CN104327032A - Esterification method of catechin or tea polyphenol - Google Patents
Esterification method of catechin or tea polyphenol Download PDFInfo
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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Abstract
The invention discloses an esterification method of catechin or tea polyphenol. In the esterification method, a catalyst for esterification is carbonyl diimidazole and/or imidazole. The esterification method comprises esterification between an organic carboxylic acid and the catechin or the tea polyphenol with catalysis of the carbonyl diimidazole, or the esterification between an anhydride or an acyl chloride and the catechin or the tea polyphenol with synergetic catalysis of the imidazole and/or the carbonyl diimidazole. The carbonyl diimidazole is a strong dehydrating agent and can eliminate influence of water on the esterification in the reaction system. The carbonyl diimidazole can effectively activate carboxylic acid so that not only can the carboxylic acid be used as an acylation reagent, but also free carboxylic acids existing in the esterification of the anhydride or the acyl chloride can be fully utilized, so that esterification degree of esterification products can be conveniently controlled according to proportion of raw materials and a residual amount of the free carboxylic acids after reaction is less. Meanwhile, the carbonyl diimidazole and the imidazole is very easy to separate from the esterification products, thereby greatly enabling separation and purification of the products to be convenient.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the esterification process of a kind of catechin or tea-polyphenol.
Background technology
The tea leaf extract of tea-polyphenol to be a kind of with catechin be main component, wherein catechin is primarily of C, EC, EGC, ECG, EGCG and GCG composition, and the highest with EGCG content.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.But catechin and tea-polyphenol soluble in water and be insoluble in grease, Determination of oil-water partition coefficient is little and bioavailability is low, limits their Application Areas, also inhibits their physiology and pharmacologically active function.
Strengthen catechin compounds method of solubleness in grease and mainly contain three kinds: solvent method, emulsion process and molecular modification method, but the above two do not change the molecular structure of catechin compounds, only make catechin compounds be dispersed in system by physical dissolution or emulsifying manner, comparatively molecular modification method is poor for its effect, the stable system that the antioxidant system of formation does not have molecular modification method to be formed yet.Molecular modification method utilizes biological or chemical route of synthesis to carry out structurally-modified to catechin compounds, and wherein, esterification techniques application is the most general.Because the product after esterification can not only improve the Determination of oil-water partition coefficient of catechin compounds, improve bioavailability, and ester can be decomposed by the lytic enzyme in animal body, and again discharge catechin, pathways metabolism is relatively clear and definite, biology and the pharmacological effect that can give full play to catechin can be realized, modified outcome can be made again not have toxicity.
Such as, EGCG enzyme process or classical chemical process synthesize the antiviral and anti-tumor activity of the EGCG mono fatty acid ester obtained higher than EGCG, and it is the strongest with the activity of EGCG monopalmitate, esterified positions difference does not affect activity simultaneously, and activity also identical (Bioorg.Med.Chem.Lett.2008,18, the 4249.Biochem.Biophys.Res.Commun.2008 of the mixture of monopalmitate and its single component, 377,1118); The EGCG of the full esterification of lipid acid also has the antiviral and anti-lipid peroxidation enzymic activity (ARKIVOC 2007,6-16.J.Agric.Food Chem.2001,49,1042.) higher than EGCG.Therefore, catechin such as the esterification of EGCG can obtain mono-esterification to the catechin of full esterification, although degree of esterification is different, Determination of oil-water partition coefficient difference, pharmacologically active and biological function variant, different esterification products can be applied in various different field.
In prior art, during using organic carboxyl acid as acylating reagent, because the acidylate ability of carboxylic acid is low, catalyst activation must be used.The direct esterification of carboxylic acid and alcohol can do catalysis with dewatering agents such as DCC (dicyclohexylcarbodiimide), but the activity of DCC catalysis carboxylic acid and phenol direct esterification is not strong, and self is transformed into dicyclohexylurea (DCU) after the esterification of catalysis phenol, the latter's separation difficulty, easy polluted product.Therefore, find that catalytic activity is better, the catalyst application of being convenient to separation and purification of products is significant in the esterification of catechin and tea-polyphenol.
Summary of the invention
The invention provides the esterification process of a kind of catechin or tea-polyphenol, this synthetic method utilizes carbonyl dimidazoles derivative and/or imdazole derivatives as the catalyzer in catechin or tea-polyphenol esterification, catalytic activity is good, and esterification products is convenient to separation and purification, and degree of esterification is controlled.
The esterification process of a kind of catechin or tea-polyphenol; comprise catechin or tea-polyphenol and acylating reagent in organic solvent to react under the effect of catalyzer; reaction product obtains esterification products after separation and purification; described catalyzer is carbonyl dimidazoles derivative and/or imdazole derivatives; the structural formula of carbonyl dimidazoles derivative is as shown in (A), and the structural formula of imdazole derivatives is as shown in (B):
Wherein, R
1~ R
9be separately the C of hydrogen, replacement
1~ C
6the C of aliphatic group, substituted oxy, replacement
2~ C
6fatty acyl group, substituted formacyl, disubstituted amino, C
1~ C
6alkylthio, cyano group, nitro, fluorine, chlorine, bromine, iodine, or, R
2-R
3, R
5-R
6, R
8-R
95 ~ 6 yuan of alicyclic rings are separately formed together with carbon atom connected separately;
The C of described replacement
1~ C
6aliphatic group, C
1~ C
6substituting group on aliphatic group is separately hydrogen, C
1~ C
6the C of alkoxyl group, replacement
2~ C
6fatty acyl group, substituted formacyl, disubstituted amino, C
1~ C
6alkylthio, cyano group, nitro, fluorine, chlorine, bromine, iodine;
Described substituted oxy, the substituting group on oxygen is selected from C
1~ C
6the C of aliphatic group, replacement
2~ C
6fatty acyl group;
The C of described replacement
2~ C
6fatty acyl group, C
2~ C
6substituting group on fatty acyl group is separately hydrogen, C
1~ C
6alkoxyl group, disubstituted amino, C
1~ C
6alkylthio, cyano group, nitro, fluorine, chlorine, bromine, iodine;
Described substituted formacyl, the substituting group on formyl radical is selected from C
1~ C
6alkoxyl group, C
1~ C
6alkylthio, disubstituted amino;
Described disubstituted amino, two substituting groups on amino are separately C
1~ C
6alkyl, C
1~ C
6fatty acyl group, or amino nitrogen atom forms 5 ~ 6 yuan of heterocycles together with its two substituting groups; When forming 5 ~ 6 yuan of heterocycles, heteroatoms can be only amino nitrogen atom, and other heteroatoms also can be had to participate in into ring, other described heteroatoms optional from-O-,-S-,-N=,-N (R')-, wherein, R' is C
1~ C
6alkyl, or C
1~ C
6fatty acyl group.
