WO2016063896A1 - Dérivé d'acide ascorbique et procédé de production de glycoside à l'aide de celui-ci - Google Patents

Dérivé d'acide ascorbique et procédé de production de glycoside à l'aide de celui-ci Download PDF

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WO2016063896A1
WO2016063896A1 PCT/JP2015/079662 JP2015079662W WO2016063896A1 WO 2016063896 A1 WO2016063896 A1 WO 2016063896A1 JP 2015079662 W JP2015079662 W JP 2015079662W WO 2016063896 A1 WO2016063896 A1 WO 2016063896A1
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formula
compound represented
group
compound
reaction
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PCT/JP2015/079662
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Japanese (ja)
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啓子 島本
龍雄 松岡
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サントリーホールディングス株式会社
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Priority to CN201580054972.1A priority Critical patent/CN106795129A/zh
Priority to JP2016555245A priority patent/JP6691483B2/ja
Publication of WO2016063896A1 publication Critical patent/WO2016063896A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms

Definitions

  • the present invention relates to a novel ascorbic acid derivative, a method for producing a glycoside [2-O- ( ⁇ -D-glucopyranosyl) ascorbic acid and the like] using ascorbic acid as an aglycone, and a novel glycoside using this derivative About the body.
  • 2-O- ( ⁇ -D-glucopyranosyl) ascorbic acid represented by the following formula is a useful compound as provitamin C. Based on its excellent properties, cosmetics, quasi drugs, pharmaceuticals, foods, etc. Are being studied in various fields (Patent Document 1).
  • 2-O- ( ⁇ -D-glucopyranosyl) ascorbic acid is an intermediate 2-O- (2,3,4,6-tetra-O-acyl- ⁇ -D-glucopyranosyl). It is disclosed that ascorbic acid can be obtained by alkaline hydrolysis (that is, the following steps).
  • each R is independently an alkyl group having 1 to 5 carbon atoms.
  • R ′ is alkyl, halogenated alkyl, or optionally substituted aryl, and Bn and R are the same as above.
  • step (1) the hydroxyl group at the 3-position of ascorbic acid needs to be benzyl etherified, but the selectivity of this reaction is not high, and the hydroxyl groups at both the 2-position and 3-position are benzyl etherified. And by-products such as dicarbonyl compounds in which the benzyl group is substituted at the 2-position carbon.
  • step (2) a compound (3-O-benzyl-5,6-O-isopropylidene ascorbic acid) in which the 5,6 position is protected with an acid labile acetonide group is used.
  • An acid catalyst generally used for saccharification reaction cannot be used, and the reaction requires heating at 100 to 200 ° C. Heating at such a high temperature is preferable from the viewpoint of difficulty in uniform temperature control and the required performance of energy and equipment, particularly when assuming a large-scale process such as an industrial scale. Absent.
  • step (2) since only the carbonate having a ⁇ configuration reacts, it is necessary to produce the carbonate while maintaining the ⁇ configuration of the starting material, which is an expensive and high environmental impact reagent (hydrogen bromide, carbonate Silver) must be used.
  • the present inventors surprisingly found that when the acyl acylate of ascorbic acid was deacylated using a base (such as a secondary amine), the acylate at the 3-position was Deacylation with high selectivity yields a novel ascorbic acid derivative (compound in which only the 2, 5 and 6 positions of ascorbic acid are acylated) (particularly in high yield), and Specific benzyl ethers obtained from a novel ascorbic acid derivative (ascorbic acid 5 and 6 positions acylated, 3 position benzyl etherified, 2 position deacylated compound) It is highly stable, reacts efficiently with sugar donors (eg, sugar imidates) in the presence of an acid (glycosidic linkage), and acid-induced imidate activation As a sugar donor, not only ⁇ anomer ( ⁇ form) but also ⁇ anomer ( ⁇ form) imidate is used as a sugar donor, but a 1,2-trans form (for
  • the compound of the present invention (ascorbic acid derivative) has the following formula (A)
  • R 1 represents an acyl group. It is represented by
  • R 1 is the same as above.
  • the compound represented by formula (A) is subjected to a deacylation treatment (specifically, the group —OR 1 which substitutes at the 2-position of the compound represented by formula (A ′) is selectively deacylated).
  • a deacylation treatment specifically, the group —OR 1 which substitutes at the 2-position of the compound represented by formula (A ′) is selectively deacylated.
  • the method of manufacturing the compound (ascorbic acid derivative) represented by these is included.
  • the base may be a secondary amine (for example, N-monosubstituted piperazine).
  • an equivalent or almost equivalent (for example, 0.8 to 1.2 molar equivalent) of a base may be used with respect to the compound represented by the formula (A ′).
  • Su represents a group obtained by removing a glycosidic hydroxyl group from sugar.
  • a derivative thereof represented by the following formula (B):
  • a production method comprising a glycosylation step for obtaining a compound represented by formula (D) and a desorption step for eliminating the group R 1 and the group R 2 of the compound represented by formula (D) is also included.
  • the compound represented by the formula (A) is further reacted with an arylmethylating agent (for example, arylmethyl halide such as benzyl halide), and then a base is used.
  • arylmethylating agent for example, arylmethyl halide such as benzyl halide
  • a step of producing a compound represented by the formula (B) by deacylation treatment may be included.
  • an arylmethylated product of the compound represented by the above formula (A), that is, a compound represented by the following formula (B ′) is obtained by reaction with arylmethyl halide.
  • the compound represented by the formula (C) may be a mixture of ⁇ -form and ⁇ -form, in particular.
  • the glycoside that is the final product can be obtained as a 1,2-trans isomer.
  • X may be, for example, an imidate group (such as a 2,2,2-trichloroacetimidoyloxy group).
  • the method of the present invention (manufacturing method of glycoside) further uses a base to produce the following formula (C ′)
  • a step of obtaining a compound represented by the formula (C) by reacting a compound represented by the formula (C ′′) with a compound corresponding to the leaving group X. May be included.
  • the compound represented by the formula (C ′) may be a mixture of ⁇ -form and ⁇ -form.
  • the base may also be a secondary amine (such as N-monosubstituted piperazine).
  • the compound represented by the formula (B) and the compound represented by the formula (C) may be reacted in the presence of an acid. Moreover, you may perform reaction of the compound represented by Formula (B), and the compound represented by Formula (C) under non-heating.
  • the desorption step is a hydrogenation treatment of the compound represented by the formula (D), and
  • the sugar may be, for example, a monosaccharide (for example, hexose such as glucose or galactose).
  • the present invention includes all novel compounds (such as glycosides, dividend precursors or intermediates) produced by the method of the present invention.
  • a new compound does not necessarily have to be produced by the above method.
  • novel compounds include in particular novel glycosides.
