, 2012, vol. 6, 1480-1483.

  An object of the present invention is to provide a production method suitable for industrial mass production of a 1,5-anhydro-1-substituted phenyl-D-glucitol compound useful as a medicine.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have devised a method for producing compound (XI) that avoids the ultra-low temperature reaction step and the silica gel column chromatography purification step via compound (I) as a production intermediate. The headline and the present invention were completed.

That is, the present invention is as follows.
(1) A method for producing a 1,5-anhydro-1-substituted phenyl-D-glucitol compound represented by the formula (XI),

（ｉ）式（II）で表される化合物を式（III）で表される化合物に変換する工程と、

(I) converting the compound represented by formula (II) into the compound represented by formula (III);

（ii）前記式（III）で表される化合物を式（IV）で表される化合物に変換する工程と、

(Ii) converting the compound represented by the formula (III) into a compound represented by the formula (IV);

（iii）前記式（IV）で表される化合物を式（V）で表される化合物に変換する工程と、

(Iii) converting the compound represented by the formula (IV) into a compound represented by the formula (V);

（iv）前記式（V）で表される化合物を式（VI）で表される化合物に変換する工程と、

(Iv) converting the compound represented by the formula (V) into a compound represented by the formula (VI);

（v）前記式（VI）で表される化合物を式（VII）で表される化合物に変換する工程と、

(V) converting the compound represented by the formula (VI) into a compound represented by the formula (VII);

（vi）前記式（VII）で表される化合物を式（XII）で表される化合物に変換する工程と、

(Vi) converting the compound represented by the formula (VII) into a compound represented by the formula (XII);

（vii）前記式（XII）で表される化合物を式（XIII）で表される化合物に変換する工程と、

(Vii) converting the compound represented by the formula (XII) into a compound represented by the formula (XIII);

（viii）前記式（XIII）で表される化合物を式（Ｉ）で表される化合物に変換する工程と、

(Viii) converting the compound represented by the formula (XIII) into a compound represented by the formula (I);

（ix）前記式（Ｉ）で表される化合物を式（XIV）で表される化合物に変換する工程と、

(Ix) converting the compound represented by the formula (I) into a compound represented by the formula (XIV);

（ｘ）前記式（XIV）で表される化合物を式（XV）で表される化合物に変換する工程と、

(X) converting the compound represented by the formula (XIV) into a compound represented by the formula (XV);

（xi）前記式（XV）で表される化合物を前記式（XI）で表される化合物に変換する工程
を含むことを特徴とする１，５−アンヒドロ−１−置換フェニル−Ｄ−グルシトール化合物の製造方法。
（２）式（Ｉ）で表される１，５−アンヒドロ−１−置換フェニル−Ｄ−グルシトール化合物の製造方法であって、

(Xi) 1,5-anhydro-1-substituted phenyl-D-glucitol compound comprising the step of converting the compound represented by the formula (XV) into the compound represented by the formula (XI) Manufacturing method.
(2) A method for producing a 1,5-anhydro-1-substituted phenyl-D-glucitol compound represented by formula (I),

（ｉ）式（II）で表される化合物を式（III）で表される化合物に変換する工程と、

(I) converting the compound represented by formula (II) into the compound represented by formula (III);

（ii）前記式（III）で表される化合物を式（IV）で表される化合物に変換する工程と、

(Ii) converting the compound represented by the formula (III) into a compound represented by the formula (IV);

（iii）前記式（IV）で表される化合物を式（Ｖ）で表される化合物に変換する工程と、

(Iii) converting the compound represented by the formula (IV) into a compound represented by the formula (V);

（iv）前記式（Ｖ）で表される化合物を式（VI）で表される化合物に変換する工程と、

(Iv) converting the compound represented by the formula (V) into a compound represented by the formula (VI);

（ｖ）前記式（VI）で表される化合物を式（VII）で表される化合物に変換する工程と、

(V) converting the compound represented by the formula (VI) into a compound represented by the formula (VII);

（vi）前記式（VII）で表される化合物を式（VIII）で表される化合物に変換する工程と、

(Vi) converting the compound represented by the formula (VII) into a compound represented by the formula (VIII);

（vii）前記式（VIII）で表される化合物を式（IX）で表される化合物に変換する工程と、

(Vii) converting the compound represented by the formula (VIII) into a compound represented by the formula (IX);

（viii）前記式（IX）で表される化合物を式（Ｘ）で表される化合物に変換する工程と、

(Viii) converting the compound represented by the formula (IX) into a compound represented by the formula (X);

（ix）前記式（Ｘ）で表される化合物を前記式（Ｉ）で表される化合物に変換する工程
を含むことを特徴とする１，５−アンヒドロ−１−置換フェニル−Ｄ−グルシトール化合物の製造方法。

(Ix) 1,5-anhydro-1-substituted phenyl-D-glucitol compound comprising the step of converting the compound represented by the formula (X) into the compound represented by the formula (I) Manufacturing method.

  INDUSTRIAL APPLICABILITY According to the present invention, industrial mass production of compound (XI) useful as a pharmaceutical having SGLT1 inhibitory activity has become possible.

  Hereinafter, specific embodiments of the present invention, definitions of substituents and the like will be described.

  In the present invention, “n” is normal, “i” is iso, “s” and “sec” are secondary, and “t” and “tert” are tertiary. ), “C” represents cyclo, “o” represents ortho, “m” represents meta, and “p” represents para. “Ac” represents acetyl, “TMS” represents trimethylsilyl, and “Piv” represents pivaloyl.

  Hereinafter, the form for implementing this invention is demonstrated concretely.

  The present invention can be carried out, for example, by the methods shown in the following schemes 3 to 5, but is not construed as being limited by this method.

The compound represented by the formula (I) which is a production intermediate can be obtained by the method shown in the following scheme 3.
Scheme 3

Step (i):
Compound (2) can be obtained by reacting compound (1) with a methylating agent in an inert solvent in the presence or absence of an additive. Compound (1) as a starting material is available as a commercial product.
As the methylating agent, for example, methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, methyl lithium and the like can be used.
Examples of the inert solvent include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran. A hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, or a mixed solvent thereof can be used.
Examples of the additive include cerium (III) chloride, zinc chloride, lanthanum chloride (III) bis (lithium chloride) complex, and the like.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of −40 to 100 ° C., more preferably in the range of 20 to 40 ° C.
The amount of the methylating agent used can be in the range of 2 to 6 molar equivalents relative to the starting compound (1), preferably in the range of 2.5 to 4 molar equivalents, more preferably 2. It is in the range of 5 to 3 molar equivalents.
The solvent can be used in an amount of 1 to 100 times by mass, preferably 1 to 30 times by mass, more preferably 1 to 10 times by mass of the raw material compound (1). It is a range.
The compound (2) can be obtained as a refined product by recrystallization, a refined product by a method such as reslurry or chromatography, or as an unrefined product.

Step (ii):
Compound (3) can be obtained by reacting compound (2) with a reducing agent and an acid in an inert solvent or in the absence of a solvent.
Examples of the reducing agent include triethylsilane, triisopropylsilane, triphenylsilane, tert-butyldimethylsilane, chlorodimethylsilane, chlorodiisopropylsilane, dimethylphenylsilane, 1,1,3,3-tetramethyldisiloxane, and the like. Can be used.
Examples of the acid include Lewis acids such as boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, aluminum chloride, trifluoromethanesulfonic acid trimethylsilyl ester, or trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid. Bronsted acids such as can be used.
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, Tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, ether solvents such as 1,2-dimethoxyethane, diethoxymethane, ethyl acetate, acetonitrile, N, N-dimethylformamide, N-methyl Pyrrolidone, dimethyl sulfoxide, acetic acid, water, or a mixed solvent thereof can be used.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 60 ° C.
The reducing agent can be used in an amount of 1 to 10 molar equivalents relative to the raw material compound (2), preferably 1 to 5 molar equivalents, more preferably 1.5 to 3 A range of molar equivalents.
The amount of the acid used can be in the range of 1 to 20 molar equivalents relative to the raw material compound (2), preferably in the range of 1 to 10 molar equivalents, more preferably 1.5 to 5 moles. Equivalent range.
The amount of the solvent used can be used in the range of 1 to 100 times by mass relative to the raw material compound (2), preferably in the range of 1 to 30 times by mass, more preferably 1 to 10 times by mass It is a range.
Compound (3) can be obtained as a purified product by a method such as distillation or chromatography, or an unpurified product. Compound (3) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

Step (iii):
Compound (3) is reacted with magnesium in an inert solvent in the presence of an activator to prepare Grignard reagent (4), and then reacted with 4-bromobenzaldehyde (5) to obtain compound (6). Can do.
As the activator, for example, iodine, 1,2-dibromoethane, diisobutylaluminum hydride and the like can be used.
Examples of the inert solvent include ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, A hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, cyclohexane, or a mixed solvent thereof can be used.
The reaction temperature during the preparation of the Grignard reagent (4) is usually from 0 ° C. to the boiling point of the solvent used, but is preferably in the range of 20 to 100 ° C., more preferably in the range of 40 to 80 ° C. .
The reaction temperature of the Grignard reagent (4) and the compound (5) is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of −20 to 100 ° C., more preferably 0 to 30. It is in the range of ° C.
The usage-amount of magnesium can be used in the range of 1-5 molar equivalent with respect to the compound (3) of a raw material, Preferably it is the range of 1-3 molar equivalent, More preferably, it is 1-1.2 mol Equivalent range.
The use amount of the activator can be used in the range of 0.0001 to 1 molar equivalent, preferably in the range of 0.001 to 0.1 molar equivalent, relative to the starting compound (3). Preferably it is the range of 0.001-0.01 molar equivalent.
The amount of the compound (5) used can be in the range of 1 to 3 molar equivalents relative to the starting compound (3), preferably in the range of 1 to 1.5 molar equivalents, more preferably 1 It is the range of -1.1 molar equivalent.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably in the range of 1 to 30 times by mass, more preferably 1 to the compound (3) and compound (5) of the raw material. It is the range of 10 mass times.
Compound (6) can be obtained as a purified product by a method such as distillation or chromatography, or an unpurified product. Compound (6) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

Step (iv):
Compound (7) can be obtained by reacting compound (6) with a reducing agent and an acid in an inert solvent or in the absence of a solvent.
Examples of the reducing agent include triethylsilane, triisopropylsilane, triphenylsilane, tert-butyldimethylsilane, chlorodimethylsilane, chlorodiisopropylsilane, dimethylphenylsilane, 1,1,3,3-tetramethyldisiloxane, and the like. Can be used.
Examples of the acid include Lewis acids such as boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, aluminum chloride, trifluoromethanesulfonic acid trimethylsilyl ester, or trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid. Bronsted acids such as can be used.
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, Tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, ether solvents such as 1,2-dimethoxyethane, diethoxymethane, ethyl acetate, acetonitrile, N, N-dimethylformamide, N-methyl Pyrrolidone, dimethyl sulfoxide, acetic acid, water, or a mixed solvent thereof can be used.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 60 ° C.
The reducing agent can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, more preferably 1 to 2 molar equivalents, relative to the starting compound (6). Range.
The amount of the acid used can be used in the range of 1 to 10 molar equivalents relative to the starting compound (6), preferably in the range of 1 to 5 molar equivalents, more preferably in the range of 1 to 3 molar equivalents. It is a range.
The amount of the solvent used can be used in the range of 1 to 100 times by mass with respect to the raw material compound (6), preferably in the range of 1 to 30 times by mass, more preferably 1 to 10 times by mass. It is a range.
Compound (7) can be obtained as a purified product by a method such as distillation or chromatography, or an unpurified product. Compound (7) can be used as a raw material for the next step without being purified as a concentrated residue after the reaction post-treatment or without being concentrated as a post-treatment solution.

Step (v):
Compound (8) can be obtained by reacting compound (7) with an iodinating agent in an inert solvent.
Examples of the iodinating agent include iodine monochloride, pyridine iodine monochloride, iodine-hydrogen peroxide, iodine-potassium iodate-acid, iodine-ammonium cerium (IV) nitrate, potassium iodide- Hydrogen peroxide, sodium iodide-N-chlorosuccinimide, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin-acid, N-iodosaccharin, benzyltrimethylammonium dichloroiodate-zinc chloride Etc. can be used.
As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid and the like can be used.
Examples of the inert solvent include alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, toluene, and xylene. , Hydrocarbon solvents such as benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxy Ether solvents such as methane, ethyl acetate, isopropyl acetate, acetone, 2-butanone, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, Methyl sulfoxide, acetic acid, water or a mixed solvent thereof and the like can be used.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 80 ° C.
The amount of the iodizing agent can be used in the range of 0.1 to 10 molar equivalents relative to the raw material compound (7), preferably in the range of 0.1 to 5 molar equivalents, and more preferably Is in the range of 0.2 to 2 molar equivalents.
The amount of the acid used can be 0.1 to 10 molar equivalents relative to the starting compound (7), preferably 0.1 to 5 molar equivalents, more preferably 0.00. It is in the range of 1 to 3 molar equivalents.
The amount of the solvent used can be used in the range of 1 to 100 times by mass relative to the raw material compound (7), preferably in the range of 1 to 30 times by mass, more preferably 1 to 10 times by mass. It is a range.
Compound (8) can be obtained not only as a purified product by recrystallization, but also as a purified product by a method such as reslurry or chromatography, and can also be obtained as an unrefined product.

Step (vi):
Compound (11) can be obtained by reacting compound (8) with an organic magnesium reagent in an inert solvent to prepare Grignard reagent (9) and then reacting with compound (10). In addition, a compound (10) is compoundable by the method of patent document US2002 / 0137903A1.
Examples of the organic magnesium reagent include isopropylmagnesium chloride, isopropylmagnesium chloride-lithium chloride complex, 2-butylmagnesium chloride-lithium chloride complex, isopropylmagnesium chloride-bis [2- (N, N-dimethylamino) ethyl] ether complex. Etc. can be used.
Examples of the inert solvent include ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, A hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, cyclohexane, or a mixed solvent thereof can be used.
The reaction temperature during the preparation of the Grignard reagent (9) is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of −40 to 20 ° C., more preferably −20 to 0 ° C. It is a range. The reaction temperature of the Grignard reagent (9) and the compound (10) is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of −40 to 20 ° C., more preferably −20 to 20 ° C. It is in the range of 0 ° C.
The amount of the organomagnesium reagent used can be used in the range of 0.9 to 2 molar equivalents relative to the starting compound (8), preferably in the range of 0.95 to 1.1 molar equivalents, and more Preferably it is the range of 0.95-1.05 molar equivalent.
The compound (10) can be used in an amount of 0.9 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents, more preferably relative to the starting compound (8). Is in the range of 1 to 1.1 molar equivalents.
The usage-amount of a solvent can be used in the range of 1-100 mass times with respect to the raw material compound (8) and compound (10), Preferably it is the range of 1-30 mass times, More preferably, it is 1 It is the range of 10 mass times.
Compound (11) should be used as a raw material for the next step without being purified as a concentrated residue after post-treatment of the reaction, without being concentrated as a post-treatment solution, or without post-treatment. Can do.

