CN103275053A - Esterification method for tea leaf polyphenol - Google Patents
Esterification method for tea leaf polyphenol Download PDFInfo
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- CN103275053A CN103275053A CN2013102065186A CN201310206518A CN103275053A CN 103275053 A CN103275053 A CN 103275053A CN 2013102065186 A CN2013102065186 A CN 2013102065186A CN 201310206518 A CN201310206518 A CN 201310206518A CN 103275053 A CN103275053 A CN 103275053A
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Abstract
The invention discloses an esterification method for tea leaf polyphenol. The method comprises the following steps that the tea leaf polyphenol is reacted with an acylation reagent in an organic solvent under the action of a catalyst, and the reaction product is separated and purified to form an esterification product. The tea leaf polyphenol is pure catechin or tea polyphenol; and the catalyst comprises a metallic ionic catalyst and an acid scavenger. Compared with the prior art, the method has the advantages that the metallic ionic catalyst and the acid scavenger are cooperative for catalyzing esterification of the tea leaf polyphenol, the reaction condition is mild, the reaction is quick, the catechin mother ring structure in the reaction process is stable, the esterification degree is easy to control, and the tea leaf polyphenol is easy to purify. Different esterification products can be applied in different fields of medicine, health-care products, daily cosmetics, food, edible oil, feeds, organic chemicals and the like.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of esterification process of tealeaves polyphenol.
Background technology
Tea-polyphenol be a kind of be the tea leaf extract of main component with the catechin, wherein catechin mainly is made up of C, EC, EGC, ECG, EGCG and GCG, and the highest with EGCG content; The structural formula of these six kinds of compounds is as follows:
Tea-polyphenol, especially catechin EGCG is a kind of natural antioxidant of excellent performance, has no side effect, and can remove free radical strongly, blocking-up lipid peroxidation process improves the activity of human body endoenzyme, thereby plays anti-mutation, anticancer effect; Tea-polyphenol can reduce fibrinogenic content, makes blood coagulation become clear, suppresses atherosclerosis; Can suppress the conversion enzymic activity, reduce or the maintenance blood pressure stabilization; Can realize improving the effect of human body comprehensive immunizing power, rheumatism, anti-bacteria and anti-virus by regulating immune globulin activity indirectly; Energy strongly inhibited histamine release, anti-allergic and skin allergy; Etc..
Catechin has won attracting attention of common people with its superior biology, pharmacologically active function and has favored.Along with going deep into of research, its Application Areas is constantly expanded.Be insoluble in grease but catechin and tea-polyphenol are soluble in water, the profit partition ratio is little and bioavailability is low, has limited their Application Areas, has also suppressed their physiology and pharmacologically active function.Therefore, they are carried out study on the modification receive much concern, especially esterification techniques has obtained widespread use.
For example, EGCG is higher than EGCG with the antiviral and anti-tumor activity of enzyme process or the synthetic EGCG mono fatty acid ester that obtains of classical chemical process, and it is the strongest with the activity of EGCG monopalmitate, the position of esterification simultaneously difference is to not influence of activity, and the mixture of monopalmitate and the activity of its single component also identical (Bioorg.Med.Chem.Lett.2008,18,4249.Biochem.Biophys.Res.Commun.2008,377,1118); The EGCG of the full esterification of lipid acid also has the antiviral and inhibition lipid peroxidation enzymic activity (ARKIVOC2007,6-16.J.Agric.Food Chem.2001,49,1042.) higher than EGCG.Therefore, the esterification of catechin such as EGCG can obtain mono-esterification to the catechin of full esterification, though the degree of esterification difference, profit partition ratio difference, pharmacologically active and biological function are variant, and different esterification products can be applied in various different field.
Phenolic compound becomes the ester reaction difficult usually with acid anhydrides or acyl chlorides, need use catalyst.General weak base commonly used is catalyzed into the ester reaction, as triethylamine, pyridine, 4-Dimethylamino pyridine (DMAP) etc.; But basic catalyst should not be used for the esterification of catechin or tea-polyphenol separately, because in alkaline environment, catechin is oxidation by air very easily.Protonic acid and Lewis acid can activate acyl chlorides, promote the esterification of it and catechin; But in strong acid environment, especially under high density protonic acid and Lewis acid coexistence, open loop easily takes place in the Flavonol of catechin, causes its precursor structure destroyed, and molecule coupling formation thearubigins can further take place.
Therefore, be the esterification that raw material carries out with catechin or tea-polyphenol, should not in strong basicity or high density strong acid environment, carry out.Catechin and tea-polyphenol are relatively stable in neutrality, slightly acidic or dilute acid soln, but this moment and acid anhydrides or acyl chlorides direct esterification react slower, react often also incomplete.In addition, catechin is the polyhydroxy phenol compounds, reaction lack selectivity during direct esterification, and the product that obtains is very complicated.And the factor that influences esterification is a lot, as the kind of acylating reagent and proportioning, catalyst type, temperature of reaction etc., becomes the ester condition one to change slightly, will generate different esterification products.
To the esterification of poly-hydroxy phenols lack that selectivity, degree of esterification are difficult to control, the easy open loop destruction of Flavonol ring of catechin, esterification products relative complex, this is the biggest problem that present chemosynthesis esterification catechin and fat-soluble tea polyphenol exist.
Summary of the invention
The invention provides a kind of esterification process of tealeaves polyphenol, this synthesising method reacting condition gentleness is swift in response, and catechin parent ring structure is stable in the reaction process, and degree of esterification is controlled easily, easy purification of products, and the productive rate height, quality is good.
