CN1417224A - Ginsenoside acid hydrolyzing process of preparing protopanoxadiol - Google Patents

Abstract

The present invention relates to a process of acid hydrolyzing ginsenoside to prepare protopanoxadiol. By means of adding protecting agent and inert gas, controlling reaction temperature and acid concentration and other techonlogical measures, the present invention solves the problems of ginsenoside in acid hydrolyzing condition, including being unstable, easy to destroy and easy to cyclize, and completes the process of direct acid hydrolyzing to prepare protopanoxadiol. The present invention makes it possible to prepare protopanoxadiol in simple process, low cost and great amount so as to meet the requirement of providing medicinal resource for anticancer and cardiac vascular disease resisting medicines.

Description

A kind of ginsenoside acid hydrolyzing prepares the method for protopanoxadiol

Technical field:

The present invention relates to prepare the method for protopanoxadiol (PPD), particularly relate to the acid hydrolysis preparation method by ginsenoside.

Background technology:

Studies show that ginsenoside PPD has antitumor and immunoregulation effect, microcirculation improvement effect, regulates digestive function, calms the nerves, multiple biological activitys such as anti-ageing, anti-anxiety, prevention of digestive tract ulcers, raising quality of life, memory and learning capacity.

The bavin field is held two people such as (Chem Pharm Bull 1966,14 (6) 595) and once was equipped with protopanoxadiol with the concentrated hydrochloric acid legal system, and be specially: 3g diol type saponin is dissolved in the 15ml concentrated hydrochloric acid, sticky oil sealing liquid level, ambient temperature overnight; Reaction solution is poured in the frozen water into collecting precipitation; Precipitation through washing, dry, use extracted with diethyl ether; Concentrated ethyl ether solution gets the crystalloid precipitation, is deposited in recrystallization in the benzene, obtains colourless crystallization I 250mg (crystallization I is the hydrogenchloride affixture of PPD, glucoside unit yield 18.14%).With 9g crystallization I, 10g butyl alcohol-tert potassium, 500ml butyl alcohol-tert and 800ml methyl-sulphoxide mixing, 75 ℃ were reacted 3 hours; Behind the reaction solution dilute with water, extracted with diethyl ether; Diethyl ether solution through washing, dry, concentrate colourless precipitation, be deposited in that recrystallization gets 5.8g PPD (glucoside unit yield 69.47%) in the ethyl acetate.Glucoside unit total recovery 12.6%.Tanaka (Chem Pharm Bull 1973,21 (12) 2702) etc. the oxidation degradation method of human is: 500mg ginsenoside, sodium periodate 1.69g are dissolved in methyl alcohol-alcohol-water (20ml-33.3ml-100ml), 2 ℃ were stirred 120 hours down, filter, filtrate adding 50ml water and vacuum concentration are to 150ml; Water-saturated n-butanol extraction concentrated solution, evaporated in vacuo, propyl carbinol liquid is received resistates.Resistates, 1.25g potassium hydroxide and 17.5ml water add in ethanol-methyl alcohol (2.5ml-5ml), the following 95 ℃ of reactions of nitrogen protection 4 hours; Reaction solution in 2N sulfuric acid and after use extracted with diethyl ether; Diethyl ether solution is through washing, dry, evaporated in vacuo, and silica gel column chromatography on the resistates gets PPD 14.2mg (glucoside unit yield 6.82%) with benzene-acetone (3: 1) wash-out.The common feature of these two kinds of methods is: preparation condition is violent, harsh, and glucoside unit yield is low.

And be the panoxadiol of side chain cyclisation, but not protopanoxadiol by the product of the direct acid hydrolysis gained of diol type ginsenoside.The bavin field holds two, and (Chem Pharm Bull 1974,22 (2): 421; Chem PharmBull 14 (6), and 595,1983; Tetrahedron Letters 3:207,1965), the slope intrinsic is (medicine will 95 then, 1456,1975), permanent male (the medicine will 94 of difficult ripple, 252,1974), (Chem PharmBull 20 (6): 1204 for Tanaka, 1972), (Chem Pharm Bull 20 (6): 1204 for Han, 1972), rattan Tian Luyi people such as (medicine will 82:1634,1962) has studied acid-hydrolyzed condition, and the presentation of results ginsenoside is through directly acid hydrolysis, only obtain second ring product (panoxadiol and triol), and protopanoxadiol and Protopanaxatriol one cross the property product, and acid hydrolysis causes the destruction of saponin, and panoxatriol is more unstable than panoxadiol.Thereby the simple and easy to do production method of protopanoxadiol receives much attention, and does not see as yet so far to complete successfully the report that acid hydrolysis prepares ginsenoside glucoside unit's protopanoxadiol and Protopanaxatriol.

