CN100509862C - Synthesis process of beta-cyclodextrin-poly-L-glutamic acid-benzyl ester grafted copolymer - Google Patents
Synthesis process of beta-cyclodextrin-poly-L-glutamic acid-benzyl ester grafted copolymer Download PDFInfo
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- CN100509862C CN100509862C CNB2006101347363A CN200610134736A CN100509862C CN 100509862 C CN100509862 C CN 100509862C CN B2006101347363 A CNB2006101347363 A CN B2006101347363A CN 200610134736 A CN200610134736 A CN 200610134736A CN 100509862 C CN100509862 C CN 100509862C
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Abstract
The present invention is synthesis process of beta-cylcodextrin-poly-L-glutamic acid-benzyl ester grafted copolymer. Certain amount of amino beta-cylcodextrin, gamma-benzyl ester and L-glutamic anhydride are mixed in N, N-dimethyl formamide and reacted at 25 deg.c and under nitrogen protection for 60-80 hr; the reaction product mixture is precipitated in deionized water; and the precipitate is washed with distilled water and vacuum dried at 100 deg.c to obtain the target product. The grafted copolymer has improved water solubility and regulated biodegradation speed and period, and may be used in assembling hydrophobic medicine molecule into hydrophobic core to increase the circulating time of medicine in blood, etc. It has excellent application foreground in the controlled release of medicine, targeting medicine transfer and one biomedicine fields.
Description
Technical field: the present invention relates to a kind of method of synthetic beta-cyclodextrin-poly amino acid graft copolymer, particularly a kind of method with L-L-glutamic acid and the synthetic beta-cyclodextrin-poly L-L-glutamic acid of beta-cyclodextrin-benzyl ester graft copolymer.
Background technology: polyamino acid be a class have low toxicity, good biocompatibility, easily by the biodegradable polymer of advantages such as body absorption, metabolism, therefore have at aspects such as medical field such as medicine controlled releasing, organizational projects widely and use.But its homopolymer is water-soluble relatively poor, and its application has certain limitation.
Beta-cyclodextrin (β-Cyclodextrin, abbreviation β-CD) generate through fermentation by starch, form by seven D-(+)-Glucopyranose, its each glucose is all got chair conformation, by α-1, ring molecule of the end to end formation of 4-glycosidic bond has a cylindrical structure that slightly is truncated cone shape.
β-CD molecule outside shows wetting ability because of being covered with hydroxyl, there is the hydrogen atom on the two circle carbon atoms its tapered cylinder inboard, and hydrocarbon key sandwich one circle acetal Sauerstoffatom (ether ring) structure has stronger hydrophobicity, the multiple guest molecule of energy inclusion has the laudatory title of branch ascus.β-CD has excellent biological compatibility, all is used widely in a lot of fields such as medicine, food.Such as carrying out inclusion to hydrophobic drug, improve stability of drug and solvability, prolong drug is renderd a service, and improves utilization ratio of drug.In sum, beta-cyclodextrin and hydrophobic polyamino acid are carried out copolymerization, can improve the water-soluble of polyamino acid, obtain having the novel amphipathic polymer of special property, related content is not seen reported in literature.
Summary of the invention: the objective of the invention is itself and water-soluble good beta-cyclodextrin to be made multipolymer, thereby obtain obtaining to control deliquescent multipolymer by changing each segmental content in order to overcome the relatively poor shortcoming of polyamino acid solvability in water.