As preferably, R
1~ R
9separately be selected from hydrogen, cyano group, nitro, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, the tertiary butyl, methoxyl methyl, ethoxymethyl, acetoxy-methyl, dimethylamino methyl, N-methylacetamido methyl, 2-methoxy ethyl, 2-ethoxyethyl group, 2-dimethylaminoethyl, methoxycarbonyl methyl (MeOOCCH
2-), dimethylamino formyl methyl (Me
2nCOCH
2-), trifluoromethyl, trichloromethyl, methoxyl group, oxyethyl group, methoxycarbonyl base, ethoxycarbonyl, dimethylamino formyl radical, ethanoyl, propionyl, Methoxyacetyl, trifluoroacetyl group, dimethylamino acetyl, 2-dimethylamino-3-methylthio group propionyl, dimethylamino, 1-Pyrrolidine base, piperidino, 4-methyl isophthalic acid-piperazinyl, etc.
If do not make specified otherwise, the tea leaf extract of described tea-polyphenol to be a kind of with catechin be main component; Described catechin refers to that can be only have a kind of catechin, also can be the mixture that multiple catechin forms with arbitrary proportion not containing other component in tea leaf extract, is preferably EGCG.
For dissimilar acylating reagent, the invention provides two kinds of catalyst combination:
One, when described acylating reagent is organic carboxyl acid (hereinafter referred to as carboxylic acid), described catalyzer is carbonyl dimidazoles derivative.
Carbonyl dimidazoles (CDI, R
1~ R
6=H) be the activator of carboxylic acid, it and carboxylic acid reaction obtain 1-acylimidazole, as shown in reaction (1).1-acylimidazole is a kind of high reactivity acylating reagent, with catechin ArOH, esterification fast can occur, and generates ester RCOOAr and discharges a part imidazoles, as shown in reaction (2).Imidazoles is a kind of amphoteric substance, and toxicity is little, and itself has good water-soluble, can wash away simply in aftertreatment with diluted acid or diluted alkaline, also with the removing of water-containing solvent recrystallization, can facilitate the separation and purification of esterification products widely.
Carbonyl dimidazoles has the ability of extremely strong activating carboxy acid, no matter is aromatic acid, heterocyclic acids or lipid acid, can react generate corresponding ester under carbonyl dimidazoles catalysis to catechin or tea-polyphenol.As preferably, described acylating reagent is lipid acid, is more preferably C
2~ C
32lipid acid.Carboxylic acid wide material sources, cost is low, and especially the unsaturated link(age) of this law on unsaturated acid does not affect, and is specially adapted to the esterification of unsaturated carboxylic acid and catechin or tea-polyphenol.
From reaction (1), the CDI of 1mol can activate 1mol carboxylic acid in theory, and when namely carboxylic acid makes acylating reagent, the theoretical amount of carboxylic acid and carbonyl dimidazoles is 1:1 (mol ratio).In order to make full use of CDI, excessive carboxylic acid is used to be conducive to promoting the carrying out of reaction (1), especially when excessive carboxylic acid (such as acetic acid) easily removes in aftertreatment.Simultaneously, CDI is a fabulous water-removal agent, when bringing a small amount of water into because of solvent, reaction raw materials etc. in reaction system, a part water can consume a part dewatering agent CDI, enough CDI can guarantee that carboxylic acid all participates in reaction, to make in reaction product that residual carboxylic acid is extremely low even not to be remained, especially when carboxylic acid (as palmitinic acid, oleic acid, linolic acid etc.) used is difficult to effectively be separated from reaction product simply by methods such as recrystallizations.Therefore, consider, the mol ratio of carboxylic acid and carbonyl dimidazoles is preferably 1:0.3 ~ 5, is more preferably 1:1 ~ 2.
In the present invention, not only carbonyl dimidazoles can activating carboxy acid, and other carbonyl dimidazoles derivative (A) is also all good carboxylic acid activating agent, can the esterification of effectively catalysis carboxylic acid and catechin or tea-polyphenol.Therefore, when described acylating reagent is carboxylic acid, the mol ratio of carboxylic acid and carbonyl dimidazoles derivative (A) is preferably 1:0.3 ~ 5.
From other, there is different R
1~ R
6the carbonyl dimidazoles derivative of group is compared, the esterification of catalysis carboxylic acid and catechin or tea-polyphenol, carbonyl dimidazoles (R
1~ R
6=H) activity enough; In addition, list is considered from cost, and carbonyl dimidazoles is lower than other carbonyl dimidazoles derivative cost, and ample supply of commodities on the market.So described carbonyl dimidazoles derivative is preferably carbonyl dimidazoles.
With the esterification of carbonyl dimidazoles derivatives catalysis carboxylic acid and catechin or tea-polyphenol, by controlling the proportioning of carboxylic acid and catechin or tea-polyphenol, the degree of esterification of catechin or tea-polyphenol can be controlled, obtain a series of esterification products from mono-esterification to full esterification.As aforementioned, the esterification products of different degree of esterification can be applied in different field.So the mol ratio of carboxylic acid and catechin is preferably 0.2 ~ 20:1, or the ratio of carboxylic acid and tea-polyphenol is preferably 0.1 ~ 10mol:200g.
Its two, when described acylating reagent be organic acid anhydride or organic acyl chlorides time, described catalyzer is imdazole derivatives and/or carbonyl dimidazoles derivative; That is, can be used alone imdazole derivatives, also can be used alone carbonyl dimidazoles derivative, imdazole derivatives and carbonyl dimidazoles derivative can also be used simultaneously.
Under carbonyl dimidazoles catalysis, the Viability acid amides of carboxylic acid (1-acylimidazole), from reaction (2), active 1-acylimidazole could react to catechin or tea-polyphenol and generate corresponding ester.So, as long as 1-acylimidazole can be obtained, the esterification with catechin or tea-polyphenol just can be realized.
1-acylimidazole, also can by organic acid anhydride or organic acyl chlorides and imidazoles (R except can by except carboxylic acid and carbonyl dimidazoles Reactive Synthesis
7~ R
9=H) be obtained by reacting, as shown in reaction (3), reaction (4).
