CN106749453A - A kind of method of chemical synthesis Calycosin-7-O-BETA-D-glucoside - Google Patents

A kind of method of chemical synthesis Calycosin-7-O-BETA-D-glucoside Download PDF

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CN106749453A
CN106749453A CN201510821795.7A CN201510821795A CN106749453A CN 106749453 A CN106749453 A CN 106749453A CN 201510821795 A CN201510821795 A CN 201510821795A CN 106749453 A CN106749453 A CN 106749453A
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compounds
formula
group
calycosin
combination
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黄成钢
李志雄
张玉城
高羽
谢阳
田小亭
胡培
陈明苍
孙兆林
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Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention relates to a kind of preparation method of Calycosin-7-O-BETA-D-glucoside, comprise the following steps：(as initiation material, 3 ', 7- -4 '-methoxy isoflavones of dihydroxy are obtained, diacetyl product 3 ', 7- -4 '-methoxy isoflavones of diacetoxy are then obtained by acetylization reaction using resorcinol and 3- hydroxyl -4- methoxyphenylacetic acids；The protection group that selectivity must be removed on 7 hydroxyls obtains 7- hydroxyl -4 '-methoxy isoflavones of -3 '-acetoxyl group；7 upper hydroxyl generation glycosidic bonds are obtained into 3 '-acetoxyl group -4 '-substitution base the glucosides of methoxy isoflavone -7-O- β-D- four, finally by complete hydrolysis, deprotection base obtains Calycosin-7-O-BETA-D-glucoside, i.e. calycosin-7-O-β-D-glycoside.The present invention develops the chemical synthesis process of Calycosin-7-O-BETA-D-glucoside, and the synthetic route raw material is easy to get, and cost is relatively low, and reaction condition is gentle.

Description

A kind of method of chemical synthesis Calycosin-7-O-BETA-D-glucoside
Technical field
The invention belongs to organic synthesis field, more particularly to a kind of side of synthesis of natural product Calycosin-7-O-BETA-D-glucoside Method.
Background technology
Vital myocarditis (Viral myocarditis, VMC) is mainly by coxsackie B race (Coxsackievirus ) etc. B virus invades heart, causes focal or diffusivity cardiac interstitium inflammatory to go out and myofibrosis cordis, bad Dead or dissolving disease, what is had can change with pericardium or endocarditis.Myocardial damage, expansion can be caused Property cardiomyopathy, cardiac dysfunction, arrhythmia cordis, heart failure and systemic symptom, or even dead.In crowd The incidence of disease of VMC is in rapid increase trend, is the one of the main reasons of sudden death of being grown up for less than 40 years old, only secondary In acute myocardial infarction.In recent years, the incidence of disease of VMC also increases quickly in China, especially in children and green grass or young crops In the prime of life, it has also become the new common disease of infringement human health.
So far, it is no matter international or domestic, the medicine and therapy of vital myocarditis all lack of targeted. At present still based on synthesis and supporting treatment.Conventional medicine has anti-virus formulation, immunomodulator, antioxygen Agent, adrenaline retarding agent, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker and cardiac nutrition medicine etc..Big portion Dividing medicine has obvious toxic and side effect, and on the other hand, some medicines are equal in zoopery and clinic Desired curative effect certainly is not obtained, substantial amounts of clinical data is also lacked at present.
The Radix Astragali is a kind of conventional Chinese medicine, sweet, warm in nature, promoted blood circulation with Yiqiyangyuan, strengthening vital QI to eliminate pathogenic factors, nourishing heart, Effect of invigorating spleen to remove dampness, can be used for that the motive is deficient, blood-vessel obstructive.Clinically, the Radix Astragali can not only be used for individually The disease is treated in medication, such as astragalus injection, also often with other drug matching compound applications, such as the stilbene winter chin or cheek pit of the stomach Take liquid.Patent (the patent No.：ZL200510110641.3) report from the Radix Astragali extraction purification prepare effectively into Divide calycosin -7- oxygen-β-D- glucopyranosides (Calycosin-7-O- β-D-glucoside), abbreviation hair stamen Isoflavone aglycone, proves the compound with suppression Coxsackie virus (Coxsackievirus) and controls through pharmacological testing Vital myocarditis is treated, but content of the Calycosin-7-O-BETA-D-glucoside in medicinal material is very low.Through to Inner Mongol, Gansu, river 14 batches of practical measurements of Milkvetch Root of real estate such as north and Shanxi, Calycosin-7-O-BETA-D-glucoside average content therein is only There are 0.0327% (about 3/10000ths), highest 0.0536%, minimum only 0.0116%.Thus, Mao Ruiyi is carried out Flavonoid glycoside it is fully synthetic, can save medicinal material, reduce drug cost.
