CN106795129A

CN106795129A - Ascorbic acid derivates and used the derivative glucosides manufacture method

Info

Publication number: CN106795129A
Application number: CN201580054972.1A
Authority: CN
Inventors: 岛本启子; 松冈龙雄
Original assignee: Suntory Holdings Ltd
Current assignee: Suntory Holdings Ltd
Priority date: 2014-10-21
Filing date: 2015-10-21
Publication date: 2017-05-31
Also published as: TW201629077A; JP6691483B2; WO2016063896A1; JPWO2016063896A1

Abstract

The invention reside in providing the ascorbic acid derivates useful to obtaining glucosides using ascorbic acid as aglycone.Using the compound (i.e. 2,3,6 three O acyl groups ascorbic acid) represented by said derivative as following formula (A).(in formula, R¹Represent acyl group).

Description

Ascorbic acid derivates and used the derivative glucosides manufacture method

Technical field

The present invention relates to new ascorbic acid derivates, the glucosides using the derivative using ascorbic acid as aglycone The manufacture method and novel glycoside of [2-O- (β-D- glucopyranosyls) ascorbic acid etc.].

Background technology

2-O- (β-D- glucopyranosyls) ascorbic acid represented by following formula is as the original chemical combination of vitamin C Thing, based on its excellent property, have studied the application in the every field such as cosmetics, medicine part outer article, pharmaceuticals, food (patent document 1).

Patent document 1 discloses by using as the 2-O- of intermediate (2,3,4,6- tetra--O- acyl-beta-D- glucopyras Glycosyl) ascorbic acid carries out basic hydrolysis (i.e. following operations), can obtain 2-O- (β-D- glucopyranosyls) ascorbic acid.

(in formula, each R is each independently the alkyl of carbon number 1~5.)

Secondly, the document is described can manufacture above-mentioned intermediate by following operations.

(1) 3 hydroxyls of 5,6- isopropylidene ascorbic acid are carried out into benzyl etherificate by benzyl bromide a-bromotoluene, so as to be made 3-O- Benzyl -5, the operation of 6-O- isopropylidene ascorbic acid.

(in formula, Bn is benzyl.)

(2) by 3-O- benzyl -5,6-O- isopropylidenes ascorbic acid and 2,3,4,6- tetra--O- acyl-beta-D- glucopyras Glycosyl carbonic ester (alkyl, the alkyl through halo, the aryl carbonates that can be substituted) is in non-polar solven or solvent-free In 100~200 DEG C of operations for being heated.

(in formula, R ' is alkyl, the alkyl through halo or the aryl that can be substituted, and Bn and R is identical with described.)

(3) by 2-O- (2,3,4,6- tetra--O- acyl-beta-D- glucopyranosyls) -3-O- benzyl -5,6-O- isopropylidenes The isopropylidene of ascorbic acid is hydrolyzed with acid catalyst and removed, so as to obtain 2-O- (2,3,4,6- tetra--O- acyl-beta-D- pyrans Glucosyl group) -3-O- benzyl ascorbic acid operation.

(in formula, Bn and R is identical with described.)

(4) by the benzyl of 2-O- (2,3,4,6- tetra--O- acyl-beta-D- glucopyranosyls) -3-O- benzyl ascorbic acid Carry out the operation of hydrogenative decomposition.

(in formula, Bn and R is identical with described.)

However, presence should change in the manufacturing process of above-mentioned a series of 2-O- (β-D- glucopyranosyls) ascorbic acid Kind aspect.

, it is necessary to 3 hydroxyls of ascorbic acid are carried out into benzyl etherificate for example in operation (1), but the reaction selectivity It is not high, so as to two hydroxyls of 2 and 3 secondary can be born by the compound of benzyl etherificate or the benzyl generation on 2 carbon Substituted dicarbapentaborane body etc..

In addition, in operation (2), due to having used 5,6 to be protected by the unstable contracting acetonyl (aceton ide) of acid Compound (3-O- benzyl -5,6-O- isopropylidenes ascorbic acid), so general acid in glycosylation reaction cannot be used Catalyst, needs 100~200 DEG C of heating in the reaction.Heating at such elevated temperatures, is especially assumed to be commercial scale etc. Extensive operation when, from be difficult to it is uniform it is temperature controlled in terms of, the viewpoint of the required performance of energy or device goes out Hair, it is impossible to argue and think.

And then, in operation (2), because the carbonic ester of only β configurations is reacted, so needs are in holding initiation material Carbonic ester is manufactured in the state of β configurations, so as to have to use expensive and environmental pressure reagent high (hydrogen bromide, silver carbonate).

Patent document 1：No. 4713832 publications of Japanese Patent No. (claim, paragraph [0024]~[0029], embodiment)

The content of the invention

Technical task to be solved by this invention is to provide new ascorbic acid derivates and its manufacture method.

Other technical tasks to be solved of the invention are to provide high efficiency manufacture using ascorbic acid as aglycone The method of glucosides.

Further technical task to be solved of the invention is to provide the new sugar using ascorbic acid as aglycone Glycosides.

Specific embodiment

Present inventor has made intensive studies to solve above-mentioned problem, as a result finds to make four acylates of ascorbic acid When carrying out deacylation with alkali (secondary amine etc.), surprisingly the acylate of 3 with high selectivity by deacylation so that available New ascorbic acid derivates (only 2,5 and 6 compounds being acylated of ascorbic acid) (can be obtained with extra high yield To), it has further been found that using such new ascorbic acid derivates as the specific benzylic ether body (Vitamin C obtained by raw material 5 and 6 of acid are acylated, the compound of 3 benzyls etherificate, 2 deacylations) relative to acid stabilization, can be in the presence of acid With saccharide donor (such as sugared imine matrix etc.) highly effective reaction (glycoside link), it has further been found that due to the Asia by acid can be carried out Amido is activated, so as to either still use the Asia of α anomers (α bodies) using the imido grpup of β anomers (β bodies) as saccharide donor Amido, optionally only obtains the trans bodies of 1,2- (such as β glucosides, β galactosides), and further enter repeatedly as glucosides Research gone so as to complete the present invention.

Compound (ascorbic acid derivates) i.e. of the invention is represented by following formula (A).

(in formula, R¹Represent acyl group.)

The present invention includes following manufacture method：The compound represented by following formula (A ') is carried out into deacylation treatment using alkali (specifically, will be in 2 of the compound represented by formula (A ') group-OR of substitution¹Optionally deacylation), so as to make Make the compound represented by the formula (A).

(in formula, R¹It is identical with described.)

In the manufacture method of such ascorbic acid, alkali can be secondary amine (the monosubstituted piperazines of such as N-).In addition, described In method, it is also possible to use relative to the compound represented by formula (A ') be equivalent or substantially equivalent (such as 0.8~1.2 mole work as Amount) alkali.

In addition, the method for the compound of the present invention represented by manufacture following formula (1) or derivatives thereof (glucosides), also including such as Lower manufacture method：

Glycosylation operation, makes the compound represented by following formula (B) be reacted with the compound represented by following formula (C), so that To the compound represented by following formula (D)；

Depart from operation, make the group R of the compound represented by formula (D)¹And group R²Depart from.

(in formula, Su represents the group that glucosides hydroxyl is eliminated from sugar.)

(in formula, R²Represent arylmethyl, R¹It is identical with described.)

ASu-X (C)

(in formula, ASu represents the group that glucosides hydroxyl is eliminated from the sugar being acylated, and X represents leaving group.)

(in formula, R¹、R²And ASu is identical with described.)

The method (manufacture method of glucosides) can also further include following operation：Make the chemical combination represented by the formula (A) After the reaction of thing and arylmethyl agent (such as the arylmethyl halogen of benzyl halide etc.), deacylation treatment is carried out using alkali so as to manufacture Compound (arylmethyl deacylation operation) represented by formula (B).

And, the arylmethyl compound of the compound represented by the formula (A) is can obtain by the reaction with arylmethyl halogen, i.e., under Compound represented by formula (B ').

(in formula, R¹And R²It is identical with described.)

In arylmethyl deacylation operation, the compound represented by formula (C) especially can also be that α bodies are mixed with β bodies Compound.In the present invention, even if also can obtain the glucosides as the trans bodies of 1,2- of final product using such mixture.

In addition, in the formula (C), X for example can also be imido grpup (imidate) (2,2,2- tribromo-acetyl imines acyl-oxygens Base etc.).

The method of the present invention (manufacture method of glucosides) can also be further included：

The compound represented by following formula (C ') is carried out into deacylation treatment using alkali, it is represented so as to obtain following formula (C ") Compound operation；And

The compound represented by the formula (C ") is set to be reacted with the compound for corresponding to leaving group X, it is described so as to obtain The operation of the compound represented by formula (C).

ASu-OR¹ (C′)

(in formula, R¹And ASu is identical with described.)

ASu-OH (C")

(in formula, ASu is identical with described.)

In such method, the compound represented by formula (C ') can also be the mixture of α bodies and β bodies.In addition, alkali also may be used It is secondary amine (monosubstituted piperazines of N- etc.).

In the method for the present invention (manufacture method of glucosides), can also in the presence of acid make the chemical combination represented by formula (B) Thing and the compound reaction represented by formula (C).In addition, the compound represented by formula (B) is anti-with the compound represented by formula (C) Can should also be carried out under non-heated.

And then, in the method for the present invention (manufacture method of glucosides), depart from operation and may also include：

Compound represented by formula (D) is carried out into hydrogenation treatment, so as to obtain the work of the compound represented by following formula (E) Sequence；And

Compound represented by formula (E) is carried out into deacylation treatment, so as to obtain the work of the compound represented by formula (1) Sequence.

(in formula, R¹And ASu is identical with described.)

In the method for the invention, sugar for example can also be monose (such as hexose of glucose, galactolipin etc.).

In addition to the ascorbic acid derivates, present invention additionally comprises manufactured so-called new in the method for the invention Type compound (glucosides, the precursor of glucosides or intermediate etc.).And, such new compound is not necessarily required to by the side Method is manufactured.

Such new compound can especially include novel glycoside.Such glucosides can also in formula (1) Su be not D- Portugals The sugared compound of grape sugar, for example, can also be compound represented by following formula (1B) or derivatives thereof.

In addition, the present invention includes compound represented by the formula (1) or derivatives thereof.Such compound or its derivative Thing generally can also be obtained by methods described.

And then, the present invention includes the composition comprising the compound represented by the formula (1) or derivatives thereof.Such group Compound for example can also be diet product, pharmaceuticals, medicine part outer article, cosmetics etc..

And then, the present invention includes the constituent by compound represented by the formula (1) or derivatives thereof with composition (other compositions) mix so as to the method for manufacturing the composition.

In the present invention, can be by 3 of four acylates of ascorbic acid optionally deacylations.Therefore, in the present invention In, (the new type ascorbic acid that i.e. 2,5 and 6 of ascorbic acid are acylated derives to can obtain new ascorbic acid derivates Thing).

(sugar is bonded to Vitamin C to novel glycoside of such derivative to high efficiency manufacture using ascorbic acid as aglycone 2 glucosides of (glycoside link) of acid) it is useful.

In addition, in the present invention, it is possible to provide using ascorbic acid as the novel glycoside of aglycone.Such glucosides has The sugar (such as galactolipin) of non-conventional β-D-Glucose has carried out the new structure of glycoside link on 2 of ascorbic acid, Same with 2-O- (β-D- glucopyranosyls) ascorbic acid is as the original compound of vitamin C.Therefore, can be applied to The every field such as cosmetics, medicine part outer article, pharmaceuticals, food.