A kind of esterification process of tealeaves polyphenol is included in that tealeaves polyphenol and acylating reagent react in the organic solvent under the effect of catalyzer, reaction product obtains esterification products through separation and purification, and described catalyzer is metal ion catalyst and acid scavenger.
Adopt the esterification of metal ion catalyst and acid scavenger concerted catalysis tealeaves polyphenol, thereby can the degree of esterification of tealeaves polyphenol be control effectively.
Esterification on the tealeaves polyphenol phenolic hydroxyl group is difficult, must adopt active acylating reagent just can carry out.Acylating reagent of the present invention is acyl chlorides, is preferably C
2～C
32Fat acyl chloride.
If do not do specified otherwise, the polyphenol of tealeaves described in the present invention refers to contain the raw material of catechin compounds, can be simple catechin, also can be tea-polyphenol.Described simple catechin refers to not contain other component in the tea leaf extract, can be to have only a kind of catechin, also can be the mixture that multiple catechin is formed with arbitrary proportion, is preferably EGCG; Described tea-polyphenol be a kind of be the tea leaf extract of main component with the catechin.
As one of embodiment, described tealeaves polyphenol is simple catechin, and described acylating reagent is C
2～C
32Fat acyl chloride, the mol ratio of fat acyl chloride and catechin is 0.5～10:1.
As another embodiment, described tealeaves polyphenol is tea-polyphenol, and described acylating reagent is C
2～C
32Fat acyl chloride, the ratio of fat acyl chloride and tea-polyphenol is 0.1～2.5mol:100g.
Be easier the carrying out of esterification that makes catechin and acyl chlorides, also for to make acyl chlorides have certain regioselectivity to the esterification of catechin, the present invention utilizes metal ion catalyst that catechin is activated.
Reaction (1) is reaction (a) and total reaction (b); Wherein, ArOH represents catechin, can be simple catechin, also can be the catechin in the tea-polyphenol; RCOCl represents acyl chlorides (being acylating reagent); Metal ions M
+Ignored valence state; ArOM represents the catechin-metal ionic complex, but has ignored their complexing mode; ArOCOR represents the catechin fatty acid ester.M is the metal acid scavenger, and B is the bases acid scavenger.
Shown in reaction (a), catechin has the ability of extremely strong bind metal ion.Though catechin has a plurality of phenolic hydroxyl groups, the binding ability of ortho position dihydroxyl and metal ion is the strongest, makes on the easier B ring and D ring that occurs in catechin of complex reaction; And phenolic hydroxyl group became the phenol negative oxygen ion after metal ion was combined with catechin, the phenol negative oxygen ion has extremely strong nucleophilic activity, easier and acyl chlorides generation esterification (shown in reaction b), make esterification have regioselectivity, i.e. easier generation esterification on the B of catechin ring and D ring.
Metal ion catalyst of the present invention should be that a class contains and can activate the catechin phenolic hydroxyl group, and the compound of the metal ion of can react with catechin (a), described compound is at least a in the metal oxide that contains this metalloid ion, oxyhydroxide, the salt;
Described metal ion is preferably rare earth ion, Mg
2+, Ca
2+, Sr
2+, Ba
2+, Al
3+, Ga
3+, In
3+, Ge
2+, Ge
4+, Sn
2+, Sn
4+, Ti
2+, Ti
4+, V
3+, Mn
2+, Fe
2+, Fe
3+, Co
2+, Ni
2+, Cu
2+, Zn
2+In at least a; Mg more preferably
2+, Ca
2+, Al
3+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+, Sn
2+, La
3+In at least a.
Wherein, described salt can be selected salt of weak acid or strong acid salt for use, and described salt of weak acid can be preferably carbonate, supercarbonate, phosphoric acid salt, hydrophosphate, dihydrogen phosphate or C
2～C
32Soap; Described strong acid salt can be preferably vitriol, mesylate, fluoroform sulphonate, fluorochemical, muriate or bromide.
When selecting for use two or more to make metal ion catalyst, unrestricted to the combination between above-mentioned metal oxide, oxyhydroxide, the salt and ratio, generally, the mol ratio of metal ion catalyst and acylating reagent is preferably 10
-6～5:1.
By reaction (1) as seen, when becoming ester, also generated strong acid HCl, and along with the carrying out that reacts, reaction system acidity improves constantly.And the combination of catechin and metal ion can be replaced by proton when acidity is higher, i.e. reaction (a) is reversible, and metal ion has lost the activation capability to phenolic hydroxyl group, catalytic activity is suppressed, reaction is slowed down, and under strong acidic environment the catechin instability, side reactions such as open loop, polymerization easily take place.
Therefore, the present invention adds acid scavenger in reaction system, in time acidity is reduced in reaction process, and the balance of reaction (a) is moved right.The present invention adopts active metal or alkali to make acid scavenger.
By reaction (2) as seen, select for use the active metal to make acid scavenger, not only can remove the acid in the reaction system, also can produce new metal ion, this balance that more is conducive to reaction (a) moves right, and activates phenolic hydroxyl group.Simultaneously, the Lewis acid of generation also can the catalytic activation acyl chlorides, to the dual activation of catechin and acyl chlorides esterification is finished fast.
By reaction (3) as seen, alkali is made acid scavenger control solution acidity better effects if, as adopting the alkali (as pyridine, DMAP etc.) that acyl chlorides is had activation, then more is conducive to the carrying out of esterification.The combination of catechin and metal ion takes place to effective control of solution acidity in alkali smoothly, and the phenolic hydroxyl group of catechin is activated.As seen, the dual activation of catechin and acyl chlorides makes esterification to carry out smoothly.