  • a glycoside is a compound in which, in the formula (1), Su is a sugar other than D-glucose, for example, the following formula (1B)
  • the present invention includes a compound represented by the formula (1) or a derivative thereof. Such a compound or a derivative thereof may be usually obtained by the above method. Furthermore, the present invention includes a composition containing the compound represented by the formula (1) or a derivative thereof. Such a composition may be, for example, a food / beverage product, a pharmaceutical product, a quasi-drug, a cosmetic product, and the like. Furthermore, this invention includes the method of manufacturing the said composition by mixing the compound or its derivative (s) represented by said Formula (1), and the structural component (other components) of a composition.
  • the 3-position of tetraacylate of ascorbic acid can be selectively deacylated. Therefore, in the present invention, a novel ascorbic acid derivative (that is, a novel ascorbic acid derivative in which the 2, 5, and 6 positions of ascorbic acid are acylated) can be obtained. Such a derivative is useful for efficiently producing a novel glycoside having ascorbic acid as an aglycone (a glycoside having a sugar bonded to the 2-position of ascorbic acid (glycoside bond)).
  • a novel glycoside having ascorbic acid as an aglycone can be provided.
  • Such a glycoside has a novel structure in which a sugar other than conventional ⁇ -D-glucose (eg, galactose) is glycosidically bonded to the 2-position of ascorbic acid, and 2-O- ( ⁇ - Like D-glucopyranosyl) ascorbic acid, it is a useful compound as provitamin C. Therefore, it can be applied to various fields such as cosmetics, quasi drugs, pharmaceuticals, and foods.
  • the compound (ascorbic acid derivative) of the present invention is represented by the following formula (A). That is, the ascorbic acid derivative of the present invention can be referred to as a compound (2,5,6-tri-O-acylascorbic acid) in which only the 2, 5 and 6 positions of ascorbic acid are acylated (acyl esterified). .
  • R 1 represents an acyl group.
  • the acyl group R 1 is a group obtained by removing a hydroxyl group from a carboxylic acid as an oxo acid, such as an aliphatic acyl group [for example, an alkanoyl group (for example, a formyl group, an acetyl group, a propionyl group).
  • an alkanoyl group for example, a formyl group, an acetyl group, a propionyl group.
  • a saturated aliphatic acyl group such as a C 1-10 alkanoyl group such as a butyryl group, preferably a C 1-6 alkanoyl group, more preferably a C 1-4 alkanoyl group), an aromatic acyl group [for example, an aroyl group ( For example, C 6-10 aroyl group such as benzoyl group)] and the like.
  • the acyl group also includes a group obtained by removing a hydroxyl group from a non-carboxylic acid (such as sulfonic acid or phosphoric acid) as an oxo acid [eg, alkanesulfonyl group (eg, methanesulfonyl group)].
  • the three R 1 s may be the same or different acyl groups, and may usually be the same acyl group.
  • Exemplary ascorbic acid derivatives include compounds in which all three R 1 at positions 2, 5, and 6 are all acetyl groups (ie, 2,5,6-tri-O-acetylascorbic acid).
  • Such an ascorbic acid derivative is useful as, for example, an aglycone in a glycoside or a precursor (intermediate) thereof.
  • an ascorbic acid derivative since such an ascorbic acid derivative has a hydroxyl group only at the 3-position, it can efficiently bind (glycosylated) a sugar [a sugar described below such as a monosaccharide (glucose, galactose, etc.)] at the 3-position.
  • the ascorbic acid derivative of the present invention is a raw material (intermediate, precursor) of a specific compound represented by the formula (1) (that is, a glycoside in which a sugar is bonded to the 2-position of ascorbic acid). Body).
  • the ascorbic acid derivative is not particularly limited.
  • a compound represented by the following formula (A ′) that is, 2,3,5,6-tetra-O-acylascorbic acid
  • a group —OR 1 the following formula ( A group —OR 1 ) substituted at the 3-position of the compound represented by A ′
  • deacylation deacylation treatment
  • R 1 is the same as in the above formula (A).
  • a representative compound (A ′) is a compound in which all four R 1 in the 2, 3, 5 and 6 positions are acetyl groups (ie, 2,3,5,6-tetra-O-acyl ascorbic acid). Is included.
  • the compound represented by the formula (A ′) can be obtained by reacting ascorbic acid (L-ascorbic acid) with an acylating agent.
  • the acylating agent include an acylating agent corresponding to the group R 1 , such as an acid anhydride (eg, acetic anhydride), an acid halide (eg, acetic chloride), an acid ester, and the like.
  • the acylating agents may be used alone or in combination of two or more.
  • the acylating agent may be used in a range that allows all four hydroxyl groups of ascorbic acid to be acylated (acyl esterification). For example, 4 mol or more (for example, 4 to 10 mol) per mol of ascorbic acid. ).
  • the reaction may be carried out in the absence of a solvent or in a solvent (such as a solvent described later) depending on the type of acylating agent.
  • the reaction between ascorbic acid and the acylating agent may be performed in the presence of an acid catalyst (for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, etc.). Further, the reaction may be carried out under heating [eg, reaction temperature of 50 ° C. or higher (eg, 60 to 180 ° C., preferably 80 to 150 ° C.), more preferably 100 to 140 ° C.]). The reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • an acid catalyst for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, etc.
  • reaction may be carried out under heating [eg, reaction temperature of 50 ° C. or higher (eg, 60 to 180 ° C., preferably 80 to 150 ° C.), more preferably 100 to 140 ° C.]).
  • the reaction may be performed under stirring, or may be performed in air or in an iner
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), more preferably 5 minutes or longer (for example, 10 minutes). (About 12 hours).
  • reaction mixture mixture containing the compound represented by the formula (A ′)
  • the reaction mixture may be subjected to the deacylation reaction described later without separation (or recovery), and separated (or recovered). May be.
  • separation (or purification) from the reaction mixture a conventional method (for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be used.
  • Deacylation (deacylation reaction) of the compound represented by the formula (A ′) can be usually performed using a base (or reacting with a base).
  • the base examples include organic bases [amines, alkoxides (for example, metal alkoxides such as alkali metal alkoxides (for example, sodium alkoxides such as sodium methoxide, sodium isopropoxide))], inorganic bases [for example, carbonates (for example, carbonates (for example, , Weak acid salts of alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate and potassium carbonate, etc.].
  • amines may be suitably used as the base from the viewpoint of purification.
  • deacylation at the 2-position acyl group of ascorbic acid hardly occurs, and the 3-position acyl group can be deacylated with high selectivity.
  • amines primary amines, secondary amines and the like can be used, and secondary amines may be particularly preferably used.
  • the primary amine include chain aliphatic amines (for example, alkylamines such as ethylamine and isopropylamine) and araliphatic amines (for example, benzylamine).