The technology contents of invention:

Unstable under acidolysis condition in order to solve ginsenoside, the problem of destructible, the invention provides a kind of method that can prepare protopanoxadiol simply, conveniently, low-costly and in high volume by the direct acid hydrolysis of ginsenoside, comprise acid hydrolysis and collect step, it is characterized in that: the hydrolysis of ginsenoside is carried out under the protection of inert gas in containing protectant organic solvent acidic aqueous solution; Wherein

The consumption of ginsenoside is 5～100g/L;

The compound that protective material is xitix, sodium bisulfite, the gallic acid reductibility is strong, consumption is 2～10g/l;

Organic solvent is a kind of or its mixture of methyl alcohol, ethanol, propyl alcohol, butanols, acetone, dioxane, methyl-sulphoxide, pyridine, acetonitrile, and concentration range is 50～90%V/V;

Acid is a kind of of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, a gifblaar poison, trichoroacetic acid(TCA), two dichloro acetic acid, Monochloro Acetic Acid, citric acid, oxysuccinic acid, oxalic acid, Glacial acetic acid, and concentration range is 0.1～10mol/L;

Protective gas is meant rare gas element such as nitrogen, carbonic acid gas, helium, argon gas, neon etc.;

Hydrolysis temperature is 30～80 ℃, 2 hours～10 days time.

Genseng saponin acid hydrolysis of the present invention prepares in the method for protopanoxadiol, and raw materials used ginsenoside purity is necessary 〉=and 90%, can not contain triol type saponin in the diol type saponin, material concentration is 5～100g/L.

Genseng saponin acid hydrolysis of the present invention prepares in the method for protopanoxadiol, and acid can be selected a wider range for use, but nitric acid is big to saponin destruction, should not use; The factors such as difficulty or ease, cost and quality of comprehensive hydrolysis time, yield, art breading, best with hydrochloric acid and sulfuric acid; Acid concentration is relevant with hydrolysis temperature with the kind (acid strong and weak) of acid, and if acid concentration is greater than optimum point, and the destructiveness of saponin increases and increases with acid concentration, and if acid concentration will make the hydrolysis time prolongation less than optimum point; Optimum temperuture is relevant with the kind and the concentration of acid, and if temperature is greater than optimum point, and the destructiveness of saponin increases and increases with temperature; If temperature will make hydrolysis time prolong less than optimum point.When using hydrochloric acid or sulfuric acid, concentration is 1～4mol/L, and hydrolysis temperature is 37 ± 3 ℃.When using phosphoric acid, concentration is 7～9mol/L, and hydrolysis temperature is 50～80 ℃.

Genseng saponin acid hydrolysis of the present invention prepares in the method for protopanoxadiol, and the effect of organic solvent is to guarantee that intermediate product is in dissolved state, and hydrolysis reaction is carried out thoroughly.It is good taking all factors into consideration with methyl alcohol and ethanol.Organic solvent difference, concentration are also different.As propyl carbinol water saturated solution, acetone is with 50% the aqueous solution, and methyl alcohol is with 70～90% the aqueous solution, and ethanol is with 60～80% the aqueous solution.

Genseng saponin acid hydrolysis of the present invention prepares in the method for protopanoxadiol, and protective material is best with the xitix, and consumption is 3～6g/L.

Genseng saponin acid hydrolysis of the present invention prepares in the method for protopanoxadiol, and final collection process is:

Reaction solution after the hydrolysis neutralizes with alkali, and neutralizing agent is alkali-metal oxide compound or its oxyhydroxide, and working concentration is 1～2mol/L, must guarantee local temperature≤20 ℃;

To low boiling point organic solvent with decompression steam, the route of chloroform extraction; Route to high boiling organic solvent dilute with water, collecting precipitation.

Genseng saponin acid hydrolysis of the present invention prepares the method for protopanoxadiol, the hydrolysising condition gentleness, thus solved ginsenoside unstable easy ruined problem under acidolysis condition, and technology is simple and convenient, cost is low, the rate of recovery is high, quality is good.Use PPD content 〉=90% of present method preparation, glucoside unit yield 〉=80%.

Embodiment:

Embodiment 1

5g panoxadiol type saponin, to be dissolved in the 1000ml concentration of hydrochloric acid be 2mol/L, contain xitix 5g, concentration is in 80% the methanol aqueous solution, under 37 ℃ of temperature, nitrogen protection condition, to stir hydrolysis 7 days; With 2mol/L sodium hydroxide neutralization reaction liquid, decompression steams methyl alcohol; Use the chloroform extraction reaction solution; It is 1.85g that chloroform extraction gets PPD through washing, anhydrous sodium sulfate drying, evaporate to dryness collection resistates.Through check PPD content 〉=90%, glucoside unit yield 〉=80%.

Embodiment 2

5g panoxadiol type saponin, to be dissolved in the 1000ml sulfuric acid concentration be 2mol/L, contain xitix 5g, concentration is in 80% the methanol aqueous solution, under 37 ℃ of temperature, nitrogen protection condition, to stir hydrolysis 7 days; With 2mol/L sodium hydroxide neutralization reaction liquid, decompression steams methyl alcohol; Use the chloroform extraction reaction solution; It is 1.80g that chloroform extraction gets PPD through washing, anhydrous sodium sulfate drying, evaporate to dryness collection resistates.

