CN1249075C - Method for preparing true aglycone of ginseng saponin - Google Patents
Method for preparing true aglycone of ginseng saponin Download PDFInfo
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- CN1249075C CN1249075C CN 02144773 CN02144773A CN1249075C CN 1249075 C CN1249075 C CN 1249075C CN 02144773 CN02144773 CN 02144773 CN 02144773 A CN02144773 A CN 02144773A CN 1249075 C CN1249075 C CN 1249075C
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- ppd
- ppt
- ginsenoside
- protopanoxadiol
- saponin
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Abstract
The present invention relates to a method for preparing ginsenoside true aglycone 20(R)-PPD, 20(S)-PPD, 20(R)-PPT and 20(S)-PPT from various ginsenosides, particularly from low polar ginsenoside raw materials whose 3 position hydroxyl, 6 position hydroxyl or 20 position hydroxyl is free or from intermediates. The method comprises raw material glycosyl removing, product separation and purification, etc.; the method of removing glycosyl comprises unit operation such as catalytic pyrolysis, selective dewatering, acidolysis, alkaline hydrolysis, etc.; a conventional method is used for separation and purification; different technological lines are formed according to the difficulty degree of final product separation, unit operation of the combination and the operation order; different raw materials can be treated by using identical or different technological lines, and identical raw materials can be treated by using different technological lines. The present invention overcomes the defects of intense and harsh reaction condition, serious aglycone destroy, low yield, etc. and meets the requirements of preparing 20(R)-PPD, 20(S)-PPD, 20(R)-PPT and 20(S)-PPT; the technological process used is simple, reliable, flexible and convenient, and the ginsenoside true aglycone can be prepared in quantity.
Description
Technical field:
The present invention relates to be prepared by multiple ginsenoside protopanoxadiol and Protopanaxatriol's method, particularly relating to 3,6 or the low polarity ginsenosides of 20 hydroxyl free is the preparation method of raw material or intermediate product.
Background technology:
For late period dispersivity and transitivity malignant tumour, pharmacological agent is indispensable therapy.In the decades in past, the cell toxicity medicament therapy is that chemotherapy has obvious development and progress, becomes the backbone of tumor pharmacother.But the chemotherapeutics at present clinical has following defective: 1, endogenous resistance; 2, acquired resistance is embodied in structure and the diverse medicine of mechanism of action is produced resistance, claims multidrug resistance (being called for short MDR).At present, spendable clinically reversal agent of drug resistance has verapamil (Verapamil) and cyclosporin A (Cyclosporin A), relevant studies show that, they truly have reversion MDR and increase the effect of chemotherapy drug susceptibility, but owing to serious toxic side effect, the clinical use of these medicines is severely limited regrettably.Therefore, find and exploitation low toxicity or nontoxic antitumor drug or its sensitizer extremely urgent.
The natural ginseng saponin(e is difficult to be absorbed, but is the original shape that the natural ginseng saponin(e is brought into play its drug effect by low polarity saponin, aglycon or both derivatives that natural saponin(e is transformed.Recently, the antitumor research of low polarity saponin and derivative thereof is very active, has found that they when having multiple antitumor action, have no side effect substantially.Wherein, find that the true aglycon protopanoxadiol of ginsenoside (protopanaxadiol is called for short PPD) and Protopanaxatriol's (protopanaxatriol is called for short PPT) have remarkable reversing tumor MDR, its mechanism of action is different from the anti-MDR medicine in the present research, has great exploitation and is worth.
Hold in the bavin field, and second-class (Chem Pharm Bull 1966,14 (6) 595) prepares intermediate product with concentrated hydrochloric acid ambient temperature overnight hydrolysis diol type ginsenoside---the hydrogenchloride affixture (aglycon yield 18.14%) of protopanoxadiol; Intermediate product mixes elimination hydrogenchloride at butyl alcohol-tert potassium, butyl alcohol-tert and methyl-sulphoxide and obtains protopanoxadiol (aglycon yield 69.47%).Aglycon total recovery 12.6%.Oxidative degradation+the basic hydrolysis of Tanaka humans such as (Chem Pharm Bull1973,21 (12) 2702) prepares PPD, and the aglycon yield is 6.82%.The common feature of these two kinds of methods is: preparation condition is violent, harsh, and the aglycon yield is low, all is unsuitable for industrial preparation.
