Method for producing protected glycoside derivative

Abstract

Provided is a method for producing a protected glycoside derivative in which a phenol compound is bonded to an anomeric position of a sugar and another hydroxyl group of the sugar is protected, the method comprises reacting a sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the 1-position hydroxyl group and the 2-position hydroxyl group are acyl groups, and a phenolic compound in the presence of at least one catalyst selected from the group consisting of trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate.

Description

Technical Field

[0001] The present invention relates to a method for preparing a protected glycoside derivative. The protected glycoside derivative has a phenol compound bonded to the anomeric position of sugar, and the other hydroxyl groups of the sugar are protected.

[0002] This application claims priority based on Japanese Patent Application No. 2022-148337 filed in Japan on September 16, 2022, and the contents are incorporated herein by reference. Background Art

[0003] One of the compounds synthesized as glycosides is tocopherol glucoside, which is a tocopherol derivative having various pharmacological activities such as peripheral vasodilator effect and histamine release inhibitory effect.

[0004] Glycoside is a general term for compounds in which an alcohol or phenol compound is bonded only to the anomeric position of a cyclic sugar (position 1 of a pyranose ring or a furanose ring) through an ether bond. All other hydroxyl groups of the cyclic sugar are unprotected. Glycoside derivatives are compounds in which any hydroxyl group on the sugar backbone is modified. In this specification, "protected glycoside derivatives" refer to compounds in which the hydroxyl groups on the sugar backbone of the above-mentioned glycoside or glycoside derivative are protected.

[0005] Examples of the glycoside include glucoside having a glucose backbone, fructoside having a fructose backbone, mannoside having a mannose backbone, and galactoside having a galactose backbone.

[0006] Patent Documents 1 and 2 disclose examples of manufacturing tocopherol glucoside, wherein a glycoside derivative with protected hydroxyl groups on the sugar backbone is obtained by reacting a fully acetylated sugar with vitamin E, and then the protected hydroxyl groups are deprotected to obtain tocopherol glucoside. Patent Document 1 describes a method for manufacturing a glycoside derivative with protected hydroxyl groups on the sugar backbone using acid catalysts such as ferric chloride, cupric chloride, zinc chloride, aluminum chloride, boron trifluoride, titanium tetrachloride, and tin tetrachloride. In addition, Patent Document 2 describes a method for manufacturing a glycoside derivative with protected hydroxyl groups on the sugar backbone using acid catalysts such as p-toluenesulfonic acid.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent Application Laid-Open No. 2-144151

[0010] Patent Document 2: Japanese Patent Publication No. 1-55278 Summary of the invention

[0011] Problems to be solved by the invention

[0012] In the methods described in Patent Documents 1 and 2, the yield of the glycoside derivative in which the hydroxyl group of the sugar is protected in the reaction between the sugar and the phenol compound cannot be said to be high. Therefore, there is a problem that the yield of the deprotected glycoside derivative obtained after the subsequent deprotection reaction is also low.

[0013] Therefore, an object of the present invention is to provide a method for producing a protected glycoside derivative, which method can produce a glycoside derivative in which the hydroxyl group of a sugar is protected in high yield.

[0014] Means of solving the problem

[0015] The present invention includes the following aspects.

[0016] [1] A method for producing a protected glycoside derivative, wherein a phenol compound is bonded to the anomeric position of a sugar and the other hydroxyl groups of the sugar are protected, the method comprising reacting a sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups, and a phenol compound in the presence of at least one catalyst selected from trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate.

[0017] [2] The method for producing a protected glycoside derivative according to [1], wherein the acyl group is an acetyl group.

[0018] [3] The method for producing a protected glycoside derivative according to [1] or [2], wherein the sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups is a fully acetylated sugar.

[0019] [4] The method for producing a protected glycoside derivative according to any one of [1] to [3], wherein the sugar is glucose in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups, and the phenolic compound is vitamin E.

[0020] [5] The method for producing a protected glycoside derivative according to any one of [1] to [4], wherein in the reaction, 1 to 10 mol of the catalyst is used per 100 mol of the phenol compound.

[0021] Effects of the Invention

[0022] According to the present invention, there is provided a method for producing a protected glycoside derivative, which is capable of producing a glycoside derivative in which a hydroxyl group of a sugar is protected at a high yield. DETAILED DESCRIPTION

[0023] Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described below.