So, activate organic acyl chlorides with imidazoles or organic acid anhydride can substitute CDI activating carboxy acid, similarly can react with catechin or tea-polyphenol and generate ester.Described organic acyl chlorides (hereinafter referred to as acyl chlorides) or organic acid anhydride (hereinafter referred to as acid anhydrides) can be aromatic series, heterocyclic or aliphatic acyl chlorides or acid anhydrides.As preferably, described acylating reagent is aliphatic acyl chlorides or acid anhydrides, is more preferably C
2~ C
32fat acyl chloride or acid anhydrides.
Obviously, imidazoles also can with having different R
7~ R
9the imdazole derivatives of group substitutes, but similarly, imidazoles activity has been enough to the reaction of catalysis acyl chlorides or acid anhydrides and catechin or tea-polyphenol, and list is considered from cost, imidazoles (R
7~ R
9=H) than other, there is different R
7~ R
9the imdazole derivatives cost of group is low, and ample supply of commodities on the market.Therefore, described imdazole derivatives is preferably imidazoles.
From reaction (3) and reaction (2); the 1-acylimidazole of 1mol is obtained after acid anhydrides and 1mol imidazoles react; discharge again 1mol imidazoles after the 1-acylimidazole of 1mol and catechin or tea-polyphenol react, imidazoles is not consumed in reaction process.So, when making acylating reagent with acid anhydrides, only need the imidazoles of catalytic amount.Certainly, excessive imidazoles can accelerated reaction, also can remove simply and effectively in aftertreatment, but the cost of recycling can be increased, therefore, though the research on maximum utilized quantity of imidazoles can not do strict restriction, but as preferred, the mol ratio of described organic acid anhydride and imidazoles is 1:0.001 ~ 5.
From reaction (3), after a part anhydride reaction except generating a part 1-acylimidazole, also generate a part carboxylic acid.Carboxylic acid can not be activated by imidazoles, is difficult to and catechin or tea-polyphenol generation esterification.In order to make full use of that this part reaction produces and bring in anhydride starting material, in acid anhydrides and reaction system, water etc. acts on the free carboxy acid produced on a small quantity, in reaction system, also can add carbonyl dimidazoles.Although do not add carbonyl dimidazoles, only also can the esterification of catalysis acid anhydrides or acyl chlorides and catechin or tea-polyphenol with imidazoles, but acid anhydrides or acyl chlorides very easily react with the water in reaction system, and the degree of esterification of water to catechin or tea-polyphenol in reaction system exists great effect.Such as, 1kg water can consume 15.3kg palmityl chloride or 27.5kg palmitic anhydride; In 1 ton of solvent, EGCG and the 24kg palmityl chloride of 20kg or 43.2kg palmitic anhydride generation double esterification reaction, but even if the water content of solvent is only 0.0786%, just can consume 12kg palmityl chloride or 21.6kg palmitic anhydride, reaction becomes mono-esterification thereupon.As can be seen here, reaction system water content slightly changes, and will have a strong impact on composition and the degree of esterification of product, even if proportioning raw materials is identical, quality product is but difficult to stablize, and is difficult to the problem solved completely when this is also the fat-soluble tea polyphenol of prior art composite part esterification especially double esterification.But when imidazoles and carbonyl dimidazoles concerted catalysis; carbonyl dimidazoles can remove the water in reaction system; guarantee that reaction is carried out in anhydrous conditions; and make acylating reagent all can participate in reaction; the degree of esterification of esterification products can control by proportioning raw materials easily, then stable processing technique, the constant product quality of esterification products; and free acid residual in esterified prod can drop to minimum, quality product is better.
When there is free carboxy acid or water in reaction system; CDI can react with free carboxy acid or water and produce imidazoles; now; not additional imidazoles; the synergy of imidazoles and CDI also can occur, and CDI itself can directly and anhydride reaction; 1 mole of CDI and 1 equimolar acid anhydride reactant generate 2 moles of 1-acylimidazoles, as shown in reaction formula (5).Therefore, separately also can the esterification of catalysis acid anhydrides and catechin or tea-polyphenol with CDI.
When CDI and anhydride reaction generate 1-acylimidazole, the theoretical amount of CDI and acid anhydrides is 1:1 (mol ratio), but discharge imidazoles after 1-acylimidazole and catechin or tea-polyphenol esterification, imidazoles can complete reaction as catalyzer thereupon, as can be seen here, the CDI of catalytic amount also can the esterification of catalysis acid anhydrides and catechin or tea-polyphenol; Excessive CDI can remove the water in reaction system simultaneously.Therefore, when adopting separately CDI catalysis, the mol ratio of acid anhydrides and carbonyl dimidazoles is preferably 1:0.001 ~ 5.
In sum, when described acylating reagent is acid anhydrides, described catalyzer is imidazoles and/or carbonyl dimidazoles; The mol ratio of acid anhydrides and imidazoles is preferably 1:0 ~ 5, the mol ratio of acid anhydrides and carbonyl dimidazoles is preferably 1:0 ~ 5, and the total amount of imidazoles and carbonyl dimidazoles and the mol ratio of acid anhydrides are preferably 0.001 ~ 10:1 (namely the mol ratio of acid anhydrides, imidazoles, carbonyl dimidazoles is 1:0 ~ 5:0 ~ 5, and is 0 when imidazoles is different with carbonyl dimidazoles).When imidazoles and carbonyl dimidazoles concerted catalysis, additional imidazoles can accelerate esterification, especially can improve the speed of response of reaction initial period, and acylating reagent can be made full use of by enough carbonyl dimidazoles.
When acyl chlorides makes acylating reagent, the water etc. that also may be able to exist in, acyl chlorides impure because of acyl chlorides raw material itself and reaction system reacts and produces free carboxy acid.In reaction system, now add CDI can remove water in reaction system, guarantee that reaction is carried out in anhydrous conditions, meanwhile, the free carboxy acid of this part can also be made full use of and make acylating reagent all can participate in reaction.