Step (vii):
Compound (12) can be obtained by reacting compound (11) in the presence of an acid in a methanol solvent.
Examples of the acid that can be used include hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, methanesulfonic acid, paratoluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and the like.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 50 ° C.
The acid can be used in an amount of 0.01 to 10 molar equivalents relative to the starting compound (11), preferably 0.1 to 5 molar equivalents, more preferably 0.00. It is in the range of 2 to 2 molar equivalents.
The amount of methanol used can be used in the range of 1 to 100 times by mass with respect to the raw material compound (11), preferably in the range of 1 to 30 times by mass, more preferably 1 to 10 times by mass. It is a range.
Compound (12) can be obtained as a refined product by recrystallization, a refined product by a method such as reslurry or chromatography, or as an unrefined product. The compound (12) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

Step (viii):
Compound (13) can be obtained by reacting compound (12) with an acetylating agent in the presence of a base in an inert solvent.
As the acetylating agent, for example, acetyl chloride, acetyl bromide, acetic anhydride and the like can be used.
As the base, for example, pyridine, collidine, 2,6-lutidine, triethylamine, diisopropylethylamine and the like can be used. Pyridine can also be used as a solvent. 4-Dimethylaminopyridine can be used as a catalyst.
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, Tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane and other ether solvents, ethyl acetate, isopropyl acetate, acetone, 2-butanone, acetonitrile, N , N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent thereof can be used.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 40 ° C.
The amount of the acetylating agent can be used in the range of 4 to 30 molar equivalents relative to the starting compound (12), preferably in the range of 6 to 20 molar equivalents, more preferably 8 to 15 moles. Equivalent range.
The amount of the base used can be 4 to 30 molar equivalents relative to the starting compound (12), preferably 6 to 20 molar equivalents, more preferably 8 to 15 molar equivalents. It is a range.
The solvent can be used in an amount of 1 to 100 times by mass, preferably 1 to 30 times by mass, more preferably 1 to 10 times by mass, relative to the raw material compound (12). It is a range.
Compound (13) can be obtained as a purified product by a method such as chromatography or an unpurified product. Compound (13) can be used as a starting material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

Process (ix):
Compound (I) can be obtained by reacting compound (13) with a reducing agent and an acid in an inert solvent in the presence or absence of water.
Examples of the reducing agent include triethylsilane, triisopropylsilane, triphenylsilane, tert-butyldimethylsilane, chlorodimethylsilane, chlorodiisopropylsilane, dimethylphenylsilane, 1,1,3,3-tetramethyldisiloxane, and the like. Can be used.
Examples of the acid include Lewis acids such as boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, aluminum chloride, trifluoromethanesulfonic acid trimethylsilyl ester, or trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid. Bronsted acids such as can be used.
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, Tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, ether solvents such as 1,2-dimethoxyethane, diethoxymethane, ethyl acetate, acetonitrile, N, N-dimethylformamide, N-methyl Pyrrolidone, dimethyl sulfoxide, acetic acid, water, or a mixed solvent thereof can be used.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 50 ° C.
The reducing agent can be used in an amount of 1 to 10 molar equivalents relative to the starting compound (13), preferably 1 to 5 molar equivalents, more preferably 1 to 2 molar equivalents. Range.
The amount of the acid used can be in the range of 1 to 20 molar equivalents relative to the starting compound (13), preferably in the range of 1 to 10 molar equivalents, more preferably 1 to 5 molar equivalents. It is a range.
The amount of water used can be in the range of 0.5 to 5 molar equivalents relative to the starting compound (13), preferably in the range of 1 to 2 molar equivalents, more preferably 1 molar equivalent. is there.
The amount of the solvent used can be used in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, more preferably 1 to 10 times by mass with respect to the raw material compound (13). It is a range.
Compound (I) can be obtained not only as a purified product by recrystallization, but also as a purified product by a method such as reslurry or chromatography, and can also be obtained as an unrefined product. Compound (I) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

The compound represented by the formula (I) can also be obtained by the method shown in the following scheme 4.
Scheme 4

Step (i):
A diaryl zinc reagent (14) can be obtained by reacting a zinc halide with an organolithium reagent in an inert solvent and then reacting with the compound (8). Subsequently, the compound (16) can be obtained by adding an ether solvent to the compound (14) and reacting with the compound (15).
Alternatively, the compound (8) is reacted with an organolithium reagent in an inert solvent and then reacted with a dibutyl ether solution of zinc halide and lithium bromide to obtain a diarylzinc reagent (14). Compound (16) can also be obtained by reacting with (15).
As the zinc halide, for example, zinc chloride, zinc bromide, and zinc iodide can be used.
Examples of the inert solvent include hydrocarbon solvents such as toluene, xylene, and benzene, and these hydrocarbon solvents and tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl. A mixed solvent with an ether solvent such as methyl ether or cyclopentyl methyl ether can be used.
As the organic lithium reagent, for example, methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium and the like can be used.
As the ether solvent, for example, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether and the like can be used.
Compound (15) can be synthesized by the methods described in Patent Document 5 and Non-Patent Document 1.
The reaction temperature during the preparation of the diarylzinc reagent (14) can usually be from -80 ° C to the boiling point of the solvent used, but is preferably in the range of -40 to 30 ° C, more preferably -20 to 30 ° C. Range.
The reaction temperature of the diaryl zinc reagent (14) and the compound (15) is usually from 0 ° C. to the boiling point of the solvent used, but is preferably in the range of 50 to 110 ° C., more preferably 90 to 100 ° C. Range.
The amount of zinc halide used can be used in the range of 0.3 to 2 molar equivalents relative to the starting compound (8), preferably in the range of 0.5 to 1 molar equivalents, and more preferably The range is 0.5 to 0.6 molar equivalent.
The amount of the organic lithium reagent used can be 0.9 to 2 molar equivalents relative to the starting compound (8), preferably 0.9 to 1.5 molar equivalents, and more Preferably it is the range of 1-1.1 molar equivalent.
The amount of lithium bromide used can be in the range of 0.3 to 2 molar equivalents relative to the starting compound (8), preferably in the range of 0.5 to 1 molar equivalents, more preferably The range is 0.5 to 0.6 molar equivalent.
The amount of the compound (15) used can be used in the range of 0.9 to 3 molar equivalents relative to the starting compound (8), preferably in the range of 1 to 1.5 molar equivalents, and more preferably Is in the range of 1 to 1.1 molar equivalents.
The amount of the solvent used can be used in the range of 0.5 to 100 times by mass, preferably in the range of 0.5 to 30 times by mass with respect to the raw material compound (8) and compound (15), More preferably, it is the range of 0.5-10 mass times.
Compound (16) can be obtained as a purified product by a method such as chromatography or an unpurified product. Compound (16) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

Step (ii):
Compound (17) can be obtained by reacting compound (16) in the presence of a base or acid in a methanol solvent or a methanol-water mixed solvent.
As the base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide and the like can be used.
Examples of the acid that can be used include hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, methanesulfonic acid, paratoluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and the like.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 50 to 80 ° C.
The amount of the base or acid used can be in the range of 0.01 to 10 molar equivalents relative to the raw material compound (16), preferably in the range of 0.1 to 5 molar equivalents, more preferably The range is 0.2 to 2 molar equivalents.
The amount of the solvent used can be 1 to 100 times by mass, preferably 1 to 30 times by mass, more preferably 1 to 10 times by mass with respect to the raw material compound (16). It is a range.
Compound (17) can be obtained not only as a purified product by recrystallization, but also as a purified product by a method such as reslurry or chromatography, and can also be obtained as an unpurified product. Compound (17) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

Step (iii):
Compound (I) can be obtained by reacting compound (17) with an acetylating agent in the presence of a base in an inert solvent.
As the acetylating agent, for example, acetyl chloride, acetyl bromide, acetic anhydride and the like can be used.
As the base, for example, pyridine, collidine, 2,6-lutidine, triethylamine, diisopropylethylamine and the like can be used. Pyridine can also be used as a solvent. 4-Dimethylaminopyridine can be used as a catalyst.
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, Tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane and other ether solvents, ethyl acetate, isopropyl acetate, acetone, 2-butanone, methyl isobutyl ketone , Acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent thereof can be used.
The reaction temperature is usually from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 0 to 40 ° C.
The amount of the acetylating agent can be used in the range of 4 to 30 molar equivalents relative to the starting compound (17), preferably in the range of 6 to 20 molar equivalents, more preferably 8 to 15 moles. Equivalent range.
The amount of the base used can be 4 to 30 molar equivalents relative to the starting compound (17), preferably 6 to 20 molar equivalents, more preferably 8 to 15 molar equivalents. It is a range.
The amount of the solvent used can be used in the range of 1 to 100 times by mass, preferably in the range of 1 to 30 times by mass, more preferably 1 to 10 times by mass with respect to the starting compound (17). It is a range.
As described above, compound (I) can be obtained as a refined product by recrystallization, a refined product by a method such as reslurry or chromatography, and can also be obtained as an unrefined product. Compound (I) can be used as a raw material for the next step without being purified as a concentrated residue after the post-treatment of the reaction or without being concentrated as a post-treatment solution.

The compound represented by the formula (XI) can be obtained by the method shown in the following scheme 5.
Scheme 5

Step (i):
Compound (I) is reacted with Compound (18) in the presence of a palladium catalyst, a phosphine ligand and a base in an inert solvent (Heck reaction), and then a salt is formed with n-hexylamine in an inert solvent. (19) can be obtained.
Compound (18) can be synthesized by the method described in the literature (Tetrahedron, 1998, vol. 54, 4357-4366).
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, Tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane and other ether solvents, ethyl acetate, isopropyl acetate, acetone, 2-butanone, methyl isobutyl ketone , Acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or a mixed solvent thereof is used. Rukoto can.
Examples of the palladium catalyst include palladium acetate, palladium chloride, palladium carbon, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium dichloride, Bis (benzonitrile) palladium dichloride, bis (acetonitrile) palladium dichloride, and the like can be used.
As the phosphine ligand, for example, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, 1,3-bis (diphenylphosphino) propane and the like can be used.
As the base, for example, triethylamine, tri-n-butylamine, N, N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate, potassium tert-butoxide and the like can be used.
The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 60 to 100 ° C.
The amount of compound (18) used can be in the range of 1 to 3 molar equivalents, preferably in the range of 1 to 2 molar equivalents, more preferably 1 to 1, relative to the starting compound (I). .5 molar equivalent range.
The amount of the palladium catalyst used can be used in the range of 0.01 to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, more preferably relative to the starting compound (I). Is in the range of 0.1 to 0.2 molar equivalents.
The amount of the phosphine ligand used can be used in the range of 0.01 to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, more preferably relative to the starting compound (I). Is in the range of 0.1 to 0.3 molar equivalents.
The amount of the base used can be 1 to 10 molar equivalents relative to the starting compound (I), preferably 2 to 6 molar equivalents, more preferably 3 to 5 molar equivalents. It is a range.
The reaction solvent can be used in an amount of 1 to 100 times by mass, preferably 1 to 30 times by mass, more preferably 1 to 10 times by mass of the starting compound (I). Range.
The amount of n-hexylamine used can be in the range of 1 to 2 molar equivalents relative to the starting compound (I), preferably in the range of 1 to 1.5 molar equivalents, more preferably 1 It is the range of -1.1 molar equivalent.
Examples of the inert solvent when synthesizing the n-hexylamine salt (19) include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, and benzene, Ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, ethyl acetate, isopropyl acetate, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof or the like can be used.
The compound (19) can be obtained as a refined product by a method such as reslurry or recrystallization in addition to a refined product by crystallization, or can be obtained as an unpurified product.

Step (ii):
Compound (19) can be treated with an acid aqueous solution in an inert solvent to obtain a carboxylic acid free form of compound (19). Compound (20) can be treated with an aqueous base solution in an inert solvent to obtain the amine free form of compound (20). The carboxylic acid free form of compound (19) and the amine free form of compound (20) are reacted in the presence of a dehydration condensing agent and a base in an inert solvent, and then a salt is formed with oxalic acid in the inert solvent. Compound (21) can be obtained.
Compound (20) can be synthesized by the method described in Patent Document 4.
As the inert solvent for obtaining the carboxylic acid free form of compound (19) and the amine free form of compound (20), for example, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, toluene, xylene , Hydrocarbon solvents such as benzene, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane , Ethyl acetate, isopropyl acetate, methyl isobutyl ketone, or a mixed solvent thereof can be used.
As the acid aqueous solution, for example, hydrochloric acid, sulfuric acid aqueous solution, citric acid aqueous solution and the like can be used.
Examples of the aqueous base solution include sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution and the like.
Examples of the inert solvent in the dehydration condensation reaction include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, hydrocarbon solvents such as toluene, xylene, and benzene, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydro Ether solvents such as pyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, acetonitrile, N, N- Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent thereof can be used.
Examples of the dehydrating condensing agent include N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and 1- (3-dimethylaminopropyl). -3-Ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate, 1,1′-carbonyldiimidazole, 1-propanephosphonic anhydride and the like can be used.
As the base in the dehydration condensation reaction, for example, triethylamine, tri-n-butylamine, N, N-diisopropylethylamine, N-methylmorpholine and the like can be used.
As an inert solvent when synthesizing the oxalate (21), for example, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, tetrahydrofuran, Ether solvents such as 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, ethyl acetate, isopropyl acetate, acetone, 2- Butanone, acetonitrile, or a mixed solvent thereof can be used.
The temperature at which the carboxylic acid educt of compound (19) and the amine educt of compound (20) are obtained can usually be from 0 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 50 ° C. More preferably, it is the range of 15-35 degreeC.
The temperature of the dehydration condensation reaction is usually from 0 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 100 ° C., more preferably in the range of 10 to 40 ° C.
The amount of the compound (20) used can be in the range of 1 to 3 molar equivalents, preferably in the range of 1 to 2 molar equivalents, more preferably 1 to 1 with respect to the starting compound (19). .6 molar equivalent range.
The amount of the dehydrating condensing agent can be used in the range of 1 to 3 molar equivalents relative to the starting compound (19), preferably in the range of 1 to 2 molar equivalents, more preferably 1-1. The range is 5 molar equivalents.
The amount of the base used can be in the range of 1 to 5 molar equivalents relative to the raw material compound (19), preferably in the range of 1 to 3 molar equivalents, more preferably 2 to 2.5 mols. Equivalent range.
The amount of oxalic acid used can be in the range of 1 to 3 molar equivalents relative to the raw material compound (19), preferably in the range of 1 to 1.5 molar equivalents, more preferably 1 to 1. .1 molar equivalent range.
The solvent can be used in an amount of 1 to 100 times by mass, preferably 1 to 30 times by mass, more preferably 1 to 10 times by mass, relative to the starting compound (19). It is a range.
The compound (21) can be obtained as a refined product by a method such as reslurry or recrystallization in addition to a refined product by crystallization, or it can be obtained as an unrefined product.

Step (iii):
Compound (21) can be treated with an aqueous base solution in an inert solvent to obtain the amine free form of compound (21). Compound (XI) can be obtained by reacting the amine free form of compound (21) in a solvent in the presence of a base.
Examples of the inert solvent for obtaining the amine free form of the compound (21) include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, hydrocarbon solvents such as toluene, xylene, benzene, tetrahydrofuran, and the like. , 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethoxymethane, and other ether solvents, ethyl acetate, isopropyl acetate, methyl isobutyl ketone Alternatively, a mixed solvent thereof or the like can be used.
Examples of the aqueous base solution include sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution and the like.
As a solvent for obtaining the compound (XI), for example, an alcohol solvent such as methanol or ethanol or a mixed solvent of these alcohol solvent and water can be used.
Examples of the base include triethylamine, tri-n-butylamine, N, N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide. Etc. can be used.
The temperature of the deacetylation reaction can usually be from 0 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 80 ° C., more preferably in the range of 10 to 40 ° C.
The amount of the base used can be 0.1 to 4 molar equivalents relative to the starting compound (21), preferably 0.5 to 2 molar equivalents, more preferably 1 to 4 molar equivalents. The range is 1.6 molar equivalents.
The amount of the solvent used can be used in the range of 1 to 100 times by mass relative to the raw material compound (21), preferably in the range of 1 to 30 times by mass, more preferably 1 to 10 times by mass. It is a range.
Compound (XI) can be obtained as a purified product by a method such as chromatography or an unpurified product.
As described in Patent Document 2, compound (XI) is an amorphous compound, but from a solution in which compound (XI) is dissolved in ethanol or an organic solvent having a property to be mixed with ethanol and ethanol. By crystallizing, an ethanol solvate of compound (XI) can be obtained as crystals.

The present invention will be described in more detail below with reference to examples, but the present invention should not be construed as being limited by these descriptions. Moreover, you may change in the range which does not deviate from the range of this invention.
The yields in the following examples are affected by the reaction conditions and post-treatment / isolation conditions. By selecting optimized reaction conditions and post-treatment / isolation conditions, higher yields can be obtained. Is possible.