When selecting the metal acid scavenger for use, metallic element in the metal acid scavenger can be identical with the metallic element in the metal ion catalyst, also can be different, but must be the active metal, be preferably at least a among rare earth metal, Mg, Ca, Al, Ga, In, Ge, Sn, Ti, V, Mn, Fe, Co, Ni, the Zn; At least a among Mg, Al, Fe, Co, Ni, Zn, the Sn more preferably.
When selecting two or more metal for use, the mixture that the above-mentioned metal of optional usefulness is formed with arbitrary combination, arbitrary proportion; Except metal, also can select the alloy that contains above-mentioned metal for use.
For farthest effectively reducing the acidity of reaction system, preferably, the mol ratio of metal acid scavenger and acylating reagent is at least 0.2:1, and excessive metal acid scavenger can finish to remove by simple filtration in reaction.But consider that from the angle that simplifies the operation the mol ratio of metal acid scavenger and acylating reagent is 0.2～20:1 more preferably.For the metal acid scavenger of alloy or mixture, its mol ratio refers to the total amount of the active metal that alloy or mixture contain.
By reaction (2) as seen, behind the adding metal acid scavenger, also produced a large amount of metal ions when reducing acidity in the reaction system, these metal ions can impel reaction (a) to carry out to the right.Therefore, when selecting the metal acid scavenger for use, the metal ion catalyst that adds catalytic amount when reacting initial gets final product, and the consumption increase can be accelerated the speed of response of starting stage certainly, and the mol ratio of metal ion catalyst and acylating reagent is 0.0001～2:1 more preferably.
Though can reduce the consumption of metal ion catalyst, in the reaction system of reaction initial period, before acylating reagent added, the existence of metal ion catalyst was necessary.If metal ion catalyst does not exist; the acidity of reaction system is still lower when reacting initial; reaction (2) is difficult to carry out; can't produce metal ion; acylating reagent and catechin reaction exist in solution very slowly and in a large number, and the surface of metal acid scavenger has further been stoped the carrying out of reaction (2) by the acylating reagent passivation; the esterification of catechin or tea-polyphenol can not be carried out smoothly, and the esterification products esterification that obtains is insufficient, quality is unstable.
Only there is metal ion catalyst and during with the concerted catalysis of metal acid scavenger, just can forms the benign cycle of reaction (a)-reaction (b)-reaction (2) at the reaction initial period, esterification can be carried out fast smoothly.
Except can adding metal ion catalyst and metal acid scavenger respectively, reaction also can be selected the composite catalyst of metal ion catalyst and metal acid scavenger for use.The acquiring way of described composite catalyst comprises:
(I) metal of surface oxidation, as have magnesium rod, aluminum strip, zinc metal sheet, rust iron powder, tinfoil paper of surface oxide layer etc.;
(II) through chemical corrosion and stay the metal of zone of oxidation on the surface, as the nickel through galvanic corrosion; The aluminium foil of crossing through sodium-hydroxide treatment, alumino nickel, zinc powder etc.;
(III) excessive metal acid scavenger reacts to no hydrogen with small amount of acid earlier and emits;
(IV) reactions such as a small amount of acyl chlorides elder generation and less water produce HCl, add the excess metal acid scavenger then, and reaction is emitted to no longer including hydrogen;
(I) and (II) zone of oxidation on surface is metal ion catalyst, and inner metal is the metal acid scavenger; (III) and (IV) be to produce metal ion catalyst by the active metal indirectly with adding or react the acid-respons that obtains, also have excessive unreacted metal acid scavenger simultaneously.
When selecting the bases acid scavenger for use, described bases acid scavenger should be selected weak base compound for use; Be preferably at least a in the following compounds:
Fat amine R
1R
2R
3N:R
1, R
2, R
3Independent separately is C
1～C
4Alkyl;
Alicyclic ring amine: N-methyl Pyrrolidine, N-ethyl Pyrrolidine, N-methyl piperidine, N-ethylpiperidine, N, N'-lupetazin or N, N'-diethyl piperazine;
Pyridines: the substituting group on each carbon of pyridine ring is hydrogen, C independently of one another
1～C
4Alkyl, C
2～C
6Fatty acyl group, C
1～C
4Alkoxyl group, C
2～C
6Fat acyloxy, C
1～C
4Alkoxyl formyl, substituted-amino R
4R
5N-, substituted-amino formyl radical R
6R
7NCO-, nitro, cyano group, fluorine, chlorine, bromine or iodine; Wherein, R
4, R
5Independent separately is C
1～C
4Alkyl, C
1～C
6Fatty acyl group; Or R
4R
5=(CH
2)
n, n=4～5; Or R
4R
5=-CH
2CH
2NR
8CH
2CH
2-, R
8Be C
1～C
4Alkyl, C
1～C
6Fatty acyl group; R
6, R
7Independent separately is C
1～C
4Alkyl.
At least a in triethylamine, pyridine, 4-Dimethylamino pyridine (DMAP), the 2-chloropyridine more preferably.
For farthest effectively reducing the acidity of reaction system, the bases acid scavenger is preferably 0.2～20:1, more preferably 0.5～1.5:1 with the ratio of the mole number of acylating reagent.
In the presence of weak base, metal ion is easier is combined with catechin, activates phenolic hydroxyl group, makes it to become ester (shown in reaction formula b), the proton of Shi Fanging and weak base B reaction simultaneously to generate its conjugate acid HB(shown in reaction formula (3) with the acyl chlorides rapid reaction).HB and B form buffer system, control the acidity of reaction system effectively, avoid catechin and esterification products thereof oxidized; And be conducive to into the metal ion and the catechin complexing again (shown in reaction formula a) that dissociate and behind the ester, reaction (a)-reaction (b)-reaction (3) forms benign cycle.