[0024] (Method for producing glycoside derivative)

[0025] In one embodiment, the present invention provides a method for producing a protected glycoside derivative, wherein a phenol compound is bonded to the anomeric position of a sugar (a portion having a ring structure), and the other hydroxyl groups of the sugar are protected. The production method of this embodiment comprises a step of reacting a sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups, with a phenol compound in the presence of at least one catalyst selected from trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate (hereinafter also referred to as "step A").

[0026] [Process A]

[0027] In step A, a sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups (hereinafter also referred to as "protected sugar") is reacted with a phenol compound in the presence of at least one catalyst selected from trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate.

[0028] <Protected Sugar>

[0029] The above-mentioned protecting groups in the sugar in which all hydroxyl groups are protected by protecting groups are preferably protecting groups that do not cause side reactions in the reaction with the phenol compound. Examples of the protecting groups include acyl-type protecting groups such as acetyl and benzoyl; ether-type protecting groups such as methyl, allyl, and benzyl; acetal-type protecting groups such as isopropylidene and benzylidene. Sugars can be converted into protected sugars by known methods.

[0030] The protecting groups of the hydroxyl group at position 1 and the hydroxyl group at position 2 of the protected sugar used in the production method of this embodiment are acyl groups. Examples of acyl-type protecting groups include acetyl, methoxyacetyl, and benzoyl. Among them, acetyl is preferred.

[0031] As the protected sugar, sugars in which all hydroxyl groups are protected by acyl groups are preferred because they are easy to synthesize. Among them, sugars in which all hydroxyl groups are protected by acetyl groups are more preferred because they are easily available. In this specification, sugars in which all hydroxyl groups are protected by acetyl groups are also referred to as "fully acetylated sugars".

[0032] The sugar whose hydroxyl group is protected is not particularly limited. Examples of the sugar include hexose sugars such as glucose, mannose, galactose, fucose, and rhamnose; and pentose sugars such as ribose and arabinose. As the protected sugar, sugars in which all hydroxyl groups of these sugars are protected by acyl groups can be used.

[0033] As an example, a protected sugar derived from β-glucose (protected glucose) is shown in the following formula (1).

[0034]

[0035] In the formula, X each independently represents an acyl group, and Z each independently represents a protecting group.

[0036] In the above formula (1), the acyl group in X includes the same ones as mentioned above, and is preferably an acetyl group. The protecting group in Z includes the same ones as mentioned above, and is preferably an acyl group, and is more preferably an acetyl group.

[0037] The sugar to be protected is preferably a fully acetylated sugar of a hexose sugar, because it has sufficient reactivity and is easily available. Examples of the hexose sugar include glucose, mannose, galactose, fucose, and rhamnose.

[0038] Peracetylated sugars can be produced by acetylation of desired sugars by known acetylation methods. Examples of known acetylation methods include methods using acetic anhydride, sodium acetate, acetyl chloride, and the like.

[0039] Specific examples of fully acetylated sugars include penta-O-acetyl-β-D-glucopyranose (pentaacetyl-β-D-glucose), penta-O-acetyl-α-D-glucopyranose (pentaacetyl-α-D-glucose), 1,2,3,4,6-penta-O-acetyl-D-mannopyranose, penta-O-acetyl-β-D-galactopyranose, 1,2,3,4-tetra-O-acetyl-α-L-fucopyranose, etc. As fully acetylated sugars, pentaacetyl-β-D-glucose and pentaacetyl-α-D-glucose are preferred, and penta-O-acetyl-β-D-glucose is more preferred.

[0040] <Phenol compounds>

[0041] "Phenolic compound" refers to a compound containing a phenol skeleton. The phenol skeleton is a structure in which at least one hydrogen atom of a benzene ring is replaced by a hydroxyl group. The aromatic hydrocarbon ring in the above-mentioned phenol skeleton can form a condensed ring with other aromatic rings or aliphatic rings. Phenolic compounds are compounds selected from phenols. There is no particular limitation on the phenolic compound, and known phenolic compounds can be used. As phenolic compounds, for example, phenol, catechol, cresol, methoxyphenol, bromophenol, xylenol, ethylphenol, naphthol, resorcinol, hydroquinone, salicyl alcohol, vitamin E, etc. can be listed. As phenolic compounds, vitamin E is preferably listed.

[0042] Vitamin E is tocopherol and tocotrienol. Tocopherol is a compound represented by the following formula (2). Tocotrienol is a compound represented by the following formula (3).

[0043]

[0044] In the formula, R 1 , R 2 and R 3 Each independently represents a hydrogen atom or a methyl group.