The instrumental analysis data described in this example was measured with the following measuring instrument.
Melting point: Melting point measuring instrument B-545 (BUCHI)
Nuclear magnetic resonance spectroscopy (NMR):
JNM-ECA600 (JEOL RESONANCE); ¹ H 600 MHz, ¹³ C 150 MHz
JNM-ECA500 (JEOL RESONANCE); ¹ H 500 MHz, ¹³ C 125 MHz
Mass spectrometry (MS):
GCT (micromass); ionization method EI
LCMS-IT-TOF (Shimadzu Corporation), LCMS-2010EV (Shimadzu Corporation); ionization method ESI / APCI
CHN elemental analysis: vario MICRO cube (elementar)
Ion chromatographic analysis: XS-100 (Mitsubishi Chemical)
Infrared spectroscopy (IR): Spectrum One (Perkin Elmer)

The abbreviations used in this specification are as follows.
NMR: nuclear magnetic resonance
_{DMSO-d 6:} dimethylsulfoxide _-d 6 _{(dimethylsulfoxide-d} 6)
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
dd: doublet of doublets
td: triplet of doublets
ddd: doublet of doublets of doublets (doublet of doublets of doublets)
J: Spinning constant (coupling constant)
Hz: Hertz
MS: Mass Spectrometry
HRMS: high resolution mass spectrometry
EI: electron ionization (electron ionization)
ESI: Electrospray ionization method
APCI: Atmospheric pressure chemical ionization
mp: melting point
v / v: volume / volume wt%: weight percent concentration

  In naming compounds, software such as ACD / Name 2015 (Advanced Chemistry Development Inc.) may be used.

  In this specification, room temperature refers to 20 to 30 ° C. unless otherwise specified.

The compound represented by the formula (I) could be obtained by the methods shown in Examples 1 to 9 below.
Example 1
Synthesis of 2- (2-bromo-5-methoxyphenyl) propan-2-ol (2)

アルゴン雰囲気下、臭化メチルマグネシウムのテトラヒドロフラン溶液（1.1 mol / L）1160 mLに2-ブロモ-5-メトキシ安息香酸メチルエステル（１）125.1 gのテトラヒドロフラン（216 mL）溶液を1〜11℃にて1時間45分間かけて滴下した。氷水浴をはずし、室温（〜25℃）にて19.5時間撹拌した。反応液を塩化アンモニウム水溶液（NH₄Cl 200 g / H₂O 800 g）に5〜23℃にて5分間かけて滴下し、トルエン1000 gを加えて有機層と水層に分液した。有機層を水1000 gにて洗浄後、有機層と水層に分液し、有機層を減圧下濃縮した。得られた粗生成物136 gに酢酸エチル−ヘプタン（1 / 9, v/v）混合液250 mLを加えて、22〜25℃にて16時間撹拌した。得られたスラリーを吸引ろ過後、酢酸エチル−ヘプタン（1 / 9, v/v）混合液125 mLにて洗浄した。得られた固体を減圧乾燥（40℃、1時間15分間）して白色固体の2-(2-ブロモ-5-メトキシフェニル)プロパン-2-オール（２）90.6 g（収率72.4%）を得た。
mp : 99℃.
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.74 ( 6H, s ), 2.69 ( 1H, s, exchangeable with D₂O ), 3.80 ( 3H, s ), 6.65 ( 1H, dd, J = 8.7 and 3.2 Hz ), 7.26 ( 1H, d, J = 3.2 Hz ), 7.46 (1H, d, J = 8.7 Hz ).
MS (EI) : m/z 246 [(M+2)⁺], 244 (M⁺), 226 (base).
実施例２
１−ブロモ−４−メトキシ−２−（プロパン−２−イル）ベンゼン（３）の合成

Under an argon atmosphere, 1160 mL of methylmagnesium bromide in tetrahydrofuran (1.1 mol / L) and 125.1 g of 2-bromo-5-methoxybenzoic acid methyl ester (1) in tetrahydrofuran (216 mL) at 1-11 ° C. The solution was added dropwise over 1 hour 45 minutes. The ice-water bath was removed and the mixture was stirred at room temperature (˜25 ° C.) for 19.5 hours. The reaction solution was dropped into an aqueous ammonium chloride solution (NH ₄ Cl 200 g / H ₂ O 800 g) at 5 to 23 ° C. over 5 minutes, and 1000 g of toluene was added to separate the organic layer and the aqueous layer. The organic layer was washed with 1000 g of water and then separated into an organic layer and an aqueous layer, and the organic layer was concentrated under reduced pressure. To 136 g of the obtained crude product, 250 mL of an ethyl acetate-heptane (1/9, v / v) mixed solution was added and stirred at 22 to 25 ° C. for 16 hours. The obtained slurry was subjected to suction filtration, and then washed with 125 mL of an ethyl acetate-heptane (1/9, v / v) mixed solution. The obtained solid was dried under reduced pressure (40 ° C., 1 hour and 15 minutes) to obtain 90.6 g (yield 72.4%) of 2- (2-bromo-5-methoxyphenyl) propan-2-ol (2) as a white solid. Obtained.
mp: 99 ° C.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.74 (6H, s), 2.69 (1H, s, exchangeable with D ₂ O), 3.80 (3H, s), 6.65 (1H, dd, J = 8.7 and 3.2 Hz), 7.26 (1H, d, J = 3.2 Hz), 7.46 (1H, d, J = 8.7 Hz).
MS (EI): m / z 246 [(M + 2) ⁺ ], 244 (M ⁺ ), 226 (base).
Example 2
Synthesis of 1-bromo-4-methoxy-2- (propan-2-yl) benzene (3)

窒素雰囲気下、2-(2-ブロモ-5-メトキシフェニル)プロパン-2-オール（２）4.00 g、トルエン40 mL及びｔｅｒｔ-ブチルジメチルシラン9.51 gの混合物にトリフルオロメタンスルホン酸トリメチルシリルエステル7.4 mLを1〜11℃にて3分間かけて滴下した。1℃にて1時間撹拌後、氷水浴をはずし、室温（〜22℃）にて21.5時間撹拌した。反応液を15 wt%炭酸ナトリウム水溶液40 mLに10〜28℃にて20分間かけて滴下し（反応容器をトルエン5 mLにて共洗いして加えた）、水15 mLを加えて有機層と水層に分液した。有機層を10 wt%塩化ナトリウム水溶液40 mLにて洗浄後、有機層と水層に分液した。得られた有機層64.3 gのうち、16.1 gを減圧濃縮し、黄色油状物の1-ブロモ-4-メトキシ-2-(プロパン-2-イル)ベンゼン（３）の粗生成物1.25 gを得た。
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.23 ( 6H, d, J = 6.9 Hz ), 3.31 ( 1H, septet, J = 6.9 Hz ), 3.79 ( 3H, s ), 6.61 ( 1H, dd, J = 8.7 and 3.2 Hz ), 6.83 ( 1H, d, J = 3.2 Hz ), 7.41 (1H, d, J = 8.7 Hz ).
MS (EI) : m/z 230 [(M+2)⁺], 228 (M⁺), 213 (base).
実施例３
（４−ブロモフェニル）［４−メトキシ−２−（プロパン−２−イル）フェニル］メタノール（６）の合成

Under a nitrogen atmosphere, add 7.4 mL of trifluoromethanesulfonic acid trimethylsilyl ester to a mixture of 4.00 g of 2- (2-bromo-5-methoxyphenyl) propan-2-ol (2), 40 mL of toluene and 9.51 g of tert-butyldimethylsilane. The solution was added dropwise at 1 to 11 ° C over 3 minutes. After stirring at 1 ° C. for 1 hour, the ice-water bath was removed and the mixture was stirred at room temperature (˜22 ° C.) for 21.5 hours. The reaction solution was dropped into 40 mL of 15 wt% aqueous sodium carbonate solution at 10 to 28 ° C. over 20 minutes (added by washing the reaction vessel with 5 mL of toluene), and 15 mL of water was added to the organic layer. The aqueous layer was separated. The organic layer was washed with 40 mL of 10 wt% sodium chloride aqueous solution, and then separated into an organic layer and an aqueous layer. Of the obtained organic layer (64.3 g), 16.1 g was concentrated under reduced pressure to obtain 1.25 g of a crude product of 1-bromo-4-methoxy-2- (propan-2-yl) benzene (3) as a yellow oil. It was.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.23 (6H, d, J = 6.9 Hz), 3.31 (1H, septet, J = 6.9 Hz), 3.79 (3H, s), 6.61 (1H, dd, J = 8.7 and 3.2 Hz), 6.83 (1H, d, J = 3.2 Hz), 7.41 (1H, d, J = 8.7 Hz).
MS (EI): m / z 230 [(M + 2) ⁺ ], 228 (M ⁺ ), 213 (base).
Example 3
Synthesis of (4-bromophenyl) [4-methoxy-2- (propan-2-yl) phenyl] methanol (6)

窒素雰囲気下、マグネシウム0.099 g及びよう素0.011 gの混合物に1-ブロモ-4-メトキシ-2-(プロパン-2-イル)ベンゼン（３）の粗生成物1.25 gのテトラヒドロフラン（8 mL）溶液を加え、2.5時間加熱還流した。氷水浴にて冷却した反応液に4-ブロモベンズアルデヒド（５）0.756 gのテトラヒドロフラン（2 mL）溶液を3〜18℃にて2分間かけて滴下した。2℃にて1時間撹拌後、氷水浴をはずして室温まで昇温（〜22℃）しながら1.5時間撹拌した。氷水浴にて冷却した反応液に20 wt%塩化アンモニウム水溶液60 mL、引き続きトルエン20 mLを加えて有機層と水層に分液した。有機層を20 wt%塩化アンモニウム水溶液20 mL、引き続き10 wt%塩化ナトリウム水溶液20 mLにて洗浄後、有機層と水層に分液した。有機層を無水硫酸マグネシウムにて乾燥後、不溶物をろ別し、ろ液を減圧濃縮して黄色油状物の(4-ブロモフェニル)[4-メトキシ-2-(プロパン-2-イル)フェニル]メタノール（６）の粗生成物1.36 gを得た。
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.11 ( 3H, d, J = 6.8 Hz ), 1.18 ( 3H, d, J = 6.8 Hz ), 2.04 ( 1H, d, J = 3.7 Hz, exchangeable with D₂O ), 3.21 ( 1H, septet, J = 6.8 Hz ), 3.81 ( 3H, s ), 6.05 ( 1H, d, J = 3.7 Hz ), 6.72 ( 1H, dd, J = 8.7 and 2.9 Hz ), 6.85 ( 1H, d, J = 2.9 Hz ), 7.18-7.23 ( 3H, m ), 7.43-7.46 ( 2H, m ).
MS (EI) : m/z 336 [(M+2)⁺] , 334 (M⁺), 222 (base).
実施例４
１−［（４−ブロモフェニル）メチル］−４−メトキシ−２−（プロパン−２−イル）ベンゼン（７）の合成

Under a nitrogen atmosphere, add a solution of crude 1.25 g of 1-bromo-4-methoxy-2- (propan-2-yl) benzene (3) in tetrahydrofuran (8 mL) to a mixture of 0.099 g of magnesium and 0.011 g of iodine. In addition, it was heated to reflux for 2.5 hours. To a reaction solution cooled in an ice-water bath, a solution of 4-bromobenzaldehyde (5) 0.756 g in tetrahydrofuran (2 mL) was added dropwise at 3-18 ° C. over 2 minutes. After stirring at 2 ° C for 1 hour, the ice-water bath was removed and the mixture was stirred for 1.5 hours while warming to room temperature (~ 22 ° C). To the reaction solution cooled in an ice water bath, 60 mL of a 20 wt% ammonium chloride aqueous solution and then 20 mL of toluene were added, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with 20 mL of 20 wt% aqueous ammonium chloride solution and then with 20 mL of 10 wt% aqueous sodium chloride solution, and then separated into an organic layer and an aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to give (4-bromophenyl) [4-methoxy-2- (propan-2-yl) phenyl as a yellow oil. ] 1.36 g of a crude product of methanol (6) was obtained.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.11 (3H, d, J = 6.8 Hz), 1.18 (3H, d, J = 6.8 Hz), 2.04 (1H, d, J = 3.7 Hz, exchangeable with D ₂ O), 3.21 (1H, septet, J = 6.8 Hz), 3.81 (3H, s), 6.05 (1H, d, J = 3.7 Hz), 6.72 (1H, dd, J = 8.7 and 2.9 Hz), 6.85 (1H, d, J = 2.9 Hz), 7.18-7.23 (3H, m), 7.43-7.46 (2H, m).
MS (EI): m / z 336 [(M + 2) ⁺ ], 334 (M ⁺ ), 222 (base).
Example 4
Synthesis of 1-[(4-bromophenyl) methyl] -4-methoxy-2- (propan-2-yl) benzene (7)

窒素雰囲気下、(4-ブロモフェニル)[4-メトキシ-2-(プロパン-2-イル)フェニル]メタノール（６）の粗生成物1.36 g、トルエン20 mL及びｔｅｒｔ-ブチルジメチルシラン0.953 gの混合物にトリフルオロメタンスルホン酸トリメチルシリルエステル1.2 mLを1〜7℃にて3分間かけて滴下した後、1℃にて1時間撹拌した。反応液に15 wt%炭酸ナトリウム水溶液20 mLを1〜9℃にて8分間かけて滴下後、22℃まで昇温しながら70分間撹拌した。有機層と水層に分液し、有機層を10 wt%塩化ナトリウム水溶液20 mLにて洗浄した。分液した有機層を減圧濃縮し、黄色油状物の1-[(4-ブロモフェニル)メチル]-4-メトキシ-2-(プロパン-2-イル)ベンゼン（７）の粗生成物1.26 gを得た。
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.11 ( 6H, d, J = 6.8 Hz ), 3.01 ( 1H, septet, J = 6.8 Hz ), 3.80 ( 3H, s ), 3.93 ( 2H, s ), 6.69 ( 1H, dd, J = 8.3 and 2.5 Hz ), 6.85 ( 1H, d, J = 2.5 Hz ), 6.94-6.98 ( 2H, m ), 7.00 (1H, d, J = 8.3 Hz ), 7.34-7.38 ( 2H, m ).
MS (EI) : m/z 320 [(M+2)⁺], 318 (M⁺), 275 (base).
実施例５
１−［（４−ブロモフェニル）メチル］−５−ヨード−４−メトキシ−２−（プロパン−２−イル）ベンゼン（８）の合成

A mixture of 1.36 g of crude product of (4-bromophenyl) [4-methoxy-2- (propan-2-yl) phenyl] methanol (6), 20 mL of toluene and 0.953 g of tert-butyldimethylsilane under nitrogen atmosphere To the mixture, 1.2 mL of trimethylsilyl trifluoromethanesulfonate was added dropwise at 1-7 ° C. over 3 minutes, followed by stirring at 1 ° C. for 1 hour. To the reaction solution, 20 mL of a 15 wt% aqueous sodium carbonate solution was added dropwise at 1-9 ° C. over 8 minutes, followed by stirring for 70 minutes while raising the temperature to 22 ° C. The organic layer and the aqueous layer were separated, and the organic layer was washed with 20 mL of a 10 wt% sodium chloride aqueous solution. The separated organic layer was concentrated under reduced pressure, and 1.26 g of a crude product of 1-[(4-bromophenyl) methyl] -4-methoxy-2- (propan-2-yl) benzene (7) as a yellow oil was obtained. Obtained.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.11 (6H, d, J = 6.8 Hz), 3.01 (1H, septet, J = 6.8 Hz), 3.80 (3H, s), 3.93 (2H, s), 6.69 (1H, dd, J = 8.3 and 2.5 Hz), 6.85 (1H, d, J = 2.5 Hz), 6.94-6.98 (2H, m), 7.00 (1H, d, J = 8.3 Hz), 7.34-7.38 (2H, m).
MS (EI): m / z 320 [(M + 2) ⁺ ], 318 (M ⁺ ), 275 (base).
Example 5
Synthesis of 1-[(4-bromophenyl) methyl] -5-iodo-4-methoxy-2- (propan-2-yl) benzene (8)