Structural formula as the beta-cyclodextrin of skeleton:
Structural formula as the polyamino acid of grafted chain:
Wherein, R is:
To achieve these goals; the invention provides the synthetic method of a kind of beta-cyclodextrin-poly L-L-glutamic acid-benzyl ester graft copolymer; it is characterized in that a certain amount of amino beta-cyclodextrin, γ-benzyl ester L-L-glutamic acid ring inner-acid anhydride (NCA) are at N; after mixing in the dinethylformamide (DMF); stirring reaction 60～80h under 25 ℃ of temperature of reaction, nitrogen protection, reaction mixture is poured in the deionized water and is precipitated, suction filtration; with the distilled water wash precipitation, get target product 100 ℃ of vacuum-dryings.Wherein:
The mol ratio of beta-cyclodextrin and amino acid ring inner-acid anhydride (NCA) is 1:10～70;
The every gram γ-benzyl ester-used N of L-L-glutamic acid ring inner-acid anhydride, dinethylformamide is 70～80mL;
N, the volume ratio of dinethylformamide and deionized water is 1:3～5
Reaction mechanism of the present invention is: make the tosyl group beta-cyclodextrin by beta-cyclodextrin and p-methyl benzene sulfonic chloride through esterification earlier; Make the azide beta-cyclodextrin through azido reaction again; After ammonolysis reaction makes the amination beta-cyclodextrin; L-L-glutamic acid and phenylcarbinol make L-L-glutamic acid-benzyl ester through esterification, make γ-benzyl ester-L-L-glutamic acid ring inner-acid anhydride (NCA) with solid phosgene through cyclization again; At last, the NH in the amino beta-cyclodextrin molecule
2Monomeric 5 carbonylic carbon atoms of base attack NCA form intermediate A, the rapid cancellation CO of this intermediate
2The back generates intermediate B, and B continues to form graft copolymer with the NCA monomer reaction more then.
Contriver's chamber test has by experiment been synthesized beta-cyclodextrin-poly amino acid graft copolymer, and has been confirmed product by infrared spectra and nucleus magnetic resonance etc.
Experimental example 1
Material: L-L-glutamic acid (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Phenylcarbinol (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Solid phosgene (AR, the chemical company limited of connection in Haining)
Beta-cyclodextrin (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
P-methyl benzene sulfonic chloride (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Sodium azide (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
N, dinethylformamide (DMF) (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Triphenylphosphine (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Pyridine (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Potassiumiodide (AR, Chemical Reagent Co., Ltd., Sinopharm Group)
Instrument: PE Spectrum one Fourier transformation infrared spectrometer
Varian XL-300 nuclear magnetic resonance spectrometer
MalvernNano ZS nano particle size and Zeta potential analyser
(1) L-L-glutamic acid-benzyl ester is synthetic:
Take by weighing 11.1g L-L-glutamic acid in the 250mL there-necked flask, add 53mL phenylcarbinol and 18mL Hydrogen bromide.Slowly heating under magnetic stirs then, temperature of reaction is controlled at about 70 ℃, treats that L-L-glutamic acid all dissolves back (about 1h of time), reaction mixture is cooled to 30 ℃, pour into then in the mixing solutions by 22mL pyridine and the preparation of 147mL 95% ethanol, place 12h down, it is fully precipitated for 3 ℃.With 30mL ethanol and the washing of 30mL ether, the gained white solid is crude product respectively for suction filtration, precipitation.Crude product is with 5% ethyl alcohol recrystallization, and 50 ℃ of vacuum-dryings get product 5.658g, and productive rate 31.6%, product fusing point are 172～174 ℃.
(2) γ-benzyl ester-L-L-glutamic acid ring inner-acid anhydride is synthetic:
L-L-glutamic acid-benzyl the ester that takes by weighing the 5.658g prepared fresh adds the 75mL anhydrous tetrahydro furan again in the 250mL there-necked flask that reflux condensing tube, thermometer and alkali absorption unit are housed, be warming up to 50 ℃, and magnetic stirs and adds the 8.5g solid phosgene down.The question response suspension liquid becomes clarification back (about 40min), and logical nitrogen 30min is to remove hydrogenchloride and the remaining phosgene that dereaction generates.The reaction mixture rotary evaporation is removed the part tetrahydrofuran (THF), pours in the 150mL sherwood oil after being cooled to room temperature, places 12h at-20 ℃, and it is crude product that suction filtration gets white needle-like crystals.Crude product dissolves, filters with the 30mL tetrahydrofuran (THF), and filtrate is poured in the 70mL sherwood oil and must be precipitated.Sedimentation and filtration gets white needle-like crystals 3.332g after the seasoning, be product.Productive rate 53.1%, fusing point are 95～96 ℃.Reaction formula is as follows:
(3) amino beta-cyclodextrin is synthetic:
10g beta-cyclodextrin, 2.5g p-methyl benzene sulfonic chloride and 140mL pyridine are added in the 250mL there-necked flask, under the nitrogen protection, 40 ℃ of stirring reaction 4h of control reaction temperature.With Rotary Evaporators concentration response mixed solution, pour into then in the 100mL acetone and precipitate, wait to precipitate complete back suction filtration, with the washing with acetone precipitation, 50 ℃ of vacuum-dryings get the 5.454g white powder and are the tosyl group beta-cyclodextrin, productive rate 48.6%.