The content of the invention
The present situation low it is an object of the invention to be directed to Calycosin-7-O-BETA-D-glucoside content, there is provided one kind has raw material easy , the preparation method that technique is simple and direct, yield is higher.
In the first aspect of the present invention, there is provided a kind of preparation method of Calycosin-7-O-BETA-D-glucoside, including step：
A () is reacted formula S3 compounds and acetylation reagent in atent solvent, so as to form formula S4 compounds；
B formula S4 compounds in the presence of a base, are carried out deprotection reaction, so that shape by () in atent solvent Accepted way of doing sth S5 compounds；
C () in the presence of a base, formula S5 compounds and glycosylation reagents is reacted in atent solvent, So as to form formula S6 compounds；
In formula, each R is each independently selected from the following group：Acetyl group, benzyl acyl group and benzyl；
D formula S6 compounds in the presence of a base, are carried out deprotection reaction by () in atent solvent, so that de- Except protection group, the Calycosin-7-O-BETA-D-glucoside that formed formula TM is represented, i.e. calycosin-7-O-β-D-glycoside：
In another preference, in step (a), described atent solvent is selected from the group：Dichloromethane, chloroform, Tetrahydrofuran or its combination.
In another preference, in step (a), described acetylation reagent is selected from the group：Chloroacetic chloride, acetic acid Acid anhydride or its combination.
In another preference, in step (a), described acetylation reagent is acetic anhydride.
In another preference, in step (a), acetylization reaction is carried out in the presence of a catalyst.
In another preference, in step (a), described catalyst is selected from the group：Triethylamine, diisopropyl Ethamine, piperidines, pyridine, DMAP, the carbon -7- alkene of 1,8- diazabicylos 11 or its combination.
In another preference, in step (a), described catalyst is triethylamine.
In another preference, in step (a), reaction temperature be -20 DEG C -60 DEG C, preferably 0 DEG C -40 DEG C, More preferably 0 DEG C~5 DEG C.
In another preference, in step (a), the reaction time is 0.1-72h, preferably 0.5-24h.
In another preference, in step (b), described atent solvent is selected from the group：DCM, chloroform, MeOH, ethanol, DMF, DMSO, NMP, acetone, acetonitrile or its combination.
In another preference, in step (b), described atent solvent is DMF.
In another preference, in step (b), described alkali is selected from the group：LiOH、NaOH、KOH、 Cs2CO3、Na2CO3、K2CO3Or its combination.
In another preference, in step (b), described alkali is K2CO3。
In another preference, in step (b), reaction temperature is 0 DEG C -80 DEG C, preferably 10 DEG C~30 DEG C.
In another preference, in step (b), the reaction time is 0.1-72h, preferably 0.5-24h.
In another preference, in step (c), described atent solvent is selected from the group：Water, chloroform, dichloro Methane, 1,2- dichloroethanes, methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol, THF, 1,4- dioxane, DMF, DMSO, acetone or its combination.
In another preference, in step (c), described atent solvent is water and the mixed solvent of chloroform.
In another preference, in step (c), in described water and the mixed solvent of chloroform, water and chloroform The ratio between volume is (0.8-1.5)：(2-3), preferably 1：2.5.
In another preference, in step (c), described glycosylation reagents are selected from the group：The acetyl of 2,3,4,6- tetra- Epoxide-α-D- bromos glucopyranose, the benzoyl-α-D- bromos glucopyranoses of 2,3,4,6- tetra-, four acetyl Base glucosyl group tri- chloroacetimidate, four benzoyl glucosyl group tri- chloroacetimidates, tetrabenzyl Portugal Grape glycosyl tri- chloroacetimidate or its combination.
In another preference, in step (c), described glycosylation reagents are 2,3,4,6- tetra- acetoxyl group-α-D- Bromo glucopyranose.