窒素雰囲気下、1-[(4-ブロモフェニル)メチル]-4-メトキシ-2-(プロパン-2-イル)ベンゼン（７）の粗生成物1.26 gの酢酸（10 mL）溶液によう素酸カリウム水溶液（KIO₃ 0.281 g / H₂O 5 mL）及びよう素0.821 gを加えて49〜51℃にて17時間撹拌した。反応液に酢酸10 mLを加えて52℃にて6.5時間撹拌した。反応液を炭酸カリウム水溶液（K₂CO₃ 30.1 g / H₂O 60 mL）に13〜31℃にて24分間かけて滴下後、トルエン40 mLを加えて1時間撹拌した。水10 mLを加えた後、有機層と水層に分液した。有機層をチオ硫酸ナトリウム水溶液（Na₂S₂O₃ 8.01 g / H₂O 40 mL）、引き続き水40 mLにて順次洗浄した。有機層を減圧濃縮して得られた黄色油状物1.51 gにメタノール6 mLを加え、室温にて61.5時間撹拌した後、氷水浴にて冷却しながら3.5時間撹拌した。析出した固体をろ過、冷メタノール3 mLにて洗浄後、減圧乾燥して白色固体の1-[(4-ブロモフェニル)メチル]-5-ヨード-4-メトキシ-2-(プロパン-2-イル)ベンゼン（８）0.417 g［化合物（２）からの通算換算収率23.0%］を得た。
mp : 93℃.
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.11 ( 6H, d, J = 6.8 Hz ), 3.00 ( 1H, septet, J = 6.8 Hz ), 3.88 ( 5H, s ), 6.74 ( 1H, s ), 6.93-6.97 ( 2H, m ), 7.36-7.40 ( 2H, m ), 7.49 ( 1H, s ).
MS (EI) : m/z 446 [(M+2)⁺], 444 (M⁺, base).
実施例６
１−Ｃ−｛５−［（４−ブロモフェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−２，３，４，６−テトラキス−Ｏ−（トリメチルシリル）−Ｄ−グルコピラノース（１１）

Iodic acid was added to a solution of 1.26 g of the crude product of 1-[(4-bromophenyl) methyl] -4-methoxy-2- (propan-2-yl) benzene (7) in acetic acid (10 mL) under a nitrogen atmosphere. A potassium aqueous solution (KIO ₃ 0.281 g / H ₂ O 5 mL) and iodine 0.821 g were added, and the mixture was stirred at 49 to 51 ° C. for 17 hours. 10 mL of acetic acid was added to the reaction solution, and the mixture was stirred at 52 ° C. for 6.5 hours. The reaction solution was added dropwise to an aqueous potassium carbonate solution (K ₂ CO ₃ 30.1 g / H ₂ O 60 mL) at 13 to 31 ° C. over 24 minutes, and then 40 mL of toluene was added and stirred for 1 hour. After adding 10 mL of water, it was separated into an organic layer and an aqueous layer. The organic layer was washed successively with an aqueous sodium thiosulfate solution (Na ₂ S ₂ O ₃ 8.01 g / H ₂ O 40 mL) and subsequently with 40 mL of water. Methanol 6 mL was added to 1.51 g of the yellow oil obtained by concentrating the organic layer under reduced pressure, and the mixture was stirred at room temperature for 61.5 hours and then stirred for 3.5 hours while cooling in an ice-water bath. The precipitated solid was filtered, washed with 3 mL of cold methanol, and dried under reduced pressure to give 1-[(4-bromophenyl) methyl] -5-iodo-4-methoxy-2- (propan-2-yl) as a white solid. ) 0.417 g of benzene (8) [23.0% of total conversion yield from compound (2)] was obtained.
mp: 93 ° C.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.11 (6H, d, J = 6.8 Hz), 3.00 (1H, septet, J = 6.8 Hz), 3.88 (5H, s), 6.74 (1H, s), 6.93-6.97 (2H, m), 7.36-7.40 (2H, m), 7.49 (1H, s).
MS (EI): m / z 446 [(M + 2) ⁺ ], 444 (M ⁺ , base).
Example 6
1-C- {5-[(4-Bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -2,3,4,6-tetrakis-O- (trimethylsilyl) -D -Glucopyranose (11)

アルゴン雰囲気下、1-[(4-ブロモフェニル)メチル]-5-ヨード-4-メトキシ-2-(プロパン-2-イル)ベンゼン（８）2.00 gにテトラヒドロフラン8.0 mLを加えて溶解し、塩化イソプロピルマグネシウム−塩化リチウム錯体のテトラヒドロフラン溶液（1.3 mol / L）3.30 mLを−21〜−18℃にて10分間かけて滴下し、−21℃にて1時間15分間撹拌した。反応液に塩化イソプロピルマグネシウム−塩化リチウム錯体のテトラヒドロフラン溶液（1.3 mol / L）0.15 mLを−21〜−20℃にて1分間かけて滴下し、−21℃にて42分間撹拌した。反応液に塩化イソプロピルマグネシウム−塩化リチウム錯体のテトラヒドロフラン溶液（1.3 mol / L）0.20 mLを−21℃にて2分間かけて滴下し、−21℃にて50分間撹拌した。反応液に2,3,4,6-テトラキス-O-(トリメチルシリル)-D-グルコノ-1,5-ラクトン（１０）（97.9 wt%）2.36 gのテトラヒドロフラン（8.0 mL）溶液を−21〜−18℃にて10分間かけて滴下し、−10℃に昇温して1時間撹拌後、０℃に昇温して4時間撹拌した。反応液を飽和塩化アンモニウム水溶液30.0 mL及び水30.0 mLの混合液に加えた後、酢酸エチル100 mLを加えて有機層と水層に分液した。有機層を飽和塩化ナトリウム水溶液30.0 mLにて洗浄後、無水硫酸マグネシウムにて乾燥した。不溶物をろ別し、ろ液を減圧濃縮して淡黄色油状物の1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-2,3,4,6-テトラキス-O-(トリメチルシリル)-D-グルコピラノース（１１）の粗生成物3.80 gを得た。
MS (ESI/APCI dual source) : m/z 809 {[(M+2)+Na]⁺}, 807 [(M+Na)⁺].
実施例７
メチル １−Ｃ−｛５−［（４−ブロモフェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−α−Ｄ−グルコピラノシド（１２）の合成

Under an argon atmosphere, 1-[(4-bromophenyl) methyl] -5-iodo-4-methoxy-2- (propan-2-yl) benzene (8) (2.00 g) was dissolved in 8.0 mL of tetrahydrofuran, and the solution was chlorinated. 3.30 mL of a tetrahydrofuran solution (1.3 mol / L) of isopropylmagnesium-lithium chloride complex was added dropwise at −21 to −18 ° C. over 10 minutes, and the mixture was stirred at −21 ° C. for 1 hour and 15 minutes. To the reaction solution, 0.15 mL of a isopropylmagnesium chloride-lithium chloride complex tetrahydrofuran solution (1.3 mol / L) was added dropwise at -21 to -20 ° C over 1 minute, and the mixture was stirred at -21 ° C for 42 minutes. To the reaction solution, 0.20 mL of a tetrahydrofuran solution (1.3 mol / L) of isopropylmagnesium chloride-lithium chloride complex was added dropwise at −21 ° C. over 2 minutes and stirred at −21 ° C. for 50 minutes. To the reaction solution, a solution of 2.36 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucono-1,5-lactone (10) (97.9 wt%) in tetrahydrofuran (8.0 mL) was added at −21 to − The mixture was added dropwise at 18 ° C. over 10 minutes, heated to −10 ° C. and stirred for 1 hour, then heated to 0 ° C. and stirred for 4 hours. The reaction solution was added to a mixed solution of 30.0 mL of saturated aqueous ammonium chloride and 30.0 mL of water, and then 100 mL of ethyl acetate was added to separate the organic layer and the aqueous layer. The organic layer was washed with 30.0 mL of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 1-C- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl as a pale yellow oil. } -2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranose (11) crude product 3.80 g was obtained.
MS (ESI / APCI dual source): m / z 809 {[(M + 2) + Na] ⁺ }, 807 [(M + Na) ⁺ ].
Example 7
Synthesis of methyl 1-C- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -α-D-glucopyranoside (12)

1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-2,3,4,6-テトラキス-O-(トリメチルシリル)-D-グルコピラノース（１１）の粗生成物3.80 gにメタンスルホン酸0.117 gのメタノール（10.0 mL）溶液を加え、アルゴン雰囲気下、24〜25℃にて3時間撹拌した。氷水浴にて冷却した反応液に飽和炭酸水素ナトリウム水溶液10.0 mLを4〜16℃にて2分間かけて滴下後、水15.0 mL及び酢酸エチル70.0 mLを加え、有機層と水層に分液した。水層を酢酸エチル30.0 mLにて抽出した有機層を先の有機層と併せて飽和塩化ナトリウム水溶液30.0 mLにて洗浄した。有機層を無水硫酸マグネシウムにて乾燥後、不溶物をろ別し、ろ液を減圧濃縮して淡褐色固体のメチル 1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-α-D-グルコピラノシド（１２）の粗生成物1.95 gを得た。化合物（１２）の粗生成物1.95 gに酢酸エチル4.00 mL及びトルエン12.0 mLを加えて溶解させた溶液に25℃にて化合物（１２）の種晶0.5 mgを添加し、25℃にて30分間撹拌した。氷水浴にて冷却し、0〜16℃にて19時間、引き続き0℃にて4時間撹拌した。析出した固体をろ過、トルエン−酢酸エチル混合溶媒（3/1, v/v）6.0 mLにて洗浄後、減圧乾燥して白色固体のメチル 1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-α-D-グルコピラノシド（１２）0.697 g［化合物（８）からの通算収率30.3%］を得た。
mp : 160℃.
¹H NMR ( 600 MHz, DMSO-d₆ ) : δ 1.01 ( 3H, d, J = 6.7 Hz ), 1.09 ( 3H, d, J = 6.7 Hz ), 2.99 ( 1H, septet, J = 6.7 Hz ), 3.08 ( 3H, s ), 3.17 ( 1H, td, J = 9.7 and 5.4 Hz ), 3.28-3.33 ( 1H, m ), 3.37 ( 1H, ddd, J = 9.7, 6.0 and 1.9 Hz ), 3.46-3.54 ( 2H, m ), 3.69-3.74 ( 1H, m ), 3.76 ( 3H, s ), 3.89, 3.99 ( 2H, AB quartet, J = 15.9 Hz ), 4.21 ( 1H, d, J = 7.4 Hz, exchangeable with D₂O ), 4.27 ( 1H, t, J = 6.0 Hz, exchangeable with D₂O ), 4.65 ( 1H, d, J = 5.0 Hz, exchangeable with D₂O ), 4.91 ( 1H, d, J = 5.4 Hz, exchangeable with D₂O ), 6.90 ( 1H, s ), 7.02-7.07 ( 2H, m ), 7.16 ( 1H, s ), 7.42-7.47 ( 2H, m ).
¹³C NMR ( 125 MHz, DMSO-d₆ ) : δ 23.5, 28.7, 36.9, 48.6, 56.3, 61.3, 70.1, 74.3, 74.4, 75.7, 79.2, 101.5, 110.6, 118.7, 124.4, 127.9, 130.4, 131.0, 131.7, 141.2, 147.7, 156.5.
MS (ESI/APCI dual source) : ポジティブモード；m/z 535 {[(M+2)+Na]⁺}, 533 [(M+Na)⁺], ネガティブモード；m/z 511 {[(M+2)-H]⁻}, 509 [(M-H)⁻].
実施例８
メチル ２，３，４，６−テトラ−Ｏ−アセチル−１−Ｃ−｛５−［（４−ブロモフェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−α−Ｄ−グルコピラノシド（１３）の合成

1-C- {5-[(4-Bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -2,3,4,6-tetrakis-O- (trimethylsilyl) -D -A solution of 0.117 g of methanesulfonic acid in methanol (10.0 mL) was added to 3.80 g of the crude product of glucopyranose (11), and the mixture was stirred at 24 to 25 ° C for 3 hours under an argon atmosphere. To the reaction solution cooled in an ice-water bath, 10.0 mL of a saturated aqueous sodium bicarbonate solution was added dropwise at 4-16 ° C. over 2 minutes, and then 15.0 mL of water and 70.0 mL of ethyl acetate were added to separate the organic layer and the aqueous layer. . The aqueous layer was extracted with 30.0 mL of ethyl acetate, and the organic layer was combined with the previous organic layer and washed with 30.0 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to give methyl 1-C- {5-[(4-bromophenyl) methyl] -2-methoxy as a light brown solid. 1.95 g of a crude product of -4- (propan-2-yl) phenyl} -α-D-glucopyranoside (12) was obtained. To a solution obtained by dissolving 4.00 mL of ethyl acetate and 12.0 mL of toluene in 1.95 g of the crude product of compound (12), 0.5 mg of the seed crystal of compound (12) was added at 25 ° C., and 30 minutes at 25 ° C. Stir. The mixture was cooled in an ice-water bath and stirred at 0 to 16 ° C. for 19 hours and subsequently at 0 ° C. for 4 hours. The precipitated solid was filtered, washed with 6.0 mL of a toluene-ethyl acetate mixed solvent (3/1, v / v), and then dried under reduced pressure to obtain methyl 1-C- {5-[(4-bromophenyl) as a white solid. 0.697 g of [methyl] -2-methoxy-4- (propan-2-yl) phenyl} -α-D-glucopyranoside (12) [total yield 30.3% from compound (8)] was obtained.
mp: 160 ° C.
¹ H NMR (600 MHz, DMSO-d ₆ ): δ 1.01 (3H, d, J = 6.7 Hz), 1.09 (3H, d, J = 6.7 Hz), 2.99 (1H, septet, J = 6.7 Hz), 3.08 (3H, s), 3.17 (1H, td, J = 9.7 and 5.4 Hz), 3.28-3.33 (1H, m), 3.37 (1H, ddd, J = 9.7, 6.0 and 1.9 Hz), 3.46-3.54 ( 2H, m), 3.69-3.74 (1H, m), 3.76 (3H, s), 3.89, 3.99 (2H, AB quartet, J = 15.9 Hz), 4.21 (1H, d, J = 7.4 Hz, exchangeable with D ₂ O), 4.27 (1H, t, J = 6.0 Hz, exchangeable with D ₂ O), 4.65 (1H, d, J = 5.0 Hz, exchangeable with D ₂ O), 4.91 (1H, d, J = 5.4 Hz , exchangeable with D ₂ O), 6.90 (1H, s), 7.02-7.07 (2H, m), 7.16 (1H, s), 7.42-7.47 (2H, m).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 23.5, 28.7, 36.9, 48.6, 56.3, 61.3, 70.1, 74.3, 74.4, 75.7, 79.2, 101.5, 110.6, 118.7, 124.4, 127.9, 130.4, 131.0, 131.7, 141.2, 147.7, 156.5.
MS (ESI / APCI dual source): positive mode; m / z 535 {[(M + 2) + Na] ⁺ }, 533 [(M + Na) ⁺ ], negative mode; m / z 511 {[(M +2) -H] ⁻ }, 509 [(MH) ⁻ ].
Example 8
Methyl 2,3,4,6-tetra-O-acetyl-1-C- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -α- Synthesis of D-glucopyranoside (13)

