CN106008644A - Method for converting panaxatriol saponin to produce ginsenoside Rk3 on a large scale - Google Patents
Method for converting panaxatriol saponin to produce ginsenoside Rk3 on a large scale Download PDFInfo
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- CN106008644A CN106008644A CN201610346366.3A CN201610346366A CN106008644A CN 106008644 A CN106008644 A CN 106008644A CN 201610346366 A CN201610346366 A CN 201610346366A CN 106008644 A CN106008644 A CN 106008644A
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Abstract
The invention discloses a method for converting panaxatriol saponin to produce ginsenoside Rk3 on a large scale. The method comprises the following steps: dissolving the panaxatriol saponin in de-ionized water in a fermentation tank, introducing N2 for protection, performing online sterilization, adding a solution of an organic acid and a catalytic amount of a heteropoly acid HxYW12O40 nH2O catalyst of a Keggin structure, Y being selected from P, Si, Fe or Zn, x being 3 or 4 and n being a positive integer of 0 to 30, performing constant temperature and constant pressure oriented conversion reaction under the protection of N2, and finally collecting and purifying a reaction product to obtain high-purity ginsenoside Rk3, wherein the online sterilization condition is 121 DEG C, and is kept for 20min, N2 is introduced for protection before online sterilization, and the added organic acid is one or a combination of more of a lactic acid, a malic acid, a citric acid, an alpha-ketoglutaric acid, a succinic acid, an alpha-crotonic acid and a pyruvic acid. According to the method, a process is simple, easy and less in side reaction, and the product is high in purity and easy to industrially produce.
Description
Technical field
The present invention relates to a kind of method utilizing triol group ginsenoside to convert production 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside on a large scale, belong to biological chemical field.
Background technology
The complex chemical composition of Radix Ginseng, containing cellulose, saponin, volatile oil, saccharide, protein, vitamin etc..Modern medicine and pharmaceutical research prove, ginsenoside is the principle active component of Radix Ginseng, and it can represent the major physiological activity of Radix Ginseng.Ginsenoside (ginsenoside) is the principle active component of Radix Ginseng, the most it has been investigated that ginsenoside already more than 50 kinds.Wherein recent researches is at most and relevant to apoptosis of tumor cells for ginsenoside Rg3 and ginsenoside Rh2.Both ginsenosides have certain anti-tumor activity, the most nontoxic to normal cell, have Synergistic attenuation effect with other chemotherapeutics (such as cisplatin, gefitinib etc.) use in conjunction.Ginsenoside plays antitumor action by modulate tumor cell generation cycle, Cell differentiation inducing activity and apoptosis.Tumor cell induction being divided into normal cell and is conducive to controlling tumor development, inducing apoptosis of tumour cell forms apoptotic body after making cytoclasis, does not cause surrounding tissue inflammatory reaction.
Ginsenoside can be obtained by plant extract such as Araliaceae Radix Ginseng, Radix Panacis Quinquefolii, Radix Notoginseng, Panax pseudoginseng Wall., Panax zingiberensis C. Y. Wu. Et Feng．, Rhizoma Panacis Japonicis.Japanese scholars Beichuan merit extracts from Radix Ginseng successively in beginning in 1980 and has obtained ginsenoside 20 (R)-Rg3, ginsenoside Rh2, and finds there is kinds of tumor cells obvious inhibitory action.nullFrom the point of view of the current result of study to ginseng saponin series compound，The glucosides carried on the natural ginsenoside in plant extract typically has 3 ~ 5，And along with the minimizing of glucosides quantity，Active anticancer gradually strengthens，We associate the ginsenoside of multiple removal some glucosides such as 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside all can good anticancer effect，Through our retrieval to life saponin Patents，Inquire patent CN 103193846 A and invent a kind of 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside and the preparation method of Ginsenoside Rh4 .'s cis-trans-isomer，Relate to the separation method of 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside and Ginsenoside Rh4 .'s cis-trans-isomer，Yield is also only up to milligram level level，Not yet it is found to have and converts large-scale production 3beta,6alpha,12beta-Trihydroxydammar-20's method with triol group ginsenoside for raw material orientation，Main cause is that current ginsenoside removes in the technique of glucosides and much will introduce strong acid、Highly basic，Reaction controlling is the most difficult，Side reaction is more，Destruction also ratio for ginsenoside's female ring is more serious，Cause the by-product in addition to target product more，On the one hand the yield after converting is the lowest，Cause the biggest difficulty on the other hand to the purification in later stage，Industrialization is relatively costly，Product development for the later stage brings difficulty，Lack competitiveness.
Summary of the invention
It is an object of the invention to provide a kind of method utilizing triol group ginsenoside to convert production 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside on a large scale.
The present invention to realize process as follows:
A kind of method utilizing triol group ginsenoside to convert production 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside on a large scale, comprises the steps: in fermentation tank, triol group ginsenoside is dissolved in deionized water, logical N2After protection, online sterilizing, then adds the heteropoly acid H of the structure with Keggin of organic acid soln and catalytic amountxYW12O40·nH2O catalyst, wherein Y is selected from P, Si, Fe or Zn, and x is 3 or 4, and n is the positive integer of 0-30, reacts 24 ~ 48h, then through precipitating, wash, being dried to obtain target product at 80 ~ 105 DEG C.