[0045] For tocopherol and tocotrienol, depending on the R in the above general formula (2) and (3), 1 , R 2 , R 3 , the presence of α-tocopherol and α-tocotrienol (R 1 , R 2 , R 3 =CH3), β-tocopherol and β-tocotrienol (R 1 , R 3 =CH3, R 2 =H), γ-tocopherol and γ-tocotrienol (R 1 =H, R 2 , R 3 =CH3), δ-tocopherol and δ-tocotrienol (R 1 , R 2 =CH3, R 3 =H).

[0046] When vitamin E is used as the phenolic compound, any one of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol and δ-tocotrienol may be used.

[0047] Tocopherol and tocotrienol each have an asymmetric carbon atom at the 2-position of the chroman ring, and therefore have stereoisomers of d configuration and l configuration, as well as dl configuration. Tocopherol and tocotrienol each may be any of these stereoisomers.

[0048] <Catalyst>

[0049] In the reaction of the protected sugar and the phenol compound, at least one catalyst selected from trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate is used as a catalyst. The catalyst may be either trifluoromethanesulfonic acid or copper (II) trifluoromethanesulfonate alone, or a mixture of trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate may be used.

[0050] In the reaction using trifluoromethanesulfonic acid and / or copper (II) trifluoromethanesulfonate as a catalyst, the hydroxyl group of the phenolic compound attacks the anomeric position of the protected sugar, and the acyl group protecting the hydroxyl group at the anomeric position is replaced by the phenolic compound. At this time, if the 2-hydroxyl group of the sugar is protected by an acyl group, the adjacent group participates and preferentially obtains a 1,2-trans glycoside derivative.

[0051] <Reaction>

[0052] The reaction of the protected sugar with the phenol compound can be carried out by adding the above reactants and the catalyst to a solvent. Examples of usable solvents include toluene, benzene, ethylbenzene, xylene, ethyl acetate, methyl acetate, methylcyclohexane, etc. As the solvent, toluene, xylene, ethylbenzene, benzene are preferred, and toluene is more preferred.

[0053] The reaction temperature and reaction time can be appropriately adjusted according to the type of solvent and catalyst used. The reaction temperature and reaction time can be determined according to the progress of the reaction. Usually, the target reaction can be achieved by reacting at about 0.5 to 24 hours at normal pressure and about 0 to 100°C. The reaction temperature can be, for example, 10 to 80°C, 20 to 70°C, 20 to 60°C, 20 to 50°C, or 20 to 40°C. In step A, by using trifluoromethanesulfonic acid or copper (II) trifluoromethanesulfonate as a catalyst, the reaction can be carried out under relatively mild temperature conditions.

[0054] The reaction time also depends on the amount of reactants, and may be, for example, 1 to 20 hours, 1 to 15 hours, 1 to 10 hours, 1 to 5 hours, or 2 to 5 hours.

[0055] The amount of the protected sugar used is preferably 1 to 1.5 molar equivalents based on the phenol compound.

[0056] The total amount of the catalyst used is preferably 1 to 10 mol, more preferably 1 to 3 mol, based on 100 mol of the phenol compound.

[0057] By reacting a protected sugar with a phenolic compound, a glycoside derivative (hereinafter also referred to as a "protected glycoside derivative") in which the phenolic compound is bonded to the anomeric position of the sugar and the hydroxyl group of the sugar is protected can be obtained. The glycosidic bond formed by the reaction of the sugar with the phenolic compound can be an α-glycosidic bond or a β-glycosidic bond. According to the method of this embodiment, a glucoside derivative in which the relationship between the glycosidic bond and the 2-position acyl group is a trans relationship can be obtained with good selectivity. When the product is not a mixture of glucoside derivatives with a cis relationship, the necessary product separation operation is not required depending on the situation, and thus it is excellent. When the phenolic compound is vitamin E, the bond between the sugar and the 6-O- of the chroman ring of vitamin E forms a trans relationship with the 2-position hydroxyl group. The reason for obtaining a trans relationship glucoside derivative with good selectivity is the effect of the participation of the adjacent group of the acyl group as the 2-position protecting group.

[0058] As an example, the reaction between protected β-glucose and a phenol compound is shown in the following reaction formula (I). By the following reaction, a β-glucoside derivative in which a phenol compound is bonded to the anomeric position of β-glucose and the hydroxyl group of β-glucose is protected can be obtained.

[0059]

[0060] In the formula, X each independently represents an acyl group, Z each independently represents a protecting group, A-OH represents a phenol compound, and A represents an atomic group other than a hydroxyl group.

[0061] In step A, trifluoromethanesulfonic acid or copper (II) trifluoromethanesulfonate is used as a catalyst in the reaction of the sugar whose hydroxyl group is protected with the phenolic compound. This allows the protected glycoside derivative to be obtained at a high yield of 70% or more.