The technology contents of invention:
The objective of the invention is to solve the key issue of present PPD and PPT preparation, for its preparation provides method simple, reliable, convenient and that can prepare in enormous quantities.
In the method provided by the present invention, raw material can be following any saponin monomer, or the mixture of multiple monomer saponin:
Natural ginseng saponin(e: Rb
1, Rb
2, Rb
3, Rc, Rd, Rg
1, Re and Rf etc.;
3 hydroxyl free diol type ginsenosides: 20-O-β-D-glucose-20 (S)-protopanoxadiol, [20-O-β-D-glucopyranosyl-20 (S)-protopanaxadiol, be called for short C-K], 20-O-β-D-wood sugar-β-D-glucose-20 (S)-protopanoxadiol [20-O-β-D-xylopyranosyl (1 → 6)-β-D-glucopyranosyl-20 (S)-protopanaxadiol, be called for short Mx], 20-O-α-L-arabinose (1 → 6)-β-D-glucose-20 (S)-protopanoxadiol [20-O-α-L-arabinopyranosyl (1 → 6)-β-D-glucopyranosyl-20 (S)-protopanaxadiol, be called for short C-Y] and 20-O-α-L-arabinose (1 → 6)-β-D-glucose-20 (S)-protopanoxadiol [20-O-α-L-arabinofuranosyl (1 → 6)-β-D-glucopyranosyl-20 (S)-protopanaxadiol is called for short Mc].
6 hydroxyl free triol type ginsenosides: [20-O-β-D-glucopyranosyl-20 (S)-protopanaxatriol is called for short F to 20-O-β-D-glucose-20 (S)-protopanoxadiol
1].
20 hydroxyl free diol type ginsenosides: ginsenoside 20-(R)-Rg
3, 20-(S)-Rg
3, 20-(R)-Rh
2And 20-(S)-Rh
2
20 hydroxyl free triol type ginsenosides: ginsenoside 20-(R)-Rg
2, 20-(S)-Rg
2, 20-(R)-Rh
1And 20-(S)-Rh
1
In the method provided by the present invention, the glycosyl that the preparation target product relates to raw material is removed and step such as product separation and purification.The method of removing glycosyl has catalyse pyrolysis, acidolysis and alkaline hydrolysis.
In the method provided by the present invention, catalyse pyrolysis refers to that the raw material ginsenoside is catalyzer with acid, steams 0.5～10 hour through 110～180 ℃ of high temperature.The transformation efficiency of catalyse pyrolysis＞95% is mainly used in and removes 20 O glycosyls.Four primary products (20-(R)-Rg of diol type saponin(e
3, 20-(S)-Rg
3, Δ
20 (21)-ginsenoside and Δ
20 (22)-Ginsenoside) respectively accounts for 1/4 basically.
In the method provided by the present invention, the used acid of acidolysis is mineral acid or organic acid (as sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid etc.); Acidolysis is carried out in organic solvent (as methyl alcohol, ethanol, dioxane, the methyl-sulphoxide etc.) aqueous solution, and acid concentration is 3%～10%, and material quantity is 1%～10% of an aqueous solutions of organic solvent; Acidolysis temperature is 40～90 ℃; Acidolysis in anaerobic, have in the encloses container of whipping appts and carry out.Acidolysis has two kinds of using method: (1) low-temperature and low-concentration acidolysis (20～40 ℃, 15～20 hours) is used to remove 20 O glycosyls.During hydrolysis diol type natural ginseng saponin(e, four primary product (20-(R)-Rg
3, 20-(S)-Rg
3, Δ
20 (21)-ginsenoside and Δ
20 (22)-Ginsenoside) 20-(R) in-Rg
3, Δ
20 (22)-ginsenoside is preponderated, and product aglycon total recovery is lower than catalyse pyrolysis (being about 70%).This method mild condition can not be removed 3 O or 6 O glycosyls.(2) high temperature lower concentration acidolysis (60～80 ℃, 6～8 hours) is used to remove Δ
20 (21,22)3 O or 6 O glycosyls on-the ginsenoside.Because of under this method condition, side chain cyclisation generates panoxadiol or panoxatriol, and this method can not be used to remove 20 O glycosyls on 3 hydroxyls and 6 the hydroxyl free ginsenosides.