5.454g tosyl group beta-cyclodextrin, 2.00g sodium azide, 0.20g potassiumiodide and 40mL DMF are added in the 250mL there-necked flask, under the nitrogen protection, 80 ℃ of stirring reaction 24h of control reaction temperature.With the DMF evaporate to dryness in the reaction mixture, add 100mL deionized water dissolving crude product, be poured into then in the 300mL ethanol and precipitate, suction filtration, 50 ℃ of vacuum-dryings get azide beta-cyclodextrin 4.060g, productive rate 77.6%.
With 4.060g azido-beta-cyclodextrin, the 1.80g triphenylphosphine, 80mLDMF, 15mL ammoniacal liquor adds in the reactor, under the nitrogen protection, at 40 ℃ of stirring reaction 24h.Reaction mixture is poured in the 200mL acetone and is precipitated, suction filtration, and 50 ℃ of vacuum-dryings get amination beta-cyclodextrin 3.568g, productive rate 87.9%.Product is through affirmations such as infrared spectra and nucleus magnetic resonance.Reaction formula is as follows:
(4) beta-cyclodextrin-poly L-L-glutamic acid-benzyl ester graft copolymer (β's-CDPBLG1) is synthetic:
The amino beta-cyclodextrin of 0.431g (0.38mmol) and 1.0g (3.8mmol) γ-benzyl ester L-L-glutamic acid ring inner-acid anhydride are put into reaction flask, add the 75mL dry DMF, at 25 ℃, stirring reaction 72h under the nitrogen protection.With reaction mixture pour into obtain in the 300mL deionized water precipitation.Suction filtration, with the distilled water wash precipitation, 100 ℃ of vacuum-dryings get target product, productive rate 43.6%.Reaction formula is as follows:
Confirm product by infrared spectra, nucleus magnetic resonance etc.In the IR spectrogram, 600cm
-1～800cm
-1Two characteristic absorbance that characteristic absorbance is a phenyl ring in the poly-L-glutamic acid-benzyl ester segment at place; 1600cm
-1And 1500cm
-1Two absorption peaks at place are two characteristic absorbance of amido linkage in the poly-L-glutamic acid-benzyl ester segment; Be commonly referred to acid amides I band and acid amides II band; 1700cm
-1The absorption peak at place is the characteristic absorbance of carbonyl on the ester bond in the benzyl ester; 3200cm
-1About absorption peak be amino characteristic absorbance in hydroxyl and the poly-L-glutamic acid-benzyl ester in the beta-cyclodextrin.In spectrogram, can observe two segmental characteristic absorbance of beta-cyclodextrin and poly-L-glutamic acid acid benzyl ester, and in the NCA molecule two carbonyls at 1855cm
-1And 1785cm
-1The absorption peak at place disappears, and preliminary explanation has formed multipolymer.