Compound (ascorbic acid derivates) of the invention is represented by following formula (A).Ascorbic acid derivates i.e. of the invention Can be described as only 2,5 and 6 compound for being acylated (acyl group esterification) (2,5,6- tri--O- acyl group Vitamin Cs of ascorbic acid Acid).

(in formula, R¹Represent acyl group.)

In above formula (A), as acyl group R¹, can enumerate from the group that hydroxyl is eliminated as the carboxylic acid of ketone acid, such as fat Fat race acyl group [such as alkanoyl (such as C of formoxyl, acetyl group, propiono, bytyry etc._1-10Alkanoyl, preferably C_1-6Alkane acyl Base, further preferred C_1-4Alkanoyl) etc. representative examples of saturated aliphatic acyl group], aromatic acyl [such as aroyl (such as benzoyl Deng C_6-10Aroyl)] etc..In addition, acyl group from non-carboxylic acid (sulfonic acid, the phosphoric acid etc.) as ketone acid also including eliminating hydroxyl Group [such as alkane sulfonyl (such as methane sulfonyl) etc.].

The aliphatic acyl radical of preferred alkanoyl etc., particularly preferred acetyl group in above-mentioned substance.

And, in the formula (A), 3 R¹Can be identical or different acyl group, generally be alternatively identical acyl group.

Representational ascorbic acid derivates are to include 2,5 and 63 R¹It is the compound (i.e. 2,5,6- of acetyl group Three-O- acetyl group ascorbic acid).

Such ascorbic acid derivates are for example useful as the aglycone in glucosides or its precursor (intermediate).For example Such ascorbic acid derivates at 3 due to only having hydroxyl, so (glycosylation) sugar [monose can be efficiently bonded at 3 The sugar described later of (glucose, galactolipin etc.) etc.].Especially, ascorbic acid derivates of the invention, as described later, as formula (1) raw material (intermediate, precursor) of the specific compound (i.e. sugar is bonded to 2 glucosides of ascorbic acid) represented by is useful.

[manufacture methods of ascorbic acid derivates]

Ascorbic acid derivates for example can be by by compound (i.e. 2,3,5, the 6- tetra--O- acyl groups represented by following formula (A ') Ascorbic acid) (specifically, in 3 group-OR of substitution of the compound represented by following formula (A ')¹) carry out deacylation (deacylation treatment) is manufactured, without being particularly limited to.

(in formula, R¹It is identical with described.)

In above formula (A '), R¹It is identical with the formula (A).Representational compound (A ') includes 4 R of 2,3,5 and 6¹ It is the compound (i.e. 2,3,5,6- tetra--O- acyl groups ascorbic acid) of acetyl group.

(manufacture method of the compound represented by formula (A '))

Compound represented by formula (A ') can be obtained by making ascorbic acid (L-AA) be reacted with acylation agent.

As acylation agent, can enumerate corresponding to group R¹Acylation agent, such as acid anhydrides (such as acetic anhydride etc.), carboxylic acid halides (such as chloroacetic chloride etc.), acid esters etc..Acylation agent can individually or also can be combined two or more.

As long as the use ratio of acylation agent can be acylated in the range of (acyl group esterification) in 4 hydroxyls of ascorbic acid , for example can also be relative to 1 molar ascorbic acid be more than 4 moles (such as 4~10 moles).

And, reaction solvent-free can be carried out according to species of acylation agent etc., can also be entered in solvent (solvent described later etc.) OK.

Ascorbic acid can also be in acid catalyst (such as inorganic acid of sulfuric acid, hydrochloric acid, nitric acid etc. with the reaction of acylation agent Deng) in the presence of carry out.In addition, reaction can also under heating [for example more than 50 DEG C of reaction temperature (such as 60~180 DEG C, preferably 80~150 DEG C), further preferred 100~140 DEG C] carry out.In addition, reaction can also carry out under agitation, can also in atmosphere or Carried out in inert atmosphere (nitrogen, rare gas etc.).

Reaction time is not particularly limited, for example can be more than 1 minute (such as 2 minutes~48 hours), preferably 3 minutes with Upper (such as 4 minutes~24 hours), further preferred more than 5 minutes (such as 10 minutes~12 hours) Zuo You.And, also can use thin The conventional process of layer chromatography (TLC) etc. come confirm reaction carrying out.

And, (or recovery) reactant mixture (mixture of the compound represented by contained (A ')) can not be separated and directly supplied In deacylation described later reaction, also can be separated (or recovery).

Separation (or purifying) from reactant mixture is using customary way (such as filtering, extraction, concentration, cleaning, suction Attached, UF membrane, chromatogram etc.).

(deacylation)

The deacylation (deacylation reaction) of the compound represented by formula (A ') generally can be used alkali (or being reacted with alkali) Come carry out.

As alkali, can enumerate organic base [amine, alkoxide (for example alkali metal alcoholates (such as sodium methoxide, sodium isopropylate etc. Sodium alkoxide) etc. metal alkoxide) etc.], inorganic base [for example carbonate (the alkali metal carbonate salt of such as sodium carbonate, potassium carbonate etc. or Carbonic acid alkali salt) the salt of weak acid etc.] etc..Especially, from the viewpoint grade of purifying, can also compatibly be used as alkali Amine.In the present invention, surprisingly be difficult to occur 2 deacylations of acyl group of ascorbic acid such that it is able to by 3 acyl groups with High selectivity deacylation.

As amine, primary amine, secondary amine etc. can be used, especially can also compatibly use secondary amine.

As primary amine, for example, can enumerate chain fatty race amine (such as alkylamine of ethylamine, isopropylamine etc.), fragrant fat Fat race amine (such as benzyl amine etc.) etc..

In addition, as secondary amine, such as chain amine [such as chain fatty race amine (such as the two of diisopropylamine etc. can be enumerated Alkylamine)], cyclic amine [or hetero ring type amine, such as monosubstituted piperazine of pyrrolidines, pyrazolidine, imidazoline, piperazine, N- (such as 1- The 1- alkyl piperazines of methyl piperazine, 1- ethyl piperazidines etc., preferably 1-C_1-4Alkyl piperazine), morpholine, the monocyclic of thiomorpholine etc. Amine] etc..

In above-mentioned secondary amine, the secondary amine with tertiary amino such as particularly preferred monosubstituted piperazines of N- (1- alkyl piperazines etc.).Make During with such secondary amine, it is easy to easily reclaim (purifying) product (compound represented by formula (A ')) by acid cleaning.

Alkali (amine etc.) individually or can also be combined two or more.

In deacylation, the amount of alkali can be selected according to species of alkali etc., such as relative to the change represented by formula (A ') Compound, can be for more than 0.3 molar equivalent (such as 0.4~10 molar equivalent), more than 0.5 molar equivalent (such as 0.6~5 mole Equivalent), more than preferably 0.7 molar equivalent (such as 0.8~3 molar equivalent) left and right.

Especially, by using equivalent or the substantially alkali of equivalent, the compound represented by formula (A ') is prone to the choosing of 3 The deacylation reaction of selecting property.Accordingly, with respect to the compound represented by formula (A '), equivalent or substantially equivalent (example are it is also possible to use Such as 0.7~1.5 molar equivalent, preferably 0.8~1.2 molar equivalent, further preferred 0.9~1.1 molar equivalent, particularly preferably 0.95~1.05 molar equivalent) alkali.

And, using 2 equivalents or substantially 2 equivalents alkali when, it is easy to by 2 and 3 optionally deacylations.I.e. by making During with the alkali of 2 equivalents or substantially 2 equivalents, (i.e.-O- acyl groups of 5,6- bis- resist the compound that can also efficiently obtain represented by following formula (A ") Bad hematic acid).

(in formula, R¹It is identical with described.)

Deacylation can also be carried out in a solvent.As solvent, as long as do not suppress the solvent of deacylation, then without spy Do not limit, can for example enumerate hydro carbons [for example aliphatic hydrocarbon (such as hexane, heptane, hexamethylene etc.), it is aromatic hydrocarbon (for example Benzene,toluene,xylene etc.) etc.], halogenated hydrocarbon (such as dichloromethane, chloroform etc.), ethers [such as chain ethers (such as diethyl Base ether etc.), ring-type ethers (such as tetrahydrofuran, dioxanes etc.) etc.], amide-type [such as N substituted amide (N, N- dimethyl methyl The N- alkyl alkane substitutes acid amides of acid amides etc.)], alcohols (the alkane alcohol of such as methyl alcohol, ethanol, isopropanol etc.) etc..

Especially, for optionally deacylation, deacylation reaction can also compatibly use inactive solvent (example Such as hydro carbons, ethers, halogenated hydrocarbon) etc..

Above-mentioned solvent individually or can also be combined two or more.

During using solvent, the usage amount of solvent is not particularly limited, such as relative to the change represented by 1 weight portion formula (A ') Compound (and alkali), for example, can also be 0.5~100 weight portion, and preferably 1~50 weight portion, further preferred 2~30 weight portion is left It is right.

Reaction can also be carried out under normal temperature (or room temperature), under cooling or under heating.

In addition, reaction can also be carried out under agitation, can also enter in atmosphere or in inert atmosphere (nitrogen, rare gas etc.) OK.

Reaction time is not particularly limited, for example can be more than 1 minute (such as 2 minutes~48 hours), preferably 3 minutes with Upper (such as 4 minutes~24 hours), further preferred more than 5 minutes (such as 10 minutes~12 hours) Zuo You.And, it is also possible to use The conventional process of thin-layer chromatography (TLC) etc. come confirm reaction carrying out.

As described above, ascorbic acid derivates (compound represented by formula (A)) be can obtain.Can not separate (or recovery) Reactant mixture (mixture of the compound represented by contained (A ')) is direct for reaction described later, also can be separated (or return Receive).

Separation (or purifying) from reactant mixture is using customary way (such as filtering, extraction, concentration, cleaning, suction Attached, UF membrane, chromatogram etc.).Especially, as described, when using specific alkali, it is easy to by from the acid cleaning of extract It is easily separated the accessory substance (carboxylic acid amide etc.) for removing and being produced by deacylation.

The present invention includes the compound represented by following formula (1) or derivatives thereof (glucosides).

In above formula (1), Su is that the group for eliminating glucosides hydroxyl (hemiacetal hydroxyl) from sugared (or sugar chain) is (residual Base).In other words, group-OSu is also referred to as being eliminated from sugar the hydrogen original of composition glucosides hydroxyl (being bonded to the hydroxyl of anomeric carbon) The group (residue) of son.

That is, the compound represented by formula (1) can be described as O-glycosides using ascorbic acid as aglycone (in ascorbic acid 2 hydroxyls and the glucosides hydroxyl of sugar between condensation (glycoside link) glucosides).

In formula (1), as the sugar (i.e. Su-OH) corresponding to group Su, it is not particularly limited, can is also monose (monose Class), oligosaccharides, polysaccharide (polysaccharide) etc..And, oligosaccharides and polysaccharide can also be any one in homopolysaccharide, heteroglycan.

In monose, carbon number is not particularly limited, for example, can also be pentose, hexose.In addition, monose for example can also be Furanose or pyranose.

Specific sugar can enumerate monose [such as pentose (such as ribose, arabinose, xylose, deoxyribose etc.), hexose (such as fructose, Tagatose, allose, altrose, glucose, mannose, galactolipin, rhamnose, aminoglucose, galactosamine, Portugal Uronic acid) etc.], the oligosaccharides of above-mentioned monosaccharide bonding or polysaccharide [such as disaccharides (such as maltose, kojibiose, cellobiose, different Maltose, gentiobiose (gentiobiose), lactose etc.) etc.] etc..

In above-mentioned sugar, representational sugar includes monose (such as hexose of glucose, galactolipin etc.).

And, sugar can be any one in D bodies, L bodies, their mixture.