Therefore, when described acylating reagent is organic acyl chlorides, described catalyzer is imidazoles and/or carbonyl dimidazoles; The mol ratio of organic acyl chlorides, imidazoles, carbonyl dimidazoles is preferably 1:0 ~ 5:0 ~ 5, and the mol ratio of the total amount of imidazoles and carbonyl dimidazoles and described organic acyl chlorides is 0.3 ~ 10:1.Only can use the esterification of the organic acyl chlorides of Catalyzed by Imidazole and catechin or tea-polyphenol, especially when acyl chlorides purity is very high and reaction system water content is extremely low; Carbonyl dimidazoles and water react, act on and complete esterification with free carboxy acid all can produce imidazoles, this part carbonyl dimidazoles in fact partly or entirely can substitute additional imidazoles, therefore, also only catalyzer can be made with carbonyl dimidazoles, when being now specially adapted to that acyl chlorides purity is not high, reaction system water content is higher; In order to reduce the unnecessary loss of carbonyl dimidazoles, raw material, solvent etc. all should carry out necessary drying treatment, but even so, inevitable during the having of minor amount of water, and often containing a small amount of free carboxy acid in acyl chlorides, therefore the esterification of imidazoles and the organic acyl chlorides of carbonyl dimidazoles concerted catalysis and catechin or tea-polyphenol can also be adopted.In addition, although excessive imidazoles can accelerated reaction, also can remove simply and effectively in aftertreatment, but the cost of recycling can be increased, therefore, though the research on maximum utilized quantity of imidazoles can not be restricted, but as preferred, the research on maximum utilized quantity of imidazoles and the mol ratio of acyl chlorides are 5:1.
From reaction (4), the HCl produced after acyl chlorides and imidazoles react can be absorbed by imidazoles, thus consumes a part of imidazoles.This is because imidazoles is amphiprotic substance (is acid be also alkali), can as Alkali absorption HCl.Therefore, in order to reduce the consumption of imidazoles, other alkali except imidazoles also can be added to absorb HCl in reaction system.
Other described alkali is at least one in following compounds:
Fatty amines R
11r
12r
13n:R
11, R
12, R
13respective is independently C
1~ C
6alkyl;
Alicyclic ring amine: N-(C
1~ C
6alkyl) Pyrrolidine, N-(C
1~ C
6alkyl) piperidines, N-(C
1~ C
6alkyl) morpholine, N, N'-bis-(C
1~ C
6alkyl) piperazine;
Pyridines: the substituting group on each carbon of pyridine ring is hydrogen, C independently of one another
1~ C
6alkyl, C
2~ C
6fatty acyl group, C
1~ C
6alkoxyl group, C
1~ C
6fat acyloxy, C
1~ C
6alkoxyl formyl, substituted-amino R
14r
15n-, substituted-amino formyl radical R
16r
17nCO-, nitro, cyano group, fluorine, chlorine, bromine or iodine; Wherein, R
14, R
15be C independently of one another
1~ C
6alkyl, C
1~ C
6fatty acyl group; Or R
14r
15=-(CH
2)
n-, n=4 ~ 5; Or R
14r
15=-CH
2cH
2nR
18cH
2cH
2-, R
18for C
1~ C
6alkyl or C
1~ C
6fatty acyl group; Or R
14r
15=-CH
2cH
2oCH
2cH
2-; R
16, R
17be C independently of one another
1~ C
6alkyl.
From reaction (4) and reaction (2); in the presence of a base; a part imidazoles and acyl chloride reaction generate a part 1-acylimidazole, and discharge again a part imidazoles after 1-acylimidazole and catechin or tea-polyphenol react, in whole reaction process, imidazoles is not consumed.So, in the presence of a base, only need the imidazoles with catalytic amount, certainly, increase imidazoles consumption, favourable to accelerated reaction.
Therefore, in the present invention, when the esterification of the organic acyl chlorides of catalysis and catechin or tea-polyphenol, catalyzer can be only imidazoles, or replaces imidazoles by other alkali part; Also can be imidazoles and carbonyl dimidazoles, or partly or entirely replace imidazoles wherein with other alkali; Can moreover be only carbonyl dimidazoles.Then the mol ratio of organic acyl chlorides, other described alkali, imidazoles, carbonyl dimidazoles is 1:0 ~ 5:0 ~ 5:0 ~ 5, and imidazoles different with carbonyl dimidazoles time be 0, the described total amount of other alkali, imidazoles and carbonyl dimidazoles and the mol ratio of acyl chlorides are preferably 0.3 ~ 10:1.
When other described alkali and imidazoles and/or carbonyl dimidazoles concerted catalysis, reaction can be carried out smoothly, but reaction terminates both there is imidazoles in rear system and also there is other alkali, although imidazoles can be separated with esterification products with other alkali, do not affect the purifying of product, but need imidazoles to be further separated with other alkali toward contact, being separated and the complicacy of recycling of increase catalyzer imidazoles and other alkali.Therefore, when the esterification of the organic acyl chlorides of catalysis and catechin or tea-polyphenol, can without other alkali, catalyzer is preferably imidazoles and/or carbonyl dimidazoles.
Obviously, when described acylating reagent be acid anhydrides or acyl chlorides time, catalyzer imidazoles can with other imdazole derivatives (B) substitute; Carbonyl dimidazoles can substitute with other carbonyl dimidazoles derivative (A); The consumption of other imdazole derivatives or carbonyl dimidazoles derivative is identical with the consumption of above-mentioned imidazoles or carbonyl dimidazoles.
So when described acylating reagent is acid anhydrides, described catalyzer can be imdazole derivatives and/or carbonyl dimidazoles derivative.The mol ratio of acid anhydrides, imdazole derivatives, carbonyl dimidazoles derivative is preferably 1:0 ~ 5:0 ~ 5, and the total amount of imdazole derivatives and carbonyl dimidazoles derivative and the mol ratio of acid anhydrides are preferably 0.001 ~ 10:1;
When described acylating reagent is organic acyl chlorides, described catalyzer is preferably imdazole derivatives and/or carbonyl dimidazoles derivative.The mol ratio of described organic acyl chlorides, imdazole derivatives, carbonyl dimidazoles derivative is preferably 1:0 ~ 5:0 ~ 5, and the mol ratio of the total amount of imdazole derivatives and carbonyl dimidazoles derivative and described organic acyl chlorides is 0.3 ~ 10:1.
Similarly, control the proportioning of acid anhydrides or acyl chlorides and catechin or tea-polyphenol, a series of esterification products from mono-esterification to full esterification can be obtained.So the mol ratio of acid anhydrides or acyl chlorides and catechin is preferably 0.2 ~ 20:1, or the ratio of acid anhydrides or acyl chlorides and tea-polyphenol is preferably 0.1 ~ 10mol:200g.