  • Secondary amines include, for example, chain amines [eg chain aliphatic amines (eg dialkylamines such as diisopropylamine)], cyclic amines [or heterocyclic amines such as pyrrolidine, pyrazolidine, imidazo.
  • Monocyclic amines such as lysine, piperazine, N-monosubstituted piperazines (eg 1-alkylpiperazines such as 1-methylpiperazine, 1-ethylpiperazine, preferably 1- C1-4 alkylpiperazines), morpholine, thiomorpholine, etc. ] Etc. are mentioned.
  • secondary amines having a tertiary amino group such as N-monosubstituted piperazine (such as 1-alkylpiperazine) are particularly preferable.
  • the product compound represented by the formula (A ′)
  • the product can be easily recovered (purified) by acid washing.
  • Bases (such as amines) may be used alone or in combination of two or more.
  • the amount of the base can be selected according to the type of the base and the like, and for example, 0.3 molar equivalent or more (for example, 0.4 to 10 with respect to the compound represented by the formula (A ′)).
  • Molar equivalent 0.5 molar equivalent or more (eg, 0.6 to 5 molar equivalent), preferably 0.7 molar equivalent or more (eg, 0.8 to 3 molar equivalent).
  • the compound represented by the formula (A ′) tends to cause a selective deacylation reaction at the 3-position by using an equivalent or almost equivalent amount of a base. Therefore, the base is equivalent to or approximately equivalent to the compound represented by the formula (A ′) (for example, 0.7 to 1.5 molar equivalent, preferably 0.8 to 1.2 molar equivalent, more preferably 0.9 to 1.1 molar equivalents, particularly 0.95 to 1.05 molar equivalents).
  • the 2- and 3-positions are easily selectively deacylated. That is, by using 2 equivalents or almost 2 equivalents, a compound represented by the following formula (A ′′) (that is, 5,6-di-O-acyl ascorbic acid) can be efficiently obtained.
  • Deacylation may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit deacylation.
  • hydrocarbons eg, aliphatic hydrocarbons (eg, hexane, heptane, cyclohexane, etc.), aromatic hydrocarbons (eg, , Benzene, toluene, xylene, etc.)], halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ethers [eg, chain ethers (eg, diethyl ether), etc.], cyclic ethers (eg, tetrahydrofuran) ), Amides [eg N-substituted amides (N-alkyl-substituted alkaneamides such as N, N-dimethylformamide)], alcohols (eg alkanols such as methanol, ethanol, isopropanol), etc.
  • hydrocarbons eg
  • a solvent inert to the deacylation reaction for example, hydrocarbons, ethers, halogenated hydrocarbons, etc.
  • solvents may be used alone or in combination of two or more.
  • the amount of the solvent used is not particularly limited, and for example, 0.5 to 100 parts by weight with respect to 1 part by weight of the compound (and base) represented by the formula (A ′), The amount may preferably be about 1 to 50 parts by weight, more preferably about 2 to 30 parts by weight.
  • reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), more preferably 5 minutes or longer (for example, 10 minutes). (About 12 hours).
  • an ascorbic acid derivative (compound represented by the formula (A)) is obtained.
  • the reaction mixture mixture containing the compound represented by the formula (A)
  • reaction mixture For separation (or purification) from the reaction mixture, conventional methods (for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be used.
  • by-products such as carboxylic acid amides due to deacylation are easily separated and removed by acid washing from the extract when a specific base is used as described above.
  • the present invention includes a compound represented by the following formula (1) or a derivative thereof (glycoside).
  • Su represents a group obtained by removing a glycosidic hydroxyl group from sugar.
  • Su is a group (residue) obtained by removing a glycosidic hydroxyl group (hemiacetal hydroxyl group) from a sugar (or sugar chain).
  • the group -OSu can also be referred to as a group (residue) obtained by removing a hydrogen atom constituting a glycosidic hydroxy group (a hydroxyl group bonded to an anomeric carbon) from a sugar.
  • the compound represented by the formula (1) is an O-glycoside having ascorbic acid as an aglycon (condensation (glycoside bond) between the hydroxyl group at the 2-position of ascorbic acid and the glycosidic hydroxyl group of the sugar). Body).
  • the sugar corresponding to the group Su is not particularly limited, and may be a monosaccharide (monosaccharide), an oligosaccharide, a polysaccharide (polysaccharide), or the like.
  • the oligosaccharide and polysaccharide may be either homopolysaccharide or heteropolysaccharide.
  • the number of carbon atoms is not particularly limited, and may be, for example, pentose or hexose. Further, the monosaccharide may be, for example, furanose or pyranose.
  • sugars include monosaccharides [eg, pentose (eg, ribose, arabinose, xylose, deoxyribose, etc.), hexose (eg, fructose, tagatose, allose, altrose, glucose, mannose, galactose, rhamnose, glucosamine, Galactosamine, glucuronic acid, etc.), oligosaccharides or polysaccharides [eg, disaccharides (eg, maltose, cordobiose, cellobiose, isomaltose, gentibiose, lactose, etc.), etc.].
  • pentose eg, ribose, arabinose, xylose, deoxyribose, etc.
  • hexose eg, fructose, tagatose, allose, altrose, glucose, mannose, galactose, rhamnose
  • typical sugars include monosaccharides (eg, hexoses such as glucose and galactose).
  • the sugar may be any of D-form, L-form, and a mixture thereof.
  • the compound represented by the formula (1) may be any of ⁇ -form ( ⁇ -anomer, ⁇ -glycoside), ⁇ -form ( ⁇ -anomer, ⁇ -glycoside), and a mixture thereof. It may be.
  • a compound represented by the formula (1) which is a 1,2-trans form can be obtained.
  • the sugar is glucose
  • a ⁇ form is obtained
  • the sugar is mannose
  • an ⁇ form is obtained.
  • Representative compounds represented by the formula (1) include, for example, compounds represented by the following formula (1A) ( ⁇ -glycosides in which the sugar is D-glucose in the formula (1)), and the following formula (1B ) (That is, ⁇ -glycoside whose sugar is D-galactose in the formula (1)) and the like.
  • the present invention includes such novel compounds (new glycosides).
  • the hydroxyl group (the hydroxyl group constituting the ascorbic acid skeleton and the sugar (Su) skeleton) of the compound represented by the formula (1) formed a salt.
  • examples thereof include a compound (that is, a salt of the compound represented by formula (1)) and a compound substituted with a leaving group.
  • the salt include metal salts (for example, alkali or alkaline earth metal salts such as sodium salt, potassium salt and calcium salt), and salts with alkali such as amine salt and ammonium salt.
  • examples of the leaving group include an acyloxy group (for example, an aliphatic acyloxy group such as an acetyloxy group, a propionyloxy group, a butyryloxy group, an octanoyloxy group, a palmitoyloxy group, and a stearoyloxy group).