In addition, the compound represented by formula (1) can also be α bodies (α anomers, α-glucosides), β bodies (β anomers, β-sugar Glycosides), any one in their mixture, especially can also be β bodies.In the present invention, as described later, even if using α as sugar The mixture of body, α bodies and β bodies also can obtain the compound represented by the formula (1) as the trans bodies of 1,2- mostly.

For example when sugar is glucose β bodies are can obtain, α bodies are can obtain when being mannose.

Compound represented by representational formula (1) include for example represented by following formula (1A) compound (in formula (1), Sugar is as the β-glucosides of D-Glucose), (i.e. in formula (1), sugar is as D- galactolipins to the compound represented by following formula (1B) β-glucosides) etc..

In the compound represented by formula (1), except the compound represented by formula (1A), (i.e. in formula (1), sugar is as D- β-the glucosides of glucose) beyond compound [such as the compound represented by formula (1B)] be new compound.Therefore, the present invention Also include such new compound (novel glycoside).

As the derivative of the compound represented by formula (1), the hydroxyl of compound that for example can be represented by enumerative (1) The compound (salt of the compound i.e. represented by formula (1)) of (hydroxyl of composition ascorbic acid skeleton and sugar (Su) skeleton) forming salt Or the compound replaced on leaving group etc..As salt, for example, can enumerate slaine (such as sodium salt, sylvite, calcium salt etc. Alkaline or alkaline-earth salts), amine salt, the salt with alkali of ammonium salt etc..

In addition, as leaving group, acyloxy (such as acetoxyl group, propionyloxy, butyryl acyloxy, decoyl oxygen can be enumerated Aliphatic acyloxy group of base, palm acyloxy, stearoyl-oxy etc. etc.) etc..Compound with such acyloxy can be described as The acylate (acyl ester) of the compound represented by formula (1).

Secondly, glucosides (compound represented by formula (1) or derivatives thereof) of the invention generally can be by following operation system Make：Glycosylation operation, makes the compound represented by following formula (B) be reacted so as to obtain following formula with the compound represented by following formula (C) (D) compound represented by；And depart from operation, make the group R of the compound represented by formula (D)¹And group R²Depart from.

(in formula, R²Represent arylmethyl, R¹It is identical with described.)

ASu-X(C)

(in formula, R¹、R²And ASu is identical with described.)

Hereinafter, it is described in detail on manufacture method.

In formula (B), R²It is arylmethyl.As arylmethyl (R²), can for example enumerate benzyl, substituted benzyl [such as alkyl benzyl Base (such as C of 4- methyl-benzyls etc._1-4Alkyl benzyl) etc.] etc..It is preferred that arylmethyl is benzyl.

In addition, in formula (B), R¹With identical (i.e. the acyl group), preferred embodiment is also identical with described.

Include the R of 5 and 6 in the compound represented by representational formula (B)¹It is acetyl group, R²It is the compound of benzyl (i.e. 3-O- benzyl -5,-O- acetyl group of 6- bis--ascorbic acid).

[manufacture method of the compound represented by formula (B)]

Compound represented by formula (B) can for example manufacture the formula (A) as raw material (intermediate, precursor).That is, formula (B) compound represented by can be obtained by following operation：The compound represented by formula (A) is set to be reacted with arylmethyl agent Deacylation treatment is carried out after (arylmethylization reaction) (specifically, will be in the compound represented by ascorbic acid or formula (A) 2 group-OR of substitution¹Carry out deacylation) (arylmethyl deacylation operation).

And, in order to obtain the compound represented by formula (B), it is believed that it is also possible to use only 5,6 ascorbic acid being acylated (5,6- diacyl ascorbic acid).

However, obtained by 5,6- diacyl ascorbic acid are to make ascorbic acid be reacted with acylation agent (such as acetic anhydride etc.) Compound, but be difficult to optionally by 5 and 6 acylation, usually as comprising only 5 or 6 Vitamin Cs being acylated The mixture of the accessory substance of acid, only 3 ascorbic acid being acylated etc. and obtain.Secondly, it is difficult to from the mixture selectivity Ground only separates 5,6- diacyl ascorbic acid.Even if in addition, separable 5,6- diacyl ascorbic acid, it is also difficult to optionally only 3 arylmethyls are etherified (benzyl etherificate etc.).

Therefore, in the present invention, as the raw material of the compound represented by formula (B), 5,6- diacyl Vitamin Cs are not used Acid, and use the compound (2,5,6- tri- acyl group ascorbic acid) represented by formula (A).

As arylmethyl agent, for example, can enumerate arylmethyl halogen (or halogenated methyl aromatic hydrocarbons, such as benzyl chloride, benzyl bromide a-bromotoluene etc. Benzyl halide) etc. corresponding to arylmethyl reagent.

In arylmethylization reaction, relative to the compound represented by 1 mole of formula (A), the use ratio of arylmethyl agent For example can be more than 0.8 mole (such as 0.9~10 mole), preferably more than 1 mole (such as 1.1~5 moles), further preferably More than 1.2 moles (such as 1.3~3 moles).

Arylmethylization reaction can be carried out in the presence of base.As alkali, for example, can enumerate carbonate (such as sodium carbonate, carbon The alkali metal carbonate salt of sour potassium, cesium carbonate etc.), silver oxide, pyridines (pyridine, picoline) etc..Alkali can individually or also group Close two or more.

For example relative to the compound (or arylmethyl agent) represented by formula (A), the use ratio of alkali for example can be 1 mole More than equivalent (such as 1~5 molar equivalent).

In addition, arylmethylization reaction can also be in the reducing agent of sodium hydrogensulfite (sodium dithionite), sodium thiosulfate etc. In the presence of carry out.For example relative to the compound represented by formula (A), the use ratio of reducing agent for example can also be 1 mole and work as More than amount (such as 1~5 molar equivalent).

And, arylmethylization reaction can also be carried out in a solvent.As solvent, can enumerate the illustration solvent (such as N, The amide-type of dinethylformamide etc.) etc..

During using solvent, the usage amount of solvent is not particularly limited, such as relative to the change represented by 1 weight portion formula (A) Compound, for example, can be 1~100 weight portion, preferably 2~50 weight portions or so.

Reaction can also be carried out under normal temperature (or room temperature), under cooling or under heating.Reaction temperature for example can be 30~150 DEG C, preferably 40~120 DEG C, further preferred 50~100 DEG C or so.Reaction can be carried out under agitation, can also be in atmosphere or non- Carried out in reactive atmosphere (nitrogen, rare gas etc.).

Reaction time for example can be more than 1 minute (such as 1.5 minutes~24 hours), preferably more than 2 minutes (such as 3 points Clock~12 hour), further preferred more than 5 minutes (such as 10 minutes~3 hours) Zuo You.And, it is also possible to use thin-layer chromatography Etc. (TLC) conventional process confirms the carrying out of reaction.

As described above, the arylmethyl compound of the compound represented by formula (A), i.e. change represented by following formula (B ') be can obtain Compound.

(in formula, R¹And R²It is identical with described.)

And, include the R of 2,5 and 6 in the compound represented by representational formula (B ')¹It is acetyl group, R²It is benzyl Compound (i.e. 3-O- benzyl -2,5,6- tri--O- acetyl group-ascorbic acid).

Can not separate (or reclaim) reactant mixture (mixture of the compound represented by contained (B ')) directly for Reaction (deacylation) described later, also can be separated (or recovery).Separation (or purifying) from reactant mixture is using usual Method (such as filtering, extraction, concentration, cleaning, absorption, UF membrane, chromatogram etc.).

(deacylation)

Deacylation is carried out by and then arylmethyl, the compound represented by formula (B) is can obtain.

The generally usable alkali (or being reacted with alkali) of deacylation (deacylation reaction) is carried out.

As alkali, amine can be also compatibly used.As amine, amine (such as secondary amine) of the illustration etc. can be enumerated. As amine, using monosubstituted piperazines of N- (1- alkyl piperazines etc.) etc. during secondary amine with tertiary amino, with described again by acid Cleaning is easy to easily reclaim (purifying) product (compound represented by formula (B)).

In deacylation, the amount of alkali can be selected according to species of alkali etc., such as relative to the chemical combination represented by formula (A) Compound represented by thing or formula (B '), can be more than 0.5 molar equivalent (such as 0.7~10 molar equivalent), 0.8 molar equivalent Above (such as 0.9~5 molar equivalent), more than preferably 1 molar equivalent (such as 1~3 molar equivalent) left and right.

Deacylation can also be carried out in a solvent.As solvent, as long as do not suppress the solvent of deacylation, then without spy Do not limit, solvent of the illustration etc. can be used.

And, by arylmethyl reactant mixture directly for deacylation when, also can will arylmethylization reaction in use Solvent used as the solvent of deacylation.

In addition, reaction can be carried out under agitation, can also enter in atmosphere or in inert atmosphere (nitrogen, rare gas etc.) OK.

Reaction time is not particularly limited, for example can be more than 1 minute (such as 2 minutes~48 hours), preferably 3 minutes with Upper (such as 4 minutes~24 hours), further preferred more than 5 minutes (such as 10 minutes~12 hours) Zuo You.And it is also possible to use The conventional process of thin-layer chromatography (TLC) etc. come confirm reaction carrying out.

As described above, can obtain the compound represented by formula (B).(or recovery) reactant mixture can not be separated (to include The mixture of the compound represented by formula (B)) directly for reaction described later (glycosylation reaction), also can be separated (or recovery).

In formula (C), ASu be from the sugar for being acylated (acyl group esterification) eliminate glucosides hydroxyl (hemiacetal hydroxyl, Be bonded to the hydroxyl of anomeric carbon) group (residue).In other words, ASu is except glucosides hydroxyl in the group Su in the formula (1) The group (or hydroxyl is substituted by the group of acyloxy) that all hydroxyls beyond base are acylated.

Therefore, in addition to by acylation, ASu is identical with Su, and situation of the preferred embodiment also with Su is identical.

In the sugar (or acyloxy) being acylated, as acyl group, can illustrate and the R¹(acetyl group etc.) is same Acyl group.Acyl group can also be identical or different acyl group.

And, the compound (or group ASu) represented by formula (C) can be α bodies (α anomers, α-glucosides), β bodies (the different heads of β Thing, β-glucosides), any one in their mixture.Especially, in the present invention, from from the viewpoint for the treatment of effeciency, may be used also Compatibly use α bodies and the mixture of β bodies.

As specific group ASu, for example including the group represented by following formula (ASu-1), represented by following formula (ASu-2) (i.e. Su corresponds to group, four-O- acyl group-D- glucopyranosyls, the four-O- acyl groups-D- of D-Glucose or D- galactolipins to group Galactopyranosyl glycosyl) etc..

(in formula, wave represents α bodies, β bodies or its mixture, R¹It is identical with described.)

In formula (C), group X is leaving group.Compound i.e. represented by formula (C) can be described as group X and be bonded to ASu's The compound (or the glucosides hydroxyl of ASu is substituted by the compound of leaving group) of anomeric carbon.

As leaving group X, as long as can be reacted with the hydroxyl (2 hydroxyls) of the compound represented by formula (B) and be formed The group (making the group of the anomeric carbon of ASu or the activation of different head position) of glycosidic bond, is just not particularly limited, for example, can enumerate imido grpup { such as 2,2,2- tribromo-acetyl imines acyloxy (group-O-C (=NH)-CCl₃), (N- phenyl) trifluoroacetyl imines acyloxy (group-O-C (=NPh)-CF₃) etc., carbonyldioxy (or carbonate group, such as 2,2,2- tri-chloroethoxy base carbonyloxy groups etc.), acyl-oxygen Base (group-the OR of such as acetoxyl group etc.¹Represented group), halogen atom (fluorine atom, chlorine atom, bromine atoms etc.) Deng.

