CN102634033A - Dextran-based amphiphilic segmented copolymer preparation method - Google Patents
Dextran-based amphiphilic segmented copolymer preparation method Download PDFInfo
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Abstract
The invention relates to a dextran-based amphiphilic segmented copolymer and a preparation method. A hydrophilic chain segment in the dextran-based amphiphilic segmented copolymer refers to dextran, and a hydrophobic chain segment refers to polyamino acids or polyester. The dextran-based amphiphilic segmented copolymer is prepared by means of highly-active click reaction of terminal alkynyl dextran with terminal group azidation polyamino acid or terminal group azidation polyester. A dextran chain segment is preferably dextran in the number-average molecular weight of 6000-60000; a polyamino acid chain segment is preferably poly(gamma-benzyl-L-glutamate), poly(beta-benzyl-L-aspartate), poly(epsilon-carbobenzoxy-L- lysine), poly(O-benzyl-L-serine), poly(L-phenylalanine), poly(L-alanine) and poly(L-leucine) in the number-average molecular weight of 3000-10000; and a polyester chain segment is preferably poly(epsilon-caprolactone) and polylactic acid in the number-average molecular weight of 3000-10000.
Description
Technical field
The present invention relates to a kind of VISOSE base amphipathic nature block polymer and preparation method.
Background technology
Malignant tumour is becoming one of serious disease that threatens human health.At present, in treatment for cancer, chemotherapy remains one of main means, and the key of raising chemotherapy effect is the inducing tumor cell programmed death, i.e. apoptosis.Because present employed small molecules chemotherapeutics is relatively poor to the specificity of cancer cells; Lack tumor-selective; Can be distributed to each position of health with blood, not only increase patient's economical load, even more serious is that human normal tissue and organ are had toxic side effect.In addition, in the medication process, cancer cells is prone to produce multidrug resistance, causes most of antitumor drugs and such effective unlike expection.In order to address these problems, can combine antitumor drug with pharmaceutical carrier, change the water-soluble and stable of medicine, medicine is discharged in vivo, so that bring into play drug effect better with suitable concentration and speed through modes such as diffusion, infiltrations.Common pharmaceutical carrier organic and/or inorganic materials nanoparticle, branch-shape polymer, liposome, polymer nanocomposite hydrogel and polymer micelle etc.
Polymer nano micelle is the aggregate with nucleocapsid structure by the amphipathic multipolymer nano-scale that spontaneous assembling forms in water with hydrophilic segment and hydrophobic segment.Amphipathic copolymer self-assembled micelle has the following advantages as pharmaceutical carrier: (1) polymer micelle has tangible nucleocapsid structure; In self assembling process; Hydrophobic block constitutes the micellar kernel, and hydrophilic block then constitutes the micellar shell around the micella kernel.Significantly nucleocapsid structure can effectively improve the water-soluble of medicine.(2) the polymer micelle carrier can strengthen the stability of medicine in blood circulation, prolong drug cycling time in vivo.(3) size of polymer micelle is controlled, and suitable size helps the gathering of carrier at tumor tissues, realizes its passive target to tumor tissues, improves bioavailability of medicament, reduces the toxic side effect of medicine.Therefore, amphipathic copolymer self-assembled micelle has a good application prospect.
At present, in the research as the amphipathic multipolymer of pharmaceutical carrier, the kind of hydrophobic segment is more, and like aliphatic polyester, polyamino acid benzyl ester, polyoxytrimethylene etc., and the hydrophilic segment majority is selected polyoxyethylene glycol (PEG) for use.PEG has good hydrophilicity and biocompatibility, toxicity is low, can avoid the identification of human body reticuloendothelial system, can protect the material that is modified not receive immune destruction, increases medicine cycling time in vivo.But but the reactive activity group only is confined to terminal hydroxy group in the PEG molecule, is unfavorable for the micella shell is modified, and gives initiatively target property or that micelle surface is carried out the crosslinked micella that makes again is stable of carrier micelle as connecting the target group.Given this, seek the more good hydrophilic segment of performance and seem very important.