  • an acyloxy group for example, an aliphatic acyloxy group such as an acetyloxy group, a propionyloxy group, a butyryloxy group, an octanoyloxy group, a palmitoyloxy group, and a stearoyloxy group.
  • an acyloxy group for example, an aliphatic acyloxy group such as an acetyloxy group, a propionyloxy group, a butyryloxy group, an octanoyloxy group, a palmitoyloxy group, and a stearoyloxy group.
  • the glycoside (compound represented by Formula (1) or its derivative (s)) of the present invention usually comprises a compound represented by the following formula (B) and a compound represented by the following formula (C). It can be manufactured through a glucosylation step for obtaining a compound represented by the following formula (D) by reaction and a desorption step for eliminating the group R 1 and the group R 2 of the compound represented by the formula (D).
  • R 2 represents an arylmethyl group, and R 1 is the same as described above.
  • ASu represents a group obtained by removing a glycosidic hydroxyl group from an acylated sugar, and X represents a leaving group.
  • R 2 is an arylmethyl group.
  • the arylmethyl group (R 2 ) include a benzyl group and a substituted benzyl group [for example, an alkylbenzyl group (for example, C 1-4 alkylbenzyl such as 4-methylbenzyl group)] and the like.
  • a preferred arylmethyl group is a benzyl group.
  • R 1 is the same as described above (that is, an acyl group), and the preferred embodiment is also the same as described above.
  • Representative compounds represented by the formula (B) include compounds in which R 1 at the 5 and 6 positions is an acetyl group and R 2 is a benzyl group (ie, 3-O-benzyl-5,6-di-O -Acetyl-ascorbic acid).
  • the compound represented by the formula (B) can be produced, for example, using the formula (A) as a raw material (intermediate, precursor). That is, the compound represented by the formula (B) is prepared by reacting the compound represented by the formula (A) with an arylmethylating agent (arylmethylation reaction) and then performing a deacylation treatment (specifically, ascorbic acid). Alternatively, it can be obtained through a step (arylmethylation / deacylation step) in which the group -OR 1 substituted at the 2-position of the compound represented by formula (A) is deacylated.
  • arylmethylating agent arylmethylation reaction
  • deacylation treatment specifically, ascorbic acid
  • the compound represented by the formula (A) (2,5,6-triacylascorbic acid is not used as a raw material of the compound represented by the formula (B). ) Is used.
  • arylmethylating agent examples include reagents corresponding to arylmethyl groups such as arylmethyl halide (or halomethylarene, for example, benzyl halide such as benzyl chloride and benzyl bromide).
  • arylmethyl halide or halomethylarene, for example, benzyl halide such as benzyl chloride and benzyl bromide.
  • the amount of the arylmethylating agent used is, for example, 0.8 mol or more (for example, 0.9 to 10 mol), preferably 1 mol with respect to 1 mol of the compound represented by the formula (A). It may be 1 mol or more (for example, 1.1 to 5 mol), more preferably 1.2 mol or more (for example, 1.3 to 3 mol).
  • the arylmethylation reaction may be performed in the presence of a base.
  • a base examples include carbonates (for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate) silver oxide, pyridines (pyridine, picoline) and the like.
  • the bases may be used alone or in combination of two or more.
  • the use ratio of the base may be, for example, 1 molar equivalent or more (for example, 1 to 5 molar equivalents) with respect to the compound represented by the formula (A) (or arylmethylating agent), for example.
  • the arylmethylation reaction may be performed in the presence of a reducing agent such as sodium hydrosulfite (sodium dithionite) or sodium thiosulfate.
  • a reducing agent such as sodium hydrosulfite (sodium dithionite) or sodium thiosulfate.
  • the ratio of the reducing agent used may be, for example, 1 molar equivalent or more (for example, 1 to 5 molar equivalents) with respect to the compound represented by the formula (A).
  • the arylmethylation reaction may be performed in a solvent.
  • the solvent include those exemplified above (for example, amides such as N, N-dimethylformamide).
  • the amount of the solvent used is not particularly limited, and for example, 1 to 100 parts by weight, preferably 2 to 50 parts by weight with respect to 1 part by weight of the compound represented by the formula (A). It may be a degree.
  • the reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction temperature may be, for example, about 30 to 150 ° C., preferably 40 to 120 ° C., more preferably about 50 to 100 ° C.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is, for example, 1 minute or more (eg, 1.5 minutes to 24 hours), preferably 2 minutes or more (eg, 3 minutes to 12 hours), more preferably 5 minutes or more (eg, 10 minutes to 3 hours). ) Degree.
  • representative compounds represented by the formula (B ′) include compounds in which R 1 at the 2, 5 and 6 positions is an acetyl group and R 2 is a benzyl group (that is, 3-O-benzyl-2, 5,6-tri-O-acetyl-ascorbic acid).
  • the reaction mixture (mixture containing the compound represented by the formula (B ′)) may be subjected to the reaction (deacylation) described below as it is without being separated (or recovered), and separated (or recovered). May be.
  • a conventional method for example, filtration, extraction, concentration, washing, adsorption, chromatography, etc. can be used.
  • a compound represented by the formula (B) can be obtained by performing deacylation subsequent to arylmethylation.
  • Deacylation deacylation reaction
  • amines may be suitably used.
  • examples of amines include the amines exemplified above (for example, secondary amines).
  • a secondary amine having a tertiary amino group such as N-monosubstituted piperazine (such as 1-alkylpiperazine) is used as the amine, the product (formula (B)) can be easily washed by acid washing as described above. Is easily recovered (purified).
  • the amount of the base can be selected according to the kind of the base, for example, 0.5 mol relative to the compound represented by the formula (A) or the compound represented by the formula (B ′).
  • Equivalent or more for example, 0.7 to 10 molar equivalent, 0.8 molar equivalent or more (for example, 0.9 to 5 molar equivalent), preferably about 1 molar equivalent or more (for example, 1 to 3 molar equivalent). May be.
  • Deacylation may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit deacylation, and the solvents exemplified above can be used.
  • the solvent used in the arylmethylation reaction may be used as a solvent in the deacylation.
  • reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), more preferably 5 minutes or longer (for example, 10 minutes). (About 12 hours).
  • the reaction mixture (mixture containing the compound represented by the formula (B)) may be subjected to the reaction (glycoside reaction) as described below without being separated (or recovered) or may be separated (or recovered). Good.
  • reaction mixture For separation (or purification) from the reaction mixture, conventional methods (for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be used.
  • by-products such as carboxylic acid amides due to deacylation are easily separated and removed by acid washing from the extract when a specific base is used as described above.
  • ASu is a group (residue) obtained by removing a glycoside hydroxyl group (a hemiacetal hydroxyl group, a hydroxyl group bonded to an anomeric carbon) from an acylated (acyl esterified) sugar.