In the method provided by the present invention, the used alkali of alkaline hydrolysis is basic metal (as sodium Metal 99.5, potassium metal), alkali metal alcoholate (as sodium ethylate, butyl alcohol-tert potassium) or alkali metal hydroxide (as sodium hydroxide, potassium hydroxide): alkaline hydrolysis carries out in low-carbon alcohol (as ethanol, propyl carbinol, butyl alcohol-tert etc.), alkali concn is 5%～50%, and material quantity is 1%～10% of a low-carbon alcohol; Alkaline hydrolysis pressure is 0.1～3KPa, and the alkaline hydrolysis temperature is 100～300 ℃; Alkaline hydrolysis in anaerobic, have in the encloses container of whipping appts and carry out.The 20-O-glycosidic link is higher than 3 O and 6 O glycosidic links to the reactive behavior of alkaline hydrolysis, and the retention of configuration of 20-C is constant in the alkaline hydrolysis process.Alkaline hydrolysis is mainly used in 20 O glycosyls removing on 3 hydroxyls and 6 the hydroxyl free ginsenosides, and when being used to remove 3 O and 6 O glycosidic links, reaction conditions is violent, feed stock conversion low (＜30%), and saponin(e destroys serious.
Method provided by the present invention comprises unit operation such as catalyse pyrolysis, acidolysis, alkaline hydrolysis and separation and purification, how much forms different operational paths with order by what assembled unit was operated; According to the needs of purpose product, same materials or different material all can use operational path not of the same race.The selection of starting raw material and operational path depends on that raw material separates the relative difficulty or ease that prepare with the product separation and purification, and the simplicity of operational path.
In the method provided by the present invention, the natural ginseng saponin(e can have two approach to enter flow process: enzymolysis is 3 hydroxyls or 6 hydroxyl free saponin(es; Catalyse pyrolysis or acidolysis are 20 hydroxyl free saponin(es, Δ
20 (21)-and Δ
20 (22)-low polarity ginsenoside.
In the method provided by the present invention, 3 hydroxyl free diol type saponin(es are mixture [20-(R)-PPD, 20-(S)-PPD, Δ through the product of catalyse pyrolysis or low temperature acidolysis
20 (21)-PPD and Δ
20 (22)-PPD], mixture obtains 20-(R)-PPD and 20-(S)-pure product of PPD after chromatogram and conventional the separation; 6 hydroxyl free triol type saponin(es are through handling 20-(R)-PPT and 20-(the S)-pure product of PPT of obtaining with method.
In the method provided by the present invention, 3 hydroxyl free diol type ginsenosides are raw material saponin(e aglycon 20 (S)-PPD through the product of alkaline hydrolysis, obtain the pure product of 20 (S)-PPD after routine is separated; 6 hydroxyl free triol type saponin(es are through handling 20-(the S)-pure product of PPT that obtain with method.
In the method provided by the present invention, 20 hydroxyl free ginsenosides are raw material saponin(e aglycon PPD or PPT through the product of alkaline hydrolysis, and basic hydrolysis does not influence the configuration of 20 carbon atoms of aglycon; Monomer saponin alkaline hydrolysis product separates through routine, or mixing raw material alkaline hydrolysis product through routine separate with chromatogram after promptly obtain the identical PPD of configuration or the pure product of PPT of 20 carbon atoms with the raw material saponin(e.