In another preference, in step (c), acetylization reaction is carried out in the presence of a catalyst.
In another preference, in step (c), described catalyst is selected from the group：Benzyltriethylammoinium chloride, TBAB, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecane Base trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18- crown ethers -6,15- crown ethers -5 or its combination.
In another preference, in step (c), described catalyst is TBAB.
In another preference, in step (c), described alkali is selected from the group：Cs2CO3、Na2CO3、K2CO3、 Or its combination.
In another preference, in step (c), described alkali is K2CO3。
In another preference, in step (c), reaction temperature is 20 DEG C -80 DEG C, preferably 40 DEG C~50 DEG C.
In another preference, in step (c), the reaction time is 0.1-72h, preferably 0.5-24h.
In another preference, in step (d), described deprotection reaction is hydrolysis.
In another preference, in step (d), described atent solvent is selected from the group：Methyl alcohol, ethanol, four Hydrogen furans, 1,4- dioxane, water or its combination.
In another preference, in step (d), described alkali is selected from the group：LiOH、NaOH、KOH、 NaHCO3、Cs2CO3、Na2CO3、K2CO3, sodium methoxide, caustic alcohol, sodium tert-butoxide or its combination.
In another preference, in step (d), described alkali is sodium methoxide.
In another preference, in step (d), reaction temperature be -20 DEG C -80 DEG C, preferably 0 DEG C~50 DEG C, More preferably 0 DEG C~5 DEG C.
In another preference, the reaction time is 0.1-72h, preferably 0.5-24h.
In another preference, methods described also includes, the formula S3 compounds before step (a) The step of：
(a0) in atent solvent, formula S1 compounds and S2 compounds are carried out into acylation reaction and ring closure reaction, So as to form formula S3 compounds
In another preference, described acylation reaction and ring closure reaction are successive reaction.
In another preference, in step (a0), described atent solvent is selected from the group：DMF、DMSO、 NMP, acetone, Isosorbide-5-Nitrae dioxane, acetonitrile, THF.
In another preference, in step (a0), described atent solvent is DMF.
In another preference, in step (a0), acylation reaction and ring closure reaction are carried out in the presence of a catalyst.
In another preference, in step (a0), described catalyst is selected from the group：Polyphosphoric acids, first sulphur Acid, TFMS, H2SO4、AlCl3、BF3·Et2O or its combination.
In another preference, in step (a0), described catalyst is BF3·Et2O。
In another preference, in step (a0), described ring closure reaction reagent is DMF and PCl5It is anti- Answer product.
In another preference, in step (a0), reaction temperature be 60 DEG C~120 DEG C, preferably 70 DEG C~ 90℃。
In another preference, in step (a0), the reaction time is 0.1-72h, preferably 0.5-24h.
In the second aspect of the present invention, there is provided a kind of intermediate, the intermediate is formula S5 compounds：
In the third aspect of the present invention, there is provided a kind of preparation side of the intermediate described in second aspect present invention Method, including step：
A () is reacted formula S3 compounds and acetylation reagent in atent solvent, so as to form formula S4 compounds；
B formula S4 compounds in the presence of a base, are carried out deprotection reaction, so that shape by () in atent solvent Accepted way of doing sth S5 compounds：
In the present invention,
Formula S1 compounds, chemical entitled resorcinol；
Formula S2 compounds, chemical entitled 3- hydroxyls -4- methoxyphenylacetic acids；
Formula S3 compounds are chromocor compound, chemistry entitled 3 ', 7- -4 '-methoxy isoflavones of dihydroxy；
Formula S4 compounds, chemistry entitled 3 ', 7- -4 '-methoxy isoflavones of diacetoxy；
Formula S5 compounds, the entitled 3 '-acetoxyl group -4 of chemistry '-substitution base the Portugals of methoxy isoflavone -7-O- β-D- four Polyglycoside；
Formula S6 compounds, the entitled 3 '-acetoxyl group -4 of chemistry '-substitution base the Portugals of methoxy isoflavone -7-O- β-D- four Polyglycoside, wherein substitution base is selected from the group：Acetyl group, benzyl acyl group, benzyl.
