CN102382094A - Preparation method of acetylated epigallocatechin gallate - Google Patents
Preparation method of acetylated epigallocatechin gallate Download PDFInfo
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- CN102382094A CN102382094A CN2011103573529A CN201110357352A CN102382094A CN 102382094 A CN102382094 A CN 102382094A CN 2011103573529 A CN2011103573529 A CN 2011103573529A CN 201110357352 A CN201110357352 A CN 201110357352A CN 102382094 A CN102382094 A CN 102382094A
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Abstract
The invention discloses a preparation method of acetylated epigallocatechin gallate. The preparation method comprises the following steps of taking dissolved EGCG (epigallocatechin gallate) as a raw material; adding an acetylating reagent and an esterification catalyst; performing acetylization reaction on EGCG at 0-120 DEG C while stirring; after reacting for 1-24 hours and when a system becomes from a yellow turbid liquid into a transparent hazel liquid, ending the acetylization reaction; and purifying to obtain the acetylated epigallocatechin gallate. The preparation method of the acetylated epigallocatechin gallate has the characteristics that the acetylation is complete, the conversion rate is higher than 98%, and the yield is high.
Description
Technical field
The present invention relates to a kind of method for preparing the acetylize NVP-XAA 723.
Background technology
(-)-NVP-XAA 723 (EGCG) is a kind of major ingredient that from Chinese green tea, extracts; It is main activity of green tea and water-soluble components; Be the highest component of content in the catechin, account for the 9%-13% of green tea gross weight, because have special stereochemical structure; EGCG has very strong anti-oxidant activity, is taking on important role aspect anticancer and the cardiovascular disorder.In addition, it is also as the reversal agent of multi-drug resistance of the tumor, can improve cancer cells to the susceptibility of chemotherapy and alleviate the toxicity to heart.
(-)-NVP-XAA 723 (EGCG) is the most effective anti-oxidant polyphenol in the green tea, has anti-oxidant, anticancer, mutation isoreactivity.Anti-oxidant activity is ascorbic more than 100 times at least; Be 25 times of vitamin E; Can protect cell and DNA undermined, this infringement is believed relevant with other major diseases with cancer, heart disease, and these effects of EGCG ascribe their removing (anti-oxidant) ability to oxyradical to.
But everybody also notices because the good anti-oxidation characteristics of EGCG in the middle of the use of (-)-NVP-XAA 723, and EGCG is more oxidized and rotten than the influence that is easier in the middle of processing and storage, to receive heat and oxygen; Be difficult to have good distribution in vivo because the EGCG good water-solubility makes EGCG absorb the back in addition, unstable in vivo also greatly reduces the bioavailability of EGCG.
When 8 hydroxyls of EGCG were acetylation (Pro-EGCG also has the EGCG-P of being called), its stability was far above (-)-EGCG, and the absorption in cell and accumulation have improved more than 2.4 times.Pro-EGCG can be in cell after in getting into cell changes (-)-EGCG under the effect of lipase, and the quantity of (-) in cell-EGCG can increase by 2.8～30 times.With Pro-EGCG feed raise rat with hello raise (-)-EGCG and compare, in blood, small intestine and colon, compare, higher bioavailability is arranged.Pro-EGCG also shows the obvious higher biological activity than EGCG, like the tumor growth to rat breast cancer and androgen independence prostate cancer the obvious suppression effect is arranged.Usefulness human body MDA-MB-231 breast cancer cells such as the KR Landis.Piwowar proof that experimentizes; The pro-EGCG of 50 gmol/L and f-EGCG handle the back, and (every 24h once; Continuous 3 times) behind the 72h, during pro-EGCG handled, the propagation of breast cancer cell was suppressed 55%; And EGCG only handles 16%, and effect differs 3.5 times.Growth of tumor speed obviously weakens; Like the experiment made on the living of carrying out with mouse; Handle with 50mg/kg pro-EGCG and (-)-EGCG, the tumour size of control treatment mouse is 1582 4-29 gL behind the 3 l d, and it is 1223 ± 21 L that (-)-EGCG handles mouse; And pro-EGCG to handle the tumour size of mouse be 723 ± 50LLL, this explanation EGCG behind structural modification to the growth-inhibiting of breast cancer cell 54%.Because the chymotrypsin protein enzyme activity inhibited of proteolytic enzyme is normal and lead to the apoptosis of cancer cells to be related, therefore often measure the active retarding effect of chymotrypsin protein enzyme of proteolytic enzyme simultaneously.Research shows, after the pro-EGCG with 50gmol/L handled 24h, the chymotrypsin protein enzyme is active to suppress 48%, and is merely 8% with the inhibition effect of (-)-EGCG of dosage.(-)-EGCG amount that is recovered in every milligram of albumen is: pro-EGCG is treated to 530pmol, and (-)-EGCG is treated to 222 pmol, shows being absorbed by cell that pro-EGCG (Mw:818.4g/mol) can be more, and is converted into EGCG.The experiment of carrying out with KYSE150 human body esophageal cancer cell also obtains similar result.