Because metal ion only is a kind of catalyzer in reaction, do not consume in the reaction process, therefore, when selecting the bases acid scavenger for use, the consumption of metal ion catalyst also only needs catalytic amount.But different with reaction (2), reaction (3) does not produce new metal ion.For accelerating the carrying out of esterification, improve the consumption of metal ion catalyst to reacting favourable.So when selecting the bases acid scavenger for use, the mol ratio of metal ion catalyst and acylating reagent is 0.01～2:1 more preferably.
The organic solvent that the inventive method adopts should be able to dissolve acylating reagent and catechin or tea-polyphenol well, and with them chemical reaction does not take place; Be preferably at least a in the following solvent:
Esters solvent R
9COOR
10: R
9=C
1～C
5Alkyl, R
10=C
1～C
6Alkyl;
Ether solvent: ether, glycol dimethyl ether, ethylene glycol methyl ether, ethylene glycol diethyl ether, 1,2-Propylene Glycol Dimethyl Ether, 1, ammediol dme, tetrahydrofuran (THF), 1,4-dioxane;
Ketones solvent R
11COR
12: R
11, R
12Independent separately is C
1～C
4Alkyl; Cyclopentanone or pimelinketone; When selecting ketones solvent for use, can only adopt the bases acid scavenger;
Acetonitrile, N, dinethylformamide (DMF), N,N-dimethylacetamide (DMAc), methyl-sulphoxide;
Reaction solvent is at least a among ethyl acetate, tetrahydrofuran (THF), glycol dimethyl ether, acetonitrile, DMF, the DMAc more preferably.
The weightmeasurement ratio of tealeaves polyphenol and organic solvent is preferably 1g:2～500mL, more preferably 1g:10～100mL.
When selecting the metal acid scavenger for use, reaction has hydrogen to emit, and shows that reaction is to carry out in reducing atmosphere, can protect catechin, tea-polyphenol and their not oxidation by air of esterification products effectively.But consider that from production safety reaction is preferably carried out under protection of inert gas.Preferred rare gas element is nitrogen or argon gas.
When selecting the bases acid scavenger for use, be reflected in the buffered soln and carry out, the tea-polyphenol oxidation by air is very slow, and reaction can be carried out in the presence of unprotect gas.But catechin and tea-polyphenol esterification products in order to obtain high-quality reduce the generation of unnecessary oxidizing reaction as far as possible, and reaction is also preferably carried out under protection of inert gas.Preferred rare gas element is nitrogen or argon gas.
The inventive method is by the dual activation to phenolic hydroxyl group and acyl chlorides; reaction can be carried out under quite gentle condition; catechin and tea-polyphenol esterification are finished fast, and avoided the polymerization of catechin or tea-polyphenol and protected the stable of catechin ring structure.Reaction can be carried out under-10 ℃～solvent refluxing temperature, is preferably room temperature～80 ℃.
After reaction is finished, after filtration, washing, concentrating under reduced pressure, remove excessive acid scavenger, salt, by product and organic solvent, dehydrate then, after recrystallization or chromatographic separation technology etc. is further purified, get solid product, be esterification catechin or esterification tea-polyphenol product.
Under the concerted catalysis effect of metal ion catalyst and acid scavenger, the esterification of catechin has splendid selectivity and controllability.Trace it to its cause, mainly be that metal ion easily activates the phenolic hydroxyl group that contains on the dihydric catechin B ring in ortho position and the D ring, in case will reduce with the dihydric content in ortho position behind the esterification of acyl chloride, and metal ion and isolated phenolic hydroxyl group binding ability a little less than, make degree of esterification be easy to control: only need to adjust the proportioning of catechin or tea-polyphenol and acyl chlorides, can obtain different degree of esterification is main esterification products.Just as mentioned before, different esterification products can be applied in different field.
Compared with prior art, beneficial effect of the present invention is:
The present invention utilizes metal ion catalyst and the synthetic esterification catechin of acid scavenger concerted catalysis or esterification tea-polyphenol, and the reaction conditions gentleness is swift in response, and degree of esterification is easy to control, and the female ring structure of catechin is stable in the reaction process, and product is best in quality.
Description of drawings
Fig. 1 (I) is that the TLC of reaction product among EGCG and embodiment one and the embodiment two detects figure, and the developping agent of employing is ethyl acetate/petroleum ether 2:1 (v/v);
Fig. 1 (II) is that the TLC of reaction product among EGCG and embodiment three and the embodiment four detects figure, and the developping agent of employing is ethyl acetate/petroleum ether 4:1 (v/v);
Fig. 1 (III) is that the TLC of reaction product among EGCG and embodiment one, Comparative Examples one and the embodiment four detects figure, and the developping agent of employing is ethyl acetate/petroleum ether 1:2 (v/v);
Wherein, A1, B1, D1 are the EGCG monopalmitate, and A2, B2, D2 are the EGCG acid dipalmitate, and A1', A2', A3, A4, D3, D4, E1'～E6', F1'～F6' are the high cetylate of EGCG; E1 is made up of E1'～E6'; Also contain EGCG and single, double cetylate thereof on the initial point of F.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail.
Embodiment one
0.23g(0.50mmol) EGCG, 0.068g(0.50mmol) ZnCl
2Be dissolved in the 10mL ethyl acetate; add 0.10g(0.82mmol) DMAP, under nitrogen protection, drip 10mL and be dissolved with 0.23g(0.83mmol) ethyl acetate solution of palmityl chloride; behind the about 2h of heating reflux reaction product is carried out TLC and detect, detected result is shown in Fig. 1 (I).