In above-mentioned, even if because the compound (or ASu) represented by formula (C) is any one in α bodies, β bodies, imido grpup Also glycoside link (further can obtain the trans bodies of 1,2-) can be carried out with the compound represented by formula (B), so as formula (C) institute The compound of expression, it is more suitable in the case where α bodies, the mixture of α bodies and β bodies is used etc..Especially since need not divide From α bodies and β bodies, so can also compatibly use α bodies and the mixture of β bodies.

As the compound represented by representational formula (C), including imine matrix, such as chemical combination represented by following formula (C1) (i.e. ASu is the D-Glucose or D- galactolipins, X being acylated for 2- tribromo-acetyls are sub- to compound represented by thing, following formula (C2) The compound of amine acyloxy) etc..

[manufacture method of the compound represented by formula (C)]

As long as can obtain the compound represented by formula (C) then can be used commercially available product, it is possible to use synthesis (manufacture) product.

As the manufacture method of the compound represented by formula (C), it is not particularly limited, for example, can be obtained by following operation Arrive：Compound represented by following formula (C ') is carried out into deacylation treatment (deacylation), it is represented so as to obtain following formula (C ") Compound operation (deacylation operation)；And make the compound represented by formula (C ") and the chemical combination corresponding to leaving group X The operation (leaving group importing operation) of thing reaction.

And, the compound represented by formula (C ') is with the compound phase represented by formula (C) with [i.e. leaving group X is in formula (C) Acyloxy (- OR¹)] when, it is not necessary to by such operation.

ASu-OR¹ (C′)

(in formula, R¹And ASu is identical with described.)

ASu-OH (C")

(in formula, ASu is identical with described.)

(compound represented by formula (C '))

In formula (C '), R¹With identical (i.e. the acyl group).As described, ASu is to be eliminated from the sugar being acylated The group of glucosides hydroxyl, group-OR¹For acyloxy (be acylated or acyl group esterification hydroxyl).I.e. formula (C ') is represented Compound be the compound that (acyl group esterification) is acylated including all hydroxyls including glucosides hydroxyl.

And, as described, the compound represented by formula (C ') can be corresponding to α bodies (α anomers, α-glucosides), β bodies The group of any one in (β anomers, β-glucosides), their mixture.In the present invention, no matter α bodies, β bodies can obtain Glucosides.

Compound represented by representational formula (C ') includes compound, following formula (C ' 2) institute table represented by following formula (C ' 1) [i.e. ASu is the D-Glucose or D- galactolipins, R being acylated to the compound for showing¹It is the compound (five-O- acyl groups-D- of acyl group Glucose, five-O- acyl group-D- galactolipins)] etc..

(manufacture method of the compound represented by formula (C '))

Compound represented by formula (C ') can be obtained by making sugar be reacted with acylation agent.

As sugar, sugar (such as monose of glucose, galactolipin etc.) of the illustration etc. can be enumerated.And, sugar can also be α Any one in body, β bodies, their mixture.

As acylation agent, can enumerate corresponding to group R¹Acylation agent, such as acid anhydrides (such as acetic anhydride etc.), carboxylic acid halides (such as chloroacetic chloride etc.) etc..Acylation agent can individually or also can be combined two or more.

As long as can be acylated all hydroxyls of sugar in the range of (acyl group esterification) by the use ratio of acylation agent , such as can be more than 1 mole (such as 1~5 mole, preferably 1.2~3 moles) relative to 1 mole of hydroxyl of sugar.

And, reaction solvent-free can be carried out according to species of acylation agent etc., can also be entered in solvent (described solvent etc.) OK.

Sugar can also be in alkali [such as salt (sodium acetate etc.) of weak acid, hydroxide (NaOH with the reaction of acylation agent Deng)], carry out in the presence of sour (such as inorganic acid of sulfuric acid, hydrochloric acid, nitric acid etc. etc.) etc..

In addition, reaction can also be carried out under heating or under backflow.In addition, reaction can be carried out under agitation, can also be in air In or inert atmosphere (nitrogen, rare gas etc.) in carry out.

And, (or recovery) reactant mixture (mixture of the compound represented by contained (C ')) can not be separated and directly supplied In deacylation described later reaction, also can be separated (or recovery).

As described above, can obtain the compound represented by formula (C ').As sugar, using α bodies and β bodies mixture when (when further using only α bodies or β bodies), the mixture of α bodies and β bodies is also can obtain in the compound represented by formula (C ').

And, such mixture can also be separated α bodies with β bodies by the method for recrystallization etc., can not be entered in the present invention The such separation of row and by mixture directly for deacylation described later.

(deacylation operation)

The deacylation (deacylation reaction) of the compound represented by formula (C ') generally can be used alkali (or being reacted with alkali) Come carry out.

As alkali, amine, hydrazides (the carboxylic hydrazides of vinegar hydrazides etc.) etc. can be also compatibly used.As amine, institute can be enumerated State amine (such as secondary amine) of illustration etc..As amine, there is tertiary amino using monosubstituted piperazines of N- (1- alkyl piperazines etc.) etc. Secondary amine when, it is same with described, by acid cleaning be easy to easily reclaim (purifying) product (compound represented by formula (C ")).

In deacylation, the amount of alkali can be selected according to species of alkali etc., such as relative to the change represented by formula (C ') Compound can also be for more than 0.5 molar equivalent (such as 0.7~10 molar equivalent), more than 0.8 molar equivalent (such as 0.9~5 mole Equivalent), more than preferably 1 molar equivalent (such as 1~3 molar equivalent) left and right.

Reaction time is not particularly limited, for example can be more than 1 minute (such as 2 minutes~72 hours), preferably 5 minutes with Upper (such as 10 minutes~48 hours), further preferred more than 30 minutes (such as 1~36 hour) left and right.And, it is also possible to use thin The conventional process of layer chromatography (TLC) etc. come confirm reaction carrying out.

As described above, can obtain the compound represented by formula (C ").(or recovery) reactant mixture can not be separated (to include The mixture of the compound represented by formula (C ")) directly for reaction described later, also can be separated (or recovery).

And, compound represented by representational formula (C ") includes compound represented by following formula (C " 1), following formula (C " 2) Represented compound (i.e. ASu is the compound of the D-Glucose or D- galactolipins being acylated) etc..

(leaving group importing operation)

In leaving group imports operation, make the compound and the compound for corresponding to leaving group X represented by formula (C ") Reaction.

As the compound corresponding to leaving group X, as long as can make represented by the leaving group and formula (C ") Compound is reacted so as to import the compound of leaving group X, for example, can enumerate imido grpup imported agent (such as tribromo-acetyl nitrile Deng), carbonyldioxy imported agent (such as chloro-carbonic acid 2,2,2- trichloro ethyl esters (Tr ocCl) etc.), halogen imported agent (such as hydrogen chloride, The halocarbon of hydrogen bromide etc.) etc..

For example relative to the compound represented by 1 mole of formula (C "), corresponding to the use ratio of the compound of leaving group X Can be more than 1 mole (such as 1~5 mole, preferably 1.2~3 moles).

Species according to the compound corresponding to leaving group X etc., reaction can also be carried out in the presence of base.As alkali (or base catalyst), can enumerate the alkali of the illustration, such as amine (secondary amine etc.), pyridines, carbonate etc..

For example relative to the compound represented by 1 mole of formula (C "), the use ratio of alkali can be for more than 0.01 molar equivalent (such as 0.05~3 molar equivalent, preferably 0.1~2 molar equivalent, further preferred 0.2~1.5 molar equivalent).

Reaction can also be carried out in a solvent.As solvent, as long as not suppressing the solvent of reaction, it is not particularly limited, Solvent (such as halogenated hydrocarbon) of the illustration etc. can be used.

Reaction time is not particularly limited, for example can be more than 1 minute (such as 2 minutes~72 hours), preferably 5 minutes with Upper (such as 10 minutes~48 hours), further preferred more than 30 minutes (such as 1~36 hour) left and right.And, also can use thin layer The conventional process of chromatogram (TLC) etc. come confirm reaction carrying out.

As described above, (or recovery) reactant mixture (mixing of the compound represented by contained (C) can not be separated Thing) directly for reaction described later (glycosylation reaction), also can be separated (or recovery).

In operation is glycosylated, the compound represented by formula (B) is set to obtain formula with the compound reaction represented by formula (C) (D) compound represented by.And, for react formula (C) represented by compound with it is described it is same for α bodies, β bodies, they Mixture in any one.

In operation is glycosylated, the use ratio of the compound represented by compound and formula (C) represented by formula (B), example The compound (mol ratio)=1/0.5~1/2 represented by compound/formula (C) as represented by can be formula (B), preferably 1/0.7~ 1/1.5, further preferred 1/0.8~1/1.2 or so.

Glycosylation operation can especially be carried out in the presence of sour (acid catalyst).Due to the compound phase represented by formula (B) For acid stabilization, so glycosylation can be in the presence of acid carried out in the present invention.Therefore, it is possible to be entered with reaction efficiency high Row glycosylation.

As acid, Bronsted acid { such as inorganic acid [such as halocarbon (hydrogen chloride, hydrogen bromide, hydrogen iodide etc.), sulphur can be enumerated Acid, nitric acid, phosphoric acid etc.], organic acid [such as carboxylic acids (such as formic acid, acetic acid, trifluoroacetic acid etc.), sulphonic acids (such as methane sulphur Acid, trifluoromethayl sulfonic acid)] etc., sulfonic acid esters (the TFMS esters of such as trimethylsilyl triflate etc.), road Lewis acid { such as boron complex [such as boron trifluoride complex (such as boron trifluoride Anaesthetie Ether complex compound, boron trifluoride list Alkyl amine complex, boron trifluoride water and thing etc.)] etc. nonmetallic complex compound；Metal alkoxide [such as aluminium-alcohol salt (triethoxy Aluminium etc.), Titanium alkoxides (purity titanium tetraethoxide etc.), zirconium alkoxide (tetrabutyl zirconate etc.) etc.], metal halide thing (such as iron chloride, chlorination Zinc, aluminium chloride, titanium tetrachloride), metal trifluoroacetate mesylate, metal complex (or the metal compound of metal acetylacetonate salt etc. Thing) etc. etc..Acid can individually or also can be combined two or more.

The use ratio of acid can be according to the appropriate selection such as species of acid, such as relative to the chemical combination represented by 1 mole of formula (B) Thing (or the compound represented by formula (C)), can for it is more than 0.001 molar equivalent (such as 0.001~2 molar equivalent, preferably 0.005~1 molar equivalent, further preferred 0.01~0.5 molar equivalent), generally can also be 0.001~0.3 molar equivalent (example Such as 0.01~0.2 molar equivalent).

Reaction can also be carried out under normal temperature (or room temperature), under cooling or under heating.Especially, in the present invention, due to can Using acid catalyst, even if so being reacted (under normal temperature or cooling) under non-heated, also can efficiently carry out glycosylating instead Should.Therefore, in the present invention, for example can also below 40 DEG C (such as -20 DEG C~35 DEG C), preferably less than 30 DEG C (such as -10 DEG C~25 DEG C) left and right reaction temperature under react.

Reaction time is not particularly limited, for example can be more than 1 minute (such as 2 minutes~48 hours), preferably 5 minutes with Upper (such as 10 minutes~24 hours), further preferred more than 20 minutes (such as 30 minutes~12 hours) Zuo You.And, also can use The conventional process of thin-layer chromatography (TLC) etc. come confirm reaction carrying out.

As described above, can obtain the compound represented by formula (D).(or recovery) reactant mixture can not be separated (to include The mixture of the compound represented by formula (D)) directly for reaction described later, also can be separated (or recovery).