Summary of the invention
The purpose of this invention is to provide a kind of employing acetylation reagent and esterifying catalyst, EGCG is carried out acetylize, the synthetic method for preparing the acetylize NVP-XAA 723.
The objective of the invention is to realize like this: a kind of method for preparing the acetylize NVP-XAA 723 is a raw material with the EGCG after the dissolving, adds acetylation reagent and esterifying catalyst; Under the stirring EGCG is carried out acetylization reaction down at 0-120 ℃; Through 1-24 hour reaction, when system gradually became transparent filbert liquid by yellow turbid solution, acetylization reaction finished; After purification process, obtain the acetylize NVP-XAA 723.
Described purification process is to add saturated sodium bicarbonate in the material accomplished of acetylization reaction, isolates ethyl acetate layer, with ETHYLE ACETATE water is extracted again; Dry methacrylate layer; Rotary evaporation is removed ethyl ester, gets transparent oily matter, adopts the absolute ethyl alcohol recrystallization once; Light yellow crystallization, i.e. acetylize NVP-XAA 723.
Described acetylation reagent is diacetyl oxide, acetate or Acetyl Chloride 98Min..
Described esterifying catalyst is a zinc salt.
Described zinc salt is ZnCl
2, Zn (Ac)
2Or ZnSO.
Described esterifying catalyst is a lewis acid catalyst.
Described lewis acid catalyst is CoCl
2, Sc (OTf)
3, Sc (NTf
2)
3, TiCl
4/ AgClO
4, In (OTf)
3, TMSOTf, Cu (OTf)
2, Bi (OTf)
3, TaCl
5, WO
32ZrO
2And like FeCl3, Fe2 (SO4) 3.xH2O
[15]
The temperature of acetylization reaction is 20-40 ℃.
The time of acetylization reaction is 3-8 hour.
The method for preparing the acetylize NVP-XAA 723 provided by the invention; The Pro-EGCG purity that obtains can reach more than 98%; (purity is 98.3%, and HPLC) to test its purity after 30 days be 98.1% (HPLC) to sample 1g 60 ° of C held in constant temperature oven with the Pro-EGCG for preparing; With finished product (-)-NVP-XAA 723 EGCG in green source (purity is 98.2%, HPLC) sample 1g 60 ° of C held 30 days in constant temperature oven, test its purity in dissolving back is 18.3% (HPLC).Above accelerated warming oxidation experiment shows that full acetylated (-)-NVP-XAA 723 has goodish stability, can prolong its preservation period greatly under the similarity condition.
Answer principle to be for of the present invention:
Principle summary is following:
A kind of method for preparing the acetylize NVP-XAA 723 is characterized in that: the EGCG with after the dissolving is a raw material, adds acetylation reagent and esterifying catalyst, and acetylation reagent is selected diacetyl oxide, acetate or Acetyl Chloride 98Min. for use; Esterifying catalyst is zinc salt such as ZnCl
2, Zn (Ac)
2Or ZnSO
4, under the stirring EGCG is carried out acetylization reaction down at 0-120 ℃, through 1-24 hour reaction; When system gradually becomes transparent filbert liquid by yellow turbid solution; Acetylization reaction finishes, and after purification process, obtains the acetylize NVP-XAA 723.
Described purification process is to add saturated sodium bicarbonate in the material accomplished of acetylization reaction, isolates ethyl acetate layer, with ETHYLE ACETATE water is extracted again; Dry methacrylate layer; Rotary evaporation is removed ethyl ester, gets transparent oily matter, adopts the absolute ethyl alcohol recrystallization once; Light yellow crystallization, i.e. acetylize NVP-XAA 723.
Esterifying catalyst is a lewis acid catalyst, like CoCl
2, Sc (OTf)
3, Sc (NTf
2)
3, TiCl
4/ AgClO
4, In (OTf)
3, TMSOTf, Cu (OTf)
2, Bi (OTf)
3, TaCl
5, WO
32ZrO
2, FeCl
3Or Fe
2(SO
4)
3.xH
2O.