VISOSE (Dextran) is claimed Expex again, and a kind of water-soluble natural polysaccharide can be degraded to the VISOSE monomer in vivo, and is nontoxic, harmless.VISOSE has functions such as the good bio-compatibility, non-immunogenicity, anti-protein adsorption of similar PEG, helps carrier circulation for a long time in vivo.VISOSE has similar PEG's the characteristics of " long circulation " and " stealth " when using as pharmaceutical carrier, in blood, can reduce albumen and absorb, and protects medicine not to be destroyed.VISOSE has 5% branched structure, and containing in the molecular structure in a large number can be by the hydroxyl of functionalization, and the reactivity through hydroxyl is easy to other target groups or fluorescence molecule are bonded on the VISOSE very much.At present; Utilize the hydroxyl synthesizing amphipathic graft copolymer research of VISOSE very extensive; A kind of polycaprolactone-g-VISOSE amphipathic graft copolymer is disclosed like Biomaterials (Vol.30, p1363～1371,2009); It can form micella in the aqueous solution, and can be effectively as pharmaceutical carrier.The graft copolymer of comparing, the structure of segmented copolymer is clear and definite more, and utilizes the also rare report of research of the synthetic amphipathic nature block polymer based on VISOSE of the terminal aldehyde group of VISOSE.
To the deficiency of prior art, the present invention relates to VISOSE base amphipathic nature block polymer and preparation method.Preparing method provided by the invention is efficiently simple; The amphipathic nature block polymer that obtains has favorable biological degradability, biocompatibility; Be easy to the VISOSE shell of chemically modified in addition, can be by further functionalization, obviously improved medicine cycling time in vivo as pharmaceutical carrier; Help improving and improving the performance of medicine, realize that the long time constant of medicine discharges.
One of the object of the invention provides amphipathic VISOSE based medicine carrier, and its hydrophilic chain is a VISOSE, and hydrophobic chain is polyamino acid or polyester.The number-average molecular weight scope of described VISOSE is 6000-60000, and the number-average molecular weight scope of polyamino acid is 3000-10000, and the number-average molecular weight scope of polyester is 3000-10000.Described polyamino acid comprises and gathers (γ-phenmethyl-L-glutamate), gathers (β-phenmethyl-L-aspartate), gathers (ε-carbobenzoxy-(Cbz)-L-Methionin), gathers (O-benzyl-L-Serine), gathers (L-phenylalanine(Phe)), gathers (L-L-Ala), gathers (L-leucine); Described polyester comprises POLYACTIC ACID, gathers (6-caprolactone).
Two of the object of the invention provides the preparation method of VISOSE base amphipathic nature block polymer.The preparation method of VISOSE-b-polyamino acid and VISOSE-b-polyester amphiphilic block polymer, step and reaction conditions are following:
(1) preparation of Terminal Acetylenes base VISOSE
VISOSE is dissolved in acetic acid/sodium acetate buffer solution of pH=5; Add propargylamine and sodium cyanoborohydride under the whipped state successively; Wherein, the mol ratio of described VISOSE, propargylamine, sodium cyanoborohydride is 1: 10: 10, and 50 ℃ of agitation conditions react 96h down.After reaction finishes, with the reaction product 96h that dialyses, continue to change water to remove water miscible small-molecule substance with the 3500Da dialysis tubing.With the product freeze-drying, promptly get Terminal Acetylenes base VISOSE after the dialysis.
(2) preparation of end group azide polyamino acid benzyl ester
Carboxylic acid anhydride in amino acid-N-is dissolved in anhydrous N, in the dinethylformamide, under the stirrer whipped state, adds the nitrine propylamine, wherein, the ratio of the mole of carboxylic acid anhydride is 1: 30～70 in nitrine propylamine and the amino acid-N-.25 ℃ of agitation conditions react 72h down.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, washing obtains throw out.25 ℃ of vacuum-drying 24h promptly obtain the polyamino acid benzyl ester of end group azide.
(3) preparation of end group azide polyester
A. the preparation of differing mol weight polyester
The aliphatics cyclic monomer is dissolved in the toluene, adds stannous octoate and Virahol, the mol ratio of cyclic monomer, stannous octoate is 1: 1000, and the mol ratio of cyclic monomer and Virahol is that 1: 20～70,120 ℃ stirrers stir reaction 24h down.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, wash and obtain throw out, 25 ℃ of vacuum-drying 24h promptly get the polyester of different number-average molecular weights.
B. the preparation of methyl sulphonyl polyester
Polyester is dissolved with anhydrous methylene chloride, and stirrer stirs down and adds triethylamine, slowly drips Methanesulfonyl chloride with tap funnel then, and wherein, the mol ratio of described polyester, triethylamine, Methanesulfonyl chloride is 1: 10: 10.Under the condition of ice bath, continue stirring reaction 24h.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, washing obtains throw out, and 25 ℃ of vacuum-drying 24h promptly obtain the methyl sulphonyl polyester.