Present invention employs following main technical scheme：The Mao Ruiyi that a kind of chemical synthesis formula TM is represented is yellow The method of ketoside, its preparation process is reacted including 5 steps：
(1) using resorcinol (formula S1 compounds) and 3- hydroxyl -4- methoxyphenylacetic acids (formula S2 compounds) as rising Beginning raw material, the chromocor compound that formula S3 is represented, i.e. 3 ', 7- bis- are obtained by acylation reaction and ring closure reaction Hydroxyl -4 '-methoxy isoflavone,
(2) two hydroxyls on formula S3 compounds aromatic ring obtain diacetyl product, i.e. formula by acetylization reaction S4 compounds, i.e. 3 ', 7- -4 '-methoxy isoflavones of diacetoxy；
(3) protection group that formula S4 compounds must be selectively removed on 7 hydroxyls obtains formula S5 compounds, i.e. 7- hydroxyls Base -3 '-acetoxyl group -4 '-methoxy isoflavone；
(4) the 7 hydroxyls generation glycosidic bond on formula S5 compounds phenyl ring obtains formula S6 compounds, i.e. 3 '-acetyl oxygen Base -4 '-substitution base the glucosides of methoxy isoflavone -7-O- β-D- four, wherein R is selected from acetyl group, benzyl acyl Base, benzyl；
(5) by hydrolysis, deprotection base obtains target compound, i.e., the hair that formula TM is represented to formula S6 compounds Stamen isoflavone aglycone, i.e. calycosin-7-O-β-D-glycoside, its synthetic route are as follows：
In another preference, the feature in the preparation process includes：
A in () first step, the reaction for preparing flavones S3 for resorcinol is two step successive reactions, road used Lewis acid catalyst is selected from polyphosphoric acids, methanesulfonic acid, TFMS, H2SO4、AlCl3、BF3·Et2O, Or the catalyst combination of the arbitrary proportion of any two kinds and the above；Solvent be selected from DMF, DMSO, NMP, Acetone, Isosorbide-5-Nitrae dioxane, acetonitrile, THF, or the mixing of the arbitrary proportion of any two kinds and the above are molten Agent, reaction temperature is 60 DEG C~120 DEG C；DMF/PCl is selected from the reagent of ring-closure reaction later5,
In (b) the 3rd step, for 7 selectively removings of the Acetyl Protecting Groups of hydroxyl of compound shown in formula S4 Alkali be selected from LiOH, NaOH, KOH, Cs2CO3、Na2CO3、K2CO3, solvent is selected from DCM, chlorine Imitative, MeOH, ethanol, DMF, DMSO, NMP, acetone, acetonitrile, or any two kinds and more than Arbitrary proportion catalyst combination, reaction temperature be 0 DEG C~80 DEG C,
C in () the 4th step, the glycosylation reagents for formula S5 compounds are selected from 2,3,4,6- tetra- acetoxyl group-α-D- Bromo glucopyranose, 2,3,4,6- tetra- benzoyl-α-D- bromos glucopyranoses, tetra-acetylated Portugal Grape glycosyl tri- chloroacetimidate, four benzoyl glucosyl group tri- chloroacetimidates, tetra-O-benzyl glucopyranose Base tri- chloroacetimidate, phase transfer catalyst is selected from benzyltriethylammoinium chloride, TBAB, four Butyl ammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC, Tetradecyl trimethyl ammonium chloride, 18- crown ethers -6,15- crown ether -5, alkali are selected from Cs2CO3、Na2CO3、K2CO3, Solvent be selected from water, chloroform, dichloromethane, 1,2- dichloroethanes, methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol, THF, Isosorbide-5-Nitrae-dioxane, DMF, DMSO, acetone, or any two kinds and the above arbitrary proportion Mixed solvent, reaction temperature is 20 DEG C~80 DEG C.
The above-mentioned method for preparing calycosin, its feature is further that one is for resorcinol The catalyst for preparing the reaction of flavones S3 is selected from BF3·Et2O, solvent is selected from DMF；Two is for formula S4 chemical combination The alkali of thing is selected from K2CO3, selected from DMF, temperature is 10 DEG C~30 DEG C to solvent；Three is for formula S5 compounds Glycosylation reagents be selected from 2,3,4,6- tetra- acetoxyl group-α-D- bromo glucopyranoses, phase transfer catalysis (PTC) Agent is selected from TBAB, and alkali is selected from K2CO3, solvent is selected from water and the mixed solvent of chloroform, reaction temperature It is 40 DEG C~50 DEG C to spend, and further, the ratio of water and chloroform is water/chloroform=1/2.5.