Reaction of the present invention is carried out in organic solvent, and the organic solvent adopted should be able to dissolve acylating reagent and catechin or tea-polyphenol well, and with them, chemical reaction does not occur; Be preferably at least one in following solvent:
A) esters solvent R
19cOOR
20: R
19=C
1~ C
5alkyl, R
20=C
1~ C
6alkyl;
B) ether solvent: ether, glycol dimethyl ether, ethylene glycol methyl ether, ethylene glycol diethyl ether, 1,2-PD dme, 1,3-PD dme, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane;
C) ketones solvent R
21cOR
22: R
21, R
22be C independently of one another
1~ C
6alkyl; Cyclopentanone, pimelinketone;
D) acetonitrile, DMF, N,N-dimethylacetamide, methyl-sulphoxide;
Be more preferably at least one in ethyl acetate, tetrahydrofuran (THF), glycol dimethyl ether, acetone, acetonitrile, DMF, DMAc.
Because carbonyl dimidazoles derivative is good dewatering agent, the impact of water on esterification can be eliminated, therefore, this technological method does not make special restriction to the water content of solvent, but in order to avoid the loss that carbonyl dimidazoles derivative is unnecessary, as preferably, solvent etc. all should dry after use.Known Solvent drying processes has a lot, can select to adopt.
If the moist direct use of solvent, especially the solvent (as tetrahydrofuran (THF), glycol dimethyl ether, acetone, acetonitrile, DMF etc.) that can dissolve each other with water is used, then their water content sometimes can be very high, cause a large amount of carbonyl dimidazoles derivatives to be consumed, consumption even can exceed its research on maximum utilized quantity mentioned above.Therefore; as the water content of reaction system too high (mol ratio of reaction system water content and acylating reagent is more than 0.5:1); the consumption of carbonyl dimidazoles derivative is not then subject to above to the restriction of the carbonyl dimidazoles derivative consumption upper limit; the consumption upper limit can correspondingly increase, and the mol ratio of the amount that the consumption upper limit increases and reaction system total Water is pressed 1:1 and calculated.Obviously, when reaction system water content is too high, drying treatment should be carried out before the reaction, to reduce the unnecessary loss of carbonyl dimidazoles.In addition, ether solvent is if tetrahydrofuran (THF) is usually containing superoxide, and superoxide can be oxidized catechin and tea-polyphenol.Therefore, ether solvent also should remove superoxide wherein before use.The method removing superoxide in ether there will be a known multiple, can select to adopt.
In addition, the weightmeasurement ratio of catechin or tea-polyphenol and organic solvent is preferably 1g:1 ~ 500mL, is more preferably 1g:10 ~ 100mL.
1-acylimidazole is very active, and with catechin or tea-polyphenol, esterification fast can occur, therefore, reaction can be carried out under relatively mild condition, and temperature of reaction can be-10 DEG C ~ solvent reflux temperature, is preferably room temperature ~ 100 DEG C.
Under the above-described reaction conditions, catechin and tea-polyphenol are all more stable, and reaction can be carried out in physical environment.But catechin, tea-polyphenol and their partial esterification products are all oxidation inhibitor, atmospheric oxidation unnecessary in reaction process, reaction is preferably carried out under protection of inert gas.Preferred rare gas element is nitrogen or argon gas.
Compared with prior art, beneficial effect of the present invention is:
(1) the present invention can using carboxylic acid as acylating reagent, carboxylic acid source is wide, cost is low, easy to use, especially more difficult when being prepared into pure acid anhydrides or acyl chlorides (acyl chlorides that such as high boiling carboxylic acid and unsaturated carboxylic acid are as not easily obtained pure in palmitinic acid, stearic acid, oleic acid, linolic acid, linolenic acid, arachidonic acid etc.) in actually operating, direct carboxylic acid is made acylating reagent and to be more easy to get the catechin of high-quality or the esterification products of tea-polyphenol, and the various impurity that bring when can avoid synthesizing acyl chlorides, as the pollution to esterification products such as dioxin; Enough carbonyl dimidazoles can guarantee that carboxylic acid all participates in esterification, and the degree of esterification of esterification products is controlled by proportioning raw materials easily;
(2) the present invention is with the esterification of Catalyzed by Imidazole acid anhydrides or acyl chlorides and catechin or tea-polyphenol, carries out esterification when this method is specially adapted to easily obtain pure acid anhydrides or acyl chlorides to catechin or tea-polyphenol; The present invention also can with the esterification of imidazoles and carbonyl dimidazoles concerted catalysis acid anhydrides or acyl chlorides and catechin or tea-polyphenol, acylating reagent (carboxylic acid that the acid anhydrides added before comprising reaction or acyl chlorides, various approach produce) is not only made to be fully used, and carbonyl dimidazoles can also the composition of water on product and the impact of degree of esterification in eliminative reaction system, the degree of esterification of esterification products is controlled by proportioning raw materials easily, guarantees the constant product quality of esterification products;
(3) the present invention is with the esterification of imidazoles and/or carbonyl dimidazoles catalytie esterification reagent and catechin or tea-polyphenol, carbonyl dimidazoles can not only effective activation carboxylic acid, improve its acidylate active, and acidylate the esterification that reagent can fully participate in catechin or tea-polyphenol; And excessive carbonyl dimidazoles also by water fast decoupled, can discharge CO
2and imidazoles; Imidazoles have toxicity little, water-soluble large, be easy to be separated the features such as removing and recycling.Therefore, make catalyzer with imidazoles and/or carbonyl dimidazoles, not only catalytic capability is strong, and greatly can also simplify the purification procedures of esterification products.
Accompanying drawing explanation
Fig. 1 is the TLC detection figure of reaction product in embodiment six.
Fig. 2 is hydrogen spectrum (500MHz, the DMSO-d of EGCG monopalmitate
6).
Fig. 3 is the TLC detection figure of reaction product in EGCG, embodiment seven and embodiment eight;
Wherein, EGCG raw material is shown in EGCG list, A, B, C, D, E, F arrange the octanoate, laurate, cetylate, stearate, oleic acid ester and the linoleate that are respectively EGCG, (namely C row indicate product corresponding to " 1 " place to C1, below in like manner) identical with the product corresponding to C1 in Fig. 1, be EGCG monopalmitate; C2 (identical with the product in Fig. 1 corresponding to C2) is EGCG acid dipalmitate; Accordingly, A1, B1, D1, E1 and F1 are respectively single octanoate of EGCG, mono-laurate, monostearate, monoleate and single linoleate; A2, B2, D2, E2 and F2 are respectively two octanoates of EGCG, bilaurate, two stearate, dioleic acid ester and dilinoleic acid ester; A3 ~ F3 is corresponding EGCG tri-fatty acid ester.