The temperature of acetylization reaction is preferably 20-40 ℃; The time of acetylization reaction is preferably 3-8 hour.
Embodiment 1
In being placed with the 250ml there-necked flask of magneton, add 9.2g (about 0.02mol) EGCG; Use the 40-200ml acetic acid ethyl dissolution; Preferably select for use 60-100ml ETHYLE ACETATE as solvent, (about 0.1 ~ 0.8mol), optimum quantum of utilization is 30-60ml to add acetic anhydride 20-160ml.
Add catalyzer ZnCl
21.36 (about 0.01 ~ 0.2mol), (0.05 ~ 0.15mol) consumption is as catalyzer preferably to select 6.8 ~ 20.4g for use for ~ 27.6g.At room temperature stir 3 ~ 8h, along with the system homogeneity of constantly carrying out of reacting constantly strengthens, system gradually becomes transparent filbert liquid by yellow turbid solution, and the TLC detection reaction finishes.Add 80 ~ 200ml saturated sodium bicarbonate, continue to stir 1 h, tell ethyl acetate layer; Use ETHYLE ACETATE (100ml/ time) to water extraction 3 times again, merge dry methacrylate layer, rotary evaporation is removed ethyl ester; Get the filbert transparent oily matter of 16g, yield 98% adopts the absolute ethyl alcohol recrystallization once; Obtain the light yellow crystallization of 14g, yield 85%, purity 98.2% (HPLC).
Embodiment 2
In being placed with the 250ml there-necked flask of magneton, add 9.2g (about 0.02mol) EGCG; Use the 40-200ml acetic acid ethyl dissolution; Preferably select for use 60-100ml ETHYLE ACETATE as solvent, (about 0.1 ~ 0.8mol), optimum quantum of utilization is 30-60ml to add acetic anhydride 20-160ml.
Add catalyzer ZnAc
24.25 ~ 37g (about 0.025 ~ 0.2 mol) optimum amount can select 13.88 ~ 24 (about 0.075 ~ 0.12mol).Under 80 ° of C, stir 5h, along with the system homogeneity of constantly carrying out of reacting constantly strengthens, system gradually becomes transparent Vandyke brown liquid by yellow turbid solution, and the TLC detection reaction finishes.Add the 80ml saturated sodium bicarbonate, continue to stir 1 h, tell ethyl acetate layer; Use ETHYLE ACETATE (100ml/ time) to water extraction 3 times again, merge dry methacrylate layer, rotary evaporation is removed ethyl ester; Get the transparent oily matter of 15.7g Vandyke brown, yield 96% adopts the absolute ethyl alcohol recrystallization once; Obtain the crystallization of 13g brown, yield 79%, purity 96.7% (HPLC).
Embodiment 3
In the middle of mechanical stirring 50L reaction kettle is housed, add 1840g (about 4mol) EGCG, with 8 ~ 36L acetic acid ethyl dissolution, the optimum solvent amount is 12 ~ 24L, add acetic anhydride 6-16L (about 30 ~ 80mol), add catalyzer ZnCl
2(about 1.25 ~ 10mol) optimum amounts are that (about 3.65 ~ 7.5mol), system is a nonhomogeneous system to 510 ~ 1020g to 170 ~ 1360g.At room temperature stir 7h, along with the system homogeneity of constantly carrying out of reacting constantly strengthens, system gradually becomes transparent khaki liquid by yellow turbid solution, and the TLC detection reaction finishes.Add the 16L saturated sodium bicarbonate, continue to stir 1 h, tell ethyl acetate layer; In extraction tower, use ETHYLE ACETATE (20L/ time) to water extraction 3 times again, merge dry methacrylate layer, rotary evaporation is removed ethyl ester; Get the filbert transparent oily matter in the 3100g left and right sides, yield 94.7% adopts the absolute ethyl alcohol recrystallization once; Obtain the light yellow crystallization of 2880g, yield 88%, purity 98.3% (HPLC).
Claims (9)
1. method for preparing the acetylize NVP-XAA 723 is characterized in that: the EGCG with after the dissolving is a raw material, adds acetylation reagent and esterifying catalyst; Under the stirring EGCG is carried out acetylization reaction down at 0-120 ℃; Through 1-24 hour reaction, when system gradually became transparent filbert liquid by yellow turbid solution, acetylization reaction finished; After purification process, obtain the acetylize NVP-XAA 723.
2. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: described purification process is to add saturated sodium bicarbonate in the material accomplished of acetylization reaction, isolates ethyl acetate layer; With ETHYLE ACETATE water is extracted again, dry methacrylate layer, rotary evaporation is removed ethyl ester; Get transparent oily matter; Adopt the absolute ethyl alcohol recrystallization once, light yellow crystallization, i.e. acetylize NVP-XAA 723.
3. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: described acetylation reagent is diacetyl oxide, acetate or Acetyl Chloride 98Min..
4. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: described esterifying catalyst is a zinc salt.
5. the method for preparing the acetylize NVP-XAA 723 according to claim 4 is characterized in that: described zinc salt is ZnCl
2, Zn (Ac)
2Or ZnSO
4
6. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: described esterifying catalyst is a lewis acid catalyst.
7. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: described lewis acid catalyst is CoCl
2, Sc (OTf)
3, Sc (NTf
2)
3, TiCl
4/ AgClO
4, In (OTf)
3, TMSOTf, Cu (OTf)
2, Bi (OTf)
3, TaCl
5, WO
32ZrO
2, FeCl
3Or Fe2 (SO
4)
3.xH
2O.
8. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: the temperature of acetylization reaction is 20-40 ℃.
9. the method for preparing the acetylize NVP-XAA 723 according to claim 1 is characterized in that: the time of acetylization reaction is 3-8 hour.
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Cited By (4)
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|---|---|---|---|---|
| CN102787146A (en) * | 2012-07-28 | 2012-11-21 | 江南大学 | Method utilizing microwave assisted lipase catalysis to synthesize esterification modified EGCG |
| CN102809592A (en) * | 2012-07-13 | 2012-12-05 | 江苏大学 | Electro-polymerization preparation method of electrochemical sensor for quickly detecting EGCG (Epigallocatechin-3-Gallate) |
| CN103275053A (en) * | 2013-05-29 | 2013-09-04 | 浙江大学 | Esterification method for tea leaf polyphenol |
| CN105884738A (en) * | 2015-10-20 | 2016-08-24 | 江南大学 | Microwave-assisted synthesis method for EGCG fatty acid ester |
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| WO2007105280A1 (en) * | 2006-03-10 | 2007-09-20 | Osaka University | Process for production of acylated derivative of epigallocatechin gallate |
| CN101190910A (en) * | 2006-11-29 | 2008-06-04 | 江和源 | Method for preparing epigallocatechin gallate acetylate |
| CN101519395A (en) * | 2008-10-16 | 2009-09-02 | 中国农业科学院茶叶研究所 | Preparation method of fully substituted acetylate of epigallocatechin-gallate (EGCG) |
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2011
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| CN101190910A (en) * | 2006-11-29 | 2008-06-04 | 江和源 | Method for preparing epigallocatechin gallate acetylate |
| CN101519395A (en) * | 2008-10-16 | 2009-09-02 | 中国农业科学院茶叶研究所 | Preparation method of fully substituted acetylate of epigallocatechin-gallate (EGCG) |
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| 刘晓辉，等: "乙酰化EGCG衍生物的合成、纯化及应用特性研究", 《中国农业科学院硕士学位论文》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102809592A (en) * | 2012-07-13 | 2012-12-05 | 江苏大学 | Electro-polymerization preparation method of electrochemical sensor for quickly detecting EGCG (Epigallocatechin-3-Gallate) |
| CN102809592B (en) * | 2012-07-13 | 2014-03-12 | 江苏大学 | Electro-polymerization preparation method of electrochemical sensor for quickly detecting EGCG (Epigallocatechin-3-Gallate) |
| CN102787146A (en) * | 2012-07-28 | 2012-11-21 | 江南大学 | Method utilizing microwave assisted lipase catalysis to synthesize esterification modified EGCG |
| CN102787146B (en) * | 2012-07-28 | 2014-02-19 | 江南大学 | Method for utilizing microwave assisted lipase catalysis to synthesize esterification modified EGCG |
| CN103275053A (en) * | 2013-05-29 | 2013-09-04 | 浙江大学 | Esterification method for tea leaf polyphenol |
| CN105884738A (en) * | 2015-10-20 | 2016-08-24 | 江南大学 | Microwave-assisted synthesis method for EGCG fatty acid ester |
| CN105884738B (en) * | 2015-10-20 | 2018-06-01 | 江南大学 | A kind of method of Microwave-assisted synthesis EGCG aliphatic esters |
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Application publication date: 20120321 |