Embodiment 3

5g panoxadiol type saponin, to be dissolved in the 1000ml phosphoric acid concentration be 9mol/L, contain xitix 5g, concentration is in 80% the methanol aqueous solution, under 37 ℃ of temperature, nitrogen protection condition, to stir hydrolysis 7 days; With 2mol/L sodium hydroxide neutralization reaction liquid, decompression steams methyl alcohol; Use the chloroform extraction reaction solution; It is 1.95g that chloroform extraction gets PPD through washing, anhydrous sodium sulfate drying, evaporate to dryness collection resistates.

Embodiment 4

5g panoxadiol type saponin, to be dissolved in the 1000ml concentration of hydrochloric acid be 2mol/L, contain sodium bisulfite 10g, concentration is in 80% the methanol aqueous solution, under 37 ℃ of temperature, carbon dioxide gas protective condition, to stir hydrolysis 7 days; With 2mol/L sodium hydroxide neutralization reaction liquid, decompression steams methyl alcohol; Use the chloroform extraction reaction solution; It is 1.78g that chloroform extraction gets PPD through washing, anhydrous sodium sulfate drying, evaporate to dryness collection resistates.Through check PPD content 〉=90%.

Embodiment 5

5g panoxadiol type saponin, to be dissolved in the 1000ml concentration of hydrochloric acid be 2mol/L, contain xitix 5g, concentration is in 60% aqueous ethanolic solution, under 42 ℃ of temperature, nitrogen protection condition, stirs hydrolysis 7 days; With 2mol/L potassium hydroxide neutralization reaction liquid, decompression steams ethanol; Use the chloroform extraction reaction solution; It is 1.84g that chloroform extraction gets PPD through washing, anhydrous sodium sulfate drying, evaporate to dryness collection resistates.Through check PPD content 〉=90%.

Embodiment 6

5g panoxadiol type saponin, to be dissolved in the 1000ml concentration of hydrochloric acid be 2mol/L, contain in the solution of xitix 5g, 50% methyl-sulphoxide, under 37 ℃ of temperature, nitrogen protection condition, stirs hydrolysis 7 days; With 2mol/L sodium hydroxide neutralization reaction liquid; It is 1.75g that dilute with water, collecting precipitation get PPD.Through check PPD content 〉=90%.

Claims (10)

1, a kind of ginsenoside acid hydrolyzing prepares the method for protopanoxadiol, comprises acid hydrolysis and collects step, and it is characterized in that: the hydrolysis of ginsenoside is carried out under the protection of inert gas in containing protectant organic solvent acidic aqueous solution; Wherein

The consumption of ginsenoside is 5～100g/L;

The compound that protective material is xitix, sodium bisulfite, the gallic acid reductibility is strong, consumption is 2～10g/L;

Organic solvent is a kind of or its mixture of methyl alcohol, ethanol, propyl alcohol, butanols, acetone, dioxane, methyl-sulphoxide, pyridine, acetonitrile, and concentration range is 50～90%V/V;

Acid is a kind of of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, a gifblaar poison, trichoroacetic acid(TCA), dichloro acetic acid, Monochloro Acetic Acid, citric acid, oxysuccinic acid, oxalic acid, Glacial acetic acid, and concentration range is 0.1～10mol/L;

Protective gas is meant rare gas element such as nitrogen, carbonic acid gas, helium, argon gas, neon etc.;

Hydrolysis temperature is 30～80 ℃, 2 hours～10 days time.

2, preparing the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: raw materials used ginsenoside purity is necessary 〉=and 90%, can not contain triol type saponin in the diol type saponin, material concentration is 5～100g/L.

3, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when using hydrochloric acid or sulfuric acid, concentration is 1～4mol/L, and hydrolysis temperature is 37 ± 3 ℃.

4, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when using phosphoric acid, concentration is 7～9mol/L, and hydrolysis temperature is 50～80 ℃.

5, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when organic solvent uses propyl carbinol, the water saturated solution.

6, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when organic solvent uses acetone, the aqueous solution with 50%.

7, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when organic solvent uses methyl alcohol, the aqueous solution with 70～90%.

8, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when organic solvent uses ethanol, the aqueous solution with 60～80%.

9, prepare the method for protopanoxadiol according to the described ginsenoside acid hydrolyzing of claim 1, it is characterized in that: when protective material was xitix, consumption was 3～6g/L.

10, the method for preparing protopanoxadiol according to the described ginsenoside acid hydrolyzing of one of claim 1～9 is characterized in that collection process is:

Reaction solution after the hydrolysis neutralizes with alkali, and neutralizing agent is alkali-metal oxide compound or its oxyhydroxide, and working concentration is 1～2mol/L, must guarantee local temperature≤20 ℃;

To low boiling point organic solvent with decompression steam, the route of chloroform extraction; Route to high boiling organic solvent dilute with water, collecting precipitation.