Fig. 4 is hydrogen spectrum (500MHz, DMSO-d6) of EGCG acid dipalmitate.
Fig. 5 is that the TLC of reaction product (H) in reaction product (G) and embodiment ten in tea polyphenol raw materials (TP), embodiment nine detects figure;
Wherein, the R of TP1 and EGCG
fbe worth identical, TP2 should be other catechin; The R of G1 and EGCG monopalmitate, G2 and EGCG acid dipalmitate, G3 and EGCG tripalmitate
fbe worth identical, G1-1 should be the monopalmitate of other catechin, and G2-1 should be the acid dipalmitate of other catechin; The R of the two stearate of H1 and EGCG monostearate, H2 and EGCG, H3 and EGCG tristearate
fbe worth identical, H1-1 should be the monostearate of other catechin, and H2-1 should be two stearates of other catechin;
In Fig. 1,3,5, the developping agent adopted is ethyl acetate/petroleum ether/acetic acid 66:33:2 (v/v).
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Wherein,
Ethyl acetate, analytical pure, directly uses;
Tetrahydrofuran (THF), analytical pure, first uses
molecular sieve drying 1 hour, being then back to solution with benzophenone, sodium Metal 99.5 is bluish voilet, uses immediately after reformation.
Acetone, analytical pure, uses
molecular sieve drying 6 hours, uses after reformation immediately;
Palmityl chloride, stearyl chloride are self-control, adopt currently known methods, and synthesize by palmitinic acid or stearic acid and sulfur oxychloride back flow reaction, after steaming excessive sulfur oxychloride under normal pressure, underpressure distillation obtains;
Other reagent is analytical pure.
Embodiment one
1.78g (11mmol) CDI is dissolved in 50mL ethyl acetate, adds 0.60g (10mmol) acetic acid, reflux, and stirring reaction is to releasing without gas.Solution is cooled to 60 DEG C, adds 0.47g (1.0mmol) EGCG (purity 97%, lower same), at N
2under protection, continue heating reflux reaction 2 hours.Be cooled to room temperature, add the HCl of 50mL 0.5M, after stirring 2min, divide phase of anhydrating, (washing is represented 2 times with 2 × 50mL, each consumption 50mL, lower same) saturated common salt water washing, anhydrous sodium sulfate drying, filter, revolve steaming and slough solvent, gained solid alcohol-water recrystallization after dry, obtains white solid 0.76g, H-NMR analytical results is consistent with the full acetic ester of the EGCG of bibliographical information, yield 96%.
Embodiment two
2.09g (11mmol) 1,1-carbonyl diurethane (glyoxal ethyline) is dissolved in 50mL tetrahydrofuran (THF), add 0.60g (10mmol) acetic acid, reflux, stirring reaction is to releasing without gas.Solution is cooled to 60 DEG C, adds 0.47g (1.0mmol) EGCG, at N
2under protection, continue heating reflux reaction 2 hours.Be cooled to room temperature, stir the lower HCl dripping 1.5M and be about 2 to pH value of solution, continue to be added dropwise to 100mL distilled water, suction filtration, be washed to neutrality.Gained solid tetrahydrofuran (THF)-water recrystallization, vacuum-drying, obtains EGCG full acetic ester white solid 0.75g, yield 94%.
Embodiment three
1.0g (14.7mmol) imidazoles and 0.47g (1.0mmol) EGCG are dissolved in 30mL acetone, at N
2under protection, be added dropwise to the 20mL acetone soln containing 1.1g (14mmol) Acetyl Chloride 98Min., stirring reaction.Dropwise post-heating backflow, continue stirring reaction 2 hours.Be cooled to room temperature, add the HCl of 10mL 0.1M, be then under agitation added dropwise to 150mL distilled water, suction filtration, be washed to neutrality, vacuum-drying.Silica gel column chromatography (ethyl acetate/petroleum ether 3:1, the v/v) separation and purification of gained solid, obtains EGCG full acetic ester white solid 0.78g, yield 98%.
Embodiment four
Use the glyoxal ethyline of 14.7mmol, 4-methylimidazole, 2 respectively, 4-methylimidazole, 4-bromine imidazoles, 2-5-nitro imidazole, 4-imidazole formic acid methyl esters, or 7mmol imidazoles+7.4mmol DMAP (DMAP) substitutes the imidazoles of 14.7mmol, undertaken reacting and aftertreatment by embodiment three same procedure, obtain the full acetic ester white solid of EGCG, yield is respectively 97%, 97%, 96%, 95%, 95%, 96%, 99%.
Replace Acetyl Chloride 98Min. with 1.43g (14mmol) acetic anhydride, undertaken reacting and aftertreatment by embodiment three same procedure, obtain the full acetic ester white solid of EGCG, yield is 98%.
It is worth mentioning that, as document J.Agric.Food Chem.2001,49 (2), 1042-1048 reports, 1g (2.18mmol) EGCG does catalysis with pyridine separately and acetic anhydride carries out full esterification, even if adopt pyridine (14mL, 174mmol) and the acetic anhydride (16mL of greatly excessive (9 ~ 10 times), 157mmol), reaction still needs just can complete for 20 hours.And adopt imidazoles or imidazoles/pyridine derivate to do catalysis (as embodiment three and embodiment four), with the acetylation reagent little over amount, just can carry out full esterification to EGCG, and reaction can complete in 2 hours, the yield after purifying is 95 ~ 99%.
Embodiment five
1.0g (6.2mmol) CDI is dissolved in 30mL ethyl acetate, stirs the 20mL ethyl acetate solution that lower dropping is dissolved with 0.51g (5.0mmol) acetic anhydride.After dripping, reflux is to releasing without gas.Solution is cooled to 60 DEG C, adds 0.47g (1.0mmol) EGCG, at N
2under protection, continue heating reflux reaction 2 hours.Be cooled to room temperature, filter, filtrate uses HCl, the water washing of 2 × 50mL saturated common salt of 50mL 0.5M successively, anhydrous sodium sulfate drying, filters, revolves steaming and slough solvent, gained solid alcohol-water recrystallization after dry, obtains EGCG full acetic ester white solid 0.75g, yield 95%.
Replace above-mentioned 1.0g (6.2mmol) CDI with 0.34g (5mmol) imidazoles, 1.0g (6.2mmol) CDI, undertaken reacting and aftertreatment by above-mentioned identical method, come to the same thing, yield 95%.