アルゴン雰囲気下、メチル 1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-α-D-グルコピラノシド（１２）1.00 gをピリジン5.00 mLに溶解した溶液に4-ジメチルアミノピリジン（DMAP）0.024 g及び無水酢酸1.21 gを加え、21〜38℃にて4.5時間撹拌した。冷却した反応液に水5.00 mLを1〜9℃にて8分間かけて滴下し、1℃にて20分間撹拌した。酢酸エチル60.0 mL及び10 wt%塩酸30.0 mLを加え、有機層と水層に分液した。有機層を飽和炭酸水素ナトリウム水溶液30.0 mL及び飽和塩化ナトリウム水溶液20.0 mLにて順次洗浄し、無水硫酸マグネシウムにて乾燥した。不溶物をろ別し、ろ液を減圧濃縮後、減圧乾燥して白色アモルファス固体のメチル 2,3,4,6-テトラ-O-アセチル-1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-α-D-グルコピラノシド（１３）の粗生成物1.30 gを得た。
¹H NMR ( 500 MHz, CDCl₃ ) : δ 1.08 ( 3H, d, J = 6.8 Hz ), 1.14 ( 3H, d, J = 6.8 Hz ), 1.77 ( 3H, s ), 1.97 ( 3H, s ), 2.06 ( 3H, s ), 2.08 ( 3H, s ), 2.98 ( 1H, septet, J = 6.8 Hz ), 3.30 ( 3H, s ), 3.88 ( 3H, s ), 3.92 ( 2H, s ), 4.02 ( 1H, ddd, J = 10.3, 4.7 and 2.4 Hz ), 4.20 ( 1H, dd, J = 12.3 and 2.4 Hz ), 4.30 ( 1H, dd, J = 12.3 and 4.7 Hz ), 5.25 ( 1H, dd, J = 10.3 and 9.8 Hz ), 5.40 ( 1H, d, J = 9.8 Hz ), 5.57 ( 1H, t, J = 9.8 Hz ), 6.82 ( 1H, s ), 6.86-6.91 ( 2H, m ), 7.09 ( 1H, s ), 7.33-7.37 ( 2H, m ).
¹³C NMR ( 125 MHz, CDCl₃ ) : δ 20.3, 20.6, 20.67, 20.74, 23.4, 23.8, 29.4, 37.4, 49.9, 56.0, 62.4, 68.9, 69.0, 71.5, 72.6, 101.1, 110.0, 119.6, 120.6, 128.0, 129.9, 131.30, 131.33, 140.6, 149.7, 156.9, 169.0, 169.7, 170.0, 170.6.
MS (ESI/APCI dual source) : ポジティブモード；m/z 703 {[(M+2)+Na]⁺}, 701 [(M+Na)⁺].
実施例９
（１Ｓ）−２，３，４，６−テトラ−Ｏ−アセチル−１，５−アンヒドロ−１−｛５−［（４−ブロモフェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−Ｄ−グルシトール（Ｉ）の合成

Under an argon atmosphere, 1.00 g of methyl 1-C- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -α-D-glucopyranoside (12) is pyridine To the solution dissolved in 5.00 mL, 0.024 g of 4-dimethylaminopyridine (DMAP) and 1.21 g of acetic anhydride were added, and the mixture was stirred at 21 to 38 ° C. for 4.5 hours. To the cooled reaction solution, 5.00 mL of water was added dropwise at 1-9 ° C. over 8 minutes, and the mixture was stirred at 1 ° C. for 20 minutes. Ethyl acetate 60.0 mL and 10 wt% hydrochloric acid 30.0 mL were added, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed successively with 30.0 mL of saturated aqueous sodium hydrogen carbonate solution and 20.0 mL of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain methyl 2,3,4,6-tetra-O-acetyl-1-C- {5-[(4-bromophenyl) as a white amorphous solid. ) Methyl] -2-methoxy-4- (propan-2-yl) phenyl} -α-D-glucopyranoside (13) 1.30 g of crude product was obtained.
¹ H NMR (500 MHz, CDCl ₃ ): δ 1.08 (3H, d, J = 6.8 Hz), 1.14 (3H, d, J = 6.8 Hz), 1.77 (3H, s), 1.97 (3H, s), 2.06 (3H, s), 2.08 (3H, s), 2.98 (1H, septet, J = 6.8 Hz), 3.30 (3H, s), 3.88 (3H, s), 3.92 (2H, s), 4.02 (1H , ddd, J = 10.3, 4.7 and 2.4 Hz), 4.20 (1H, dd, J = 12.3 and 2.4 Hz), 4.30 (1H, dd, J = 12.3 and 4.7 Hz), 5.25 (1H, dd, J = 10.3 and 9.8 Hz), 5.40 (1H, d, J = 9.8 Hz), 5.57 (1H, t, J = 9.8 Hz), 6.82 (1H, s), 6.86-6.91 (2H, m), 7.09 (1H, s ), 7.33-7.37 (2H, m).
¹³ C NMR (125 MHz, CDCl ₃ ): δ 20.3, 20.6, 20.67, 20.74, 23.4, 23.8, 29.4, 37.4, 49.9, 56.0, 62.4, 68.9, 69.0, 71.5, 72.6, 101.1, 110.0, 119.6, 120.6, 128.0, 129.9, 131.30, 131.33, 140.6, 149.7, 156.9, 169.0, 169.7, 170.0, 170.6.
MS (ESI / APCI dual source): Positive mode; m / z 703 {[(M + 2) + Na] ⁺ }, 701 [(M + Na) ⁺ ].
Example 9
(1S) -2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propane-2- Yl) phenyl} -D-glucitol (I) synthesis

アルゴン雰囲気下、2,3,4,6-テトラ-O-アセチル-1-C-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-α-D-グルコピラノシド（１３）の粗生成物1.30 g、アセトニトリル5.00 mL及びｔｅｒｔ-ブチルジメチルシラン0.306 gの混合物にトリフルオロメタンスルホン酸トリメチルシリルエステル0.487 gを0〜2℃にて10分間かけて滴下した後、0℃にて1時間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液20.0 mLに加えた後、酢酸エチル70.0 mLを加えて撹拌し、有機層と水層に分液した。有機層を飽和塩化ナトリウム水溶液20.0 mLにて洗浄後、無水硫酸マグネシウムにて乾燥した。不溶物をろ別後、ろ液を減圧濃縮して得られた無色ガム状物1.35 gに2-プロパノール4.00 mLを加え、減圧濃縮した。残渣に2-プロパノール4.00 mLを加え、減圧濃縮した。残渣に2-プロパノール3.00 mLを加え、63℃まで加熱して溶解後、ヘキサン8.00 mLを56〜63℃にて9分間かけて滴下した。40分間かけて41℃まで冷却し、(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-（プロパン-2-イル）フェニル}-D-グルシトール（Ｉ）の種晶1.3 mgを添加後、室温（〜22℃）にて16時間40分間撹拌した。析出した固体をろ過、ヘキサン−2-プロパノール混合溶媒（4/1, v/v）2.50 mLにて洗浄後、減圧乾燥して白色固体の(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-（プロパン-2-イル）フェニル}-D-グルシトール（Ｉ）0.837 g［化合物（１２）からの通算収率65.9%］を得た。
ｍp : 127℃.
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.04 ( 3H, d, J = 6.8 Hz ), 1.09 ( 3H, d, J = 6.8 Hz ), 1.76 ( 3H, s ), 2.00 ( 3H, s ), 2.05 ( 3H, s ), 2.06 ( 3H, s ), 2.99 ( 1H, septet, J = 6.8 Hz ), 3.80-3.86 ( 1H, m ), 3.84 ( 3H, s ), 3.89, 3.93 ( 2H, AB quartet, J = 16.1 Hz ), 4.13 ( 1H, dd, J = 12.4 and 2.5 Hz ), 4.25 ( 1H, dd, J = 12.4 and 4.5 Hz ), 4.88 ( 1H, d, J = 9.1 Hz ), 5.21 ( 1H, t, J = 9.7 Hz ), 5.31-5.40 ( 2H, m ), 6.77 ( 1H, s ), 6.90-6.95 ( 2H, m ), 7.11 ( 1H, s ), 7.33-7.38 ( 2H, m ).
MS (ESI/APCI dual source) : ポジティブモード；m/z 673 {[(M+2)+Na]⁺}, 671 [(M+Na)⁺].
Anal.Calcd for C₃₁H₃₇BrO₁₀ : C, 57.32 ; H, 5.74 ; Br, 12.30. Found : C, 57.32 ; H, 5.72 ; Br, 12.26. IR (KBr) cm^-1 : 2966, 1747, 1252, 1224, 1042.

2,3,4,6-Tetra-O-acetyl-1-C- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} under argon atmosphere -0.487 g of trifluoromethanesulfonic acid trimethylsilyl ester was added dropwise at 0 to 2 ° C. over 10 minutes to a mixture of 1.30 g of the crude product of α-D-glucopyranoside (13), 5.00 mL of acetonitrile and 0.306 g of tert-butyldimethylsilane. Then, the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was added to 20.0 mL of a saturated aqueous sodium bicarbonate solution, and then 70.0 mL of ethyl acetate was added and stirred, and the solution was separated into an organic layer and an aqueous layer. The organic layer was washed with 20.0 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To 1.35 g of the colorless gum obtained by adding 4.00 mL of 2-propanol, the solution was concentrated under reduced pressure. To the residue was added 4.00 mL of 2-propanol and concentrated under reduced pressure. To the residue was added 3.00 mL of 2-propanol, heated to 63 ° C. and dissolved, and then 8.00 mL of hexane was added dropwise at 56 to 63 ° C. over 9 minutes. Cool to 41 ° C. over 40 minutes and (1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2 After adding 1.3 mg of seed crystals of -methoxy-4- (propan-2-yl) phenyl} -D-glucitol (I), the mixture was stirred at room temperature (˜22 ° C.) for 16 hours and 40 minutes. The precipitated solid was filtered, washed with 2.50 mL of hexane-2-propanol mixed solvent (4/1, v / v), and then dried under reduced pressure to give (1S) -2,3,4,6-tetra- O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (I) 0.837 g [ Total yield 65.9% from compound (12)] was obtained.
mp: 127 ° C.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.04 (3H, d, J = 6.8 Hz), 1.09 (3H, d, J = 6.8 Hz), 1.76 (3H, s), 2.00 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.99 (1H, septet, J = 6.8 Hz), 3.80-3.86 (1H, m), 3.84 (3H, s), 3.89, 3.93 (2H, AB quartet , J = 16.1 Hz), 4.13 (1H, dd, J = 12.4 and 2.5 Hz), 4.25 (1H, dd, J = 12.4 and 4.5 Hz), 4.88 (1H, d, J = 9.1 Hz), 5.21 (1H , t, J = 9.7 Hz), 5.31-5.40 (2H, m), 6.77 (1H, s), 6.90-6.95 (2H, m), 7.11 (1H, s), 7.33-7.38 (2H, m).
MS (ESI / APCI dual source): Positive mode; m / z 673 {[(M + 2) + Na] ⁺ }, 671 [(M + Na) ⁺ ].
Anal.Calcd for C ₃₁ H ₃₇ BrO ₁₀ : C, 57.32; H, 5.74; Br, 12.30. Found: C, 57.32; H, 5.72; Br, 12.26. IR (KBr) cm ^-1 : 2966, 1747, 1252 , 1224, 1042.

Moreover, the compound represented by Formula (I) was able to be obtained also by the method shown in the following Examples 10-12.
Example 10
(1S) -1,5-Anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -2,3,4,6-tetrakis Synthesis of —O- (2,2-dimethylpropanoyl) -D-glucitol (16)

アルゴン雰囲気下、臭化亜鉛1.42 gにトルエン10.0 mLを加えた懸濁液にn-ブチルリチウム（2.65 M ヘキサン溶液）4.50 mLを23〜24℃にて2分間かけて滴下し、24〜25℃にて2時間撹拌した。この懸濁液に1-[(4-ブロモフェニル)メチル]-5-ヨード-4-メトキシ-2-(プロパン-2-イル)ベンゼン（８）5.00 gのトルエン20.0 mL溶液を1〜4℃にて20分間かけて滴下した。０℃にて1時間撹拌後、ジブチルエーテル4.00 mLを0〜4℃にて添加して26℃まで昇温しながら、1時間45分間撹拌した。この懸濁液に2,3,4,6-テトラキス-O-(2,2-ジメチルプロパノイル)-α-D-グルコピラノシルブロミド（１５）6.54 gのトルエン15.0 mL溶液を25〜26℃にて3分間かけて滴下後、95〜98℃にて4時間撹拌した。反応混合物を26℃まで冷却後、20 wt%塩化アンモニウム水溶液50.0 gを加えて24℃にて15分間撹拌した。トルエン10.0 mLを加えて有機層と水層に分液した。有機層を水25.3 gにて洗浄後、減圧濃縮して褐色油状物の(1S)-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-2,3,4,6-テトラキス-O-(2,2-ジメチルプロパノイル)-D-グルシトール（１６）の粗生成物11.0 gを得た。
¹H NMR ( 500 MHz, 50℃, acetone-d₆ )：δ 0.86 ( 9H, s ), 0.96 ( 3H, d, J = 6.9 Hz ), 1.12 ( 9H, s ), 1.14 ( 3H, d, J = 6.9 Hz ), 1.18 ( 9H, s ), 1.19 ( 9H, s ), 3.07 ( 1H, septet, J = 6.9 Hz ), 3.86 ( 3H, s ), 3.92, 4.01 ( 2H, AB quartet, J = 15.9 Hz ), 4.04 ( 1H, ddd, J = 9.5, 3.8 and 1.9 Hz ), 4.12 ( 1H, dd, J = 12.4 and 3.8 Hz ), 4.23 ( 1H, dd, J = 12.4 and 1.9 Hz ), 5.07 ( 1H, d, J = 9.5 Hz ), 5.32 ( 1H, t, J = 9.5 Hz ), 5.40 ( 1H, t, J = 9.5 Hz ), 5.43 ( 1H, t, J = 9.5 Hz ), 6.90 ( 1H, s ), 7.06-7.11 ( 2H, m ), 7.26 ( 1H, s ), 7.37-7.42 ( 2H, m ).
¹³C NMR ( 125 MHz, 50℃, acetone-d₆ )：δ 23.99, 24.02, 27.3, 27.59, 27.62, 27.8, 30.3, 38.6, 39.3, 39.45, 39.54, 39.6, 56.3, 62.9, 69.5, 73.1, 74.3, 75.2, 77.6, 109.5, 120.1, 123.4, 129.9, 131.7, 132.2, 132.4, 142.3, 150.3, 158.1, 176.9, 177.1, 177.7, 178.1.
MS (ESI/APCI dual source)：ポジティブモード；m/z 841 {[(M+2)+Na]⁺}, 839 [(M+Na)⁺].
HRMS (ESI/APCI dual source) : ポジティブモード；m/z calcd for C₄₃H₆₁BrNaO₁₀ [(M+Na)⁺] 839.3340, found :839.3321.
IR (KBr) cm^-1 : 2972, 2874, 1744, 1482, 1282, 1174, 1141.
実施例１１
（１Ｓ）−１，５−アンヒドロ−１−｛５−［（４−ブロモフェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−Ｄ−グルシトール（１７）の合成

Under argon atmosphere, 4.50 mL of n-butyllithium (2.65 M hexane solution) was added dropwise to a suspension of 1.42 g of zinc bromide and 10.0 mL of toluene at 23-24 ° C over 2 minutes. For 2 hours. To this suspension was added a solution of 10.0 [1-((4-bromophenyl) methyl] -5-iodo-4-methoxy-2- (propan-2-yl) benzene (8) in 20.0 mL of toluene at 1 to 4 ° C. At 20 minutes. After stirring at 0 ° C. for 1 hour, 4.00 mL of dibutyl ether was added at 0 to 4 ° C., and the mixture was stirred for 1 hour and 45 minutes while raising the temperature to 26 ° C. To this suspension, a solution of 6.54 g of 2,4,6-tetrakis-O- (2,2-dimethylpropanoyl) -α-D-glucopyranosyl bromide (15) in 15.0 mL of toluene After dropwise addition at 3 ° C. over 3 minutes, the mixture was stirred at 95 to 98 ° C. for 4 hours. After cooling the reaction mixture to 26 ° C, 50.0 g of a 20 wt% aqueous ammonium chloride solution was added and stirred at 24 ° C for 15 minutes. Toluene 10.0 mL was added and liquid-separated into the organic layer and the water layer. The organic layer was washed with 25.3 g of water and then concentrated under reduced pressure to give (1S) -1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- 11.0 g of a crude product of (propan-2-yl) phenyl} -2,3,4,6-tetrakis-O- (2,2-dimethylpropanoyl) -D-glucitol (16) was obtained.
¹ H NMR (500 MHz, 50 ° C, acetone-d ₆ ): δ 0.86 (9H, s), 0.96 (3H, d, J = 6.9 Hz), 1.12 (9H, s), 1.14 (3H, d, J = 6.9 Hz), 1.18 (9H, s), 1.19 (9H, s), 3.07 (1H, septet, J = 6.9 Hz), 3.86 (3H, s), 3.92, 4.01 (2H, AB quartet, J = 15.9 Hz), 4.04 (1H, ddd, J = 9.5, 3.8 and 1.9 Hz), 4.12 (1H, dd, J = 12.4 and 3.8 Hz), 4.23 (1H, dd, J = 12.4 and 1.9 Hz), 5.07 (1H , d, J = 9.5 Hz), 5.32 (1H, t, J = 9.5 Hz), 5.40 (1H, t, J = 9.5 Hz), 5.43 (1H, t, J = 9.5 Hz), 6.90 (1H, s ), 7.06-7.11 (2H, m), 7.26 (1H, s), 7.37-7.42 (2H, m).
¹³ C NMR (125 MHz, 50 ° C., acetone-d ₆ ): δ 23.99, 24.02, 27.3, 27.59, 27.62, 27.8, 30.3, 38.6, 39.3, 39.45, 39.54, 39.6, 56.3, 62.9, 69.5, 73.1, 74.3 75.2, 77.6, 109.5, 120.1, 123.4, 129.9, 131.7, 132.2, 132.4, 142.3, 150.3, 158.1, 176.9, 177.1, 177.7, 178.1.
MS (ESI / APCI dual source): positive mode; m / z 841 {[(M + 2) + Na] ⁺ }, 839 [(M + Na) ⁺ ].
HRMS (ESI / APCI dual source): Positive mode; m / z calcd for C ₄₃ H ₆₁ BrNaO ₁₀ [(M + Na) ⁺ ] 839.3340, found: 839.3321.
IR (KBr) cm ^-1 : 2972, 2874, 1744, 1482, 1282, 1174, 1141.
Example 11
Synthesis of (1S) -1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (17)