  • ASu is a group in which all hydroxyl groups other than glycosidic hydroxyl groups are acylated in the group Su in the formula (1) (or a group in which the hydroxyl groups are substituted with acyloxy groups).
  • ASu and Su are common except that they are acylated, and the preferred embodiment is the same as that of Su.
  • examples of the acyl group include the same acyl groups as those of R 1 (acetyl group and the like).
  • the acyl groups may be the same or different acyl groups.
  • the compound represented by the formula (C) may be any of ⁇ form ( ⁇ anomer, ⁇ -glycoside), ⁇ form ( ⁇ anomer, ⁇ -glycoside), or a mixture thereof. .
  • a mixture of ⁇ -form and ⁇ -form may be suitably used from the viewpoint of process efficiency.
  • group ASu examples include a group represented by the following formula (ASu-1) and a group represented by the following formula (ASu-2) (that is, Su corresponds to D-glucose or D-galactose).
  • ASu-1 a group represented by the following formula
  • ASu-2 that is, Su corresponds to D-glucose or D-galactose.
  • ASu-2 a group represented by the following formula (ASu-2)
  • Su corresponds to D-glucose or D-galactose
  • Group tetra-O-acyl-D-glucopyranosyl group, tetra-O-acyl-D-galactopyranosyl group
  • the group X is a leaving group. That is, the compound represented by the formula (C) can be said to be a compound in which a group X is bonded to an anomeric carbon of ASu (or a compound in which a glycosidic hydroxyl group of ASu is substituted with a leaving group).
  • a group capable of forming a glycosidic bond (an anomeric carbon or an anomeric position of ASu is activated by reacting with the hydroxyl group (hydroxyl group at the 2-position) of the compound represented by the formula (B).
  • an imidate group ⁇ eg, 2,2,2-trichloroacetimidoyloxy group (group —O—C ( ⁇ NH) —CCl 3 ), (N-phenyl) tri) Fluoroacetimidoyloxy group (group —O—C ( ⁇ NPh) —CF 3 ) and the like ⁇
  • carbonate group or carbonate ester group such as 2,2,2-trichloroethoxycarbonyloxy group
  • acyloxy group examples thereof include a group represented by the above-described group —OR 1 such as an acetoxy group), a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, etc.) and the like.
  • the imidate group can be glycosidically bound to the compound represented by the formula (B), regardless of whether the compound represented by the formula (C) (or ASu) is ⁇ -form or ⁇ -form ( Furthermore, since a 1,2-trans isomer can be obtained), it is suitable when the ⁇ -form or a mixture of ⁇ -form and ⁇ -form is used as the compound represented by the formula (C). In particular, since it is not necessary to separate the ⁇ form and the ⁇ form, a mixture of the ⁇ form and the ⁇ form may be preferably used.
  • an imidate for example, a compound represented by the following formula (C1), a compound represented by the following formula (C2) (that is, ASu was acylated) D-glucose or D-galactose, a compound in which X is a 2-trichloroacetimidoyloxy group) and the like.
  • the compound represented by the following formula (C ') is deacylated (deacylated), and the following formula (C' Step for obtaining a compound represented by ') (deacylation step), a step for reacting a compound represented by the formula (C'') with a compound corresponding to the leaving group X (leaving group introduction step) Can be obtained through
  • the compound represented by the formula (C ′) and the compound represented by the formula (C) are the same [that is, the leaving group X is an acyloxy group (—OR 1 ) in the formula (C)] It is not necessary to go through such a process.
  • R 1 is the same as above (that is, an acyl group).
  • ASu is a group obtained by removing a glycosidic hydroxyl group from an acylated sugar
  • the group —OR 1 is an acyloxy group (ie, an acylated or acylesterified hydroxyl group). That is, the compound represented by the formula (C ′) is a compound in which all hydroxyl groups including a glycosidic hydroxyl group are acylated (acyl esterified).
  • the compound represented by the formula (C ′) is a group corresponding to any of ⁇ form ( ⁇ anomer, ⁇ -glycoside), ⁇ form ( ⁇ anomer, ⁇ -glycoside), and a mixture thereof. There may be.
  • glycosides can be obtained regardless of ⁇ -form and ⁇ -form.
  • a typical compound represented by the formula (C ′) includes a compound represented by the following formula (C′1), a compound represented by the following formula (C′2) [that is, D in which ASu is acylated. -Glucose or D-galactose, compounds wherein R 1 is an acyl group (penta-O-acyl-D-glucose, penta-O-acyl-D-galactose)] and the like.
  • the compound represented by the formula (C ′) can be obtained by reacting a sugar with an acylating agent.
  • sugars examples include the sugars exemplified above (for example, monosaccharides such as glucose and galactose).
  • the sugar may be any of ⁇ -form, ⁇ -form, and a mixture thereof.
  • acylating agent examples include an acylating agent corresponding to the group R 1 , such as an acid anhydride (for example, acetic anhydride), an acid halide (for example, acetic chloride), and the like.
  • the acylating agents may be used alone or in combination of two or more.
  • the acylating agent may be used in a range that allows all the hydroxyl groups of the sugar to be acylated (acyl esterification). For example, 1 mol or more (for example, 1 to 5 per mol of the hydroxyl group of the sugar). Mol, preferably 1.2 to 3 mol).
  • the reaction may be carried out in the absence of a solvent or in a solvent (such as the aforementioned solvent) depending on the type of acylating agent.
  • the reaction between the sugar and the acylating agent may be performed by using a base [for example, a salt of a weak acid (such as sodium acetate), a hydroxide (such as sodium hydroxide)], an acid (for example, an inorganic acid such as sulfuric acid, hydrochloric acid, or nitric acid). May be performed in the presence of a base [for example, a salt of a weak acid (such as sodium acetate), a hydroxide (such as sodium hydroxide)], an acid (for example, an inorganic acid such as sulfuric acid, hydrochloric acid, or nitric acid). May be performed in the presence of a base [for example, a salt of a weak acid (such as sodium acetate), a hydroxide (such as sodium hydroxide)], an acid (for example, an inorganic acid such as sulfuric acid, hydrochloric acid, or nitric acid). May be performed in the presence of
  • reaction may be performed under heating or under reflux.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), more preferably 5 minutes or longer (for example, 10 minutes). (About 12 hours).
  • reaction mixture (mixture containing the compound represented by the formula (C ′)) may be subjected to the deacylation reaction described below without separation (or recovery), and separated (or recovered). May be.
  • reaction mixture For separation (or purification) from the reaction mixture, conventional methods (for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be used.
  • the compound represented by the formula (C ′) is obtained.
  • a mixture of ⁇ -form and ⁇ -form is used as the sugar (further, when only ⁇ -form or ⁇ -form is used), a mixture of ⁇ -form and ⁇ -form is also obtained in the compound represented by the formula (C ′). Is obtained.
  • such a mixture can separate ⁇ form and ⁇ form by a method such as recrystallization.