C. the preparation of end group azide polyester
The methyl sulphonyl polyester that b is obtained dissolves with THF, adds sodiumazide then, and wherein, the mol ratio of described methyl sulphonyl polyester, sodiumazide is 1: 10.40 ℃ of lasting stirring reaction 24h.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, washing obtains throw out, and 25 ℃ of vacuum-drying 24h promptly obtain end group azide polyester.
(4) preparation of VISOSE base Amphipathilic block polymer
A. the preparation of VISOSE-b-polyamino acid Amphipathilic block polymer
Terminal Acetylenes base VISOSE and end group azide polyamino acid are dissolved in the DMSO 99.8MIN., and stirrer stirs and to add the part pentamethyl-diethylenetriamine down, uses the liquefied ammonia freeze thawing then three times, when second time freeze thawing, adds cuprous bromide.Wherein, the mol ratio of VISOSE, azide polyamino acid, pentamethyl-diethylenetriamine, cuprous bromide is 1.5: 1: 1.5: 1.5.After freeze thawing finishes, 40 ℃ of click reaction 72h.After reaction finishes,, continue to change water to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.With the product freeze-drying, promptly get VISOSE-b-polyamino acid benzyl ester amphipathic nature block polymer after the dialysis.
B. the preparation of VISOSE-b-polyester amphipathic nature block polymer
Terminal Acetylenes base VISOSE and end group azide polyester are dissolved in the DMSO 99.8MIN., and stirrer stirs and to add the part pentamethyl-diethylenetriamine down, uses the liquefied ammonia freeze thawing then three times, when second time freeze thawing, adds cuprous bromide.Wherein, the mol ratio of VISOSE, azide polyester, pentamethyl-diethylenetriamine, cuprous bromide is 1.5: 1: 1.5: 1.5.After freeze thawing finishes, 40 ℃ of click reaction 72h.After reaction finishes,, continue to change water to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.With the product freeze-drying, promptly get VISOSE-b-polyester amphipathic nature block polymer after the dialysis.
Compared with prior art; The present invention is a hydrophilic chain with the VISOSE with good biocompatibility; Compare and PEG, VISOSE has 5% branched structure, and containing in the molecular structure in a large number can be by the hydroxyl of functionalization; Reactivity through hydroxyl is easy to other target groups or fluorescence molecule are bonded on the VISOSE very much, helps preparing multi-functional antitumor carrier.The segmented copolymer that obtains not only has favorable biological degradability, biocompatibility and molecular weight controllability, and is easy to the VISOSE shell of chemically modified in addition.
Description of drawings
The hydrogen nuclear magnetic resonance spectrogram of Terminal Acetylenes base VISOSE in deuterated dimethyl sulfoxide that Fig. 1 obtains for the embodiment of the invention 1.
The gathering of the end group azide that Fig. 2 obtains for the embodiment of the invention 2 (1) (γ-phenmethyl-L-glutamate) at deuterium for the hydrogen nuclear magnetic resonance spectrogram in the trifluoroacetic acid.
The infrared spectrum that gathers (γ-phenmethyl-L-glutamate) of the end group azide that Fig. 3 obtains for the embodiment of the invention 2 (1).
The hydrogen nuclear magnetic resonance spectrogram of the VISOSE that Fig. 4 obtains for the embodiment of the invention 11-gather (γ-phenmethyl-L-glutamate) segmented copolymer in deuterated dimethyl sulfoxide.
The infrared spectrum of the VISOSE that Fig. 5 obtains for the embodiment of the invention 11-gather (γ-phenmethyl-L-glutamate) segmented copolymer.
Embodiment
In order to further specify the present invention, following examples are described in detail VISOSE base amphipathic nature block polymer thing provided by the invention and preparation method thereof.
Below among each embodiment, reaction raw materials is to be buied from market or makes product quality * 100% that reaction yield=the actual product quality/theory that obtains obtains according to ordinary method.