Described alcohol group ginsenoside is selected from ginsenoside Rg1, ginsenoside Re, ginsenoside Rg2, ginsenoside Rf, ginsenoside Rh1.
The purity of described alcohol group ginsenoside is more than 80%, and concentration is between 50 ~ 300g/L.
Described fermentation tank installation of water is not more than the 70% of fermentation tank dischargeable capacity.
Described sterilising conditions is 121 DEG C, logical N before maintaining 20min, and heating2Protect.
Described N2Flow velocity is the 50%/min ~ 200%/min of fermentation tank dischargeable capacity amount, time 1min ~ 5min.
Described organic acid is selected from lactic acid, malic acid, citric acid, α-ketoglutaric acid, succinic acid, anti-butenoic acid, acetone acid, and the concentration of organic acid used in reaction system is 0.01 ~ 0.1mol/L.
The rotating speed of described fermentation tank is 50rpm ~ 200rpm.
Target product prepared by said method can utilize industrialization chromatographic column to target product polishing purification.
The 3beta,6alpha,12beta-Trihydroxydammar-20's crude drug utilizing said method to synthesize makes hard capsule, soft capsule, tablet, electuary, drop pill or injection.
The positive effect of the present invention: the present invention comprehensively uses organic acid and heteropolyacid catalyst, catalytic effect is greatly improved；The present invention uses orientation conversion under relatively mild organic acid steady-state conditions in bioreactor to obtain 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside, triol group ginsenoside orientation good for water solublity is converted into the 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside of poorly water-soluble, conversion ratio is high, yield is high, later stage polishing purification technique is simple, production cost is low, beneficially industrialized production, is remarkably improved the market competitiveness of crude drug and finished medicines.
Accompanying drawing explanation
Fig. 1 is the schematic diagram that ginsenoside Rg1 is converted into 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside；
Fig. 2 is the liquid chromatogram of 3beta,6alpha,12beta-Trihydroxydammar-20's standard substance；
Fig. 3 is that the inventive method produces the liquid chromatogram obtaining 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside.
Detailed description of the invention
Example given below, is for the ease of understanding the present invention.And limit claim and the core content of the present invention never in any form.
Embodiment 1
By automatic fermenter that dischargeable capacity is 100L adds the deionized water of 65L, it is subsequently adding ginsenoside Re's (impurity is other kinds of ginsenoside and polysaccharide) that 3500g purity is 85%, logical N2, ventilation flow rate is 50L/min, continues 5min, then stops ventilation and begins to warm up online sterilizing, and sterilising conditions is 121 DEG C, maintains 20min.After being cooled to less than 105 DEG C, add aseptic citric acid solution 5L and 10g heteropoly acid H that concentration is 0.15mol/L3PW12O40·5H2O, then heating fermentation pot liquid to 105 DEG C and maintains 24h, be kept stirring for rotating speed is 300rpm simultaneously, react and after terminating, all liq is released standing 12h in container, abandon supernatant, by abandoning supernatant containing the liquid about 6L precipitated is centrifugal bottom residue, collect precipitate and also dry, the purity obtaining 3beta,6alpha,12beta-Trihydroxydammar-20's crude product about 1940g, HPLC detection 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside is 94.6%.
Comparison example: similar with above-mentioned preparation method, the most only uses organic acid or heteropoly acid, and 3beta,6alpha,12beta-Trihydroxydammar-20's crude product is only capable of obtaining less than 1500g.
Embodiment 2
By automatic fermenter that dischargeable capacity is 500L adds the deionized water of 300L, it is subsequently adding ginsenoside Rg1's (impurity is other kinds of ginsenoside and polysaccharide) that 90kg purity is 95%, logical N2, ventilation flow rate is 350L/min, continues 4min, then stops ventilation and starts online sterilizing, and sterilising conditions is 121 DEG C, maintains 20min.After being cooled to less than 90 DEG C, adding the aseptic malic acid solution 25L that concentration is 0.6mol/L, concentration is the aseptic succinic acid solution 5L and 20g heteropoly acid H of 0.8mol/L4SiW12O40·25H2O, then heating fermentation tank to 80 DEG C and maintains 48h, and be kept stirring for rotating speed is 100rpm simultaneously, and all liq releasing is statically placed in 24h in container after terminating by reaction, abandon supernatant, bottom there are about 100L solidliquid mixture, adds 100L deionized water wash once, then abandons supernatant after standing 24h, it is centrifuged after bottom mixture is stirred and abandons supernatant, collecting precipitate and dry, the purity obtaining 3beta,6alpha,12beta-Trihydroxydammar-20's crude product about 65kg, HPLC detection 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside is 94.9%.