[0062] After step A, the hydroxyl group of the sugar can be deprotected by step B described later to obtain a glycoside in which a phenol compound is bonded to the anomeric position of the sugar. Glycosides have attracted attention as pharmaceuticals, pesticides, cosmetics, reagents, etc. The protected glycoside derivatives obtained by the production method of this embodiment can be used as intermediates of these useful glycosides.

[0063] [Optional process]

[0064] The method of this embodiment may have an optional step in addition to the above step A. Examples of the optional step include a step of deprotecting the protected hydroxyl group of the protected glycoside derivative obtained in the above step A to obtain a glycoside (hereinafter also referred to as "step B").

[0065] <Process B>

[0066] After step A, the protected hydroxyl group of the protected glycoside derivative obtained in step A can be deprotected. The reaction conditions for deprotection can be appropriately selected according to the type of protecting group. When the protecting group is an acyl group, the deprotection reaction can be carried out under alkaline conditions. As a base for forming alkaline conditions, for example, metal hydroxides such as sodium hydroxide and potassium hydroxide; metal alcoholates (metal alkoxides) such as sodium methoxide and sodium ethoxide, etc. can be cited. As a solvent used in the deacylation reaction, when a metal hydroxide is used as a base, water or alcohol can be used, and when a metal alcoholate is used as a base, alcohol can be used. As the above-mentioned alcohol, for example, methanol can be mentioned.

[0067] The reaction conditions of the deprotection reaction can be appropriately selected according to the type of protecting group. Usually, the reaction can be carried out at normal pressure and about 0 to 100° C. for 0.5 to 24 hours. The reaction temperature can be, for example, 10 to 80° C., 20 to 70° C., 20 to 60° C., 20 to 50° C., or 20 to 40° C. The reaction time also depends on the amount of the reactants, and can be, for example, 0.5 to 20 hours, 0.5 to 15 hours, 0.5 to 10 hours, 0.5 to 5 hours, or 1 to 3 hours.

[0068] According to step B, a glycoside in which a phenol compound is bonded to the anomeric position of a sugar can be obtained.

[0069] As an example, the deprotection reaction of the protected β-glucoside derivative obtained by the above reaction formula (I) is shown in the following reaction formula (II).

[0070]

[0071] Wherein, X, Z, and A are the same as above.

[0072] The method of this embodiment may include, after step A, a step of purifying the protected glycoside derivative obtained in step A. When the method of this embodiment includes step B, after step B, a step of purifying the glycoside obtained in step B may be included.

[0073] Purification can be carried out by appropriately combining known purification methods such as washing, drying under reduced pressure, solvent extraction, and chromatography.

[0074] When step B is included, the production method of the present embodiment may be a method for producing a glycoside in which a phenol compound is bonded to the anomeric position of a sugar.

[0075] According to the production method of this embodiment, a glycoside derivative in which the hydroxyl group of the sugar is protected can be produced efficiently with high yield in step A, and therefore a glycoside obtained by the deprotection reaction in step B can also be obtained efficiently.

[0076] Example

[0077] Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[0078] Example 1

[0079] Pentaacetyl-β-D-glucose (Tokyo Chemical Industry Co., Ltd., 35.9 mmol, 14 g), d-δ-tocopherol (Sigma-Aldrich, 29.8 mmol, 12 g), trifluoromethanesulfonic acid (hereinafter also referred to as "TfOH") (Kanto Chemical Co., Ltd., 0.6 mmol, 0.09 g) and toluene (Kanto Chemical Co., Ltd., 45 ml) were added to a single-necked flask and stirred for 3 hours at normal pressure and an external bath of 30°C. Then, the toluene layer after the reaction was separated and washed once with 30 g of a saturated aqueous solution of NaHCO3 and once with 30 g of distilled water. If the toluene layer is concentrated under reduced pressure, 24.5 g of a mixture of glycoside derivatives containing d-δ-tocopherol bonded to the anomeric position and the hydroxyl group of the sugar being acetylated is obtained. Among them, the target product is 19.7 g (26.8 mmol, the yield based on d-δ-tocopherol is 89.9%).

[0080]

[0081] In the formula, Ac represents an acetyl group.