Method provided by the present invention, be equally applicable to from ginsenoside other triterpenoid saponin in addition [as arasaponin (Notoginsenosides), gypenoside (Gypenosides), Vietnam's ginsenoside (Vietnamese ginsenosides), betulafolien etetraol (Betulafolientetraol), betulafolien etetraol A (Betulafolientetraol A), birch leaf alkene pentol (Betulafolienpentaol), dammarenediol (Dammarenediol), Da Ma-24-alkene-3 β, 20-glycol-3-acetic ester (Dammar-24-ene--3 β, 20-diol-3-acetate), hydroxydammarenone (Hydroxyldammarenone), bandit's ladder wooden ketone (Octillone) difficult to understand, Dipterocarpus pilosus epoxydiol (Kapurol), Dipterocarpus pilosus epoxy alcohol ketone (Kapurone), dryobalanone (Dryobalanone), dipterocarpol acid (Dryobalanonoloic acid) etc.] the true aglycon of the corresponding triterpene of preparation.
Condition was violent, harsh when the present invention had avoided the true aglycon of existing preparation, and aglycon destroys big, the defective that yield is low.For true aglycon preparation provides simple, reliable, convenient, and the method that can prepare in enormous quantities.Use method provided by the present invention, feed stock conversion height (raw material aglycon transformation efficiency 〉=96%), the aglycon rate of recovery are higher than existing method (Dan Pin 〉=40%, total recovery 〉=80%), quality controllable.
Embodiment:
Embodiment 1: enzymolysis and catalyse pyrolysis or acidolysis or alkaline hydrolysis preparation
Diol type ginsenoside (100g) in the notoginseng haulm and helicase (17g) are dissolved in phosphoric acid-citrate buffer solution 6400mL, and (pH4.5, ionic strength is 0.001molL
-1, contain 10% ethanol) in, hydrolysis is 1 day in 40 ℃ of water-baths; The centrifugal reaction solution collecting precipitation, water is made suspension liquid with throw out, ethyl acetate extraction (100mL * 5), combined ethyl acetate liquid, decompression obtains resistates 46g after removing ethyl acetate, and detecting through HPLC is the mixture of C-K and Mx.
A), resistates (46g) is behind catalyse pyrolysis, pyrolysis product is made aqueous suspension, ethyl acetate extraction (100mL * 5), combined ethyl acetate liquid, after decompression removes ethyl acetate, collect resistates, last silica gel column chromatography (eluent is petrol ether/ethyl acetate=5/1) separation and purification obtains 20-(S)-PPD (6.8g) and 20-(R)-PPD (5.3g).
B), resistates (46g) is dissolved in the propyl carbinol (100mL) and obtains A liquid, sodium Metal 99.5 (5g) is dissolved in the propyl carbinol (200mL), obtains B liquid after the cooling, A liquid and B liquid is mixed in the autoclave 120 ℃ of stirring reactions 1 hour.After the cooling stopped reaction, washed reaction liquid is to neutral, and decompression removes propyl carbinol, and resistates obtains 20-(S)-PPD (24.8g) through silica gel column chromatography (eluent is n-hexane/ethyl acetate=4/1) separation and purification.
Embodiment 2:
Diol type ginsenoside (100g), (48g detects through HPLC, is mainly 20-(R)-Rg to obtain white solid after catalyse pyrolysis and purification on adsorbent resins
3, 20-(S)-Rg
3, Rg
5And Rk
1).White solid is dissolved in the propyl carbinol (100mL) and obtains A liquid.Sodium Metal 99.5 (5g) is dissolved in the propyl carbinol (200mL), obtains B liquid after the cooling, A liquid and B liquid is mixed in the autoclave 120 ℃ of stirring reactions 3 hours.After the cooling stopped reaction, washed reaction liquid is to neutral, and decompression removes propyl carbinol, and resistates obtains 20-(S)-PPD (3.8g) and 20-(R)-PPD (2.3g) through silica gel column chromatography (eluent is n-hexane/ethyl acetate=4/1) separation and purification.