Especially, in order to remove the accessory substance (such as trichloroacetamide etc.) of glycosylation reaction, also can be by reactant mixture Carry out alkali cleaning.

In addition, including unreacted compound (such as tribromo-acetyl nitrile corresponding to leaving group X in the reactive mixture Deng) when, by recrystallization [such as the recrystallization in alcohol (methyl alcohol etc.)] also separable (purifying) product (represented by formula (D) Compound).

And, as described, the compound represented by formula (C) can also be any in α bodies, β bodies, their mixture Kind, even if when using either of which kind, generally also can obtain the compound represented by the formula (D) of the trans bodies of 1,2-.

Include compound, following formula (D2) institute represented by following formula (D1) in the compound represented by representational formula (D) Compound (i.e. ASu is the compound of the D-Glucose or D- galactolipins being acylated) of expression etc..

(in formula, R¹And R²It is identical with described.)

In operation is departed from, make the group R of the compound represented by formula (D)¹And group R²Depart from.Just depart from and (depart from anti- Should) for, group R¹With group R²Disengaging order be not particularly limited, can be by group R¹And group R²In any one base Group departs from another group again after departing from, also can be by group R¹And R²(or in same reaction system) departs from simultaneously.

Especially, can be by group R²Depart from base R after disengaging again¹.Departed from such order, can efficiently suppressed seemingly Generation of accessory substance (or impurity) etc..

[group R²Disengaging (hydrogenation treatment operation)]

In the compound represented by formula (D), group R²Disengaging method be not particularly limited, can for example enumerate formula (D) method that the compound represented by carries out hydrogenation treatment (hydrogenative decomposition).

Hydrogenation treatment can be carried out by making the compound represented by formula (D) react (contact) with hydrogen (hydrogen).

Hydrogenation treatment can also be carried out in the presence of a catalyst.As catalyst, metallic catalyst (or metal network can be enumerated Compound), such as [especially the noble metal of palladium/carbon etc. is (special for the catalyst of the transition metal comprising palladium, nickel, ruthenium, iridium, platinum, rhodium etc. Other platinum group metal) catalyst] etc..

In addition, in order to promote reaction, hydrogenation treatment can also be carried out in the presence of acid.As acid, the illustration can be enumerated Acid, such as carboxylic acids (such as acetic acid etc.) etc..

Reaction can also be carried out in a solvent.As solvent, as long as not suppressing the solvent of reaction, it is not particularly limited, Solvent (such as ethers, alcohols) of the illustration etc. can be used.

Reaction can also be carried out under normal temperature (or room temperature), under cooling or under heating.In addition, reaction can also enter under agitation OK.

Reaction time is not particularly limited, for example can be more than 10 minutes (such as 30 minutes~10 days), preferably 1 hour with Upper (such as 2 hours~5 days), further preferred more than 3 hours (such as 5~36 hours) left and right.And, also can use thin-layer chromatography Etc. (TLC) conventional process confirms the carrying out of reaction.

As described above, can obtain product.(or recovery) reactant mixture (such as mixing comprising product can not be separated Thing) directly for reaction described later, also can be separated (or recovery).

And, in group R²Group R is first carried out before disengaging¹Disengaging when, as product, can obtain represented by following formula (E) Compound.

(in formula, R¹And ASu is identical with described.)

Especially, the compound represented by representational formula (E) includes compound, the following formula represented by following formula (E1) (E2) compound (i.e. ASu is the compound of the D-Glucose or D- galactolipins being acylated) represented by etc..

(in formula, R¹It is identical with described.)

[group R¹Disengaging (deacylation operation)]

In the compound (or the compound represented by formula (E)) represented by formula (D), group R¹Disengaging (deacylation) Method is not particularly limited, for example, can by using alkali the compound represented by formula (D) be carried out into deacylation to carry out.

As alkali, for example, can enumerate the salt (such as carbonate (carbonic acid of the illustration of such as potassium carbonate etc. of weak acid Salt)), amine (amine of the illustration etc.), hydroxide (such as alkali of NaOH, potassium hydroxide etc. or alkaline-earth metal hydroxide Thing) etc..Alkali can individually or also can be combined two or more.

Deacylation can also be carried out in a solvent.As solvent, as long as do not suppress the solvent of deacylation, then without spy Do not limit, solvent (such as alcohol etc.) of the illustration etc. can be used.

As described above, can obtain the compound represented by formula (1).And, species, purification process according to the alkali for using, Sometimes the compound represented by formula (1) can be also obtained in the way of the derivative of salt (such as alkali metal salt) etc..

Compound represented by formula (1) is from the separation (or purifying) of reactant mixture using customary way (such as mistake Filter, extraction, concentration, cleaning, absorption, UF membrane, chromatogram etc.).

And, the derivative of the compound represented by formula (1) can be obtained by customary way.For example can be by making formula (1) Represented compound comes with corresponding alkali [such as alkali or alkaline earth metal hydroxide (NaOH etc.), amine, ammonia etc.] reaction Obtain salt.In addition, can by make the compound represented by formula (1) and corresponding acylation agent (such as acetic anhydride, propionic andydride etc. Acid anhydrides, carboxylic acid halides etc.) react to obtain acylate.

Glucosides (compound represented by i.e. described formula (1) or derivatives thereof) of the invention can be used for various uses.And, sugar Glycosides can also be manufactured with methods described.

Such glucosides can also constitute composition.As the purposes of such composition (or glucosides), for example, can enumerate drink Food, medicine, medicine part outer article, cosmetics etc..

As ingesta (diet product), for example, can enumerate food, beverage, flavoring, functional food (functional food), strong Health food, dietary supplement, specific health food, dietary supplements etc..

As specific ingesta, for example, can enumerate maltose, lozenge, chewing gum, Yoghourt, ice cream, pudding, jelly, soft Red bean jelly, alcoholic beverage, coffee beverage, fruit juice, fruit squash, soda, cold drink, milk, whey beverage, lactic acid bacteria drink Material etc., or powder [for example instant use powder (is for example dissolved into powder, the mixing of coffee, black tea, fruit juice, Yoghourt, soup etc. Powder used in cooking etc.)].

Medicine and medicine part outer article for example can also for oral agent (for example tablet, capsule, granule, powder, syrup, Extract etc.), external preparation or non-oral agent (such as ointment, eye ointment, lotion, frost, patch, suppository, eye drops, nasal drop, note Penetrate agent etc.) etc. mode.External preparation can also be any one in skin use, non-skin use, and skin external preparation for example includes washing Face milk, soap, oral cavity care product (gargle, tooth powder etc.), shampoo, hair conditioner, haircut hair conditioner, hair-cream, hair liquid, Hair growth liquor, educate hair preparation for baldness, toner, emulsion, frost etc..

And, composition is not limited to people's use, or composition for animal consumption [such as animal diet product (such as pet use Ingesta, livestock feed etc.) etc.].

As the constituent [composition (other compositions) in addition to the glucosides] of composition, can be according to the use of composition On the way, form is suitably selected, for example, can enumerate carbohydrate or sweetener (glucose, fructose, sucrose, maltose, sorbierite, stevia rebaudianum Glycosides, rubusoside, corn syrup, lactose, mannitol etc.), acid (citric acid, tartaric acid, malic acid, butanedioic acid, lactic acid etc.), Grease (vegetable oil, animal oil etc.), wax (lanolin, beeswax etc.), hydrocarbon (or paraffin, albolene etc.), aliphatic acid, lipid (god Through acid amides etc.), alcohol (ethanol etc.), polyalcohol (propane diols, 1,3-BDO, polyethylene glycol, glycerine etc.), higher alcohol, ester (glycerine Fatty acid ester, polyglyceryl fatty acid ester, sucrose fatty ester, sorbitan fatty acid ester, methyl glycol fatty acid ester etc.), ammonia Base acid, peptide or protein matter (collagen peptide, Elastin peptide, proteoglycan, casein, gelatin etc.), cellulose, cellulose spread out Biological (cellulose ethers of carboxymethylcellulose calcium etc.), starch (cornstarch etc.), starch machining object (dextrin etc.), mineral matter into Divide (calcium salt class etc.), vitamins [vitamine B group (niacinamide, calcium pantothenate etc.), L-AA, dl- alpha-tocopherols etc.], sea Alginates (sodium alginate etc.), Arabic gum, carragheen, pectin, milk composition, fruit juice, coffee-extract, agar, surface-active Agent, NMF, whitening agent, pigment, colouring agent, pigment, nutrition fortifier, spices, plant animal extract component are (such as from Huang Extract or crushed material obtained by the plant material of a kind of reed mentioned in ancient books, oenothera biennis, sugarcane etc.), ultra-violet absorber, antioxidant it is (different anti- Bad hematic acid sodium etc.), antioxidant, preservative agent, anticorrosion and bactericidal agent, lubricant (magnesium stearate, magnesium palmitate etc.), deodorizing ingredient [for example screening agent, adsorbent, porous material, deodorant (such as antioxidant, lipoxygenase inhibitor, antiseptic, are covered Cover mediation spices, monoethanolamine etc.) etc.], material { such as thing with effect of modulating autonomic nerves with various pharmacological actions Matter (sympathomimetic nerve material, plan parasympathetic nerve material etc.), the material with hypotensive activity, the thing with anti-obesic action Matter [has the material of Anorectic effect Alcohol system stimulation, acts on the material of satiety center, is related to the material (example of energetic supersession Such as act on the material of beta 3 receptor, the material with energy ezpenditure facilitation)] } etc..

Above-mentioned other compositions can individually or also can be combined two or more.

In the composition, the ratio of glucosides of the invention can suitably be selected according to the purposes of composition, form, for example with Solid constituent (or dry weight) conversion can be 0.0001~90 weight %, preferably 0.0005~50 weight %, further preferably 0.001~10 weight % or so.

And, the consumption of composition can suitably be selected according to subject age, body weight, health status etc., for example present invention sugar Adult's intake of every 1 day of glycosides is 1~5000mg, preferably 10~3000mg, further preferred 30~1000mg or so.

And, composition can be manufactured by the way that the glucosides is mixed with other compositions.In addition, also can profit while mixing Various forms are configured to known method.

For example when the form of composition is powder, it is also possible to use conventional excipient (such as dextrin, macromolecule Starch Hydrolysis Thing, macromolecule peptide etc.) dry powder.

In addition, when preparing pharmaceuticals, medicine part outer article, glucosides can be mixed with other compositions and is prepared into various formulations Pharmaceuticals.And, the other compositions for the preparation of various formulations are not particularly limited, and commonly used composition can be used, and make It is its example, the solid that can enumerate starch, lactose, white sugar, mannitol, carboxymethylcellulose calcium, cornstarch, inorganic salts etc. is carried Body；The liquid-carrier of alcohol, propane diols, the polyethylene glycol of distilled water, physiological saline, D/W, ethanol etc. etc.；It is various dynamic Oiliness carrier of vegetable oil, albolene, paraffin, wax class etc. etc..

Processing can be further carried out as follows：By glucosides and edible raw material hybrid process into powder, particle, spherolite, tablet Deng shape；Or diet product of the working process into the illustration according to conventional methods；Or by they mix liquid material gelatin, The film masking of sodium alginate, carboxymethylcellulose calcium etc. is so as to be configured to capsule；Or it is processed into the form of beverage (beverage class).

The example of specific composition is as follows.And, in the following examples, as glucosides, for example, can be used described Compound represented by compound, the formula (1B) represented by formula (1A) etc..