  • the mixture is directly subjected to deacylation described later without performing such separation. Can be used.
  • the deacylation (deacylation reaction) of the compound represented by the formula (C ′) can usually be performed using a base (or reacting with a base).
  • amines As the base, amines, hydrazides (carboxylic acid hydrazides such as acetic hydrazide) and the like may be suitably used.
  • amines include the amines exemplified above (for example, secondary amines).
  • a secondary amine having a tertiary amino group such as N-mono-substituted piperazine (such as 1-alkylpiperazine) is used as the amine, the product (formula (C ′ It is easy to recover (purify) the compound represented by ').
  • the amount of the base can be selected according to the type of the base and the like, and for example, 0.5 molar equivalent or more (for example, 0.7 to 10 with respect to the compound represented by the formula (C ′)).
  • Molar equivalent 0.8 molar equivalent or more (for example, 0.9 to 5 molar equivalent), preferably about 1 molar equivalent or more (for example, 1 to 3 molar equivalent).
  • Deacylation may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit deacylation, and the solvents exemplified above can be used.
  • reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 72 hours), preferably 5 minutes or longer (for example, 10 minutes to 48 hours), more preferably 30 minutes or longer (for example, 1 to 36 hours).
  • TLC thin layer chromatography
  • the reaction mixture (mixture containing a compound represented by the formula (C ′′)) may be subjected to the reaction described below as it is without being separated (or recovered) or may be separated (or recovered).
  • reaction mixture For separation (or purification) from the reaction mixture, conventional methods (for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be used.
  • by-products such as carboxylic acid amides due to deacylation are easily separated and removed by acid washing from the extract when a specific base is used as described above.
  • a typical compound represented by the formula (C ′′) is a compound represented by the following formula (C ′′ 1), a compound represented by the following formula (C ′′ 2) (that is, ASu is A compound which is acylated D-glucose or D-galactose).
  • the compound corresponding to the leaving group X may be any compound that can introduce the leaving group X by reacting the leaving group with a compound represented by the formula (C ′′), such as an imidate group introducing agent.
  • a compound represented by the formula (C ′′) such as an imidate group introducing agent.
  • C ′′ such as an imidate group introducing agent.
  • trichloroacetonitrile carbonate group introducing agent
  • carbonate group introducing agent for example, 2,2,2-trichloroethyl chloroformate (Trocl)
  • halogen introducing agent for example, hydrogen halide such as hydrogen chloride, hydrogen bromide
  • the proportion of the compound corresponding to the leaving group X is, for example, 1 mol or more (for example, 1 to 5 mol, preferably 1.2 to 3 mol) per 1 mol of the compound represented by the formula (C ′′). Mol).
  • the reaction may be performed in the presence of a base depending on the type of the compound corresponding to the leaving group X.
  • a base or base catalyst
  • examples of the base include the exemplified bases such as amines (secondary amines), pyridines, carbonates and the like.
  • the use ratio of the base is, for example, 0.01 mol equivalent or more (for example, 0.05 to 3 mol equivalent, preferably 0.1 to 2 mol) relative to 1 mol of the compound represented by the formula (C ′′). Equivalent, more preferably 0.2 to 1.5 molar equivalent).
  • the reaction may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and the solvents exemplified above (for example, halogenated hydrocarbons) can be used.
  • reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 72 hours), preferably 5 minutes or longer (for example, 10 minutes to 48 hours), more preferably 30 minutes or longer (for example, 1 to 36 hours).
  • TLC thin layer chromatography
  • the reaction mixture (mixture containing a compound represented by the formula (C)) may be subjected to the reaction described later (glycoside reaction) without being separated (or recovered) or may be separated (or recovered). Good.
  • a conventional method for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc. can be used.
  • a compound represented by formula (D) is obtained by reacting a compound represented by formula (B) with a compound represented by formula (C).
  • the compound represented by the formula (C) used for the reaction may be any of ⁇ -form, ⁇ -form, and a mixture thereof as described above.
  • the ratio of the compound represented by formula (B) and the compound represented by formula (C) is represented by, for example, the compound represented by formula (B) / formula (C).
  • Compound (molar ratio) 1 / 0.5 to 1/2, preferably 1 / 0.7 to 1 / 1.5, more preferably about 1 / 0.8 to 1 / 1.2 .
  • the glycosylation step may be performed particularly in the presence of an acid (acid catalyst). Since the compound represented by the formula (B) is stable against an acid, in the present invention, a glycosylation reaction in the presence of an acid is possible. Therefore, glycosylation can be achieved with high reaction efficiency.
  • Examples of the acid include proton acids ⁇ eg, inorganic acids [eg, hydrogen halides (hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), sulfuric acid, nitric acid, phosphoric acid, etc.], organic acids [eg, carboxylic acids (eg, Formic acid, acetic acid, trifluoroacetic acid, etc.), sulfonic acids (eg, methanesulfonic acid, trifluoromethanesulfonic acid)]], sulfonic acid esters (eg, triflates such as trimethylsilyl trifluoromethanesulfonate), Lewis acids ⁇ eg, , Boron complexes [e.g., boron trifluoride complexes (e.g., boron trifluoride diethyl ether complex, boron trifluoride monoalkylamine complex, boron trifluoride hydrate, etc.)]; metal alkoxides [ For
  • an acid can be suitably selected according to the kind of acid, etc., for example, it is 0.001 with respect to 1 mol of compounds (or a compound represented by Formula (C)) represented by Formula (B). It may be a molar equivalent or more (for example, 0.001 to 2 molar equivalents, preferably 0.005 to 1 molar equivalents, more preferably 0.01 to 0.5 molar equivalents), and usually 0.001 to 0. It may be 3 molar equivalents (eg, 0.01 to 0.2 molar equivalents).
  • the reaction may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and the solvents exemplified above (for example, halogenated hydrocarbons) can be used.
  • the reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction since an acid catalyst can be used, the glycosylation reaction can proceed efficiently even when the reaction is carried out under non-heating (normal temperature or cooling). Therefore, in the present invention, the reaction may be performed at a reaction temperature of, for example, about 40 ° C. or less (eg, ⁇ 20 ° C. to 35 ° C.), preferably about 30 ° C. or less (eg, ⁇ 10 ° C. to 25 ° C.).
  • reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 48 hours), preferably 5 minutes or longer (for example, 10 minutes to 24 hours), more preferably 20 minutes or longer (for example, 30 minutes). (About 12 hours). In addition, you may confirm progress of reaction using conventional methods, such as thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the reaction mixture (mixture containing the compound represented by the formula (D)) may be subjected to the reaction described below as it is without being separated (or recovered), or may be separated (or recovered).
  • reaction mixture For separation (or purification) from the reaction mixture, conventional methods (for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be used.
  • reaction mixture may be washed with an alkali in order to remove a by-product of the glycoside reaction (for example, trichloroacetamide).