By Fig. 1 (I) as seen, the reaction product point sample is on initial point A, and (ethyl acetate/petroleum ether 2:1 v/v) obtains four R after the expansion through developping agent
fBe worth different chromatography points, be designated 1,2,3,4, represent A1, A2, four kinds of materials of A3, A4 respectively.The small amount of solid DMAP hydrochloride of bringing into when wherein the point on the initial point A is for sampling.
Aftertreatment: product is cooled to 0 ℃, removes by filter white solid; Solution is with 3 * 20mL distilled water wash, and anhydrous sodium sulfate drying filters, and vacuum concentration reclaims solvent, and (ethyl acetate/petroleum ether 2:1, v/v) separation and purification obtain two kinds of white solid A1 and each 0.15g of A2 and 0.18g to the gained solid with silica gel column chromatography.
The H-NMR(500MHz of white solid A1, DMSO-d6): 0.82～0.95(3H, m, CH
3); 1.20～1.45(24H, m, (CH
2)
12); 1.57～1.70(2H, m,
CH 2 CH
2COO); 2.42～2.50(2H, m, CH
2COO is overlapped with the DMSO solvent peak); 2.65～2.85(1H, m, CH
2Ar); 2.90～3.10(1H, m, CH
2Ar); 5.00～5.55(2H, m, ArOCHCHO); 5.80～7.00(6H, m, ArH); 8.70～9.55(7H, m, OH).
Hydrogen spectrum data show that the female ring of EGCG is 1:1 with the mol ratio of cetylate side chain in the product A 1; 7 phenolic hydroxyl groups are only arranged in the product, lacked the hydrogen on the EGCG phenolic hydroxyl group, the female ring of EGCG is gone up other hydrogen all less than increasing or reducing, the chemical shift that female ring is gone up saturated hydrogen does not change yet, therefore ring structure is stable, but each ring hydrogen all is shown as multiplet, so product A 1 is the mixture of EGCG monopalmitate.
The H-NMR(500MHz of white solid A2, DMSO-d6): 0.75～0.90(6H, m, CH
3); 1.1～1.4(48H, m, (CH
2)
12); 1.55～1.68(4H, m,
CH 2 CH
2COO); 2.4～2.6(4H, m, CH
2COO is overlapped with the DMSO solvent peak); 2.65～2.80(1H, m, CH
2Ar); 2.90～3.05(1H, m, CH
2Ar); 4.95～5.53(2H, m, ArOCHCHO); 5.80～7.25(6H, m, ArH); 8.50～11.0(6H, m, OH).
Hydrogen spectrum data show that the female ring of EGCG is 1:2 with the mol ratio of cetylate side chain in the product A 2; 6 phenolic hydroxyl groups are only arranged in the product, lacked the hydrogen of two phenolic hydroxyl groups among the EGCG, other hydrogen does not reduce or increases, the chemical shift that female ring is gone up saturated hydrogen does not change yet, therefore ring structure is stable, but each ring hydrogen also is shown as multiplet, shows that it is the mixture of EGCG acid dipalmitate.
Embodiment two
Identical with embodiment one, only change acyl chlorides and DMAP consumption, palmityl chloride and EGCG mol ratio are 1.1:1; Namely use 0.067g(0.55mmol) DMAP and 0.151g(0.55mmol) palmityl chloride participation reaction.Back flow reaction was carried out TLC(ethyl acetate/petroleum ether 2:1 to product after 2 hours, v/v) detected, and the result is shown in Fig. 1 (I).
By Fig. 1 (I) as seen, the reaction product point sample is on initial point B, and (ethyl acetate/petroleum ether 2:1 v/v) obtains two R after the expansion through developping agent
fBe worth different chromatography points, be designated 1,2; Represent two kinds of materials of B1, B2 respectively.In addition, as seen the small amount of solid DMAP hydrochloride of bringing into when the point on the initial point B is sampling still exists the intact EGCG of minute quantity unreacted.
The reactant aftertreatment is with embodiment one, and silica gel column chromatography (ethyl acetate/petroleum ether 2:1, v/v) separation and purification gets 0.25g principal product B1, and white solid is identical with A1, is the EGCG monopalmitate, yield 72%.
Embodiment three
Identical with embodiment one, only change acyl chlorides and DMAP consumption, palmityl chloride and EGCG mol ratio are 2.2:1; Namely use 0.135g(1.10mmol) DMAP and 0.303g(1.10mmol) palmityl chloride participation reaction.Back flow reaction after half an hour with the product point sample in initial point C, carry out TLC(ethyl acetate/petroleum ether 4:1, v/v) detect;
2 hours afterreactions of back flow reaction finish, and the product point sample in initial point D, is carried out TLC(ethyl acetate/petroleum ether 4:1, v/v) detect, and the result is shown in Fig. 1 (II).
By Fig. 1 (II) as seen, contain identical material in the product of gained after back flow reaction half an hour and 2 hours, but the content difference.Be 1,2,3,4 with four chromatography point identifications; Represent D1, D2, four kinds of materials of D3, D4 respectively.Principal product was D2 when reaction finished.
The reactant aftertreatment is with embodiment one, and (ethyl acetate/petroleum ether 2:1, v/v) separation and purification gets 0.30g principal product D2 to silica gel column chromatography, is white solid, and is identical with A2, is the EGCG acid dipalmitate, yield 64%.