アルゴン雰囲気下、(1S)-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-2,3,4,6-テトラキス-O-(2,2-ジメチルプロパノイル)-D-グルシトール（１６）の粗生成物11.0 g、メタノール25.0 mL及び28 wt%ナトリウムメトキシド／メタノール溶液2.17 gの混合物を2時間加熱還流した。室温まで冷却した反応液にメタノール4.00 mL及びヘプタン25.0 mLを加えて撹拌し、上層と下層に分液した。下層にメタノール2.00 mL及びヘプタン25.0 mLを加えて撹拌し、上層と下層に分液した。得られた下層にメタノール1.00 mL、硫酸（97%）1.14 g及び水1.14 gを加えて1.5時間加熱還流後、硫酸（97%）1.15 gを加えて1.5時間加熱還流した。反応液に28 wt%ナトリウムメトキシド／メタノール溶液6.50 gを2〜10℃にて加えて室温まで昇温した。反応混合物にセルロースパウダー3.08 gを添加後、ろ過して固形物をメタノール50.0 mLにて洗浄した。ろ液を減圧濃縮後、酢酸エチル25.0 mLを添加して減圧濃縮する操作を3回実施し、黒色油状物の(1S)-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール（１７）の粗生成物11.5 gを得た。
mp : 157℃.
¹H NMR ( 500 MHz, DMSO-d₆ ) : δ 1.02 ( 3H, d, J = 6.8 Hz ), 1.06 ( 3H, d, J = 6.8 Hz ), 2.98 ( 1H, septet, J = 6.8 Hz ), 3.09-3.20 ( 2H, m ), 3.27 ( 1H, td, J = 8.5 and 4.7 Hz ), 3.35-3.44 ( 2H, m ), 3.66 ( 1H, ddd, J = 11.8, 5.7 and 1.8 Hz ), 3.76 ( 3H, s ), 3.91, 3.94 ( 2H, AB quartet, J = 15.9 Hz ), 4.37 ( 1H, t, J = 5.7 Hz, exchangeable with D₂O ), 4.44 ( 1H, d, J = 9.9 Hz ), 4.61 ( 1H, d, J = 5.7 Hz, exchangeable with D₂O ), 4.87 ( 1H, d, J = 5.0 Hz, exchangeable with D₂O ), 4.89 ( 1H, d, J = 4.7 Hz, exchangeable with D₂O ), 6.84 ( 1H, s ), 7.03-7.09 ( 2H, m ), 7.13 ( 1H, s ), 7.41-7.46 ( 2H, m ).
¹³C NMR ( 125 MHz, DMSO-d₆ ) ：δ 23.5, 23.6, 28.8, 37.0, 55.7, 61.5, 70.6, 73.6, 74.2, 78.7, 81.5, 108.5, 118.6, 125.7, 128.1, 130.4, 130.5, 131.0, 141.2, 147.2, 156.7.
MS (ESI/APCI dual source)：ポジティブモード；m/z 500 {[(M+2)+NH₄]⁺}, 498 [(M+NH₄)⁺].
MS (ESI/APCI dual source)：ネガティブモード；m/z 527 {[(M+2)+HCO₂]^-}, 525 [(M+HCO₂)^-]．
Anal.Calcd for C₂₃H₂₉BrO₆ : C, 57.39 ; H, 6.07 ; Br, 16.60. Found : C, 57.14 ; H, 6.00 ; Br, 16.47.
IR (KBr) cm^-1 : 3402, 2961, 2929, 1616, 1508, 1488, 1089, 1072, 1048, 1012.
実施例１２
（１Ｓ）−２，３，４，６−テトラ−Ｏ−アセチル−１，５−アンヒドロ−１−｛５−［（４−ブロモフェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−Ｄ−グルシトール（Ｉ）の合成

Under an argon atmosphere, (1S) -1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -2,3,4 , 6-Tetrakis-O- (2,2-dimethylpropanoyl) -D-glucitol (16) crude product 11.0 g, 25.0 mL of methanol and 2.17 g of 28 wt% sodium methoxide / methanol solution for 2 hours Heated to reflux. To the reaction solution cooled to room temperature, 4.00 mL of methanol and 25.0 mL of heptane were added and stirred, and the mixture was separated into an upper layer and a lower layer. To the lower layer, 2.00 mL of methanol and 25.0 mL of heptane were added and stirred, and the mixture was separated into an upper layer and a lower layer. To the obtained lower layer, 1.00 mL of methanol, 1.14 g of sulfuric acid (97%) and 1.14 g of water were added and heated under reflux for 1.5 hours, then 1.15 g of sulfuric acid (97%) was added and heated under reflux for 1.5 hours. To the reaction solution, 6.50 g of 28 wt% sodium methoxide / methanol solution was added at 2 to 10 ° C, and the temperature was raised to room temperature. To the reaction mixture, 3.08 g of cellulose powder was added, followed by filtration to wash the solid with 50.0 mL of methanol. The filtrate was concentrated under reduced pressure, 25.0 mL of ethyl acetate was added, and the mixture was concentrated under reduced pressure three times to obtain (1S) -1,5-anhydro-1- {5-[(4-bromophenyl) as a black oil. ) 11.5 g of a crude product of methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (17).
mp: 157 ° C.
¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.02 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 6.8 Hz), 2.98 (1H, septet, J = 6.8 Hz), 3.09-3.20 (2H, m), 3.27 (1H, td, J = 8.5 and 4.7 Hz), 3.35-3.44 (2H, m), 3.66 (1H, ddd, J = 11.8, 5.7 and 1.8 Hz), 3.76 ( 3H, s), 3.91, 3.94 (2H, AB quartet, J = 15.9 Hz), 4.37 (1H, t, J = 5.7 Hz, exchangeable with D ₂ O), 4.44 (1H, d, J = 9.9 Hz), 4.61 (1H, d, J = 5.7 Hz, exchangeable with D ₂ O), 4.87 (1H, d, J = 5.0 Hz, exchangeable with D ₂ O), 4.89 (1H, d, J = 4.7 Hz, exchangeable with D ₂ O), 6.84 (1H, s), 7.03-7.09 (2H, m), 7.13 (1H, s), 7.41-7.46 (2H, m).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 23.5, 23.6, 28.8, 37.0, 55.7, 61.5, 70.6, 73.6, 74.2, 78.7, 81.5, 108.5, 118.6, 125.7, 128.1, 130.4, 130.5, 131.0, 141.2, 147.2, 156.7.
MS (ESI / APCI dual source): positive mode; m / z 500 {[(M + 2) + NH ₄ ] ⁺ }, 498 [(M + NH ₄ ) ⁺ ].
MS (ESI / APCI dual source): negative mode; m / z 527 {[(M + 2) + HCO ₂ ] ⁻ }, 525 [(M + HCO ₂ ) ⁻ ].
Anal.Calcd for C ₂₃ H ₂₉ BrO ₆ : C, 57.39; H, 6.07; Br, 16.60. Found: C, 57.14; H, 6.00; Br, 16.47.
IR (KBr) cm ^-1 : 3402, 2961, 2929, 1616, 1508, 1488, 1089, 1072, 1048, 1012.
Example 12
(1S) -2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propane-2- Yl) phenyl} -D-glucitol (I) synthesis

アルゴン雰囲気下、(1S)-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール（１７）の粗生成物5.23 gとピリジン10.0 mLの混合物に無水酢酸5.79 gを加えて23〜26℃にて71時間45分間撹拌した。反応液に水1.00 mLを加えて22〜25℃にて30分間撹拌後、トルエン25.0 mL及び10 wt%塩酸20.0 gを加えて有機層と水層に分液した。有機層に10 wt%塩酸15.1 gを加えて撹拌後、不溶物をろ過してトルエン5.00 mLにて洗浄した。ろ液を有機層と水層に分液し、有機層を2 wt%炭酸水素ナトリウム水溶液15.1 g、引き続き、水10.0 mLにて洗浄した。有機層にトルエン3.00 mL及びNH-シリカゲル（Chromatorex NH、富士シリシア化学株式会社）2.50 gを加えて22〜23℃にて16時間撹拌した。不溶物をろ別後、トルエン10.0 mLにて洗浄し、ろ液を減圧濃縮した。得られた残渣にエタノール5.00 mLを加えて減圧濃縮する操作を2回実施した。濃縮残渣にエタノール3.50 mLを加えて60℃にて加熱溶解後、ヘプタン10.5 mLを57〜59℃にて6分間かけて滴下し、徐冷しながら撹拌した。44℃にて化合物（Ｉ）の種晶0.6 mgを添加後、室温（〜21℃）にて19時間撹拌した。析出した固体をろ過、洗浄（ヘプタン：エタノール＝3：1（v/v）、6.50 mL）後、50℃にて1時間減圧乾燥して白色粉末の(1S) -2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール（Ｉ）2.16 g得た［化合物（８）からの通算換算収率64.9%］。
ｍp : 126℃.
¹H NMR ( 600 MHz, CDCl₃ ) : δ 1.04 ( 3H, d, J = 6.9 Hz ), 1.09 ( 3H, d, J = 6.9 Hz ), 1.76 ( 3H, s ), 2.00 ( 3H, s ), 2.05 ( 3H, s ), 2.06 ( 3H, s ), 2.99 ( 1H, septet, J = 6.9 Hz ), 3.80-3.86 ( 1H, m ), 3.84 ( 3H, s ), 3.89, 3.93 ( 2H, AB quartet, J = 16.1 Hz ), 4.13 ( 1H, dd, J = 12.4 and 2.1 Hz ), 4.25 ( 1H, dd, J = 12.4 and 4.5 Hz ), 4.88 ( 1H, d, J = 9.5 Hz ), 5.22 ( 1H, t, J = 9.7 Hz ), 5.30-5.40 ( 2H, m ), 6.77 ( 1H, s ), 6.90-6.95 ( 2H, m ), 7.11 ( 1H, s ), 7.33-7.38 ( 2H, m ).
¹³C NMR ( 150 MHz, CDCl₃ ) ：δ 20.4, 20.7, 20.8, 23.4, 23.8, 29.4, 37.7, 55.7, 62.4, 68.8, 71.8, 73.9, 74.7, 76.1, 108.4, 119.6, 121.5, 128.9, 130.1, 130.6, 131.3, 140.5, 149.3, 156.7, 167.0, 169.6, 170.4, 170.8.
MS (ESI/APCI dual source) : ポジティブモード；m/z 673 {[(M+2)+Na]⁺}, 671 [(M+Na)⁺].
Anal.Calcd for C₃₁H₃₇BrO₁₀ : C, 57.32 ; H, 5.74 ; Br, 12.30. Found : C, 57.37 ; H, 5.72 ; Br, 12.28.
IR (KBr) cm^-1 : 2966, 1746, 1251, 1224, 1042.

Under an argon atmosphere, (1S) -1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (17 ) Was added to a mixture of 5.23 g of the crude product and 10.0 mL of pyridine, and the mixture was stirred at 23 to 26 ° C. for 71 hours and 45 minutes. After adding 1.00 mL of water to the reaction solution and stirring at 22 to 25 ° C. for 30 minutes, 25.0 mL of toluene and 20.0 g of 10 wt% hydrochloric acid were added to separate the organic layer and the aqueous layer. To the organic layer, 15.1 g of 10 wt% hydrochloric acid was added and stirred, and then the insoluble material was filtered and washed with 5.00 mL of toluene. The filtrate was separated into an organic layer and an aqueous layer, and the organic layer was washed with 15.1 g of a 2 wt% aqueous sodium hydrogen carbonate solution and subsequently with 10.0 mL of water. To the organic layer, 3.00 mL of toluene and 2.50 g of NH-silica gel (Chromatorex NH, Fuji Silysia Chemical Co., Ltd.) were added and stirred at 22-23 ° C. for 16 hours. The insoluble material was filtered off, washed with 10.0 mL of toluene, and the filtrate was concentrated under reduced pressure. The operation of adding 5.00 mL of ethanol to the obtained residue and concentrating under reduced pressure was performed twice. Ethanol 3.50 mL was added to the concentrated residue and dissolved by heating at 60 ° C., and then 10.5 mL of heptane was added dropwise at 57 to 59 ° C. over 6 minutes, followed by stirring with slow cooling. After adding 0.6 mg of seed crystals of compound (I) at 44 ° C., the mixture was stirred at room temperature (˜21 ° C.) for 19 hours. The precipitated solid was filtered and washed (heptane: ethanol = 3: 1 (v / v), 6.50 mL), and then dried under reduced pressure at 50 ° C. for 1 hour to obtain a white powder (1S) -2,3,4,6 -Tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (I) 2.16 g was obtained [64.9% yield in terms of total conversion from compound (8)].
mp: 126 ° C.
¹ H NMR (600 MHz, CDCl ₃ ): δ 1.04 (3H, d, J = 6.9 Hz), 1.09 (3H, d, J = 6.9 Hz), 1.76 (3H, s), 2.00 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.99 (1H, septet, J = 6.9 Hz), 3.80-3.86 (1H, m), 3.84 (3H, s), 3.89, 3.93 (2H, AB quartet , J = 16.1 Hz), 4.13 (1H, dd, J = 12.4 and 2.1 Hz), 4.25 (1H, dd, J = 12.4 and 4.5 Hz), 4.88 (1H, d, J = 9.5 Hz), 5.22 (1H , t, J = 9.7 Hz), 5.30-5.40 (2H, m), 6.77 (1H, s), 6.90-6.95 (2H, m), 7.11 (1H, s), 7.33-7.38 (2H, m).
¹³ C NMR (150 MHz, CDCl ₃ ): δ 20.4, 20.7, 20.8, 23.4, 23.8, 29.4, 37.7, 55.7, 62.4, 68.8, 71.8, 73.9, 74.7, 76.1, 108.4, 119.6, 121.5, 128.9, 130.1, 130.6, 131.3, 140.5, 149.3, 156.7, 167.0, 169.6, 170.4, 170.8.
MS (ESI / APCI dual source): Positive mode; m / z 673 {[(M + 2) + Na] ⁺ }, 671 [(M + Na) ⁺ ].
Anal.Calcd for C ₃₁ H ₃₇ BrO ₁₀ : C, 57.32; H, 5.74; Br, 12.30. Found: C, 57.37; H, 5.72; Br, 12.28.
IR (KBr) cm ^-1 : 2966, 1746, 1251, 1224, 1042.