Embodiment 3
Triol type ginsenoside (100g) is handled by embodiment 1 method and is obtained:
A), 20-(S)-PPT (7.2g) and 20-(R)-PPT (6.3g); B), 20-(S)-PPT (26.6g).
Embodiment 4
Triol type ginsenoside (100g) is handled by embodiment 2 methods and is obtained 20-(S)-(4.5g) and 20-(R)-PPT (2.8g).
Claims (2)
1, a kind ofly prepares protopanoxadiol from low polarity ginsenoside and be called for short the method that PPD and/or Protopanaxatriol are called for short PPT, it is characterized in that: will hang down the polarity ginsenoside and remove glycosyl and obtain target product through purification procedures;
Described low polarity ginsenoside is any saponin monomer in the following low polarity ginsenoside, or the mixture of multiple saponin(e:
(1) 3 hydroxyl free diol type ginsenoside
20-O-β-D-glucose-20 (S)-protopanoxadiol, abbreviation C-K,
20-O-β-D-wood sugar-β-D-glucose-20 (S)-protopanoxadiol, abbreviation Mx,
20-O-α-L-arabinose (1 → 6)-β-D-glucose-20 (S)-protopanoxadiol, abbreviation C-Y,
20-O-α-L-arabinose (1 → 6)-β-D-glucose-20 (S)-protopanoxadiol is called for short Mc;
(2) 6 hydroxyl free triol type ginsenosides
20-O-β-D-glucose-20 (S)-protopanoxadiol is called for short F
1
Described method of removing glycosyl is a catalyse pyrolysis, and catalyse pyrolysis refers to that with low polarity ginsenoside be catalyzer with acid, steams 0.5～10 hour through 110～180 ℃ of high temperature.
2, prepare the method for PPD and/or PPT according to claim 1 is described from low polarity ginsenoside, it is characterized in that: 3 hydroxyl free diol type saponin(es are 20-(R)-PPD, 20-(S)-PPD, Δ through the product of catalyse pyrolysis
20 (21)-PPD and Δ
20 (22)The mixture of-PPD, 6 hydroxyl free triol type saponin(es are 20-(R)-PPT, 20-(S)-PPT, Δ through the product of catalyse pyrolysis
20 (21)-PPT and Δ
20 (22)The mixture of-PPT; Pyrolysis product obtains 20-(R)-PPD, 20-(S)-PPD, 20-(R)-PPT and 20-(S)-pure product of PPT after routine separation and chromatographic separation.
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|---|---|---|---|
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| CN101244104B (en) * | 2008-03-24 | 2011-05-25 | 中国科学院长春应用化学研究所 | Method for increasing rare saponin content in panax ginseng total saponin extract |
| CN101768619A (en) * | 2010-02-10 | 2010-07-07 | 华侨大学 | Method for preparing rare ginsenoside IH-901 with Rd as substrate |
| CN101805388A (en) * | 2010-04-14 | 2010-08-18 | 吉林大学 | Method for preparing compounds with neuronal protection activity by using panaxatriol |
| CN105218611B (en) * | 2015-08-31 | 2017-05-17 | 金凤燮 | Preparation method of 20th carbon hydroxyl dehydrated ginseng rare saponin and aglycone |
| CN107200768B (en) * | 2017-06-15 | 2018-05-01 | 吉林大学 | A kind of method for preparing phoenix celestial being terpene tetrol aglycon |
| CN107376902B (en) * | 2017-08-04 | 2019-12-24 | 于泽 | Mn-Ce composite oxide and application thereof in selective catalytic preparation of rare-ended-alkene ginsenoside |
| CN109134579A (en) * | 2018-07-23 | 2019-01-04 | 上海交通大学 | Hypoglycemic low polarity triterpene glucoside group and preparation method thereof |
| CN114702540A (en) * | 2022-01-23 | 2022-07-05 | 吉林农业大学 | Novel preparation method and application of compound 20(S) -protopanaxadiol PPD |
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