Embodiment four
Identical with embodiment one, only change acyl chlorides and DMAP consumption, palmityl chloride and EGCG mol ratio are about 5.1:1; Namely use 0.310g(2.54mmol) DMAP and 0.703g(2.56mmol) palmityl chloride participation reaction.Back flow reaction after 4 hours with the product point sample in initial point E, respectively with developping agent ethyl acetate/petroleum ether 4:1(v/v), ethyl acetate/petroleum ether 1:2(v/v) carry out TLC and detect, detected result is seen Fig. 1 (II) and Fig. 1 (III) respectively.
With ethyl acetate/petroleum ether 4:1(v/v) when launching, have to a chromatography point, be designated 1, representative species E1; Carry out the TLC analysis because after reaction soln leaves standstill, get clear liquid, do not have the DMAP hydrochloride on the initial point E.
With ethyl acetate/petroleum ether 1:2(v/v) when launching, obtain six chromatography points, be designated 1', 2', 3', 4', 5', 6', represent E1', E2', E3', E4', these six kinds of materials of E5', E6' respectively.Inclusion compound E1'～E6' among the E1 then; E1' identical with A2' (A2' namely is A4), E2'～E6' is the product of higher gamma value.
The result shows has not had low gamma value product in the reaction product, but high gamma value product is formed comparatively complexity.
Reactant aftertreatment: product is cooled to 0 ℃, removes by filter white solid; Solution is with 3 * 20mL distilled water wash, and anhydrous sodium sulfate drying filters, and vacuum concentration reclaims solvent, and the gained solid gets the 0.76g white solid with 5mL ethanol/20mL water recrystallization, is the high cetylate product of EGCG.
Embodiment five
Identical with embodiment one, but acyl chlorides is used Acetyl Chloride 98Min. instead, and the mol ratio of Acetyl Chloride 98Min., DMAP and EGCG is 8.4:1; Namely use 0.51g(4.2mmol) DMAP and 0.33g(4.2mmol) Acetyl Chloride 98Min. participation reaction, EGCG, zinc chloride consumption are constant, back flow reaction 4 hours, be cooled to the room temperature after-filtration, filtrate is sloughed solvent through underpressure distillation, and the gained solid gets white solid 0.38g through column chromatography separating purification, nuclear magnetic resonance spectrum is consistent with the full acetic ester of EGCG of bibliographical information, yield 93%.
By embodiment one to embodiment five as can be known, adopt the inventive method, the proportioning that only need adjust EGCG and acyl chlorides can effectively be controlled mono-esterification, double esterification and the polyesterization of EGCG.Wherein mono-esterification and the separation and purification of double esterification product are simple, the yield height; High gamma value product is formed relative complex, but when the acyl chlorides consumption approaches full esterification consumption, and high gamma value product is formed just and understood simply, and separablely obtains full esterification products.Embodiment five shows clearly that also the reaction of this law is a kind of esterification from start to finish.
Comparative Examples one
Adopt classical esterification process: with embodiment one, but do not add ZnCl
2, only use DMAP catalyzed reaction and consumption constant, palmityl chloride and EGCG consumption are also constant, heating reflux reaction after 16 hours with the product point sample in initial point F, carry out TLC and detect that (ethyl acetate/petroleum ether 1:2, v/v), the result is shown in Fig. 1 (III).
By Fig. 1 (III) as seen, product obtains six R after launching
fBe worth different chromatography points, the R of these six chromatography points
fValue is identical with 6 chromatography point E1'～E6' that launch from initial point E, represents F1', F2', F3', F4', these six kinds of materials of F5', F6' respectively, the R of chromatography point F1'
fValue is also identical with the chromatography point A2' that launches from initial point A.
Detected result shows, these six products that material all is high gamma values, and material F1' identical with A4 (A2' namely is A4), and F2'～F6' is the product of higher gamma value.
In addition, also contain the EGCG that some have neither part nor lot in reaction among the initial point F, and a small amount of mono-esterification and double esterification product.Exactly because the generation of high gamma value product has consumed more acyl chlorides, make to still have part EGCG not esterified because acyl chlorides runs out of; Illustrate and acyl chlorides generation esterification that EGCG compares with the EGCG of partial esterification does not have competitive edge.As seen, with the reacting phase ratio of embodiment one, though proportioning raw materials is identical, adopt classical esterification process (Comparative Examples one), random esterification takes place in the poor selectivity of EGCG esterification easily, the product complexity that obtains.
And, though the high esterification products of Comparative Examples one and embodiment four identical (showing further that also this law is identical with classical esterification, is a kind of esterification) have not had low esterification products in the product that the embodiment four of higher acyl chlorides consumption obtains.As seen, be different from the random esterification of classical esterification, the reaction of embodiment four is the further result of esterification on the basis after finishing mono-esterification, double esterification.
Comparing embodiment two, three, four as can be known, the speed of response of EGCG esterification is mono-esterification〉double esterification polyesterization; Therefore, adopt the inventive method, by regulating the proportioning of acyl chlorides and EGCG, can control the degree of esterification of EGCG effectively.
Embodiment six
With embodiment one to embodiment five, use the zinc oxide of zinc sulfate, zinc acetate, Zinic stearas, single nickel salt, lanthanum trichloride, tin protochloride or 1/10th molar weights of equimolar amount, zinc hydroxide to substitute zinc chloride respectively, all obtain identical product.
Embodiment seven
With embodiment one, pyridine, triethylamine or the N-methyl piperidine with equimolar amount substitutes DMAP respectively, also obtains same products.