Table 1

Ice cream

Raw material	Weight portion
		Whipping cream (45% fat)	33.8
Skimmed milk power	11.0
		Berry sugar	14.8
Sugared egg yolk	0.3
		Vanillon	0.1
Water	39.998
		Glucosides	0.002
Total amount	100.00

Table 2

Fruit juice

Table 3

Sour milk beverage

Raw material	Weight portion
		The acidified milk of milk solids composition 21%	14.76
Pyroglutamate liquid sugar	13.31
		Pectin	0.5
Citric acid	0.08
		Spices	0.15
Water	71.198
		Glucosides	0.002
Total amount	100.00

Table 4

Yoghourt

Raw material	Weight portion
		Fresh milk (3.4% fat)	80.0
Whipping cream (50% fat)	8.0
		Skimmed milk power	1.5
Citric acid	0.08
		Water	7.498
Lactic acid bacteria	3.0
		Glucosides	0.002
Total amount	100.00

Table 5

Coffee beverage

Raw material	Weight portion
		Berry sugar	8.0
Skimmed milk power	5.0
		Caramel	0.2
Coffee-extract	2.0
		Spices	0.1
Polyglyceryl fatty acid ester	0.05
		Salt	0.05
Water	84.598
		Glucosides	0.002
Total amount	100.00

Table 6

Alcoholic beverage

Raw material	Weight portion
		50 capacity % ethanol	32.0
Granulated sugar	8.4
		Fruit juice	2.4
Glucosides	0.002
		Purified water	57.198
Total amount	100.00

Table 7

Soap

Table 8

Soap

Raw material	Weight portion
		Soap blank	99.8
Compound represented by formula (1A)	0.1
		Compound represented by formula (1B)	0.1
Total amount	100.0

Table 9

Shampoo

Raw material	Weight portion
		Lauryl sodium sulfate	16.0
Coconut oil fatty acid monoethanolamide	4.0
		1,3-BDO	1.9
Glucosides	0.1
		Preservative, pigment, spices	In right amount
Purified water	78.0
		Total amount	100.0

Table 10

Haircut hair conditioner

Table 11

Hair growth liquor

Raw material	Weight portion
		Ethanol	70.0
Vitamin E	0.4
		MENTHOL	0.4
Dipotassium glycyrrhizinate	0.1
		Glucosides	0.1
Salicylic acid	0.5
		Glycerine	0.5
Purified water	28.0
		Total amount	100.0

Table 12

Toner

Table 13

Emulsion

Raw material	Weight portion
		Stearic acid	1.5
Cetanol	0.5
		Octyl dodecanol myristinate	5.0
Polyoxyethylene (10) monoleate	1.0
		Atoleine	5.0
Triethanolamine	0.5
		Glucosides	1.0
Sodium Hyaluronate	0.01
		Glycerine	7.0
1,3-BDO	3.0
		Ethylenediamine dihydroxy triacetic acid sodium	0.01
Purified water	75.48
		Total amount	100.0

Table 14

Spray

Table 15

Frost

Raw material	Weight portion
		Stearic acid	2.5
Glycerin monostearate	0.8
		Sorbitan sesquistearate	0.6
Monostearate polyoxyethylene sorbitol acid anhydride	0.4
		Cetostearyl alcohol	2
Saualane	12.0
		Six (hydroxy stearic acid/stearic acid/rosin acid) dipentaerythritols	2.0
Olive oil	5.0
		Octyl dodecanol myristinate	15.0
Methyl polysiloxane	0.5
		Glycerine	10
1,3-BDO	8.0
		NaOH	0.1
Methyl p-hydroxybenzoate	0.1
		Glucosides	0.3
Purified water	40.7
		Total amount	100.0

Table 16

It is instant to use powder

Raw material	Use level (mg)	Fit rate (weight %)
			Collagen peptide	5000.0	76.92
Elastin peptide	1.0	0.02
			Proteoglycan	0.1	0.01
Dextrin	1495.0	23.00
			Glucosides	3.5	0.05
Total amount	6500.0	100.00

And, when above-mentioned instant powder is dissolved in into water, fruit juice or clear soup, any one dispersiveness is excellent, resulting Beverage is suitable as instant beverage.

In addition, can by soft capsule (by gelatin 60.0%, glycerine 30.0%, methyl p-hydroxybenzoate 0.15%, The preparation that propylparaben 0.51% and appropriate water are constituted) film in fill above-mentioned instant use powder according to conventional methods End obtains soft capsule.

Table 17

Tablet

Raw material	Use level (mg)	Fit rate (weight %)
			Collagen peptide	5000.0	50.00
Elastin peptide	0.1	0.001
			Proteoglycan	0.05	0.0005
Avicel cellulose	2950.0	29.5
			Part alphalysed starch	2000.0	20.0
Magnesium stearate	0.05	0.005
			Glucosides	49.8	0.498
Total amount	10000.0	100.00

And, the mixture pelleting of above-mentioned shown cooperation and shaping can be obtained into above-mentioned tablet according to conventional methods.

Embodiment

Hereinafter, the present invention is more specifically illustrated based on embodiment, but the present invention is not limited to this, and many variations exists In technological thought of the invention, there is can implementing per capita for usual knowledge in this area.

Embodiment 1 (synthesis of 2,5,6- tri--O- acetyl group-ascorbic acid)

2,5,6- tri--O- acetyl group-ascorbic acid (compound 3) is obtained by following operations.

(in formula, Ac represents acetyl group, and Et represents ethyl.)

Compound 1 (ascorbic acid) (10.00g, 57mmol) is suspended in acetic anhydride (25mL, 250mm ol) and is heated to 120℃.Due to the violent heat production in one side while dissolving, so proceeded by 30 minutes from dissolving be heated to reflux.5mL is added after cooling Methyl alcohol makes reaction terminating.Decompression evaporates solvent, and will add the operation that toluene and decompression evaporate to carry out in residue 3 times, so that Obtain the compound 2 of oily.

(compound 2)

¹H-NMR(CDCl₃)：2.06 (3H, s), 2.09 (3H, s), 2.26 (3H, s), 2.28 (3H, s), 4.31 (1H, dd, J =7.3,11.6Hz), 4.40 (1H, dd, J=5.6,11.6Hz), 5.39 (1H, d, J=1.6Hz), 5.48 (1H, ddd, J= 1.6,5.6,7.3Hz)

¹³C-NMR(CDCl₃)：20.05,20.34,20.62,62.03,66.36,74.91,122.05,149.82, 164.78,165.08,166.12,170.00,170.28.

HRMS (ESI, M+H⁺) calculated value C₁₄H₁₇O₁₀345.0822, experiment value 345.0813.

Resulting compound 2 is dissolved in 80mL dichloromethane, 1- ethyl piperazidines were added dropwise with 5 minutes in room temperature (7.2mL, 57mmol) and dichloromethane 20mL are simultaneously stirred 30 minutes.Diluted with ethyl acetate, and with 1N hydrochloric acid (1 time), saturation (2 times) cleanings of saline solution.Organic layer magnesium sulfate is dried and solvent under reduced pressure is evaporated, so as to obtain the compound 3 of oily (16.4g, 95%).

(compound 3)

¹H-NMR(CDCl₃)：2.05 (3H, s), 2.06 (3H, s), 2.29 (3H, s), 4.27 (1H, dd, J=6.9, 11.6Hz), 4.37 (1H, dd, J=5.4,11.6Hz), 4.99 (1H, d, J=1.6Hz), 5.46 (1H, ddd, J=1.6,5.4, 6.9Hz).

¹³C-NMR(CDCl₃)：20.30,20.42,20.58,61.94,67.29,74.12,114.78,157.13, 166.87,169.74,169.88,170.68.

HRMS (ESI, M+H⁺) calculated value C₁₂H₁₅O₉303.0716, experiment value 303.0708.

Embodiment 2 (3-O- benzyl -5, the synthesis of-O- acetyl group of 6- bis--ascorbic acid)

3-O- benzyl -5,-O- acetyl group of 6- bis--ascorbic acid (compound 5) are obtained by following operations.

(in formula, Ac represents acetyl group, and Bn represents benzyl, and Et represents ethyl.)

Compound 3 (9.32g, 30mmol) obtained by embodiment 1 is dissolved in 90mL dimethylformamides (DMF), Sodium hydrogensulfite (13.1g, 75mmol), potassium carbonate (7.45g, 54mmol) are added under argon gas atmosphere and is suspended.Added in room temperature Benzyl bromide a-bromotoluene (5.34mL, 45mmol), 20 minutes (generation of compound 4) is heated in oil bath in 60 DEG C.The generation of compound 4 is used TLC (ethyl acetate/hexane=1/1) confirms.

(compound 4)

¹H-NMR(CDCl₃)：2.04 (3H, s), 2.07 (3H, s), 2.22 (3H, s), 4.28 (1H, dd, J=7.0, 11.5Hz), 4.33 (1H, dd, J=6.0,11.5Hz), 4.91 (1H, d, J=1.5Hz), 5.15 (1H, d, J=11.1Hz), 5.26 (1H, d, J=11.1Hz), 5.43 (1H, ddd, J=1.5,6.0,7.0Hz), 7.33-7.42 (5H, m)

Room temperature is cooled to, 1- ethyl piperazidines (5.7mL, 45mmol) is added and is stirred 1 hour.Insoluble matter is carried out into sellaite Filtering, and filtrate is diluted with ethyl acetate, cleaned with 1N hydrochloric acid (1 time), saturated aqueous common salt (2 times), by organic layer sulfuric acid Magnesium is dried.Decompression is evaporated into oily residue silicagel column (ethyl acetate/hexane=1/2~1/1) purifying obtained by solvent, from And obtain the compound 5 (6.05g, 58%) of yellow oily.

(compound 5)

¹H-NMR(CDCl₃)：1.94 (3H, s), 2.04 (3H, s), 4.24 (1H, dd, J=6.8,11.6Hz), 4.33 (1H, Dd, J=5.4,11.6Hz), 4.84 (1H, d, J=2.4Hz), 5.37 (1H, ddd, J=2.4,5.4,6.8Hz), 5.42 (1H, D, J=11.6Hz), 5.45 (1H, d, J=11.6Hz), 6.35 (1H, bs), 7.35-7.43 (5H, m)

¹³C-NMR(CDCl₃)：20.39,20.59,62.05,67.56,73.48,74.47,119.50,128.39, 128.64,128.81,135.34,147.59,169.54,170.44,170.87.

HRMS (ESI, M+H⁺) calculated value C₁₇H₁₉O₈341.1080, experiment value 351.1076.

Embodiment 3 (synthesis of alpha-glucose pentaacetate)

D-Glucose pentaacetate (compound 7) is obtained by following operations.

(in formula, Ac represents acetyl group.)

Sodium acetate (1.14g, 13.9mmol) is suspended in acetic anhydride (25mL, 264mmol) and backflow is slowly heated.With 15 Minute periodically adds D-Glucose (mixture of α bodies/β bodies) (compound 6) (5.00g, 27.8mmol).After the completion of addition After being further heated to reflux 15 minutes, room temperature is cooled to.Decompression evaporates solvent after addition ice slag will react chilling.Will be resulting White solid residue is dissolved in ethyl acetate, is cleaned with saturated sodium bicarbonate water (1 time), saturated aqueous common salt (2 times).By organic layer Dried with magnesium sulfate and depressurized and evaporate solvent, so as to obtain the compound 7 (10.42g, 96%) of white solid.The life of compound 7 Confirm into NMR.

Embodiment 4 (synthesis of glucose tetracetate and its imine matrix)

D-Glucose tetracetate (compound 8) and its imine matrix are obtained by following operations.

(in formula, Ac represents acetyl group.)