In addition, the feature of this method also has, and the acetylation reagent for formula S3 compounds is selected from acetyl Chlorine or acetic anhydride；Catalyst used is selected from triethylamine, diisopropylethylamine, piperidines, pyridine, 4- bis- Methylamino pyridine, the carbon -7- alkene of 1,8- diazabicylos 11, or any two kinds and the above arbitrary proportion Catalyst combination；Reaction temperature is -20 DEG C~60 DEG C.Further, for the second of formula S3 compounds Acylating reagent is selected from acetic anhydride, and catalyst used is selected from triethylamine, and reaction temperature is 0 DEG C~5 DEG C.
Finally, for formula S6 compounds hydrolysis reagent be selected from LiOH, NaOH, KOH, NaHCO3、Cs2CO3、Na2CO3、K2CO3, sodium methoxide, caustic alcohol, sodium tert-butoxide, or arbitrarily The alkali combination of the arbitrary proportion of two kinds and the above；Reaction temperature is -20 DEG C~80 DEG C.Further, it is used for The alkali of the hydrolysis of formula S6 compounds is selected from sodium methoxide, and reaction temperature is 0 DEG C~5 DEG C.
In sum, the method for preparing calycosin can be summarized as follows：
Specific embodiment
In the examples below, only to illustrate the inventive method in the way of provide section Example of the invention. However, these embodiments limit the scope of the present invention never in any form, it is right under concept thereof of the invention The simple modifications of preparation method of the present invention belong to the scope of protection of present invention.It is, with reference to listed Illustrated embodiments are described during the present invention, it should be understood that it is not intended to limit the invention to those embodiment party Case.Conversely, this invention is intended to include all of change, improvement and the equivalent form of value.Those skilled in the art's meeting Recognize with those similar or equivalent many methods described herein and material, they can be used for realize The present invention.
In the embodiment being described below, unless otherwise indicated, all temperature are given with degree Celsius.Unless Explanation in addition, reagent is purchased or customized from commercial supplier, such as traditional Chinese medicines, Aladdin, TCI, Sigma Etc..
Embodiment 1
The preparation of flavones S3 (- 4 '-methoxy isoflavone of 3 ', 7- dihydroxy)
Resorcinol 3mmol and substituted phenylacetic acid 3mmol are dissolved in the boron trifluoride ether solution of new steaming In 2mL, 85~90 DEG C, 6~10h of magnetic agitation (TLC display raw materials disappear substantially), cooling are heated to To 10 DEG C, dimethylformamide 5mL is dropwise added dropwise, obtains mixture I.
Vilsmeyer-Haack reagents：Dimethylformamide 8.1mL is cooled to 10 DEG C, pentachloro- is dividedly in some parts Change phosphorus 5mmol, be heated to 55 DEG C, magnetic agitation reaction 1h obtains pale red or yellow mixture II.
At room temperature, mixtures II is added in mixture I in batches in 30min, after 3h is stirred at room temperature, by this Reaction solution is poured into hydrochloric acid (0.1mol/L) 30mL of methanolizing, is heated to 70 DEG C, constant temperature 50min, cooling Stand.After vacuum distillation, washed with water 150mL, be then extracted with ethyl acetate 150mL × 3 time, then use water 150mL × 2 time are washed, ethyl acetate is spin-dried for and (is contemplated that in a large amount of preparation and acetic acid ethyl acetate extract is filtered into silicon It is spin-dried for again after diatomaceous earth, has removed some not tolerant impurity), it is suspended with a small amount of ethanol and precipitates dissolving partial pigment, Centrifugal filtration, takes precipitation and uses ethanol hot recrystallization under nitrogen protection.At present with silicagel column with MeOH:CH2Cl2=1:35 separate for solvent, obtain product 1.6mmol, yield 50%~60%.(GRACE VisionHT C18HL (250mm x 4.6mm, 5um), eluant, eluent water/acetonitrile=65：35, tR=6.1min, Purity 92% (ELSD, normalization method))
1H NMR(500MHz,DMSO)δ10.87(s,1H),9.08(s,1H),8.29(s,1H),7.97(d,J =8.7Hz, 1H), 7.05 (s, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 3.78 (s, 3H).