Embodiment six
1.0g (3.9mmol) palmitinic acid is dissolved in 20mL acetone, adds 0.70g (4.3mmol) CDI, and heating reflux reaction is to releasing without gas.At N
2under protection, above-mentioned reaction soln is added drop-wise in the 20mL acetone soln being dissolved with 1.84g (3.9mmol) EGCG.Reflux, continue stirring reaction 1 hour, TLC follows the tracks of (EtOAc/ sherwood oil/HOAc 66:33:2, v/v), and result as shown in Figure 1.Solution is cooled to room temperature, adds the HCl of 18mL 0.5M, is then under agitation added dropwise to 120mL distilled water, suction filtration, is washed to neutrality.Gained solid 25mL acetone/75mL water recrystallization, vacuum-drying, obtains white solid 2.25g, and yield 83%, TLC (EtOAc/ sherwood oil/HOAc 66:33:2, v/v) detects and shows, product composition is similar to Fig. 1, but not containing EGCG.
Getting gained solid 100mg, with silica gel column chromatography (ethyl acetate/petroleum ether 4:1, v/v) separation and purification, obtain white solid, is product C 1 (its chromatography point is positioned at the C1 place of Fig. 1).H-NMR (500MHz, DMSO-d are carried out to product C 1
6) analyze, result is as shown in Figure 2.
Hydrogen modal data shows, in product C 1, the mol ratio of EGCG female ring and cetylate side chain is 1:1; 7 phenolic hydroxyl groups (δ=8.6 ~ 9.6ppm) are only had in product, lack the hydrogen on an EGCG phenolic hydroxyl group, in EGCG female ring, other hydrogen does not all increase or reduces, in female ring, the chemical shift of saturated hydrogen does not also change, show that ring structure is stablized, esterification occurs on EGCG phenolic hydroxyl group, and is EGCG monopalmitate.But each ring hydrogen is all shown as multiplet, so product C 1 is the mixture of EGCG monopalmitate.
Embodiment seven
1.0g (3.9mmol) palmitinic acid is dissolved in 20mL acetone, adds 0.70g (4.3mmol) CDI, and heating reflux reaction is to releasing without gas.At N
2under protection, above-mentioned reaction soln is added drop-wise in the 20mL acetone soln being dissolved with 0.85g (1.8mmol) EGCG.Reflux, continues stirring reaction 1 hour.Reaction terminates rear TLC (EtOAc/ sherwood oil/HOAc 66:33:2, v/v) analytical results as shown in Fig. 3 C row.Solution is cooled to room temperature, adds the HCl of 18mL0.5M, is then under agitation added dropwise to 120mL distilled water, suction filtration, is washed to neutrality.Gained solid 25mL acetone/75mL water recrystallization, vacuum-drying, obtains white EGCG cetylate 1.66g, yield 95%.
Get gained solid 100mg, with silica gel column chromatography (ethyl acetate/petroleum ether 3:1, v/v) separation and purification, obtain the principal product C2 as C row in Fig. 3, white solid, H-NMR (500MHz, DMSO-d
6) analytical results as shown in Figure 4.
Hydrogen modal data shows, in product C 2, the mol ratio of EGCG female ring and cetylate side chain is 1:2; 6 phenolic hydroxyl groups (δ=8.0 ~ 10.6ppm) are only had in product, lack the hydrogen of two phenolic hydroxyl groups in EGCG, other hydrogen does not reduce or increases, in female ring, the chemical shift of saturated hydrogen does not also change, show that ring structure is stablized, esterification occurs on EGCG phenolic hydroxyl group, and is EGCG acid dipalmitate.But each ring hydrogen is all shown as multiplet, so product C 1 is the mixture of EGCG acid dipalmitate.
Embodiment eight
Use the n-caprylic acid of 3.9mmol (0.56g), lauric acid (0.78g), stearic acid (1.11g), oleic acid (1.10g) or linolic acid (1.09g) to replace the palmitinic acid of 3.9mmol respectively, react by the method identical with embodiment seven.Reaction terminates rear TLC (EtOAc/ sherwood oil/HOAc 66:33:2, v/v) analytical results (n-caprylic acid, lauric acid, stearic acid, oleic acid, linoleic reaction product correspond respectively to A, B, D, E, F row) respectively as shown in Figure 3.
As seen from Figure 3, the principal product of A, B, D, E, F row arranges identical with C, is EGCG double acid ester.Aftertreatment after reaction terminates, also with embodiment seven, obtains after purifying: 1.23g EGCG octanoate, yield 94% respectively; 1.45g EGCG laurate, yield 94.5%; 1.79g EGCG stearate, yield 96%; 1.69gEGCG oleic acid ester, yield 91%; 1.61g EGCG linoleate, yield 87%.TLC (EtOAc/ sherwood oil/HOAc33:66:2, v/v) analyzes and shows, except monoesters, dibasic acid esters and three esters, (comprises the EGCG cetylate of example seven) and all do not detect the product of higher gamma value in product.
Embodiment nine
0.91g (5.6mmol) CDI, 1.18g (4.6mmol) palmitinic acid is dissolved in 20mL acetone, and back flow reaction is to releasing without gas.At N
2under protection, above-mentioned reaction soln is added drop-wise to and is dissolved with in the 25mL acetone soln of 1.03g tea-polyphenol.Reflux, continues stirring reaction 1 hour.TLC (EtOAc/ sherwood oil/HOAc 66:33:2, v/v) detected result is as shown in G row in Fig. 5.Solution is cooled to room temperature, adds the HCl of 20mL 0.5M, is then under agitation added dropwise to 120mL distilled water, suction filtration, is washed to neutrality.Gained solid 25mL acetone/75mL water recrystallization, vacuum-drying, obtains light yellow tea polyphenol-palmitate 1.78g, yield 84%.
As seen from Figure 5, product is still based on EGCG acid dipalmitate (G2), also monoesters (G1) and three esters (G3) of a small amount of EGCG are had, the monoesters (G1-1) simultaneously also containing other catechin a small amount of and dibasic acid esters (G2-1).Product has good solubility in salad oil, is a kind of fat-soluble tea polyphenol.