1In the H NMR spectrogram, about δ=7.2ppm the chemical shift of H on the phenyl ring on the poly-L-glutamic acid-benzyl ester segment; About δ=5.0ppm methylene radical (CH in the benzyl
2) the upward chemical shift of H; The absorption peak at δ=2.4ppm place is in the poly-L-glutamic acid acid benzyl ester-CH
2CH
2The chemical shift of H on the-group; δ=3.9 places are the chemical shifts of methyne (CH) H in the poly-L-glutamic acid acid benzyl ester segment; It about δ=8.0ppm the chemical shift that NH goes up H in the poly-L-glutamic acid acid benzyl ester segment; The absorption peak at δ=3.3～3.6ppm place is in the beta-cyclodextrin molecule 2,3,4,5, the chemical shift of 6 H; The absorption peak of δ=4.8ppm is the chemical shift of 1 H in the beta-cyclodextrin molecule.From the nuclear magnetic spectrogram of polymkeric substance as can be seen, the characteristic peak of corresponding group all exists in beta-cyclodextrin segment and the poly-L-glutamic acid acid benzyl ester segment.Comprehensive IR and
1H NMR analyzes, and can confirm that product is beta-cyclodextrin-poly-L-glutamic acid-benzyl ester grafted copolymer.
The invention has the beneficial effects as follows: realized beta-cyclodextrin and hydrophobic polyamino acid (poly-L-glutamic acid-benzyl ester) copolymerization by the present invention, obtained having the novel beta-cyclodextrin-poly L-L-glutamic acid-benzyl ester graft copolymer with amphiphilic structure of special property.This multipolymer not only can improve the water-soluble of poly-L-glutamic acid-benzyl ester, hydrophobicity poly-L-glutamic acid-benzyl ester segment also can be regulated the biodegradation rate and the cycle of wetting ability beta-cyclodextrin simultaneously, therefore by changing the multipolymer that each segmental content obtains controlling solvability and degradation property.Beta-cyclodextrin-the poly-L-glutamic acid-benzyl ester grafted copolymer of the present invention's preparation is a kind of amphipathic multipolymer, can self-assembly form hydrophobic, the hydrophilic micella of shell of kernel in the aqueous solution.This copolymer micelle can be assembled into hydrophobic drug in its hydrophobic nuclear, has the effects such as cycling time of the medicine of raising in blood, has good application prospects in bio-medical fields such as controlled delivery of pharmaceutical agents release and targeted drug transmission.
Description of drawings:
Fig. 1 is the micella size distribution figure that synthetic β in the experimental example 1-CDPBLG1 forms;
Fig. 2 is the micella size distribution figure that synthetic β among the embodiment 4-CDPBLG2 forms;
Fig. 3 is the micella size distribution figure that synthetic β among the embodiment 5-CDPBLG3 forms.
Embodiment:
Synthesizing of embodiment 1L-L-glutamic acid-benzyl ester:
Take by weighing 11.1g L-L-glutamic acid in the 250mL there-necked flask, add 53mL phenylcarbinol and 18mL Hydrogen bromide.Slowly heating under magnetic stirs then, temperature of reaction is controlled at about 70 ℃, treats that L-L-glutamic acid all dissolves back (about 1h of time), reaction mixture is cooled to 30 ℃, pour into then in the mixing solutions by 22mL pyridine and the preparation of 147mL95% ethanol, place 12h down, it is fully precipitated for 3 ℃.To precipitate suction filtration, and use 30mL ethanol and the washing precipitation of 30mL ether respectively, the gained white solid is crude product.Crude product is with 5% ethyl alcohol recrystallization, and 50 ℃ of vacuum-dryings get product 5.658g, and productive rate 31.6%, product fusing point are 172～174 ℃.
Synthesizing of embodiment 2 γ-benzyl ester L-L-glutamic acid ring inner-acid anhydride:
Take by weighing the 5.658g prepared fresh L-L-glutamic acid-the benzyl ester is in the 250mL there-necked flask, there-necked flask is equipped with reflux condensing tube, thermometer, alkali absorption unit.Add the 75mL anhydrous tetrahydro furan, be warming up to 50 ℃, magnetic stirs down and adds the 8.5g solid phosgene, and the question response suspension liquid becomes clarification back (about 40min), and logical nitrogen 30min is to remove hydrogenchloride and the remaining phosgene that dereaction generates.The reaction mixture rotary evaporation is removed the part tetrahydrofuran (THF), pours in the 150mL sherwood oil after being cooled to room temperature, places 12h at-20 ℃, and it is crude product that suction filtration gets white needle-like crystals.Crude product dissolves, filters with the 30mL tetrahydrofuran (THF), and filtrate is poured in the 70mL sherwood oil and must be precipitated.Sedimentation and filtration gets white needle-like crystals 3.332g after the seasoning, be product.Productive rate 53.1%, fusing point is 95～96 ℃, product is through affirmations such as infrared spectra and nucleus magnetic resonance.