13C NMR(126MHz,DMSO)δ174.8,162.5,157.5,153.3,147.6,146.0,127.5, 124.8,123.5,119.9,116.8,116.4,115.2,112.0,102.2,55.7。
HRMS(ESI):m/z[M-H]-calcd forC16H11O5 -：283.0612；found：283.0607.
Embodiment 2
The preparation of S4 (- 4 '-methoxy isoflavone of 3 ', 7- diacetoxy)
Calycosin aglycon 7mmol is dissolved with anhydrous methylene chloride 900mL at 0 DEG C, acetic anhydride 7 is added ML is simultaneously added dropwise triethylamine 10mL, reacts 12h and is gradually increased to room temperature.After reaction terminates, water 1000mL is added Reaction is quenched.Organic phase is separated, water is mutually extracted with dichloromethane 900mL, merge organic phase and with anhydrous Na2SO4Dry, decompression screws out solvent.Pigment is washed away with a small amount of ethanol or ethyl acetate, white product 6 is obtained Mmol, yield 90~95%.
Embodiment 3
The preparation of S5 (- 4 '-methoxy isoflavone of 7- -3 '-acetoxyl groups of hydroxyl)
Room temperature is by 7,3 '-diacetoxy calycosin 0.35mmol DCM/MeOH (1:1) 3ml dissolvings, Anhydrous K is added under ice bath2CO30.05mmol, is slowly warmed to room temperature reaction 8h.Neutrality is dropped to 6% hydrochloric acid, Add ethyl acetate extraction, washing, anhydrous Na2SO4Dry, decompression screws out solvent, and silica gel column chromatography can Obtain target compound, yield 40~50%.
(GRACE VisionHT C18HL (250mm x 4.6mm, 5um), eluant, eluent water/acetonitrile =60:40, tR=7.9min, purity 98% (ELSD, normalization method))
1H NMR (500MHz, DMSO) δ 10.84 (s, 1H), 8.39 (s, 1H), 7.97 (d, J=8.8Hz, 1H), 7.47 (dd, J=8.5,2.1Hz, 1H), 7.36 (d, J=2.1Hz, 1H), 7.18 (d, J=8.6Hz, 1H), 6.95 (dd, J= 8.8,2.2Hz, 1H), 6.88 (d, J=2.1Hz, 1H), 3.80 (s, 3H), 2.27 (s, 3H).
13C NMR(126MHz,DMSO)δ174.41,168.49,162.69,157.42,153.59,150.56,138.87, 127.30,127.17,124.54,123.20,122.18,116.55,115.30,112.49,102.16,55.90,20.41。
HRMS(ESI)：m/z[M-H]-calcd for C18H13O6 -：325.0718；found： 325.0750。
Embodiment 4
The preparation of S6 (3 '-acetoxyl group -4 '-acetoxyl group the glucosides of methoxy isoflavone -7-O- β-D- four)
By 3 '-acetoxyl group calycosin 120mg, tetra-n-butyl ammonium bromide 16.7mg and 2,3,4,6- Four acetoxyl group-α-D- bromo glucopyranose 410mg, are dissolved in DMF/ acetone (1:1) in 30mL, add K2CO31.45g, under nitrogen protection, room temperature reaction 24h.Organic phase is spin-dried for, water mutually uses CH2Cl290mL 2 extractions of x, merge organic phase and use anhydrous Na2SO4Dry, decompression screws out solvent.Silica gel column chromatography, can Obtain target compound, yield 50~60%.