Embodiment 1～3: the preparation of the Terminal Acetylenes base VISOSE of different number-average molecular weights
The VISOSE that takes by weighing the 5g number-average molecular weight respectively and be 6000 (0.00083mol), 30000 (0.00017mol) and 60000 (0.000083mol) is dissolved in the buffered soln of acetic acid/sodium-acetate of pH=5; Add 0.46g (0.0083mol), 0.09g (0.0017mol) and 0.046g (0.00083mol) propargylamine under the agitation condition successively, add the sodium cyanoborohydride of 0.52g (0.0083mol), 0.11g (0.0017mol) and 0.052g (0.00083mol) then respectively.50 ℃ of stirrers stir reaction 96h down.After reaction finishes, with the reaction product 96h that dialyses, continue to change water to remove water miscible small-molecule substance with the 3500Da dialysis tubing.With the product freeze-drying, promptly get the Terminal Acetylenes base VISOSE of different number-average molecular weights after the dialysis, the result joins table 1.
The preparation of the Terminal Acetylenes base VISOSE of the different number-average molecular weights of table 1
| Experiment numbers | ?Mn(g?mol -1) | ?M 1(g) | M 2(g) | M 3(g) | Reaction yield (%) |
| 1 | 6000 | 5 | 0.46 | 0.52 | 91.3 |
| 2 | 30000 | 5 | 0.09 | 0.11 | 90.6 |
| 3 | 60000 | 5 | 0.046 | 0.052 | 90.2 |
In the last table, Mn is the number-average molecular weight of VISOSE, M
1Be the quality of VISOSE, M
2Be the quality of propargylamine, M
3Quality for sodium cyanoborohydride.
Embodiment 4～6: the preparation that gathers (γ-phenmethyl-L-glutamate) of the end group azide of different number-average molecular weights
Take by weighing the interior carboxylic acid anhydride monomer of γ-phenmethyl-L-glutamate-N-of 3 parts of 2g, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation condition, add 0.025g (0.00025mol) respectively, 0.015g (0.00015mol), 0.011g (0.00011mol) nitrine propylamine initiator, stirring reaction 72h under 25 ℃ of conditions then.After reaction finishes, reaction solution with the sedimentation of 400mL ether, is filtered, washing obtains throw out.Vacuum-drying 24h under 25 ℃ of conditions promptly obtains the gathering of end group azide (γ-phenmethyl-L-glutamate) of 3 kinds of different number-average molecular weights.The result joins table 2.
The gathering of the end group azide of the different number-average molecular weights of table 2 (γ-phenmethyl-L-glutamate)
| Experiment numbers | Mn(g?mol -1) | Reaction yield (%) |
| 1 | 5793 | 90.5 |
| 2 | 9516 | 91.2 |
| 3 | 14334 | 91.6 |
In the last table, the number-average molecular weight of Mn for gathering (γ-phenmethyl-L-glutamate), by
1The HNMR test obtains.
Embodiment 7～9: the preparation that gathers (β-phenmethyl-L-aspartate) of the end group azide of different number-average molecular weights
Take by weighing carboxylic acid anhydride monomer in 3 parts of 2g β-phenmethyls-L-aspartate-N-respectively, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation add 0.027g (0.00027mol) respectively, 0.016g (0.00016mol), 0.011g (0.00011mol) nitrine propylamine initiator; Stirring reaction 72h under 25 ℃ of conditions then, after reaction finishes, with reaction solution with the sedimentation of 400mL ether; Filter, washing obtains throw out, 25 ℃ of vacuum-drying 24h; Promptly obtain the gathering of end group azide (β-phenmethyl-L-aspartate) of 3 kinds of different number-average molecular weights, the result joins table 3.
The preparation that gathers (β-phenmethyl-L-aspartate) of the end group azide of the different number-average molecular weights of table 3
| Experiment numbers | Mn(g?mol -1) | Reaction yield (%) |
| 1 | 5429 | 89.7 |
| 2 | 8914 | 90.8 |
| 3 | 11365 | 91.4 |
In the last table, the number-average molecular weight of Mn for gathering (β-phenmethyl-L-aspartate) obtained by the 1HNMR test.
Embodiment 10～12: the preparation that gathers (ε-carbobenzoxy-(Cbz)-L-Methionin) of the end group azide of different number-average molecular weights
Take by weighing carboxylic acid anhydride monomer in 3 parts of 2g ε-carbobenzoxy-(Cbz)s-L-Methionin-N-respectively, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation add 0.022g (0.00022mol) respectively, 0.013g (0.00013mol), 0.01g (0.0001mol) nitrine propylamine initiator; Then solution is reacted 72h under 25 ℃ of stirrer agitation conditions, after reaction finishes, with reaction solution with the sedimentation of 400mL ether; Filter, washing obtains throw out, dry 24h under 25 ℃ of vacuum conditions; Promptly obtain gather (ε-carbobenzoxy-(Cbz)-L-Methionin) of 3 kinds of different number-average molecular weights, the result joins table 4.