  • an alkali for example, trichloroacetamide
  • reaction mixture contains a compound corresponding to the unreacted leaving group X (for example, trichloroacetonitrile), it is generated by recrystallization [for example, recrystallization in alcohol (such as methanol)].
  • a product (compound represented by formula (D)) may be separated (purified).
  • the compound represented by the formula (C) may be any of ⁇ -form, ⁇ -form, and a mixture thereof.
  • -A compound represented by formula (D) in a trans form can be obtained.
  • Representative compounds represented by the formula (D) include a compound represented by the following formula (D1), a compound represented by the following formula (D2) (that is, D-glucose or D -Compounds that are galactose) and the like.
  • ⁇ Desorption step> In the elimination step, the group R 1 and the group R 2 of the compound represented by the formula (D) are eliminated.
  • Desorption desorption reaction
  • the order of the desorption of the radicals R 1 and groups R 2 is not particularly limited, after the one of the radicals R 1 and groups R 2 elimination, other groups May be eliminated, and the groups R 1 and R 2 may be eliminated simultaneously (or in the same reaction system).
  • the group R 1 may be eliminated after the group R 2 is eliminated. If it is desorbed in this order, it seems that the production of by-products (or impurities) can be efficiently suppressed.
  • the method for removing the group R 2 is not particularly limited, and examples thereof include a method of hydrotreating (hydrocracking) the compound represented by the formula (D). .
  • the hydrogenation treatment can be performed by reacting (contacting) the compound represented by the formula (D) with hydrogen (hydrogen gas).
  • the hydrogenation treatment may be performed in the presence of a catalyst.
  • a metal catalyst or metal complex
  • a catalyst containing a transition metal such as palladium, nickel, ruthenium, iridium, platinum, rhodium [particularly a noble metal (particularly platinum group metal) catalyst such as palladium / carbon], etc. Is mentioned.
  • the hydrogenation treatment may be performed in the presence of an acid in order to accelerate the reaction.
  • the acid include the acids exemplified above, for example, carboxylic acids (for example, acetic acid and the like).
  • the reaction may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and the solvents exemplified above (for example, ethers and alcohols) can be used. You may perform reaction under normal temperature (or room temperature), cooling, or heating. Moreover, you may perform reaction under stirring.
  • the reaction time is not particularly limited, but for example, 10 minutes or more (eg, 30 minutes to 10 days), preferably 1 hour or more (eg, 2 hours to 5 days), more preferably 3 hours or more (eg, 5 to 5 days). 36 hours).
  • TLC thin layer chromatography
  • a reaction mixture for example, a mixture containing a product
  • a conventional method for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.
  • a conventional method for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.
  • representative compounds represented by the formula (E) include compounds represented by the following formula (E1), compounds represented by the following formula (E2) (that is, D-glucose in which ASu is acylated). Or a compound which is D-galactose).
  • the base examples include weak acid salts (for example, carbonates (for example, carbonates such as potassium carbonate described above)), amines (for example, the above-described exemplary amines), hydroxides (for example, sodium hydroxide, hydroxides). Alkali or alkaline earth metal hydroxides such as potassium).
  • weak acid salts for example, carbonates (for example, carbonates such as potassium carbonate described above)
  • amines for example, the above-described exemplary amines
  • hydroxides for example, sodium hydroxide, hydroxides.
  • Alkali or alkaline earth metal hydroxides such as potassium.
  • the bases may be used alone or in combination of two or more.
  • Deacylation may be performed in a solvent.
  • the solvent is not particularly limited as long as it does not inhibit deacylation, and the above exemplified solvents (for example, alcohol) can be used.
  • reaction may be performed under normal temperature (or room temperature), cooling, or heating.
  • the reaction may be performed under stirring, or may be performed in air or in an inert atmosphere (nitrogen, rare gas, etc.).
  • the reaction time is not particularly limited. For example, it is 1 minute or longer (for example, 2 minutes to 72 hours), preferably 5 minutes or longer (for example, 10 minutes to 48 hours), more preferably 30 minutes or longer (for example, 1 to 36 hours).
  • TLC thin layer chromatography
  • the compound represented by the formula (1) is obtained.
  • the compound represented by the formula (1) may be obtained in the form of a derivative such as a salt (for example, an alkali metal salt).
  • a conventional method for example, filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc. can be used.
  • the derivative of the compound represented by the formula (1) can be obtained by a conventional method.
  • a salt can be obtained by reacting a compound represented by the formula (1) with a corresponding alkali [eg, alkali or alkaline earth metal hydroxide (such as sodium hydroxide), amine, ammonia, etc.].
  • a corresponding alkali eg, alkali or alkaline earth metal hydroxide (such as sodium hydroxide), amine, ammonia, etc.].
  • the acylated product can be obtained by reacting the compound represented by the formula (1) with a corresponding acylating agent (for example, an acid anhydride such as acetic anhydride or propionic anhydride, an acid halide, etc.). it can.
  • a acylating agent for example, an acid anhydride such as acetic anhydride or propionic anhydride, an acid halide, etc.
  • glycoside of the present invention that is, the compound represented by the formula (1) or a derivative thereof
  • the glycoside may be produced by the method described above.
  • Such a glycoside may constitute a composition.
  • examples of uses of such a composition (or glycoside) include foods and drinks, medicines, quasi drugs, and cosmetics.
  • Examples of the food and drink include foods, beverages, seasonings, functional foods (functional foods), health foods, nutritional supplements, foods for specified health use, and supplements.
  • Specific food and drink include, for example, strawberries, troches, gum, yogurt, ice cream, pudding, jelly, mizuyokan, alcoholic drinks, coffee drinks, juices, fruit drinks, carbonated drinks, soft drinks, milk, whey drinks And lactic acid bacteria beverages, etc., and powders [for example, powders for dissolution at the time of use (for example, powders to be dissolved in coffee, tea, juice, yogurt, soup, etc., powders used in cooking, etc.)].
  • Pharmaceuticals and quasi drugs include, for example, oral preparations (eg tablets, capsules, granules, powders, syrups, extracts, etc.), external preparations or parenteral preparations (eg ointments, eye ointments, lotions, creams). , Patches, suppositories, eye drops, nasal drops, injections, etc.).
  • the external preparation may be for skin or non-skin. Examples of the external preparation for skin include facial cleansers, soaps, oral care products (mouthwash, toothpaste, etc.), shampoos, rinses and conditioners. , Hair cream, hair styling, hair tonic, hair growth / wool, lotion, milky lotion, cream and the like.
  • the composition is not limited to human use, and may be an animal composition [for example, animal food and drink (for example, pet food and drink, livestock feed, etc.)].
  • animal food and drink for example, pet food and drink, livestock feed, etc.