Embodiment 5
The synthesis of final product Calycosin-7-O-BETA-D-glucoside (calycosin-7-O-β-D-glycoside)
The tetra-acetylated glucose Calycosin-7-O-BETA-D-glucoside 2mmol of 3 '-acetoxyl group -7-O- β-D- are dissolved in methyl alcohol 15mL, after frozen water is cooled to 0 DEG C, adds the methanol solution 15mL of freshly prepd 0.1mol/L sodium methoxides, Continue to stir 2h at being kept for 0 DEG C.After reaction terminates, 732 appropriate cationic ion-exchange resins are added to neutralize, Filtering, filtrate obtains crude product after vacuum distillation.Pigment is washed away with a small amount of methyl alcohol, white product 1.9mmol is obtained, Yield 85~95%.(GRACE VisionHT C18HL (250mm x 4.6mm, 5um), wash-out Agent water/acetonitrile=80：20, tR=6.1min, purity 97% (ELSD, normalization method))
1H NMR (500 MHz, DMSO) δ 9.03 (s, 1H), 8.39 (s, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 7.15 (dd, J=8.9,2.2 Hz, 1H), 7.07 (s, 1H), 6.97 (s, 2H), 5.45 (d, J=4.6 Hz, 1H), 5.16 (d, J=4.4 Hz, 1H), 5.11 (d, J=7.3 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 4.62 (t, J=5.4 Hz, 1H), 3.79 (s, 3H), 3.77-3.12 (m, 6H).
13C NMR(126 MHz,DMSO)δ174.7,161.4,157.0,153.6,147.6,146.1,127.0, 124.5,123.6,119.7,118.5,116.4,115.6,112.0,103.4,100.0,77.2,76.5,73.2,69.6, 60.7,55.7。
HRMS(ESI)：m/z[M-H]-calcd for C22H21O10 -：445.1140；found：445.1111.

Claims (10)

1. a kind of preparation method of Calycosin-7-O-BETA-D-glucoside, it is characterised in that including step：
A () is reacted formula S3 compounds and acetylation reagent in atent solvent, so as to form formula S4 compounds；
B formula S4 compounds in the presence of a base, are carried out deprotection reaction, so that shape by () in atent solvent Accepted way of doing sth S5 compounds；
C () in the presence of a base, formula S5 compounds and glycosylation reagents is reacted in atent solvent, So as to form formula S6 compounds；
In formula, each R is each independently selected from the following group：Acetyl group, benzyl acyl group and benzyl；
D formula S6 compounds in the presence of a base, are carried out deprotection reaction by () in atent solvent, so that de- Except protection group, the Calycosin-7-O-BETA-D-glucoside that formed formula TM is represented, i.e. calycosin-7-O-β-D-glycoside：
2. the method for claim 1, it is characterised in that in step (a), described acetylation reagent It is selected from the group：Chloroacetic chloride, acetic anhydride or its combination.
3. the method for claim 1, it is characterised in that in step (a), described catalyst is selected from The following group：Triethylamine, diisopropylethylamine, piperidines, pyridine, DMAP, 1,8- diazabicylos 11 carbon -7- alkene or its combination.
4. the method for claim 1, it is characterised in that in step (b), described atent solvent choosing From the following group：DCM, chloroform, MeOH, ethanol, DMF, DMSO, NMP, acetone, acetonitrile or Its combination.
5. the method for claim 1, it is characterised in that in step (b), described alkali is selected from the group： LiOH、NaOH、KOH、Cs2CO3、Na2CO3、K2CO3Or its combination.
6. the method for claim 1, it is characterised in that in step (b), reaction temperature is 0 DEG C -80 DEG C, preferably 10 DEG C~30 DEG C, and/or
In step (b), the reaction time is 0.1-72h, preferably 0.5-24h.
7. the method for claim 1, it is characterised in that in step (c), described glycosylation reagents It is selected from the group：Acetoxyl group-α-D- bromos the glucopyranoses of 2,3,4,6- tetra-, the benzoyl-α-D- of 2,3,4,6- tetra- Bromo glucopyranose, tetra-acetylated glucosyl group tri- chloroacetimidate, four benzoyl glucosyl groups three Chloroethene imide ester, tetra-O-benzyl glucopyranose base tri- chloroacetimidate or its combination.
8. the method for claim 1, it is characterised in that in step (d), described alkali is selected from the group： LiOH、NaOH、KOH、NaHCO3、Cs2CO3、Na2CO3、K2CO3, sodium methoxide, caustic alcohol, Sodium tert-butoxide or its combination.
9. a kind of intermediate, it is characterised in that the intermediate is formula S5 compounds：
10. the preparation method of the intermediate described in a kind of claim 2, it is characterised in that including step：
A () is reacted formula S3 compounds and acetylation reagent in atent solvent, so as to form formula S4 compounds；
B formula S4 compounds in the presence of a base, are carried out deprotection reaction, so that shape by () in atent solvent Accepted way of doing sth S5 compounds：
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