The preparation that gathers (ε-carbobenzoxy-(Cbz)-L-Methionin) of the end group azide of the different number-average molecular weights of table 4
| Experiment numbers | Mn(g?mol-1) | Reaction yield (%) |
| 1 | 6911 | 89.7 |
| 2 | 11365 | 90.8 |
| 3 | 17129 | 91.4 |
In the last table, the number-average molecular weight of Mn for gathering (ε-carbobenzoxy-(Cbz)-L-Methionin) obtained by the 1HNMR test.
Embodiment 13～15: the preparation that gathers (O-benzyl-L-Serine) of the end group azide of different number-average molecular weights
Take by weighing carboxylic acid anhydride monomer in 3 parts of 2g L-Serine-N-respectively, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation add 0.03g (0.00032mol) respectively, 0.018g (0.00018mol), 0.013g (0.00013mol) nitrine propylamine initiator; Then solution is reacted 72h under 25 ℃ of stirrer agitation conditions, after reaction finishes, with reaction solution with the sedimentation of 400mL ether; Filter; Washing obtains throw out, and dry 24h under 25 ℃ of vacuum conditions promptly obtains gather (the O-benzyl-L-Serine) of 3 kinds of different number-average molecular weights.The result joins table 5.
The preparation that gathers (0-benzyl-L-Serine) of the different number-average molecular weights of table 5
| Experiment numbers | Mn(g?mol -1) | Reaction yield (%) |
| 1 | 4701 | 88.9 |
| 2 | 7710 | 89.7 |
| 3 | 11604 | 90.4 |
In the last table, the number-average molecular weight of Mn for gathering (O-benzyl-L-Serine), by
1H NMR test obtains.
Embodiment 16～18: the preparation that gathers (L-phenylalanine(Phe)) of the end group azide of different number-average molecular weights
Take by weighing carboxylic acid anhydride monomer in 3 parts of 2g L-phenylalanine(Phe)-N-respectively, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation add 0.035g (0.00035mol) respectively, 0.021g (0.00021mol), 0.015g (0.00015mol) nitrine propylamine initiator; Then solution is reacted 72h under 25 ℃ of stirrer agitation conditions, after reaction finishes, with reaction solution with the sedimentation of 400mL ether; Filter; Washing obtains throw out, and dry 24h under 25 ℃ of vacuum conditions promptly obtains gather (the L-phenylalanine(Phe)) of 3 kinds of different number-average molecular weights.The result joins table 6.
The preparation that gathers (L-phenylalanine(Phe)) of the different number-average molecular weights of table 6
| Experiment numbers | Mn(g?mol -1) | Reaction yield (%) |
| 1 | 4215 | 88.7 |
| 2 | 7008 | 90.2 |
| 3 | 10095 | 91.5 |
In the last table, the number-average molecular weight of Mn for gathering (L-phenylalanine(Phe)), by
1H NMR test obtains.
Embodiment 19～21: the preparation that gathers (L-L-Ala) of the end group azide of different number-average molecular weights
Take by weighing carboxylic acid anhydride monomer in 3 parts of 2g L-L-Ala-N-respectively, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation add 0.058g (0.00025mol) respectively, 0.035g (0.00035mol), 0.025g (0.00013mol) nitrine propylamine initiator, reaction 72h under 25 ℃ of agitation conditions then.After reaction finishes, reaction solution with the sedimentation of 400mL ether, is filtered, wash and obtain throw out, dry 24h under 25 ℃ of vacuum conditions promptly obtains gather (the L-L-Ala) of 3 kinds of different number-average molecular weights.The result joins table 7.
The preparation that gathers (L-L-Ala) of the different number-average molecular weights of table 7
| Experiment numbers | Mn(g?mol -1) | Reaction yield (%) |
| 1 | 2087 | 87.6 |
| 2 | 5779 | 90.3 |
| 3 | 8619 | 90.8 |
In the last table, the number-average molecular weight of Mn for gathering (L-L-Ala) obtained by 1H NMR test.