The compound represented by the formula (XI) could be obtained by the methods shown in Examples 13 to 15 below.
Example 13
(1S) -2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1- [5-({4-[(1E) -3-carboxy-3-methylbut-1-ene- Synthesis of 1-yl] phenyl} methyl) -2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol = hexane-1-amine salt (19)

アルゴン雰囲気下、(1S) -2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-ブロモフェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール（Ｉ）3.00 g、2,2-ジメチルブタ-3-エン酸（１８）0.804 g、トリ−ｏ−トリルホスフィン0.285 g、トリエチルアミン1.88 g、アセトニトリル9.00 mL及び酢酸パラジウム0.112 gの混合物を8.5時間加熱還流した。室温まで冷却後、一晩静置した。反応混合物にアセトニトリル3.00 mLを加えて38℃にて30分間加熱撹拌後、セルロースパウダーパッドにてろ過し、アセトニトリル9.00 mLにて洗浄した。ろ液を減圧濃縮して得た残渣に酢酸エチル20.0mL及び10 wt%塩酸10.0 gを加えて有機層と水層に分液した。有機層を10 wt%塩化ナトリウム水溶液10.0 g、引き続き、水10.0 mLにて順次洗浄した。有機層を減圧濃縮後、酢酸エチル6.00 mLを加えて減圧濃縮する操作を2回実施し、残渣4.15 gを得た。この残渣に酢酸エチル12.0 g及びヘキシルアミン0.495 gを加えて加熱溶解し、ヘプタン31.5 mLを50〜55℃にて8分間かけて滴下した。51℃にて化合物（１９）の種晶0.8 mgを添加後、室温（〜23℃）にて21時間45分間撹拌した。析出した固体をろ過、洗浄（ヘプタン：酢酸エチル＝3：1（v/v）、12.0 mL）後、室温にて2時間減圧乾燥して白色粉末の(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-[5-({4-[(1E)-3-カルボキシ-3-メチルブタ-1-エン-1-イル]フェニル}メチル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトール＝ヘキサン-1-アミン塩（１９）3.01 g（収率83.2%）を得た。
ｍp : 146〜147℃.
¹H NMR ( 500 MHz, CDCl₃ ) : δ 0.82 ( 3H, t, J = 7.3 Hz ), 1.02 ( 3H, d, J = 6.9 Hz ), 1.07 ( 3H, d, J = 6.9 Hz ), 1.09-1.16 ( 4H, m ), 1.16-1.24 ( 2H, m ), 1.27 ( 6H, s ), 1.43-1.54 ( 2H, m ), 1.76 ( 3H, s ), 2.00 ( 3H, s ), 2.047 ( 3H, s ), 2.052 ( 3H, s ), 2.59-2.66 ( 2H, m ), 3.01 ( 1H, septet, J = 6.9 Hz ), 3.80-3.85 ( 1H, m ), 3.84 ( 3H, s ), 3.91, 3.93 ( 2H, AB quartet, J = 16.1 Hz ), 4.13 ( 1H, dd, J = 12.3 and 2.1 Hz ), 4.25 ( 1H, dd, J = 12.3 and 4.6 Hz ), 4.85 ( 1H, d, J = 9.5 Hz ), 5.22 ( 1H, t, J = 9.5 Hz ), 5.33 ( 1H, t, J = 9.5 Hz ), 5.41 ( 1H, t, J = 9.5 Hz ), 6.29 ( 1H, d, J_AB = 16.3 Hz ), 6.44 ( 1H, d, J_AB = 16.3 Hz ), 6.50 ( 3H, br s, exchangeable with D₂O ), 6.76 ( 1H, s ), 6.92-6.97 ( 2H, m ), 7.12 ( 1H, s ), 7.20-7.25 ( 2H, m ).
¹³C NMR ( 150 MHz, CDCl₃ ) ：δ 14.0, 20.4, 20.7, 20.8, 22.4, 23.5, 23.8, 25.9, 26.2, 28.8, 29.3, 31.3, 38.1, 39.9, 45.5, 55.7, 62.4, 68.8, 71.7, 74.8, 76.1, 108.4, 121.3, 125.8, 126.0, 128.4, 129.5, 130.7, 135.3, 136.7, 140.2, 149.4, 156.6, 169.0, 169.6, 170.4, 170.8, 183.0.
MS (ESI/APCI dual source) : ポジティブモード；m/z 784 [(M+H)⁺], 705 {[(M−C₆H₁₅N)+Na]⁺}. MS (ESI/APCI dual source) : ネガティブモード；m/z 681 {[(M−C₆H₁₅N)−H]⁻}.
Anal.Calcd for C₃₇H₄₆O₁₂・C₆H₁₅N : C, 65.88 ; H, 7.84 ; N, 1.79. Found : C, 65.83 ; H, 7.81 ; N, 1.80.
IR (KBr) cm^-1 : 2960, 2933, 2870, 1747, 1254, 1224, 1042.
実施例１４
（１Ｓ）−２，３，４，６−テトラ−Ｏ−アセチル−１，５−アンヒドロ−１−｛５−［（４−｛（１Ｅ）−４−［（１−｛［２−（ジメチルアミノ）エチル］アミノ｝−２−メチル−１−オキソプロパン−２−イル）アミノ］−３，３−ジメチル−４−オキソブタ−１−エン−１−イル｝フェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−Ｄ−グルシトール一シュウ酸塩（２１）の合成

Under an argon atmosphere, (1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- {5-[(4-bromophenyl) methyl] -2-methoxy-4- ( Propan-2-yl) phenyl} -D-glucitol (I) 3.00 g, 2,2-dimethylbut-3-enoic acid (18) 0.804 g, tri-o-tolylphosphine 0.285 g, triethylamine 1.88 g, acetonitrile 9.00 A mixture of mL and 0.112 g of palladium acetate was heated to reflux for 8.5 hours. After cooling to room temperature, it was allowed to stand overnight. To the reaction mixture was added 3.00 mL of acetonitrile, and the mixture was heated and stirred at 38 ° C. for 30 minutes, filtered through a cellulose powder pad, and washed with 9.00 mL of acetonitrile. The filtrate was concentrated under reduced pressure, 20.0 mL of ethyl acetate and 10.0 g of 10 wt% hydrochloric acid were added to the residue, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed sequentially with 10.0 g of a 10 wt% aqueous sodium chloride solution and subsequently with 10.0 mL of water. The organic layer was concentrated under reduced pressure, and then an operation of adding 6.00 mL of ethyl acetate and concentrating under reduced pressure was performed twice to obtain 4.15 g of a residue. To this residue, 12.0 g of ethyl acetate and 0.495 g of hexylamine were added and dissolved by heating, and 31.5 mL of heptane was added dropwise at 50 to 55 ° C. over 8 minutes. After adding 0.8 mg of seed crystals of compound (19) at 51 ° C., the mixture was stirred at room temperature (˜23 ° C.) for 21 hours and 45 minutes. The precipitated solid was filtered and washed (heptane: ethyl acetate = 3: 1 (v / v), 12.0 mL), and then dried under reduced pressure at room temperature for 2 hours to obtain a white powder of (1S) -2,3,4,6 -Tetra-O-acetyl-1,5-anhydro-1- [5-({4-[(1E) -3-carboxy-3-methylbut-1-en-1-yl] phenyl} methyl) -2- Methoxy-4- (propan-2-yl) phenyl] -D-glucitol = hexane-1-amine salt (19) (3.01 g, yield 83.2%) was obtained.
mp: 146-147 ° C.
¹ H NMR (500 MHz, CDCl ₃ ): δ 0.82 (3H, t, J = 7.3 Hz), 1.02 (3H, d, J = 6.9 Hz), 1.07 (3H, d, J = 6.9 Hz), 1.09- 1.16 (4H, m), 1.16-1.24 (2H, m), 1.27 (6H, s), 1.43-1.54 (2H, m), 1.76 (3H, s), 2.00 (3H, s), 2.047 (3H, s), 2.052 (3H, s), 2.59-2.66 (2H, m), 3.01 (1H, septet, J = 6.9 Hz), 3.80-3.85 (1H, m), 3.84 (3H, s), 3.91, 3.93 (2H, AB quartet, J = 16.1 Hz), 4.13 (1H, dd, J = 12.3 and 2.1 Hz), 4.25 (1H, dd, J = 12.3 and 4.6 Hz), 4.85 (1H, d, J = 9.5 Hz ), 5.22 (1H, t, J = 9.5 Hz), 5.33 (1H, t, J = 9.5 Hz), 5.41 (1H, t, J = 9.5 Hz), 6.29 (1H, d, J _AB = 16.3 Hz) , 6.44 (1H, d, J _AB = 16.3 Hz), 6.50 (3H, br s, exchangeable with D ₂ O), 6.76 (1H, s), 6.92-6.97 (2H, m), 7.12 (1H, s) , 7.20-7.25 (2H, m).
¹³ C NMR (150 MHz, CDCl ₃ ): δ 14.0, 20.4, 20.7, 20.8, 22.4, 23.5, 23.8, 25.9, 26.2, 28.8, 29.3, 31.3, 38.1, 39.9, 45.5, 55.7, 62.4, 68.8, 71.7, 74.8, 76.1, 108.4, 121.3, 125.8, 126.0, 128.4, 129.5, 130.7, 135.3, 136.7, 140.2, 149.4, 156.6, 169.0, 169.6, 170.4, 170.8, 183.0.
MS (ESI / APCI dual source): Positive mode; m / z 784 [(M + H) ⁺ ], 705 {[(M−C ₆ H ₁₅ N) + Na] ⁺ }. MS (ESI / APCI dual source ): Negative mode; m / z 681 {[(M−C ₆ H ₁₅ N) −H] ⁻ }.
Anal.Calcd for C ₃₇ H ₄₆ O ₁₂・ C ₆ H ₁₅ N: C, 65.88; H, 7.84; N, 1.79. Found: C, 65.83; H, 7.81; N, 1.80.
IR (KBr) cm ^-1 : 2960, 2933, 2870, 1747, 1254, 1224, 1042.
Example 14
(1S) -2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1- {5-[(4-{(1E) -4-[(1-{[2- (dimethyl Amino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy- Synthesis of 4- (propan-2-yl) phenyl} -D-glucitol monooxalate (21)

(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-[5-({4-[(1E)-3-カルボキシ-3-メチルブタ-1-エン-1-イル]フェニル}メチル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトール＝ヘキサン-1-アミン塩（１９）25.0 g及び酢酸エチル117 mLの混合物に氷冷下、1M塩酸133 mLを加えた。室温まで昇温後、有機層と水層に分液した。有機層を1M塩酸65.0 mL、引き続き、10 wt%塩化ナトリウム水溶液62.5 gにて順次洗浄した。有機層を無水硫酸マグネシウム6.25 gにて乾燥後、不溶物をろ別し、ろ液を減圧濃縮して黄色油状物の化合物（１９）のカルボン酸遊離体の粗生成物29.4 gを得た。
N-[2-(ジメチルアミノ)エチル]-2-メチルアラニンアミド二塩酸塩（２０）12.1 gに25 wt%水酸化ナトリウム水溶液27.6 g、水5.00 g、酢酸エチル170 g及び塩化ナトリウム5.00 gを順次加えた。有機層と水層に分液し、水層を酢酸エチル162 gにて抽出した。分液した水層を再度酢酸エチル162 gにて抽出し、全ての有機層を合わせた。有機層を無水硫酸マグネシウム6.25 gにて乾燥後、不溶物をろ別し、ろ液を減圧濃縮して無色油状物の化合物（２０）のアミン遊離体の粗生成物10.6 gを得た。
化合物（１９）のカルボン酸遊離体の粗生成物29.4 gのN,N-ジメチルホルムアミド50.0mL溶液、化合物（２０）のアミン遊離体の粗生成物10.6 gのN,N-ジメチルホルムアミド50.0mL溶液、N,N-ジメチルホルムアミド127 mL、1-ヒドロキシベンゾトリアゾール一水和物（HOBt・H₂O）6.45 g及びトリエチルアミン10.7 mLの混合物に1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩（EDC・HCl）7.70 gを加え、室温にて12.5時間撹拌した。反応液を氷冷した水100 mLに加えた後、トルエン300 mLを加えた。有機層と水層に分液し、有機層を5 wt%塩化ナトリウム水溶液112 mLで2回、5 wt%塩化アンモニウム水溶液56.3 mLで1回、5 wt%塩化ナトリウム水溶液112 mLで1回順次洗浄した。有機層を無水硫酸マグネシウム7.50 gにて乾燥後、不溶物をろ別し、ろ液を減圧濃縮して淡黄色液41.15 gを得た。得られた濃縮液にトルエン58.85 gを加えて(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-{(1E)-4-[(1-{[2-（ジメチルアミノ）エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}フェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトールの粗生成物トルエン溶液100 gを得た。
得られたトルエン溶液40.0 gを減圧濃縮し、黄色液17.2 gを得た。酢酸エチル90.0 mLを加え、37℃に加熱した。化合物（２１）の種晶0.05 g、0.5 Mシュウ酸/酢酸エチル溶液25.4 mL及び酢酸エチル30.0 mLを順次加え、1.5時間同温度にて撹拌した。室温まで放冷撹拌した後、析出した固体をろ過、洗浄（酢酸エチル50.0 mL）後、40℃にて1時間減圧乾燥して白色粉末の(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-{(1E)-4-[(1-{[2-（ジメチルアミノ）エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}フェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール一シュウ酸塩（２１）10.7 g［化合物（１９）からの換算収率90.5%］を得た。
ｍp : 184℃.
¹H NMR ( 500 MHz, CDCl₃ )：δ 1.05 ( 3H, d, J = 6.8 Hz ), 1.11 ( 3H, d, J = 6.8 Hz ), 1.35 ( 6H, s ), 1.43 ( 6H, s ), 1.79 ( 3H, s ), 2.00 ( 3H, s ), 2.05 ( 3H, s ), 2.06 ( 3H, s ), 2.87 ( 6H, s ), 3.04 ( 1H, septet, J = 6.8 Hz ), 3.22 ( 2H, t, J = 5.3 Hz ), 3.55-3.65 ( 2H, m ), 3.79-3.86 ( 1H, m ), 3.85 ( 3H, s ), 3.93, 3.99 ( 2H, AB quartet, J = 16.1 Hz ), 4.13 ( 1H, dd, J = 12.4 and 2.4 Hz ), 4.24 ( 1H, dd, J = 12.4 and 4.5 Hz ), 4.89 ( 1H, d, J = 9.0 Hz ), 5.21 ( 1H, t, J = 9.0 Hz ), 5.33 ( 1H, t, J = 9.0 Hz ), 5.37 ( 1H, t, J = 9.0 Hz ), 6.40 ( 1H, s, exchangeable with D₂O ), 6.42 ( 1H, d, J = 16.1 Hz ), 6.49 ( 1H, d, J = 16.1 Hz ), 6.77 ( 1H, s ), 6.98-7.03 ( 2H, m ), 7.13 ( 1H, s ), 7.30-7.35 ( 2H, m ), 8.31 ( 1H, t, J = 5.8 Hz, exchangeable with D₂O ).
¹³C NMR ( 125 MHz, CDCl₃ )：δ 20.4, 20.65, 20.68, 20.8, 23.4, 23.9, 24.86, 24.90, 25.06, 25.09, 29.4, 35.0, 37.9, 44.4, 45.0, 55.8, 56.8, 58.8, 62.5, 68.8, 71.9, 73.9, 74.7, 76.1, 108.3, 121.5, 126.5, 128.6, 129.3, 129.6, 130.5, 133.0, 134.2, 141.2, 149.4, 156.6, 163.1, 169.4, 169.6, 170.4, 170.8, 175.5, 177.2.
MS (ESI/APCI dual source) : ポジティブモード；m/z 838 {[(M−C₂H₂O₄)+H]⁺}.
Anal.Calcd for C₄₅H₆₃N₃O₁₂・C₂H₂O₄ : C, 60.83 ; H, 7.06 ; N, 4.53. Found : C, 60.60 ; H, 7.02 ; N, 4.50.
IR (KBr) cm^-1 : 3358, 2962, 1756, 1745, 1657, 1505, 1253, 1233.
実施例１５
（１Ｓ）−１，５−アンヒドロ−１−｛５−［（４−｛（１Ｅ）−４−［（１−｛［２−（ジメチルアミノ）エチル］アミノ｝−２−メチル−１−オキソプロパン−２−イル）アミノ］−３，３−ジメチル−４−オキソブタ−１−エン−１−イル｝フェニル）メチル］−２−メトキシ−４−（プロパン−２−イル）フェニル｝−Ｄ−グルシトール（XI）のエタノール溶媒和物の合成