Embodiment ten
Under nitrogen protection, the 20mL acetone soln containing 1.26g (4.35mmol) 95% palmityl chloride (containing 5% palmitinic acid) and 0.16g (1.0mmol) CDI is added drop-wise in the 25mL acetone soln containing 0.27g (3.95mmol) imidazoles and 1.03g tea-polyphenol.Dropwise post-heating back flow reaction 1 hour.Identical shown in TLC (EtOAc/ sherwood oil/HOAc66:33:2, v/v) detected result with Fig. 5-G, show that palmityl chloride and palmitinic acid all take part in esterification.Solution is cooled to room temperature, adds the HCl of 17mL 0.1M, is then under agitation added dropwise to 120mL distilled water, suction filtration, is washed to neutrality.Gained solid 25mL acetone/75mL water recrystallization, vacuum-drying, obtains light yellow tea polyphenol-palmitate 1.76g, yield 83%.
Embodiment 11
Under nitrogen protection, the 20mL ethyl acetate solution containing 1.40g (4.62mmol) stearyl chloride and 0.10g (0.61mmol) CDI is added drop-wise in the 25mL ethyl acetate solution containing 1.03g tea-polyphenol, 0.48g (4.7mmol) N-methylmorpholine.Dropwise post-heating backflow, continue stirring reaction 1 hour.Be cooled to room temperature, filter, filtrate uses 50mL 0.1M HCl, the water washing of 2 × 50mL saturated common salt successively, anhydrous sodium sulfate drying, filters, revolves steaming and slough solvent, gained solid alcohol-water recrystallization after vacuum-drying, obtains light yellow tea-polyphenol stearate 1.95g, yield 86%.TLC (EtOAc/ sherwood oil/HOAc 66:33:2, v/v) detected result is as shown in H row in Fig. 5, result shows, in product, principal product is the two stearate of EGCG, also have monostearate and the tristearate of a small amount of EGCG, also have monoesters and the dibasic acid esters of other catechin of minute quantity simultaneously.Do not detect the product of higher gamma value.Product also can be dissolved in salad oil well, is a kind of fat-soluble tea polyphenol.
Above-mentioned research shows, adopt this law, the catechin fatty acid ester (acetic ester as complete in EGCG) of one-component can be obtained, the catechin fatty acid ester of single degree of esterification is (as EGCG monopalmitate, EGCG acid dipalmitate, can certainly be the product of each component that the product in embodiment eight to embodiment 11 is obtained through column chromatography for separation), the product that the mixing catechin of degree of esterification or the fatty acid ester (recrystallized product as embodiment six to embodiment 11) of tea-polyphenol etc. is different, according to bibliographical information, as the prodrug of catechin or tea-polyphenol, this kind of different esterified prod does not almost have toxicity, can have antiviral, cancer-resisting, antisepsis and anti-inflammation, anti-oxidant, reducing blood-fat etc. effect, different esterified prod can at medicine, healthcare products, daily cosmetics, food, edible oil, feed, apply in the different field such as organic chemical industry's product.
Claims (9)
1. the esterification process of a catechin or tea-polyphenol; comprise catechin or tea-polyphenol and acylating reagent in organic solvent to react under the effect of catalyzer; reaction product obtains esterification products after separation and purification; it is characterized in that; described catalyzer is carbonyl dimidazoles derivative and/or imdazole derivatives; the structural formula of carbonyl dimidazoles derivative is as shown in (A), and the structural formula of imdazole derivatives is as shown in (B):
Wherein, R
1~ R
9be separately the C of hydrogen, replacement
1~ C
6the C of aliphatic group, substituted oxy, replacement
2~ C
6fatty acyl group, substituted formacyl, disubstituted amino, C
1~ C
6alkylthio, cyano group, nitro, fluorine, chlorine, bromine, iodine; Or, R
2-R
3, R
5-R
6, R
8-R
95 ~ 6 yuan of alicyclic rings are separately formed together with carbon atom connected separately.
2. synthetic method as claimed in claim 1, it is characterized in that, described acylating reagent is organic carboxyl acid, and described catalyzer is carbonyl dimidazoles derivative.
3. synthetic method as claimed in claim 2, it is characterized in that, the mol ratio of described organic carboxyl acid and carbonyl dimidazoles derivative is 1:0.3 ~ 5.
4. synthetic method as claimed in claim 1, it is characterized in that, described acylating reagent is organic acid anhydride, and described catalyzer is imdazole derivatives and/or carbonyl dimidazoles derivative.
5. synthetic method as claimed in claim 4, it is characterized in that, the mol ratio of described organic acid anhydride, imdazole derivatives, carbonyl dimidazoles derivative is 1:0 ~ 5:0 ~ 5, and the mol ratio of the total amount of imdazole derivatives and carbonyl dimidazoles derivative and described organic acid anhydride is 0.001 ~ 10:1.
6. synthetic method as claimed in claim 1, it is characterized in that, described acylating reagent is organic acyl chlorides, and described catalyzer is imdazole derivatives and/or carbonyl dimidazoles derivative.
7. synthetic method as claimed in claim 6, it is characterized in that, the mol ratio of organic acyl chlorides, imdazole derivatives, carbonyl dimidazoles derivative is 1:0 ~ 5:0 ~ 5, and the mol ratio of the total amount of imdazole derivatives and carbonyl dimidazoles derivative and described organic acyl chlorides is 0.3 ~ 10:1.
8. the synthetic method as described in as arbitrary in claim 1 ~ 7, it is characterized in that, described carbonyl dimidazoles derivative is carbonyl dimidazoles, and described imdazole derivatives is imidazoles.
9. synthetic method as claimed in claim 8, it is characterized in that, described acylating reagent and the mol ratio of catechin are 0.2 ~ 20:1; Or described acylating reagent and the ratio of tea-polyphenol are 0.1 ~ 10mol:200g.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109536278A (en) * | 2017-09-21 | 2019-03-29 | 北京林业大学 | The esterification process and oil antioxidant of chestnut spiny involucre low molecular weight polyphenol extract |
| CN111234238A (en) * | 2020-04-06 | 2020-06-05 | 刘云晖 | Organic silicon polyethylene glycol hydrogel material with self-healing characteristic and preparation method thereof |
| CN115703745A (en) * | 2021-08-10 | 2023-02-17 | 中国船舶重工集团公司第七一八研究所 | Preparation method of enzalutamide |
| CN115152841A (en) * | 2022-06-29 | 2022-10-11 | 南京浩明乳业有限责任公司 | Compound stabilizer for fermented yogurt and preparation method thereof |
| CN115152841B (en) * | 2022-06-29 | 2024-02-20 | 南京浩明乳业有限责任公司 | Compound stabilizer for fermented yoghourt and preparation method thereof |
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