Embodiment 22～24: the preparation that gathers (L-leucine) of the end group azide of different number-average molecular weights
Take by weighing carboxylic acid anhydride monomer in 3 parts of 2g L-leucine-N-respectively, put into 3 exsiccant peace bottles respectively, add the anhydrous N of 40mL respectively, dinethylformamide dissolves monomer.Under agitation add 0.042g (0.00042mol) respectively, 0.025g (0.00025mol), 0.014g (0.00014mol) nitrine propylamine initiator; Stirring reaction 72h under 25 ℃ of conditions then, after reaction finishes, with reaction solution with the sedimentation of 400mL ether; Filter; Washing obtains throw out, and dry 24h under 25 ℃ of vacuum conditions promptly obtains gather (the L-leucine) of 3 kinds of different number-average molecular weights.The result joins table 8.
The preparation that gathers (L-leucine) of the different number-average molecular weights of table 8
| Experiment numbers | Mn(g?mol -1) | Reaction yield (%) |
| 1 | 3264 | 89.5 |
| 2 | 5410 | 90.1 |
| 3 | 9704 | 91.4 |
In the last table, the number-average molecular weight of Mn for gathering (L-leucine), by
1H NMR test obtains.
Embodiment 25～26: the preparation that gathers (6-caprolactone) of the end group azide of different number-average molecular weights
(1) takes by weighing the 6-caprolactone of 2 parts of 10g respectively; Dissolve with 50mL toluene respectively; Under agitation condition, add 0.012g (0.0002mol) and 0.006g (0.0001mol) Virahol then respectively; 0.028g (0.000069mol) and 0.028g (0.000069mol) stannous octoate, stirring reaction is three days in 120 ℃ of oil baths.After reaction finishes, carry out sedimentation with the 500mL ether, filter, wash and obtain throw out, dry 24h under 25 ℃ of vacuum conditions promptly obtains gather (6-caprolactone) of 2 kinds of different number-average molecular weights.
(2) taking by weighing the 2g number-average molecular weight respectively is 4219 and 8550 gather (6-caprolactone); Put into two exsiccant peace bottles respectively; With the dissolving of 40mL anhydrous methylene chloride, under stirring condition, add 0.66mL, 0.33mL triethylamine and 0.54g (0.0047mol), 0.27g (0.0023mol) Methanesulfonyl chloride respectively respectively, then Methanesulfonyl chloride is added in the tap funnel; Slowly Methanesulfonyl chloride is splashed into reaction solution, then stirring reaction 24h under condition of ice bath.After reaction finishes, with the ether sedimentation of reaction solution with 400mL, filter, washing obtains throw out, and dry 24h under 25 ℃ of vacuum conditions promptly obtains methyl sulphonyl and gathers (6-caprolactone).
(3) gather (6-caprolactone) that to take by weighing 2 parts of above-mentioned ends of 0.5g respectively be Methanesulfonyl chloride; Dissolve with the 20mL THF respectively; Add 0.077g (0.0012mol), 0.038g (0.00058mol) sodiumazide then respectively, then at 40 ℃ of following stirring reaction 24h.After reaction finishes, reaction solution with the sedimentation of 200mL ether, is filtered, wash and obtain throw out, dry 24h under 25 ℃ of vacuum conditions promptly obtains gather (6-caprolactone) of end group azide.The result joins table 9.
The gathering of the different number-average molecular weights of table 9 (6-caprolactone)
In the last table, Mn
1Be the number-average molecular weight that the first step reaction product is gathered (6-caprolactone), reaction yield 1 is the productive rate of the first step reaction; Reaction yield 2 is the productive rate of second step reaction, and reaction yield 3 is the productive rate of three-step reaction.
Embodiment 27～28: the preparation of the POLYACTIC ACID of the end group azide of different number-average molecular weights
(1) takes by weighing the rac-Lactide of 2 parts of 5g; Dissolve with 50mL toluene respectively; Under agitation condition, add 0.012g (0.0002mol) and 0.006g (0.0001mol) Virahol then respectively; 0.028g (0.000069mol) and 0.028g (0.000069mol) stannous octoate, stirring reaction is three days in 120 ℃ of oil baths.After reaction finishes, carry out sedimentation with the 500mL ether, filter, wash and obtain throw out, dry 24h under 25 ℃ of vacuum conditions promptly obtains the POLYACTIC ACID of 3 kinds of different number-average molecular weights.