(1S) -2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1- [5-({4-[(1E) -3-carboxy-3-methylbut-1-ene- 1-yl] phenyl} methyl) -2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol = hexane-1-amine salt (19) 25.0 g and ethyl acetate 117 mL Below, 133 mL of 1M hydrochloric acid was added. After raising the temperature to room temperature, it was separated into an organic layer and an aqueous layer. The organic layer was washed sequentially with 65.0 mL of 1M hydrochloric acid and subsequently with 62.5 g of 10 wt% aqueous sodium chloride solution. The organic layer was dried over 6.25 g of anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain 29.4 g of a crude carboxylic acid free product of compound (19) as a yellow oil.
12.1 g of N- [2- (dimethylamino) ethyl] -2-methylalaninamide dihydrochloride (20) 27.6 g of 25 wt% aqueous sodium hydroxide, 5.00 g of water, 170 g of ethyl acetate and 5.00 g of sodium chloride Added sequentially. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with 162 g of ethyl acetate. The separated aqueous layer was extracted again with 162 g of ethyl acetate, and all organic layers were combined. The organic layer was dried over 6.25 g of anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain 10.6 g of a crude product of the amine free form of the colorless oily compound (20).
Compound (19) carboxylic acid free product crude product 29.4 g of N, N-dimethylformamide 50.0 mL solution, Compound (20) crude product of amine free product 10.6 g of N, N-dimethylformamide 50.0 mL solution , N, N-dimethylformamide 127 mL, 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O) 6.45 g and triethylamine 10.7 mL in a mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 7.70 g of salt (EDC · HCl) was added, and the mixture was stirred at room temperature for 12.5 hours. The reaction solution was added to 100 mL of ice-cooled water, and then 300 mL of toluene was added. Separate the organic layer and aqueous layer, and wash the organic layer twice with 112 mL of 5 wt% aqueous sodium chloride, once with 56.3 mL of 5 wt% aqueous ammonium chloride, and once with 112 mL of 5 wt% aqueous sodium chloride. did. The organic layer was dried over anhydrous magnesium sulfate (7.50 g), insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure to obtain a pale yellow liquid (41.15 g). To the obtained concentrated solution was added 58.85 g of toluene, and (1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- {5-[(4-{(1E)- 4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-ene-1 100 g of a crude product toluene solution of -yl} phenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol was obtained.
The obtained toluene solution 40.0 g was concentrated under reduced pressure to obtain 17.2 g of a yellow liquid. Ethyl acetate 90.0 mL was added and heated to 37 ° C. 0.05 g of seed crystals of compound (21), 25.4 mL of 0.5 M oxalic acid / ethyl acetate solution and 30.0 mL of ethyl acetate were sequentially added, and the mixture was stirred at the same temperature for 1.5 hours. After standing to cool to room temperature, the precipitated solid was filtered, washed (ethyl acetate 50.0 mL), and dried under reduced pressure at 40 ° C. for 1 hour to obtain a white powder of (1S) -2,3,4,6-tetra- O-acetyl-1,5-anhydro-1- {5-[(4-{(1E) -4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl-1-oxo Propan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D- 10.7 g of glucitol monooxalate (21) [converted yield from compound (19) 90.5%] was obtained.
mp: 184 ° C.
¹ H NMR (500 MHz, CDCl ₃ ): δ 1.05 (3H, d, J = 6.8 Hz), 1.11 (3H, d, J = 6.8 Hz), 1.35 (6H, s), 1.43 (6H, s), 1.79 (3H, s), 2.00 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.87 (6H, s), 3.04 (1H, septet, J = 6.8 Hz), 3.22 (2H , t, J = 5.3 Hz), 3.55-3.65 (2H, m), 3.79-3.86 (1H, m), 3.85 (3H, s), 3.93, 3.99 (2H, AB quartet, J = 16.1 Hz), 4.13 (1H, dd, J = 12.4 and 2.4 Hz), 4.24 (1H, dd, J = 12.4 and 4.5 Hz), 4.89 (1H, d, J = 9.0 Hz), 5.21 (1H, t, J = 9.0 Hz) , 5.33 (1H, t, J = 9.0 Hz), 5.37 (1H, t, J = 9.0 Hz), 6.40 (1H, s, exchangeable with D ₂ O), 6.42 (1H, d, J = 16.1 Hz), 6.49 (1H, d, J = 16.1 Hz), 6.77 (1H, s), 6.98-7.03 (2H, m), 7.13 (1H, s), 7.30-7.35 (2H, m), 8.31 (1H, t, J = 5.8 Hz, exchangeable with D ₂ O).
¹³ C NMR (125 MHz, CDCl ₃ ): δ 20.4, 20.65, 20.68, 20.8, 23.4, 23.9, 24.86, 24.90, 25.06, 25.09, 29.4, 35.0, 37.9, 44.4, 45.0, 55.8, 56.8, 58.8, 62.5, 68.8, 71.9, 73.9, 74.7, 76.1, 108.3, 121.5, 126.5, 128.6, 129.3, 129.6, 130.5, 133.0, 134.2, 141.2, 149.4, 156.6, 163.1, 169.4, 169.6, 170.4, 170.8, 175.5, 177.2.
MS (ESI / APCI dual source): positive mode; m / z 838 {[(M−C ₂ H ₂ O ₄ ) + H] ⁺ }.
Anal.Calcd for C ₄₅ H ₆₃ N ₃ O ₁₂・ C ₂ H ₂ O ₄ : C, 60.83; H, 7.06; N, 4.53. Found: C, 60.60; H, 7.02; N, 4.50.
IR (KBr) cm ^-1 : 3358, 2962, 1756, 1745, 1657, 1505, 1253, 1233.
Example 15
(1S) -1,5-Anhydro-1- {5-[(4-{(1E) -4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl-1-oxo Propan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D- Synthesis of ethanol solvate of glucitol (XI)

(1S)-2,3,4,6-テトラ-O-アセチル-1,5-アンヒドロ-1-{5-[(4-{(1E)-4-[(1-{[2-（ジメチルアミノ）エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}フェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール一シュウ酸塩（２１）10.0 g及びトルエン100 mLの混合物に5 wt%炭酸水素ナトリウム水溶液250 g、水50.0 g及びトルエン30.0 mLを加えた。有機層と水層に分液し、有機層を5 wt%塩化ナトリウム水溶液95.0 mLにて洗浄後、減圧濃縮して黄色油状物12.4 gを得た。得られた濃縮物にメタノール100 mL、水2.00 m及びトリエチルアミン2.00 gを加え、室温にて50時間撹拌後、88.5時間静置した。反応液を減圧濃縮し、得られた濃縮物にエタノール50.0 mLを加えて減圧濃縮する操作を3回繰り返し、淡黄色油状物の(1S)-1,5-アンヒドロ-1-{5-[(4-{(1E)-4-[(1-{[2-（ジメチルアミノ）エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}フェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール（XI）13.8 gを得た。エタノール16.2 gを加えて56℃に加熱し、ヘプタン10.0 gを加えた。化合物（XI）のエタノール溶媒和物の種晶0.0025 gを加えた後、6時間かけて25℃にし、同温度にて15時間撹拌した。さらに2時間かけて2℃にし、同温度にて2時間撹拌した。析出した固体をろ過、洗浄（ヘプタン：エタノール＝63：37（v/v）、60.0 mL）後、40℃にて2時間減圧乾燥して白色粉末の(1S)-1,5-アンヒドロ-1-{5-[(4-{(1E)-4-[(1-{[2-（ジメチルアミノ）エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}フェニル)メチル]-2-メトキシ-4-(プロパン-2-イル)フェニル}-D-グルシトール（XI）のエタノール溶媒和物6.08 g（収率79.4%）を得た。
ｍp : 105〜106℃.
¹H NMR ( 600 MHz, CD₃OD )：δ 1.075 ( 3H, d, J = 6.9 Hz ), 1.084 ( 3H, d, J = 6.9 Hz), 1.17 ( 2.4H, t, J = 7.2 Hz ), 1.35 ( 6H, s ), 1.45 ( 6H, s ), 2.22 ( 6H, s ), 2.39 ( 2H, t, J = 6.8 Hz ), 3.09 ( 1H, septet, J = 6.9 Hz ), 3.27 ( 2H, t, J = 6.8 Hz ), 3.36-3.41 ( 2H, m ), 3.45-3.51 ( 1H, m ), 3.57 ( 1H, t, J = 9.2 Hz ), 3.60 ( 1.6H, q, J = 7.2 Hz ), 3.63-3.68 ( 1H, m ), 3.83 ( 3H, s ), 3.85 ( 1H, dd, J = 11.8 and 1.0 Hz ), 3.98 ( 2H, s ), 4.65 ( 1H, d, J = 9.2 Hz ), 6.39 ( 1H, d, J_AB = 16.1 Hz ), 6.52 ( 1H, d, J_AB = 16.1 Hz ), 6.88 ( 1H, s ), 7.06-7.09 ( 2H, m ), 7.23 ( 1H, s ), 7.30-7.33 ( 2H, m ).
¹³C NMR ( 150 MHz, CD₃OD )：δ 18.5, 24.1, 24.2, 25.2, 25.7, 30.7, 38.4, 39.2, 45.6, 46.0, 56.5, 58.1, 58.5, 59.1, 63.4, 72.3, 75.9, 76.8, 80.3, 82.5, 109.8, 126.3, 127.5, 129.9, 130.4, 130.8, 132.1, 134.8, 136.2, 142.8, 149.7, 158.7, 177.2, 178.3.
MS (ESI/APCI dual source) : ポジティブモード；m/z 670 [(M+H)⁺].
Anal.Calcd for C₃₇H₅₅N₃O₈・0.8C₂H₆O・0.2H₂O : C, 65.27 ; H, 8.54 ; N, 5.92. Found : C, 65.13 ; H, 8.46 ; N, 5.85.
IR (KBr) cm^-1 : 3357, 2964, 1673, 1634, 1505, 1041.

(1S) -2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1- {5-[(4-{(1E) -4-[(1-{[2- (dimethyl Amino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy- To a mixture of 10.0 g of 4- (propan-2-yl) phenyl} -D-glucitol monooxalate (21) and 100 mL of toluene, add 250 g of 5 wt% aqueous sodium bicarbonate, 50.0 g of water and 30.0 mL of toluene. It was. The organic layer was separated into an aqueous layer and the organic layer was washed with 95.0 mL of a 5 wt% aqueous sodium chloride solution and then concentrated under reduced pressure to obtain 12.4 g of a yellow oil. To the obtained concentrate, 100 mL of methanol, 2.00 m of water and 2.00 g of triethylamine were added, stirred at room temperature for 50 hours, and allowed to stand for 88.5 hours. The reaction solution was concentrated under reduced pressure, and the operation of adding 50.0 mL of ethanol to the obtained concentrate and concentrating under reduced pressure was repeated three times to obtain (1S) -1,5-anhydro-1- {5-[( 4-{(1E) -4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4- 13.8 g of oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (XI) was obtained. 16.2 g of ethanol was added and heated to 56 ° C., and 10.0 g of heptane was added. After adding 0.0025 g of a seed crystal of an ethanol solvate of compound (XI), the mixture was brought to 25 ° C. over 6 hours and stirred at the same temperature for 15 hours. The mixture was further brought to 2 ° C. over 2 hours and stirred at the same temperature for 2 hours. The precipitated solid was filtered and washed (heptane: ethanol = 63: 37 (v / v), 60.0 mL), and then dried under reduced pressure at 40 ° C. for 2 hours to give a white powder of (1S) -1,5-anhydro-1 -{5-[(4-{(1E) -4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3, Ethanol solvate of 3-dimethyl-4-oxobut-1-en-1-yl} phenyl) methyl] -2-methoxy-4- (propan-2-yl) phenyl} -D-glucitol (XI) 6.08 g (Yield 79.4%) was obtained.
mp: 105-106 ° C.
¹ H NMR (600 MHz, CD ₃ OD): δ 1.075 (3H, d, J = 6.9 Hz), 1.084 (3H, d, J = 6.9 Hz), 1.17 (2.4H, t, J = 7.2 Hz), 1.35 (6H, s), 1.45 (6H, s), 2.22 (6H, s), 2.39 (2H, t, J = 6.8 Hz), 3.09 (1H, septet, J = 6.9 Hz), 3.27 (2H, t , J = 6.8 Hz), 3.36-3.41 (2H, m), 3.45-3.51 (1H, m), 3.57 (1H, t, J = 9.2 Hz), 3.60 (1.6H, q, J = 7.2 Hz), 3.63-3.68 (1H, m), 3.83 (3H, s), 3.85 (1H, dd, J = 11.8 and 1.0 Hz), 3.98 (2H, s), 4.65 (1H, d, J = 9.2 Hz), 6.39 (1H, d, J _AB = 16.1 Hz), 6.52 (1H, d, J _AB = 16.1 Hz), 6.88 (1H, s), 7.06-7.09 (2H, m), 7.23 (1H, s), 7.30- 7.33 (2H, m).
¹³ C NMR (150 MHz, CD ₃ OD): δ 18.5, 24.1, 24.2, 25.2, 25.7, 30.7, 38.4, 39.2, 45.6, 46.0, 56.5, 58.1, 58.5, 59.1, 63.4, 72.3, 75.9, 76.8, 80.3 , 82.5, 109.8, 126.3, 127.5, 129.9, 130.4, 130.8, 132.1, 134.8, 136.2, 142.8, 149.7, 158.7, 177.2, 178.3.
MS (ESI / APCI dual source): Positive mode; m / z 670 [(M + H) ⁺ ].
Anal.Calcd for C ₃₇ H ₅₅ N ₃ O ₈・ 0.8C ₂ H ₆ O ・ 0.2H ₂ O: C, 65.27; H, 8.54; N, 5.92. Found: C, 65.13; H, 8.46; N, 5.85 .
IR (KBr) cm ^-1 : 3357, 2964, 1673, 1634, 1505, 1041.

  According to the present invention, it is possible to provide a production method suitable for mass production of a 1,5-anhydro-1-substituted phenyl-D-glucitol compound useful as a pharmaceutical having SGLT1 inhibitory activity.

Claims (2)

A method for producing a 1,5-anhydro-1-substituted phenyl-D-glucitol compound represented by the formula (XI),

(I) converting the compound represented by formula (II) into the compound represented by formula (III);

(Ii) converting the compound represented by the formula (III) into a compound represented by the formula (IV);

(Iii) converting the compound represented by the formula (IV) into a compound represented by the formula (V);

(Iv) converting the compound represented by the formula (V) into a compound represented by the formula (VI);

(V) converting the compound represented by the formula (VI) into a compound represented by the formula (VII);

(Vi) converting the compound represented by the formula (VII) into a compound represented by the formula (XII);

(Vii) converting the compound represented by the formula (XII) into a compound represented by the formula (XIII);

(Viii) converting the compound represented by the formula (XIII) into a compound represented by the formula (I);

(Ix) converting the compound represented by the formula (I) into a compound represented by the formula (XIV);

(X) converting the compound represented by the formula (XIV) into a compound represented by the formula (XV);

(Xi) 1,5-anhydro-1-substituted phenyl-D-glucitol compound comprising the step of converting the compound represented by the formula (XV) into the compound represented by the formula (XI) Manufacturing method. A process for producing a 1,5-anhydro-1-substituted phenyl-D-glucitol compound represented by formula (I), comprising:

(I) converting the compound represented by formula (II) into the compound represented by formula (III);

(Ii) converting the compound represented by the formula (III) into a compound represented by the formula (IV);

(Iii) converting the compound represented by the formula (IV) into a compound represented by the formula (V);

(Iv) converting the compound represented by the formula (V) into a compound represented by the formula (VI);

(V) converting the compound represented by the formula (VI) into a compound represented by the formula (VII);

(Vi) converting the compound represented by the formula (VII) into a compound represented by the formula (VIII);

(Vii) converting the compound represented by the formula (VIII) into a compound represented by the formula (IX);

(Viii) converting the compound represented by the formula (IX) into a compound represented by the formula (X);

(Ix) 1,5-anhydro-1-substituted phenyl-D-glucitol compound comprising the step of converting the compound represented by the formula (X) into the compound represented by the formula (I) Manufacturing method.