Embodiment eight
Under nitrogen protection, 0.23g(0.5mmol) EGCG is dissolved in the 10mL tetrahydrofuran (THF), adds 0.068g(0.5mmol) ZnCl
2And 0.8g(12.2mmol) pure zinc powder stirs 2min under the room temperature, drips 10mL and is dissolved with 0.23g(0.83mmol) tetrahydrofuran solution of palmityl chloride.Dropwise the back continue stirring reaction to reaction solution pH be 2～3, remove by filter the intact zinc powder of unreacted, vacuum concentration reclaims solvent, gained solid ethyl acetate/petroleum ether 2:1 (v/v) column chromatographic isolation and purification, obtain two kinds of each 0.13g of white solid and 0.19g, with A1 and A2, be EGCG monopalmitate and EGCG acid dipalmitate respectively.
Embodiment nine
With embodiment eight, but replace zinc chloride and zinc powder respectively with tin protochloride and the metallic tin grain of equimolar amount, obtain identical product.
Embodiment ten
Under nitrogen protection; 0.23g(0.5mmol) EGCG is dissolved in the 10mL glycol dimethyl ether; (Zn is 3.06mmol to the zinc of adding 0.2g surface oxidation; ZnO is 1.23 μ mol; ZnO content is 0.05%), drip 10mL and be dissolved with 0.31g(1.13mmol) ethylene glycol dimethyl ether solution of palmityl chloride.Continue after dropwising at room temperature stirring reaction to reaction solution pH be 2～3, remove by filter the intact zinc of unreacted, vacuum concentration reclaims solvent, gained solid ethyl acetate/petroleum ether 2:1 (v/v) column chromatographic isolation and purification, obtain two kinds of each 0.08g of white solid and 0.27g, with A1 and A2, be EGCG monopalmitate and EGCG acid dipalmitate respectively.
Embodiment 11
Under nitrogen protection, 2.0g tea-polyphenol, 0.6g(4.4mmol) ZnCl
2Be dissolved in the 30mL ethyl acetate, add 0.71g(5.8mmol) 4-Dimethylamino pyridine (DMAP); Stir and to drip 30mL down and be dissolved with 1.6g(5.8mmol) ethyl acetate solution of palmityl chloride, heating reflux reaction 2h; Be cooled to 0 ℃, remove by filter white solid; Solution is with 3 * 50mL distilled water wash, and anhydrous sodium sulfate drying filters, and vacuum concentration reclaims solvent, and the gained solid is with 20mL tetrahydrofuran (THF)/60mL sherwood oil recrystallization, and vacuum-drying gets lurid tea-polyphenol cetylate 3.0g.
Get the 0.2g product, with ethyl acetate/petroleum ether 4:1 (v/v) column chromatographic isolation and purification, isolated principal product is white solid, and is identical with the A1 of embodiment one, is the EGCG monopalmitate.
Embodiment 12
Under nitrogen protection, the 2.0g tea-polyphenol is dissolved in the 40mL tetrahydrofuran (THF), adds the zinc (Zn is 30.6mmol, and ZnO is 12.3 μ mol, and ZnO content is 0.05%) of 2.0g surface oxidation; Stir 2min under the room temperature, drip 60mL and be dissolved with 3.3g(12.0mmol) tetrahydrofuran (THF) of palmityl chloride; Dropwise the back continue stirring reaction to reaction solution pH be 2～3; Remove by filter the intact zinc powder of unreacted; Be evaporated to the about 30mL of solution, add 150mL distilled water, suction filtration, gained solid 20mL ethanol/80mL distilled water recrystallization, vacuum-drying gets light yellow tea-polyphenol cetylate 4.2g.Product can be dissolved in the edible salad oil, is a kind of fat-soluble tea polyphenol.
Get the 0.2g product, with ethyl acetate/petroleum ether 2:1 (v/v) column chromatographic isolation and purification, isolated principal product is white solid, and is identical with the A2 of embodiment one, is the EGCG acid dipalmitate.
Embodiment 13
Containing 4.0g(14.6mmol) in the 20mL acetonitrile of palmityl chloride, add 1.2g(15.2mmol) pyridine/20mL acetonitrile solution; Under the nitrogen protection, add and contain 0.6g(4.4mmol) ZnCl
2With the 30mL acetonitrile solution of 2.0g tea-polyphenol, stirring reaction is 15 minutes under the room temperature, and heating reflux reaction is 1.5 hours then; Be evaporated to the about 30mL of solution, add 150mL0.02mol/mL dilute hydrochloric acid, suction filtration is washed to neutrality, the solid that obtains 20mL tetrahydrofuran (THF)/80mL distilled water recrystallization, and vacuum-drying gets light yellow fat-soluble tea polyphenol 4.8g.
Embodiment 14
Under nitrogen protection, the 2.0g tea-polyphenol is dissolved in the 40mL tetrahydrofuran (THF), adds 0.01g(0.13mmol) aluminium hydroxide and 2.0g10～20 order alumino nickels (47% nickel), stir 1min under the room temperature; Drip 60mL and be dissolved with 4.8g(17.5mmol) tetrahydrofuran (THF) of palmityl chloride; Dropwising back continuation stirring reaction to pH value of solution is 2～3; Remove by filter the intact alumino nickel of unreacted; In reaction solution, add 150mL distilled water under stirring and separate out solid, filter, be washed to water and be neutral; The gained solid is used 20mL tetrahydrofuran (THF)/80mL distilled water recrystallization again, and vacuum-drying gets light yellow fat-soluble tea polyphenol 5.5g.