(2) number-average molecular weight that takes by weighing 2 parts of 2g respectively is 4219 and 8550 POLYACTIC ACID; Put into two exsiccant peace bottles respectively; With the dissolving of 40mL methylene dichloride, under agitation condition, add 0.66mL, 0.33mL triethylamine and 0.54g (0.0047mol), 0.27g (0.0023mol) Methanesulfonyl chloride respectively respectively, then Methanesulfonyl chloride is added in the tap funnel; Slowly Methanesulfonyl chloride is splashed into reaction solution, then stirring reaction 24h in ice bath.After reaction finishes, with the ether sedimentation of reaction solution with 400mL, filter, washing obtains throw out, and dry 24h under 25 ℃ of vacuum conditions promptly obtains the sulfonyloxy methyl base polylactic acid.
(3) take by weighing sulfonyloxy methyl base polylactic acid among 2 parts of 0.5g (2) respectively, with the dissolving of 20mL THF, add 0.077g (0.0012mol) and 0.038g (0.00058mol) sodiumazide then, respectively then at 40 ℃ of following stirring reaction 24h.After reaction finishes, reaction solution with the sedimentation of 200mL ether, is filtered, washing obtains throw out, and dry 24h under 25 ℃ of vacuum conditions promptly obtains end group azide POLYACTIC ACID.The result joins table 10.
The POLYACTIC ACID of the different number-average molecular weights of table 10
In the last table, Mn
1Be the number-average molecular weight of the first step reaction product POLYACTIC ACID, reaction yield 1 is the productive rate of the first step reaction; Reaction yield 2 is the productive rate of second step reaction, and reaction yield 3 is the productive rate of three-step reaction.
Embodiment 29～31: VISOSE-b-gathers the preparation of (γ-phenmethyl-L-glutamate) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 4～6 preparations respectively is 5793,9516; 14334 end group azide gather (γ-phenmethyl-L-glutamate) 0.19g (0.0000333mol), 0.32g (0.0000333mol), 0.48g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (γ-phenmethyl-L-glutamate) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 11.
Table 11 VISOSE-b-gathers (γ-phenmethyl-L-glutamate) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 5793 | 0.19 | 83.4 |
| 2 | 0.3 | 9516 | 0.32 | 83.1 |
| 3 | 0.3 | 14334 | 0.48 | 82.5 |
In the last table, Mn
1For gathering the number-average molecular weight of (γ-phenmethyl-L-glutamate), m
1Be the quality of VISOSE, m
2For gathering the quality of (γ-phenmethyl-L-glutamate).
Embodiment 32～34: VISOSE-b-gathers the preparation of (β-phenmethyl-L-aspartate)
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 7～9 preparations respectively is 5429,8914; 13424 end group azide gather (β-phenmethyl-L-aspartate) 0.18g (0.0000333mol), 0.30g (0.0000333mol), 0.45g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (β-phenmethyl-L-aspartate) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 12.
Table 12 VISOSE-b-gathers (β-phenmethyl-L-aspartate) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 5429 | 0.18 | 83.4 |
| 2 | 0.3 | 8914 | 0.30 | 83.1 |
| 3 | 0.3 | 13424 | 0.45 | 82.5 |
In the last table, Mn
1For gathering the number-average molecular weight of (β-phenmethyl-L-aspartate), m
1Be the quality of VISOSE, m
2For gathering the quality of (β-phenmethyl-L-aspartate).Embodiment 35～37: VISOSE-b-gathers the preparation of (ε-carbobenzoxy-(Cbz)-L-Methionin) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 10～12 preparations respectively is 6911,11365; 17129 end group azide gather (ε-carbobenzoxy-(Cbz)-L-Methionin) 0.23g (0.0000333mol), 0.38g (0.0000333mol), 0.57g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (ε-carbobenzoxy-(Cbz)-L-Methionin) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 13.
Table 13 VISOSE-b-gathers (ε-carbobenzoxy-(Cbz)-L-Methionin) segmented copolymer
| Experiment numbers | M 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 6911 | 0.23 | 83.8 |
| 2 | 0.3 | 11365 | 0.38 | 84.3 |
| 3 | 0.3 | 17129 | 0.57 | 83.5 |
In the last table, Mn
1For gathering the number-average molecular weight of (ε-carbobenzoxy-(Cbz)-L-Methionin), m
1Be the quality of VISOSE, m
2For gathering the quality of (ε-carbobenzoxy-(Cbz)-L-Methionin).