Synthesizing of embodiment 3 amino beta-cyclodextrins:
10g beta-cyclodextrin, 2.5g p-methyl benzene sulfonic chloride and 140mL pyridine are added in the 250mL there-necked flask, under the nitrogen protection, at 40 ℃ of stirring reaction 4h.With Rotary Evaporators concentration response mixed solution, pour into then in the 100mL acetone and precipitate, wait to precipitate complete back suction filtration, with the washing with acetone precipitation, 50 ℃ of vacuum-dryings get white powder and are amino beta-cyclodextrin, the heavy 5.454g of product, productive rate 48.6%.
5.454g tosyl group beta-cyclodextrin, 2.00g sodium azide, 0.20g potassiumiodide and 40mL DMF are added in the 250mL there-necked flask stirring reaction 24h under 80 ℃, nitrogen protection.With the DMF evaporate to dryness in the reaction mixture, add 100mL deionized water dissolving crude product, use the 300mL ethanol sedimentation, suction filtration, 50 ℃ of vacuum-dryings get azide beta-cyclodextrin 4.060g, productive rate 77.6%.
With 4.060g azide beta-cyclodextrin, 1.80g triphenylphosphine, 80mL DMF and 15mL ammoniacal liquor adds in the reaction flask, stirring reaction 24h under 40 ℃, nitrogen protection.The reaction mixing is poured in the 200mL acetone and is precipitated, suction filtration, and 50 ℃ of vacuum-dryings get amination beta-cyclodextrin 3.568g, productive rate 87.9%.Product is through affirmations such as infrared spectra and nucleus magnetic resonance.
Embodiment 4 beta-cyclodextrin-poly L-benzyl glutamate graft copolymers (β's-CDPBLG2) is synthetic:
The amino beta-cyclodextrin of 0.144g (0.127mmol) and 1.0g (3.8mmol) γ-benzyl ester L-L-glutamic acid ring inner-acid anhydride are put into reaction flask, add the 75mL dry DMF, stirring reaction 72h under 25 ℃, nitrogen protection.With reaction mixture pour into obtain in the 300mL deionized water precipitation.Suction filtration, with the distilled water wash precipitation, 100 ℃ of vacuum-dryings get target product, productive rate 40.34%.Product is through affirmations such as infrared spectra and nucleus magnetic resonance.
Embodiment 5 beta-cyclodextrin-poly L-L-glutamic acid-benzyl ester graft copolymers (β's-CDPBLG3) is synthetic:
The amino beta-cyclodextrin of 0.086g (0.0758mmol) and 1.0g (3.8mmol) γ-benzyl ester L-L-glutamic acid ring inner-acid anhydride are put into reaction flask, add the 80mL dry DMF, stirring reaction 60h under 25 ℃, nitrogen protection.With reaction mixture pour into obtain in the 400mL deionized water precipitation.Suction filtration, with the distilled water wash precipitation, 100 ℃ of vacuum-dryings get target product, productive rate 34.2%.Product is through affirmations such as infrared spectra and nucleus magnetic resonance.
The amino beta-cyclodextrin of 0.062g (0.0547mol) and 1.0g (3.8mmol) γ-benzyl ester L-L-glutamic acid ring inner-acid anhydride are put into reaction flask, add the 70mL dry DMF, stirring reaction 80h under 25 ℃, nitrogen protection.With reaction mixture pour into obtain in the 210mL deionized water precipitation.Suction filtration, with the distilled water wash precipitation, 100 ℃ of vacuum-dryings get target product, productive rate 18.31%.Product is through affirmations such as infrared spectra and nucleus magnetic resonance.