The dichloromethane solution of the alpha-glucose pentaacetate (compound 7) (11.7g, 30mmol) obtained by embodiment 3 In after ice-cold lower addition 1- ethyl piperazidines (5.7mL, 45mmol) in (60mL), a Dinner is stirred at room temperature.Diluted with ethyl acetate And cleaned with 2N hydrochloric acid (1 time), saturated aqueous common salt (2 times).Organic layer is dried with magnesium sulfate, obtained by decompression evaporated into solvent Compound 8 (being confirmed to generate with TLC (ethyl acetate/hexane=1/1)) be dissolved in dichloromethane solution (60mL), in room temperature plus Enter potassium carbonate (2.07g, 15mmol) and stir a Dinner with tribromo-acetyl nitrile (6.45g, 45mmol).Filtering insoluble matter, filtrate is used Ethyl acetate dilutes and is cleaned with saturated aqueous common salt (2 times).Organic layer magnesium sulfate is dried and depressurized and evaporates solvent, so that To the imine matrix (compound 9) (mixture of 13.8g, 93%, α body and β bodies) of yellow oily.

(compound 9)

¹H-NMR(CDCl₃)：(due to 6 for isomers：1 mixture, so be main isomers) 2.01 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.07 (3H, s), 4.12 (1H, dd, J=1.9,12.4Hz), 4.20 (1H, ddd, J= 1.9,4.0,10.2Hz), 4.27 (1H, dd, J=4.0,12.3Hz), 5.13 (1H, dd, J=3.7,10.2Hz), 5.18 (1H, Dd, J=9.9,9.9Hz), 5.56 (1H, dd, J=9.9,9.9Hz), 6.55 (1H, d, J=3.7Hz), 8.69 (1H, s)

¹³C-NMR(CDCl₃)：20.40,20.54,20.63,61.53,67.73,69.67,69.82,69.96,92.85, 160.74,169.46,169.81,169.96,170.52.

Embodiment 5 (glycosylation)

The reaction (glycosylation) of compound 5 and compound 9 is carried out according to following operations.

By the dichloromethane solution of the compound 5 (protection ascorbic acid) (6.0g, 17mmol) obtained by embodiment 2 The dichloromethane solution (20mL) of the compound 9 (imine matrix) (11.0g, 22mmol) obtained by (20mL) and embodiment 4 is mixed Close, it is ice-cold it is lower addition boron trifluoride Anaesthetie Ether complex compound (122m L, 0.86mmol) and stir 2 hours.And, reaction is entered Capable thin-layer chromatography (TLC) (ethyl acetate/hexane=1/1) confirms.Add saturated sodium bicarbonate water (2mL) chilling and use acetic acid Ethyl ester dilutes, and is cleaned with saturated sodium bicarbonate water (2 times), saturated aqueous common salt (2 times).Organic layer is dried with magnesium sulfate, is being subtracted Methyl alcohol is added to evaporate solvent again in the oily residue that pressure evaporates obtained by solvent, so as to can obtain (the only β of compound 10 of solid Body).From recrystallizing methanol and obtain pale yellow crystals (9.22g, 80%).

(compound 10)

¹H-NMR(CDCl₃)：1.93 (3H, s), 1.997 (3H, s), 2.001 (3H, s), 2.015 (3H, s), 2.020 (3H, S), 2.11 (3H, s), 3.76 (1H, ddd, J=2.2,4.2,10.0Hz), 4.14 (1H, dd, J=2.0,12.2Hz), 4.21 (1H, dd, J=6.7,11.7Hz), 4.26-4.33 (2H, m), 4.84 (1H, d, J=2.2Hz), 5.12 (1H, dd, J=9.7, 9.7Hz), 5.16 (1H, dd, 8.2,9.4Hz), 5.25-5.36 (4H, m), 5.48 (1H, d, J=11.5Hz), 7.35 (5H, m)

¹³C-NMR(CDCl₃)：20.38,20.49,20.54,20.67,61.28,61.77,67.55,67.95,70.89, 72.16,72.31,73.75,74.39,98.71,118.11,128.43,128.65,128.94,134.73,157.67, 167.40,169.34,169.39,169.86,170.16,170.36.

HRMS (ESI, M+H⁺) calculated value C₃₁H₃₇O₁₇681.2031, experiment value 681.2034.

Embodiment 6 (debenzylation)

The debenzylation (hydrogenative decomposition) of compound 10 is carried out according to following operations.

(in formula, Ac represents acetyl group, and Bn represents benzyl.)

Tetrahydrofuran (T HF) solution of compound 10 (glucosides) (200mg, 0.29mmol) obtained by embodiment 5 Acetic acid 0.5mL and 10%Pd carbon (20mg) are added in (5mL), is stirred at room temperature under 1 hydrogen atmosphere of atmospheric pressure 3 hours. Catalyst and filtrate concentrated under reduced pressure are filtered off, so as to obtain compound 11.

(compound 11)

¹H-NMR(CDCl₃)：1.98 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.09 (3H, s), 2.096 (3H, s), 2.101 (3H, s), 3.85 (1H, m), 4.21-4.24 (2H, m), 4.26 (1H, dd, J=7.0,11.6Hz), 4.37 (1H, d, J =5.3,11.6Hz), and 4.91 (1H, d, J=2.7Hz), 5.01-5.10 (3H, m), 5.24 (1H, dd, J=9.2,9.2Hz), 5.39 (1H, m)

HRMS (ESI, M+H⁺) calculated value C₂₄H₃₁O₁₇591.1561, experiment value 591.1552.

Embodiment 7 (deacetylated)

The deacetylated of compound 11 is carried out according to following operations.

(in formula, Ac represents acetyl group, and Me represents methyl.)

1MNaOH is added dropwise in room temperature in the methanol solution (3mL) of the compound 11 (debenzylation body) obtained by embodiment 6 The aqueous solution (2.24mL) simultaneously stirs a Dinner.It is slowly added to cationic ion-exchange resin (Dow Chemical company systems, Dowex 50Wx8(H⁺Form)) and it is adjusted to pH3.Filtering resin is simultaneously cleaned with 50% methanol-water.After filtrate concentrated under reduced pressure removes methyl alcohol Freeze-drying is carried out, and by resulting residue for cationic ion-exchange resin (ORGANO company systems, Amberlite FPC3500(Na⁺Form)), wash with water.By eluent freeze-drying, so as to obtain faint yellow unbodied compound 12 (104mg, 98%).

(compound 12)

¹H-NMR (100mM phosphate buffers/D₂O, pH7.0)：3.38-3.58 (4H, m), 3.69-3.79 (3H, m), 3.86 (1H, m), 4.03 (1H, m), 4.56 (1H, d, 1.9Hz), 4.72 (1H, d, J=7.8Hz)

¹³C-NMR (100mM phosphate buffers/D₂O, pH7.0)：60.38,62.30,69.23,69.44,72.78, 75.37,76.12,78.39,103.13,114.60,176.92,179.27.

HRMS (ESI, M+H⁺) calculated value C₁₂H₁₈O₁₁Na 361.0747, experiment value 361.0722.

Embodiment 8 (not isolated compound 5 is glycosylation to carry out)

Isolated compound 5 is set to be reacted with compound 9 in embodiment 5, as follows, not isolated (purifying) is by compound 3 synthesis compounds 5 and for the reaction with compound 9.

Compound 3 (1.50g, 5.0mmol) obtained by embodiment 1 is dissolved in 8mL dimethylformamides (DMF), Potassium carbonate (1.25g, 9.0mmol) is added to be suspended under argon gas atmosphere.Benzyl bromide a-bromotoluene (0.90mL, 7.5mmol) is added in room temperature and stir Mix 1 hour.And then, add 1- ethyl piperazidines (1.2mL, 75mmol) in room temperature and stir 30 minutes.Insoluble matter is carried out into fluorine magnesium Stone is filtered, and filtrate is diluted with ethyl acetate, is cleaned with 1N hydrochloric acid (1 time), saturated aqueous common salt (2 times), by organic layer sulphur Sour magnesium is dried.The oily residue that decompression is evaporated obtained by solvent is dissolved in chloroform, the glass filtration for being coated with 15g silica gel Device, is eluted with ethyl acetate/hexane (1/1 mixed liquor, 100mL).Filtrate is concentrated, toluene will be added simultaneously to evaporate D MF Operation concentrated under reduced pressure is carried out in 55 DEG C to be repeated 3 times.

By the compound 9 obtained by the dichloromethane solution (2mL) of resulting residue and embodiment 4 (imine matrix Dichloromethane solution (2mL) mix, it is ice-cold it is lower addition boron trifluoride Anaesthetie Ether complex compound (30mL) and stir 1 hour.Plus Enter saturated sodium bicarbonate water (2mL) chilling and diluted with ethyl acetate, with saturated sodium bicarbonate water (2 times), saturated aqueous common salt (2 It is secondary) cleaning.Organic layer is dried with magnesium sulfate, methyl alcohol is added in the oily residue obtained by decompression evaporates solvent, so that To the compound 10 of pale yellow crystals (1.10g, 33%).By mother liquor concentrations again from methanol crystallization, chemical combination is further reclaimed Thing 10 (0.24g, 7%) (adds up to 1.24g, 40%).

In order to confirm also to can obtain glucosides using the sugar beyond glucose, and following experiment is carried out.

Embodiment 9 (synthesis of galactolipin tetracetate and its imine matrix)

By following operations, D- galactolipins tetracetate (compound 14) and its imine matrix are obtained.

(in formula, Ac represents acetyl group.)

In embodiment 3, D-Glucose is replaced using D- galactolipins, in addition, the second of galactolipin five is similarly obtained Acid esters (compound 13).

In the dichloromethane solution (20mL) of resulting galactolipin pentaacetate (compound 13) (2.0g, 5.0mmol) In in after ice-cold lower addition 1- ethyl piperazidines (760 μ L, 6.0mmol), a Dinner is stirred at room temperature.2N is diluted and used with ethyl acetate Hydrochloric acid (1 time), (2 times) cleanings of saturated aqueous common salt.Organic layer is dried with magnesium sulfate, decompression is evaporated the chemical combination obtained by solvent Thing 14 (being confirmed to generate with TLC (ethyl acetate/hexane=1/1)) is dissolved in dichloromethane solution (20mL), and carbon is added in room temperature Sour potassium (345mg, 2.5mmol) stirs a Dinner with tribromo-acetyl nitrile (1.1mL, 7.5mmol).Insoluble matter is filtered, filtrate is used Ethyl acetate dilutes and is cleaned with saturated aqueous common salt (2 times).Organic layer magnesium sulfate is dried and depressurized and evaporates solvent, so that To the imine matrix (compound 15) (1.98g, 80%, the mixture of α bodies/β bodies=about 2/1) of yellow oily.

(compound 15)

¹H-NMR(CDCl₃)：1.99-2.04 (9H, m), 2.16 (3Hx2/3, s), 2.18 (3Hx1/3, s), 4.04-4.45 (3H, m), 5.10-5.57 (3H, m), 5.83 (1Hx1/3, d, J=8.2Hz), 6.59 (1Hx2/3, d, J=3.4Hz), 8.66 (1Hx2/3, s), 8.71 (1Hx1/3, s)

Embodiment 10 (glycosylation)

The reaction (glycosylation) of compound 5 and compound 15 is carried out according to following operations.

By the dichloromethane solution of the compound 5 (protection ascorbic acid) (700mg, 2.0mmol) obtained by embodiment 2 The dichloromethane solution (10mL) of the compound 15 (imine matrix) (1.08g, 2.2mmo l) obtained by (10mL) and embodiment 9 Mixing, in it is ice-cold it is lower addition boron trifluoride Anaesthetie Ether complex compound (30mL, 0.1mmol) and stir 1 hour.And, reaction is entered Capable thin-layer chromatography (TLC) (methyl alcohol/chloroform=1/20) confirms.Add saturated sodium bicarbonate water (2mL) chilling and use acetic acid second Ester dilutes, and is cleaned with saturated sodium bicarbonate water (2 times), saturated aqueous common salt (2 times).Organic layer is dried with magnesium sulfate, will be depressurized Oily residue silica gel column chromatography (methyl alcohol/chloroform=1/20) purifying obtained by solvent is evaporated, so as to obtain pale yellow crystals The compound 16 of (1.10g, 81%).