[0082] Reference Example: Synthesis of d-δ-tocopheryl β-d-pyranoglucoside

[0083] 19.7 g (26.8 mmol) of the glycoside derivative in which d-δ-tocopherol is bonded to the anomeric position and the hydroxyl group of the sugar is acetylated obtained in Example 1 was dissolved in methanol (Fuji Film Wako Pure Chemical Industries, Ltd., 150 ml) by heating, and put into a one-necked flask together with a 28% sodium methoxide-methanol solution (Jusei Chemical Industries, Ltd., 0.8 ml), and deacetylation reaction was carried out in an external bath at 30° C. for 1 hour. After the reaction was completed, the filtrate was concentrated under reduced pressure to obtain 15 g (26.8 mmol, yield 100%) of d-δ-tocopheryl β-d-pyranoglucoside as a deacetylated product.

[0084]

[0085] In the formula, Ac represents an acetyl group.

[0086] Example 2

[0087] Pentaacetyl-β-D-glucose (Tokyo Chemical Industry Co., Ltd., 1.2 mmol, 0.468 g), d-δ-tocopherol (Sigma-Aldrich, 1.0 mmol, 0.403 g), copper (II) trifluoromethanesulfonate (Tokyo Chemical Industry Co., Ltd., 0.02 mmol, 0.007 g) and toluene (Kanto Chemical Co., Ltd., 1.5 ml) were added to a single-necked flask and stirred for 3 hours at normal pressure and an external bath of 30°C. Then, the toluene layer after the reaction was separated and washed once with 1 g of a saturated aqueous solution of NaHCO3 and once with 1 g of distilled water. If the toluene layer was concentrated under reduced pressure, 0.8 g of a mixture of glycoside derivatives containing d-δ-tocopherol bonded to the anomeric position and other hydroxyl hydrogens acetylated was obtained. Among them, the target product was 0.7 g (0.9 mmol, the yield based on d-δ-tocopherol was 90.0%).

[0088] Comparative Example 1

[0089] Pentaacetyl-β-D-glucose (Tokyo Chemical Industry Co., Ltd., 24.8 mmol, 10 g), d-δ-tocopherol (Sigma-Aldrich, 24.8 mmol, 10 g), 4-toluenesulfonic acid monohydrate (Junsei Chemical Co., Ltd., 1.24 mmol, 0.236 g) and toluene (Kanto Chemical Co., Ltd., 15 ml) were added to a single-necked flask and stirred for 24 hours at normal pressure and an external bath of 70°C. Then, the toluene layer after the reaction was washed three times with 25 g of a saturated aqueous solution of NaHCO3 and once with 25 g of distilled water. If the toluene layer was concentrated under reduced pressure, 18.8 g of a mixture of glycoside derivatives containing d-δ-tocopherol bonded to the anomeric position and other hydroxyl hydrogens acetylated was obtained. Among them, the target product was 10.9 g (14.9 mmol, the yield based on d-δ-tocopherol was 60%).

[0090] Comparative Example 2

[0091] Pentaacetyl-β-D-glucose (Tokyo Chemical Industry Co., Ltd., 1.2 mmol, 0.468 g), d-δ-tocopherol (Sigma-Aldrich, 1.0 mmol, 0.403 g), zinc (II) trifluoromethanesulfonate (Tokyo Chemical Industry Co., Ltd., 0.02 mmol, 0.007 g) and toluene (Kanto Chemical Co., Ltd., 1.5 ml) were added to a single-necked flask and stirred at normal pressure and an external bath of 30°C for 3 hours, but the reaction did not proceed and the raw material was recovered (yield 0%).

[0092] The preferred embodiments of the present invention have been described above, but the present invention is not limited to these embodiments. Additions, omissions, substitutions and other changes to the structure may be made without departing from the gist of the present invention. The present invention is not limited by the above description, but only by the appended claims.

Claims

1. A method for producing a protected glycoside derivative, wherein a phenol compound is bonded to the anomeric position of a sugar and the other hydroxyl groups of the sugar are protected, the method comprising reacting a sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups, and a phenol compound in the presence of at least one catalyst selected from trifluoromethanesulfonic acid and copper (II) trifluoromethanesulfonate. 2 . The method for producing a protected glycoside derivative according to claim 1 , wherein the acyl group is an acetyl group. 3 . The method for producing a protected glycoside derivative according to claim 1 , wherein the sugar in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups is a fully acetylated sugar.

4. The method for producing a protected glycoside derivative according to claim 1 or 3, wherein the sugar is glucose in which all hydroxyl groups are protected by protecting groups and the protecting groups of the hydroxyl groups at positions 1 and 2 are acyl groups, and the phenolic compound is vitamin E. 5 . The method for producing a protected glycoside derivative according to claim 1 or 3 , wherein in the reaction, 1 to 10 mol of the catalyst is used per 100 mol of the phenol compound.

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