Embodiment 15
Under nitrogen protection, the 2.0g tea-polyphenol is dissolved in the 30mL DMF solution, drips earlier 0.3mL and is dissolved with 4.8g(17.5mmol) the 30mL DMF solution of palmityl chloride, add 0.8g(12.2mmol behind the stirring reaction 10min) pure zinc powder; Treat that it is 3～4 that solution acidity is down to pH, with abundant generation zinc chloride, continue to drip remaining palmityl chloride DMF solution then; Dropwising back continuation stirring reaction to pH value of solution under 20 ℃ is 2～3; Remove by filter the intact zinc powder of unreacted, in reaction solution, add 150mL distilled water under stirring and separate out solid, filter, be washed to water and be neutral; The gained solid is used 25mL ethanol/100mL distilled water recrystallization again, and vacuum-drying gets yellow fat-soluble tea polyphenol 5.1g.
Embodiment 16
Under nitrogen protection, the 2.0g tea-polyphenol is dissolved in the 40mL tetrahydrofuran (THF), adds 0.2g(0.3mmol) Zinic stearas and 0.52g(7.9mmol) zinc powder, 40 ℃ are stirred 5min down; Drip 60mL and be dissolved with 5.0g(16.5mmol) tetrahydrofuran solution of stearyl chloride; Dropwising back continuation stirring reaction under 40 ℃ all disappears until solid; In reaction solution, add 150mL distilled water under stirring and separate out solid, filter, be washed to water and be neutral; The gained solid is used 20mL ethanol/80mL distilled water recrystallization again, filters, and vacuum-drying gets light yellow fat-soluble tea polyphenol (tea-polyphenol stearate) 4.8g.
Claims (10)
1. the esterification process of a tealeaves polyphenol; be included in that tealeaves polyphenol and acylating reagent react in the organic solvent under the effect of catalyzer; reaction product obtains esterification products through separation and purification, it is characterized in that, described catalyzer is metal ion catalyst and acid scavenger.
2. esterification process as claimed in claim 1 is characterized in that, described tealeaves polyphenol is simple catechin, and described acylating reagent is C
2～C
32Fat acyl chloride, the mol ratio of fat acyl chloride and catechin is 0.5～10:1.
3. esterification process as claimed in claim 1 is characterized in that, described tealeaves polyphenol is tea-polyphenol, and described acylating reagent is C
2～C
32Fat acyl chloride, the ratio of fat acyl chloride and tea-polyphenol is 0.1～2.5mol:100g.
4. esterification process as claimed in claim 1 is characterized in that, described metal ion catalyst is the compound that contains metal ion, and described compound is at least a in metal oxide, oxyhydroxide, the salt;
Described metal ion is rare earth ion, Mg
2+, Ca
2+, Sr
2+, Ba
2+, Al
3+, Ga
3+, In
3+, Ge
2+, Ge
4+, Sn
2+, Sn
4+, Ti
2+, Ti
4+, V
3+, Mn
2+, Fe
2+, Fe
3+, Co
2+, Ni
2+, Cu
2+, Zn
2+In at least a.
5. esterification process as claimed in claim 4 is characterized in that, the mol ratio of described metal ion catalyst and acylating reagent is 10
-6～5:1.
6. esterification process as claimed in claim 1 is characterized in that, described acid scavenger is the metal acid scavenger, and described metal acid scavenger is at least a among rare earth metal, Mg, Ca, Al, Ga, In, Ge, Sn, Ti, V, Mn, Fe, Co, Ni, the Zn.
7. esterification process as claimed in claim 6 is characterized in that, the mol ratio of described metal acid scavenger and acylating reagent is at least 0.2:1.
8. esterification process as claimed in claim 1 is characterized in that, described acid scavenger is the bases acid scavenger, and described bases acid scavenger is at least a in the following compounds:
Fat amine R
1R
2R
3N:R
1, R
2, R
3Independent separately is C
1～C
4Alkyl;
Alicyclic ring amine: N-methyl Pyrrolidine, N-ethyl Pyrrolidine, N-methyl piperidine, N-ethylpiperidine, N, N'-lupetazin or N, N'-diethyl piperazine;
Pyridines: the substituting group on each carbon of pyridine ring is hydrogen, C independently of one another
1～C
4Alkyl, C
2～C
6Fatty acyl group, C
1～C
4Alkoxyl group, C
1～C
6Fat acyloxy, C
1～C
4Alkoxyl formyl, substituted-amino R
4R
5N-, substituted-amino formyl radical R
6R
7NCO-, nitro, cyano group, fluorine, chlorine, bromine or iodine; Wherein, R
4, R
5Be C independently of one another
1～C
4Alkyl, C
1～C
6Fatty acyl group; Or R
4R
5=(CH
2)
n, n=4～5; Or R
4R
5=-CH
2CH
2NR
8CH
2CH
2-, R
8Be C
1～C
4Alkyl, C
1～C
6Fatty acyl group; R
6, R
7Independent separately is C
1～C
4Alkyl.
9. esterification process as claimed in claim 8 is characterized in that, the mol ratio of described bases acid scavenger and acylating reagent is 0.2～20:1.
10. esterification process as claimed in claim 1 is characterized in that, described organic solvent is at least a in the following solvent:
Esters solvent R
9COOR
10: R
9=C
1～C
5Alkyl, R
10=C
1～C
6Alkyl;
Ether solvent: ether, glycol dimethyl ether, ethylene glycol methyl ether, ethylene glycol diethyl ether, 1,2-Propylene Glycol Dimethyl Ether, 1, ammediol dme, tetrahydrofuran (THF), 1,4-dioxane;
Ketones solvent R
11COR
12: R
11, R
12Independent separately is C
1～C
4Alkyl; Cyclopentanone, pimelinketone;
Acetonitrile, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide;
The weightmeasurement ratio of described tealeaves polyphenol raw material and organic solvent is 1g:2～500mL.
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