(compound 16)

¹H-NMR(CDCl₃)：1.94 (3H, s), 2.00 (3H, s), 2.033 (3H, s), 2.036 (3H, s), 2.14 (3H, S), 2.15 (3H, s), 3.98 (1H, ddd, J=0.9,6.6,6.6Hz), 4.12 (1H, dd, J=6.5,11.3Hz), 4.19 (1H, dd, J=6.6,11.3Hz), 4.23 (1H, d d, J=6.8,11,6Hz), 4.32 (1H, dd, J=5.6,11.6Hz), 4.85 (1H, d, J=2.3Hz), 5.10 (1H, dd, J=3.5,10.3Hz), 5.27 (1H, d, J=8.0Hz), 5.31-5.38 (2H, m), 5.39 (1H, d, J=11.5Hz), 5.44 (1H, dd, J=0.9,3.3Hz), 5.52 (1H, d, J=11.5Hz), 5.39 (5H, m)

¹³C-NMR(CDCl₃)：20.43,20.51,20.62,20.86,60.83,61.86,66.75,67.62,68.44, 70.50,71.37,73.78,74.46,99.47,118.30,128.01,128.75,129.04,134.86,157.64, 167.51,169.41,169.87,169.97,170.04,170.25,170.30.

HRMS (ESI, M+H⁺) calculated value C₃₁H₃₇O₁₇681.2031, experiment value 681.2068.

Embodiment 11 (debenzylation)

The debenzylation (hydrogenative decomposition) of compound 16 is carried out according to following operations.

(in formula, Ac represents acetyl group, and Bn represents benzyl.)

Tetrahydrofuran (T HF) solution of compound 16 (glucosides) (1.10g, 1.6mmol) obtained by embodiment 10 Acetic acid 1mL and 10%Pd carbon (50mg) are added in (20mL), is stirred at room temperature under 1 hydrogen atmosphere of atmospheric pressure 2 hours.Filter Catalyst and filtrate concentrated under reduced pressure are gone, so as to obtain the compound 17 (840mg, 88%) of white-amorphous.

(compound 17)

¹H-NMR(CDCl₃)：2.00 (3H, s), 2.07 (3H, s), 2.09 (3H, s), 2.10 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 4.09 (1H, dd, J=5.8,6.4Hz), 4.19-4.23 (2H), 4.29 (1H, dd, J=6.8,11.6Hz), 4.40 (1H, dd, J=5.2,11.6Hz), 4.93 (1H, d, J=2.8Hz), 4.94 (1H, d, J=8.3Hz), 5.08 (1H, dd, J=3.4,10.5H z), and 5.34 (1H, dd, J=8.2,10.5Hz), 5.42-5.47 (2H, m), 8.76 (1H, bs)

¹³C-NMR(CDCl₃)：20.28,20.46,20.49,20.57,66.76,66.95,67.34,70.09,72.47, 73.40,101.33,119.11,156.91,166.57,169.68,169.72,169.78,170.35.

HRMS (ESI, M+H⁺) calculated value C₂₄H₃₁O₁₇591.1561, experiment value 591.1585.

Embodiment 12 (deacetylated)

The deacetylated of compound 17 is carried out according to following operations.

(in formula, Ac represents acetyl group, and Me represents methyl.)

The methanol solution (10mL) of the compound 17 (debenzylation body) (500mg, 0.85mmol) obtained by embodiment 11 In in room temperature be added dropwise the 1M NaOH aqueous solution (6.8mL) and stir a Dinner.It is slowly added to cationic ion-exchange resin (Dow Chemical company systems, Dowex 50Wx8 (H⁺Form)) and it is adjusted to pH3.Filtering resin is simultaneously cleaned with 50% methanol-water.Subtract Pressure concentration filtrate simultaneously carries out freeze-drying after removing methyl alcohol, so as to obtain faint yellow unbodied compound 18 (205mg, 71%).

(compound 18)

¹H-NMR (100mM phosphate buffers/D₂O, pH7.0)：3.62-3.82 (7H, m), 3.92 (1H, bs), 4.04 (1H, Dd, J=6.3,6.3Hz), 4.56 (1H, bs), 4.67 (1H, d, J=6.8Hz)

¹³C-NMR (100mM phosphate buffers/D₂O, pH7.0)：60.89,62.30,68.50,69.42,70.59, 72.47,75.44,78.38,103.73,114.73,176.95,179.16.

HRMS (ESI, M+H⁺) calculated value C₁₂H₁₉O₁₁339.0927, experiment value 361.0903.

Embodiment 13 (deacylation of the compound 2 carried out by potassium carbonate)

Compound 2 (345mg) obtained by embodiment 1 is dissolved in 7mL dimethylformamides (DMF), is added in room temperature Potassium carbonate (166mg, 1.2mmol) is simultaneously stirred 1.5 hours.Filter off insoluble matter simultaneously with ethyl acetate dilute, with 1N hydrochloric acid (1 time), (2 times) cleanings of saturated aqueous common salt.Organic layer magnesium sulfate is dried and depressurized and evaporates solvent, so as to obtain the compound 3 of oily (260mg, 86%).

Embodiment 14 (3 of compound 3 are glycosylation)

Carry out compound 33 as follows are glycosylation.

(in formula, Ac represents acetyl group, and Et represents ethyl.)

By the dichloromethane solution of the compound 3 (protection ascorbic acid) (350mg, 1.16mmol) obtained by embodiment 1 The dichloromethane solution (20mL) of the compound 9 (imine matrix) (680mg, 1.39mmol) obtained by (20mL) and embodiment 4 Mixing, it is ice-cold it is lower add boron trifluoride Anaesthetie Ether complex compound (18 μ L, 0.06mmol) dichloromethane solution 1mL and stir 2 hours.And, the carrying out of reaction is confirmed with thin-layer chromatography (TLC) (ethyl acetate/hexane=1/1).Add saturated sodium bicarbonate water (2mL) chilling is simultaneously diluted with ethyl acetate, is cleaned with saturated sodium bicarbonate water (2 times), saturated aqueous common salt (2 times).By organic layer Dried with magnesium sulfate, oily residue silica gel column chromatography (ethyl acetate/hexane=1/3) decompression evaporated obtained by solvent is pure Change, so as to obtain compound 19 (391mg, 62%).

(compound 19)

¹H-NMR(CDCl₃)：1.97 (3H, s), 1.98 (3H, s), 2.01 (3H, s), 2.02 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.25 (3H, s), 3.75 (1H, ddd, J=3.2,5.7,8.1Hz), 4.03 (1H, dd, J=2.3, 12.4Hz), 4.22-4.27 (3H, m), 4.93 (1H, d, J=1.4Hz), 5.04 (1H, dd, J=9.4,9.6Hz), 5.10 (1H, Dd, J=7.6,9.4Hz), 5.17-5.27 (3H, m)

¹³C-NMR(CDCl₃)：19.93,20.16,20.32,20.33,20.34.20.46,20.47,61.54,61.60, 66.32,67.80,70.06,71.64,72.54,73.91,98.21,115.99,155.15,165.49,166.72,169.15, 169.28,169.38,169.84,170.03,170.35.

Industrial applicability

In the present invention, can glucosides of the high efficiency manufacture using ascorbic acid as aglycone.In addition, can carry in the present invention It is provided as the useful novel glycoside such as vitamin C original.

Claims

1. a kind of compound, it is characterised in that represented by following formula (A),

In formula (A), R¹Represent acyl group.

2. a kind of manufacture method, it is characterised in that the compound represented by following formula (A ') is carried out into deacylation treatment using alkali, So as to manufacture the compound represented by the formula (A),

In formula (A '), R¹It is identical with described.

3. manufacture method according to claim 2, it is characterised in that alkali is secondary amine.

4. the manufacture method according to Claims 2 or 3, it is characterised in that alkali is the monosubstituted piperazines of N-.

5. the manufacture method according to any one of claim 2~4, it is characterised in that relative to represented by formula (A ') Compound uses the alkali of 0.8~1.2 molar equivalent.

6. a kind of manufacture method, it is the method for manufacturing compound represented by following formula (1) or derivatives thereof, it is characterised in that Including：

Glycosylation operation, makes the compound represented by following formula (B) be reacted with the compound represented by following formula (C), so as to obtain down Compound represented by formula (D)；And

Depart from operation, make the group R of the compound represented by formula (D)¹And group R²Depart from,

In formula (1), Su represents the group that glucosides hydroxyl is eliminated from sugar,

In formula (B), R²Represent arylmethyl, R¹It is identical with described,

In ASu-X (C) formula (C), ASu represents the group that glucosides hydroxyl is eliminated from the sugar being acylated, and X is represented and left away Group,

In formula (D), R¹、R²And ASu is identical with described.

7. manufacture method according to claim 6, it is characterised in that further include following operation：Make the formula (A) institute After the compound of expression and the reaction of arylmethyl halogen, deacylation treatment is carried out using alkali so as to manufacture the change represented by formula (B) Compound.

8. the manufacture method according to claim 6 or 7, it is characterised in that the compound represented by formula (C) is α bodies and β bodies Mixture.

9. the manufacture method according to any one of claim 6~8, it is characterised in that in formula (C), X is imido grpup.

10. the manufacture method according to any one of claim 6~9, it is characterised in that further include：

Deacylation treatment is carried out to the compound represented by following formula (C ') using alkali, so as to obtain the change represented by following formula (C ") The operation of compound；And

The compound represented by the formula (C ") is set to be reacted with the compound for corresponding to leaving group X, so as to obtain the formula (C) The operation of represented compound,

ASu-OR¹ (C′)

In formula (C '), R¹And ASu is identical with described,

ASu-OH (C″)

In formula (C "), ASu is identical with described.

11. manufacture methods according to claim 10, it is characterised in that the compound represented by formula (C ') is α bodies and β bodies Mixture.

12. manufacture method according to claim 10 or 11, it is characterised in that alkali is secondary amine.

13. manufacture method according to any one of claim 10~12, it is characterised in that alkali is the monosubstituted piperazines of N-.

14. manufacture method according to any one of claim 6~13, it is characterised in that in the presence of acid, make formula (B) compound represented by and the compound reaction represented by formula (C).

15. manufacture method according to any one of claim 6~14, it is characterised in that the compound represented by formula (B) Reaction with the compound represented by formula (C) is carried out under non-heated.

16. manufacture method according to any one of claim 6~15, it is characterised in that departing from operation includes：

Compound represented by formula (D) is carried out into hydrogenation treatment, so as to obtain the operation of the compound represented by following formula (E)；And

Compound represented by formula (E) is carried out into deacylation treatment, so as to obtain the operation of the compound represented by formula (1),

In formula (E), R¹And ASu is identical with described.

17. according to the described manufacture method of any one of claim 6~16, it is characterised in that sugar is monose.

18. according to the described manufacture method of any one of claim 6~17, it is characterised in that sugar is hexose.

19. a kind of compounds or derivatives thereof, it is characterised in that represented by following formula (1B).

Compound represented by a kind of 20. formulas (1) or derivatives thereof, it is characterised in that can be according in claim 6~18 Method described in any one is obtained.

21. a kind of compositions, it is characterised in that comprising compound described in claim 20 or derivatives thereof.

22. a kind of manufacture methods, it is characterised in that by the group of compound described in claim 20 or derivatives thereof and composition Into composition mixing, so that the composition described in manufacturing claims 21.