  • the component of the composition [components other than the glycoside (other components)] can be appropriately selected according to the use and form of the composition.
  • sugar or sweetener (glucose, fructose, sucrose, maltose Sorbitol, stevioside, rubusoside, corn syrup, lactose, mannitol, etc.), acidulants (citric acid, tartaric acid, malic acid, succinic acid, lactic acid, etc.), fats and oils (vegetable oil, animal oils, etc.), waxes (lanolin, beeswax etc.), Hydrocarbon (or paraffin, white petrolatum, etc.), fatty acid, lipid (ceramide, etc.), alcohol (ethanol, etc.), polyhydric alcohol (propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin, etc.), higher alcohol, ester (Glycerin fatty acid ester, polyglycerin fatty acid ester, Fatty acid este
  • the proportion of the glycoside of the present invention can be appropriately selected according to the use and form of the composition.
  • it is 0.0001 to 90% by weight, preferably 0 in terms of solid content (or dry weight). It may be about .0005 to 50% by weight, more preferably about 0.001 to 10% by weight.
  • the dose of the composition can be appropriately selected depending on the age of the subject, body weight, health condition, etc.
  • the daily intake of the glycoside of the present invention for human adults is 1 to 5000 mg, preferably 10 It may be about ⁇ 3000 mg, more preferably about 30 to 1000 mg.
  • the composition can be produced by mixing the glycoside with other components. Moreover, it can also shape
  • composition when in the form of a powder, it may be made into a dry powder using a conventional excipient (eg, dextrin, polymer starch hydrolyzate, polymer peptide, etc.).
  • a conventional excipient eg, dextrin, polymer starch hydrolyzate, polymer peptide, etc.
  • glycosides and other ingredients can be mixed to prepare various pharmaceutical forms.
  • other components used in the preparation of various dosage forms include starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch.
  • Solid carriers such as inorganic salts; liquid carriers such as distilled water, physiological saline, aqueous glucose solution, alcohol such as ethanol, propylene glycol, polyethylene glycol; oily carriers such as various animal and vegetable oils, white petrolatum, paraffin, waxes, etc. Can be mentioned.
  • glycosides and edible materials are mixed and processed into powders, granules, pellets, tablets, etc., processed into the above-mentioned examples of foods and beverages by a conventional method, or a liquid mixture obtained by mixing these with gelatin
  • the capsule can be formed by coating with a coating agent such as sodium alginate or carboxymethylcellulose, or processed into a beverage (drinks) form.
  • glycoside for example, a compound represented by the formula (1A) or a compound represented by the formula (1B) can be used.
  • soft capsules (agent comprising 60.0% gelatin, 30.0% glycerin, 0.15% methyl paraoxybenzoate, 0.51% propyl paraoxybenzoate, and an appropriate amount of water) in the skin
  • a soptocapsule can be obtained by filling the powder for dissolution with a conventional method.
  • the said tablet is obtained by granulating and shape
  • the obtained compound 2 was dissolved in 80 mL of methylene chloride, 1-ethylpiperazine (7.2 mL, 57 mmol) and 20 mL of methylene chloride were added dropwise at room temperature over 5 minutes, and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid (1 time) and saturated brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain oily compound 3 (16.4 g, 95%).
  • Example 5 The reaction (glycosylation reaction) between Compound 5 and Compound 9 was performed according to the following steps.
  • Example 6 Debenzylation (hydrogenolysis) of compound 10 was performed as in the following steps.
  • Example 8 (Glycosidation without isolation of compound 5) In Example 5, the isolated compound 5 and the compound 9 are reacted. However, the compound 5 synthesized from the compound 3 can be reacted with the compound 9 without isolation (purification) as follows. Provided.
  • a methylene chloride solution (2 mL) of the obtained residue was mixed with the compound 9 (imidate form methylene chloride solution (2 mL) obtained in Example 4, and boron trifluoride diethyl ether complex (30 mL) was cooled with ice. Quenched with saturated aqueous sodium bicarbonate (2 mL), diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (twice) and saturated brine (twice). Methanol was added to the oily residue obtained by drying with magnesium and the solvent was distilled off under reduced pressure to obtain compound 10 as light yellow crystals (1.10 g, 33%), and the mother liquor was concentrated and crystallized from methanol again. In addition, Compound 10 (0.24 g, 7%) was recovered (ie, 1.24 g, 40% total).
  • Example 3 galactose pentaacetate (Compound 13) was obtained in the same manner except that D-galactose was used instead of D-glucose.
  • 1-Ethylpiperazine (760 ⁇ L, 6.0 mmol) was added to a methylene chloride solution (20 mL) of the obtained galactose pentaacetate (compound 13) (2.0 g, 5.0 mmol) under ice-cooling, and then at room temperature. Stir overnight. The mixture was diluted with ethyl acetate and washed with 2N hydrochloric acid (1 time) and saturated brine (2 times).
  • Example 10 The reaction (glycosylation reaction) between Compound 5 and Compound 15 was performed according to the following steps.
  • Example 11 Debenzylation (hydrogenolysis) of compound 16 was carried out according to the following steps.
  • Example 13 (Deacylation of Compound 2 with Potassium Carbonate)
  • Compound 2 (345 mg) obtained in Example 1 was dissolved in 7 mL of dimethylformamide (DMF), potassium carbonate (166 mg, 1.2 mmol) was added at room temperature, and the mixture was stirred for 1.5 hours.
  • the insoluble material was removed by filtration, diluted with ethyl acetate, and washed with 1N hydrochloric acid (1 time) and saturated brine (2 times).
  • the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain oily compound 3 (260 mg, 86%).
  • Example 14 (3-position glycosylation of compound 3) As shown below, glycosylation at the 3-position of Compound 3 was performed.
  • a glycoside having ascorbic acid as an aglycone can be efficiently produced.
  • the novel glycoside useful as provitamin C etc. can be provided.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'acide ascorbique qui peut être utilisé pour obtenir un glycoside dont l'acide ascorbique est l'aglycone. Le dérivé susmentionné est le composé représenté par la formule (A) (c.-à-d. acide 2,3,6-tri-O-acyl-ascorbique). (Dans la formule, R1 désigne un groupe acyle)
PCT/JP2015/079662 2014-10-21 2015-10-21 Dérivé d'acide ascorbique et procédé de production de glycoside à l'aide de celui-ci WO2016063896A1 (fr)

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CN201580054972.1A CN106795129A (zh) 2014-10-21 2015-10-21 抗坏血酸衍生物及使用了该衍生物的糖苷的制造方法
JP2016555245A JP6691483B2 (ja) 2014-10-21 2015-10-21 アスコルビン酸誘導体及びこの誘導体を用いた配糖体の製造方法

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CN110467689A (zh) * 2019-09-09 2019-11-19 山东众山生物科技有限公司 一种透明质酸衍生物及其制备方法

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