Embodiment 3
By automatic fermenter that dischargeable capacity is 200L adds the deionized water of 120L, it is subsequently adding the ginsenoside Rh1 (impurity is other kinds of ginsenoside and polysaccharide) that 28kg purity is 90%, logical N2, ventilation flow rate is 200L/min, continues 3min, then stops ventilation and starts online sterilizing, and sterilising conditions is 121 DEG C, maintains 20min.After being cooled to less than 100 DEG C, adding the aseptic malic acid solution 10L that concentration is 0.2mol/L, concentration is α-ketoglutaric acid solution 10L, lactic acid 225mL and the 50g heteropoly acid H of 0.2mol/L3FeW12O40·30H2O, then heating fermentation tank to 95 DEG C and maintains 36h, and be kept stirring for rotating speed is 50rpm simultaneously, and all liq releasing is stood 24h after terminating by reaction in a reservoir, abandon supernatant, will liquid about 40L containing precipitation is centrifugal bottom residue abandons supernatant, add 40L deionized water wash once, then abandon supernatant after standing 24h, it is centrifuged after bottom mixture is stirred and abandons supernatant, collecting precipitate and dry, the purity obtaining 3beta,6alpha,12beta-Trihydroxydammar-20's crude product about 25kg, HPLC detection 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside is 93.8%.
Embodiment 4
Automatic fermenter that dischargeable capacity is 50L will add the deionized water of 30L, (wherein ginsenoside Rg1 is 8kg to be subsequently adding the triol group ginsenoside that 10.5kg content is 90%, ginsenoside Re is 2.5kg, and impurity is other kinds of ginsenoside and polysaccharide), logical N2, ventilation flow rate is 150L/min, continues 1min, then stops ventilation and starts online sterilizing, and sterilising conditions is 121 DEG C, maintains 20min.After being cooled to less than 100 DEG C, add aseptic anti-butenoic acid solution 5L and 20g heteropoly acid H that concentration is 0.7mol/L3ZnW12O40·15H2O, then heating fermentation tank to 100 DEG C and maintains 30h, and be kept stirring for rotating speed is 200rpm simultaneously, and all liq releasing is stood 24h after terminating by reaction in a reservoir, abandon supernatant, will liquid about 35L containing precipitation is centrifugal bottom residue abandons supernatant, add 10L deionized water wash once, then abandon supernatant after standing 24h, it is centrifuged after bottom mixture is stirred and abandons supernatant, collecting precipitate and dry, the purity obtaining 3beta,6alpha,12beta-Trihydroxydammar-20's crude product about 7.5kg, HPLC detection 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside is 95.6%.
Claims (10)
1. one kind utilizes triol group ginsenoside to convert the method producing 3beta,6alpha,12beta-Trihydroxydammar-20(21),24-diene-6-O-beta-D-glucopyranoside on a large scale, it is characterised in that: in fermentation tank, triol group ginsenoside is dissolved in deionized water, logical N2After protection, online sterilizing, then adds the heteropoly acid H of the structure with Keggin of organic acid soln and catalytic amountxYW12O40·nH2O catalyst, wherein Y is selected from P, Si, Fe or Zn, and x is 3 or 4, and n is the positive integer of 0-30, reacts 24 ~ 48h, then through precipitating, wash, being dried to obtain target product at 80 ~ 105 DEG C.
Method the most according to claim 1, it is characterised in that: described alcohol group ginsenoside is selected from ginsenoside Rg1, ginsenoside Re, ginsenoside Rg2, ginsenoside Rf, ginsenoside Rh1.
Method the most according to claim 2, it is characterised in that: the purity of described alcohol group ginsenoside is more than 80%, and concentration is between 50 ~ 300g/L.
Method the most according to claim 1, it is characterised in that: described fermentation tank installation of water is not more than the 70% of fermentation tank dischargeable capacity.
Method the most according to claim 1, it is characterised in that: described sterilising conditions is 121 DEG C, logical N before maintaining 20min, and heating2Protect.
Method the most according to claim 5, it is characterised in that: N2Flow velocity is the 50%/min ~ 200%/min of fermentation tank dischargeable capacity amount, time 1min ~ 5min.
Method the most according to claim 1, it is characterised in that: described organic acid is selected from lactic acid, malic acid, citric acid, α-ketoglutaric acid, succinic acid, anti-butenoic acid, acetone acid, and the concentration of organic acid used in reaction system is 0.01
~0.1mol/L。
Method the most according to claim 1, it is characterised in that: the rotating speed of described fermentation tank is 50rpm ~ 200rpm.
9. according to the method described in claim 1 to 8, it is characterised in that: utilize industrialization chromatographic column to target product polishing purification.
10. utilize 3beta,6alpha,12beta-Trihydroxydammar-20's crude drug of method synthesis described in claim 1 to make hard capsule, soft capsule, tablet, electuary, drop pill or injection.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109045039A (en) * | 2018-07-02 | 2018-12-21 | 西安巨子生物基因技术股份有限公司 | Pharmaceutical formulation and the application for treating lung cancer |
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| CN109045039A (en) * | 2018-07-02 | 2018-12-21 | 西安巨子生物基因技术股份有限公司 | Pharmaceutical formulation and the application for treating lung cancer |
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Application publication date: 20161012 |