The preparation of embodiment 7 micellar:
Take by weighing 0.05g β-CDPBLG1, β-CDPBLG2 respectively, β-CDPBLG3 graft copolymer is dissolved in respectively in the 5mL tetrahydrofuran (THF), after treating to dissolve fully, under agitation in this solution, slowly add the 40mL redistilled water, rotary evaporation is removed tetrahydrofuran (THF) (needing two hours approximately) wherein then, rest solution is placed the 50mL volumetric flask, obtain certain density micellar solution with the redistilled water constant volume, utilize the nano particle size instrument to measure the micellar particle diameter.
As can be seen, along with the increase of the mol ratio of amino beta-cyclodextrin and amino acid ring inner-acid anhydride (NCA), the productive rate of beta-cyclodextrin-poly L-L-glutamic acid-benzyl ester graft copolymer reduces, so optimum ratio is 1:10～50 from embodiment 4～embodiment 6.And in this proportional range, in the aqueous solution, can form the micella of particle diameter about 100nm, through test, when ratio is 1:10, can form the micella that median size is 114nm (accompanying drawing 1), ratio can form the micella that median size is 124nm (accompanying drawing 2) during for 1:30, when ratio can form the micella that median size is 96nm (accompanying drawing 3) during for 1:50.This class can be assembled into hydrophobic drug in its hydrophobic nuclear by the micella that amphipathic copolymer forms, and has the effects such as cycling time of the medicine of raising in blood, has good application prospects in fields such as controlled delivery of pharmaceutical agents release and targeted drug transmission.
Claims (2)
1, the synthetic method of a kind of beta-cyclodextrin-poly L-L-glutamic acid-benzyl ester graft copolymer, it is characterized in that a certain amount of amino beta-cyclodextrin, γ-benzyl ester-L-L-glutamic acid ring inner-acid anhydride are at N, after mixing in the dinethylformamide, stirring reaction 60～80h under 25 ℃ of temperature of reaction, nitrogen protection; Reaction mixture is poured in the deionized water and is precipitated; Suction filtration with the distilled water wash precipitation, gets target product 100 ℃ of vacuum-dryings; Wherein:
The mol ratio of amino beta-cyclodextrin and γ-benzyl ester-L-L-glutamic acid ring inner-acid anhydride is 1:10～50; The every gram γ-benzyl ester-used N of L-L-glutamic acid ring inner-acid anhydride, dinethylformamide is 70～80mL;
N, the volume ratio of dinethylformamide and deionized water is 1:3～5;
The structure of amino beta-cyclodextrin is: β-CD-NH
2, β-CD is a beta-cyclodextrin.
2, the synthetic method of beta-cyclodextrin-poly L-L-glutamic acid according to claim 1-benzyl ester graft copolymer is characterized in that the described reaction times is 72h.
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| JP5950458B2 (en) * | 2010-02-09 | 2016-07-13 | アドシア | Anionic polysaccharide functionalized with at least two hydrophobic groups carried by at least a trivalent spacer |
| JP2012214450A (en) * | 2011-03-25 | 2012-11-08 | Nippon Soda Co Ltd | Crystal polymorph of benzyl glutamate n-carboxylic anhydride |
| CN102731777B (en) * | 2012-07-06 | 2013-12-18 | 辽宁大学 | Synthesis method of poly-benzyl L-glutamate/ethyl polyphosphate block copolymer |
| CN104195618A (en) * | 2014-07-31 | 2014-12-10 | 江南大学 | Electro-deposition preparation method of magnesium-based biological nano coating material |
| CN104311820B (en) * | 2014-09-24 | 2017-06-20 | 北京化工大学 | A kind of method that degradable medicaments carrier is built based on polysaccharide graft poly-aspartate benzyl ester |
| CN105884917B (en) * | 2016-05-20 | 2018-05-25 | 江南大学 | A kind of linear dextrin base liposome and preparation method thereof |
| CN106317261A (en) * | 2016-09-13 | 2017-01-11 | 合肥工业大学 | Beta-cyclodextrin based star-shaped polymer and preparation method thereof |
| CN108329660B (en) * | 2017-01-20 | 2020-09-29 | 深圳市虹彩新材料科技有限公司 | Beta-cyclodextrin graft and preparation method and application thereof |
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