Embodiment 38～40: VISOSE-b-gathers the preparation of (O-benzyl ester-L-Serine) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 13～15 preparations respectively is 4701,7710; 11604 end group azide gather (O-benzyl ester-L-Serine) 0.16g (0.0000333mol), 0.26g (0.0000333mol), 0.39g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (O-benzyl ester-L-Serine) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 14.
Table 14 VISOSE-b-gathers (O-benzyl ester-L-Serine) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 4701 | 0.16 | 84.4 |
| 2 | 0.3 | 7710 | 0.26 | 83.7 |
| 3 | 0.3 | 11604 | 0.39 | 83.6 |
In the last table, Mn
1For gathering the number-average molecular weight of (O-benzyl ester-L-Serine), m
1Be the quality of VISOSE, m
2For gathering the quality of (O-benzyl ester-L-Serine).
Embodiment 41～43: VISOSE-b-gathers the preparation of (L-phenylalanine(Phe)) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 16～18 preparations respectively is 4215,7008; 10095 end group azide gather (L-phenylalanine(Phe)) 0.14g (0.0000333mol), 0.23g (0.0000333mol), 0.34g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (L-phenylalanine(Phe)) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 15.
Table 15 gained VISOSE-b-gathers (L-phenylalanine(Phe)) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 4215 | 0.14 | 83.6 |
| 2 | 0.3 | 7008 | 0.23 | 84.8 |
| 3 | 0.3 | 10095 | 0.34 | 84.2 |
In the last table, Mn
1For gathering the number-average molecular weight of (L-phenylalanine(Phe)), m
1Be the quality of VISOSE, m
2For gathering the quality of (L-phenylalanine(Phe)).
Embodiment 44～46: VISOSE-b-gathers the preparation of (L-L-Ala) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 19～21 preparations respectively is 2087,5779; 8619 end group azide gather (L-L-Ala) 0.07g (0.0000333mol), 0.19g (0.0000333mol), 0.29g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (L-L-Ala) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 16.
Table 16 VISOSE-b-gathers (L-L-Ala) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 2087 | 0.07 | 84.8 |
| 2 | 0.3 | 5779 | 0.19 | 83.5 |
| 3 | 0.3 | 8619 | 0.29 | 82.7 |
In the last table, Mn
1For gathering the number-average molecular weight of (L-L-Ala), m
1Be the quality of VISOSE, m
2For gathering the quality of (L-L-Ala).
Embodiment 47～49: VISOSE-b-gathers the preparation of (L-leucine) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 22～24 preparations respectively is 3264,5410; 9704 end group azide gather (L-leucine) 0.11g (0.0000333mol), 0.18g (0.0000333mol), 0.32g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (L-leucine) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 17.
Table 17 VISOSE-b-gathers (L-leucine) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 3264 | 0.11 | 83.9 |
| 2 | 0.3 | 5410 | 0.18 | 83.5 |
| 3 | 0.3 | 9704 | 0.32 | 84.3 |
In the last table, Mn
1For gathering the number-average molecular weight of (L-leucine), m
1Be the quality of VISOSE, m
2For gathering the quality of (L-leucine).
Embodiment 50～51: VISOSE-b-gathers the preparation of (6-caprolactone) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, the number-average molecular weight that adds embodiment 25～26 preparations respectively be 4191,8322 end group azide gather (6-caprolactone) 0.18g (0.0000333mo1); 0.14g (0.0000333mo1); 0.28g (0.0000333mo1) put into the peace bottle, use the 30mL dmso solution, add 10 μ L sodium cyanoborohydride parts; Use the liquefied ammonia freeze thawing then three times; When second time freeze thawing, add 7.2mg respectively, 7.2mg, 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (6-caprolactone) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 18.
Table 18 VISOSE-b-gathers (6-caprolactone) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 4191 | 0.14 | 83.4 |
| 2 | 0.3 | 8322 | 0.28 | 83.1 |
In the last table, Mn
1For gathering the number-average molecular weight of (6-caprolactone), m
1Be the quality of VISOSE, m
2For gathering the quality of (6-caprolactone).
Embodiment 52～53: the preparation of VISOSE-b-polylactic-acid block copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 6000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 27～28 preparations respectively is 5429,8914; The POLYACTIC ACID 0.18g (0.0000333mol) of 13424 end group azide, 0.30g (0.0000333mol), 0.45g (0.0000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-polylactic-acid block copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 19.
Table 19 VISOSE-b-polylactic-acid block copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 4314 | 0.14 | 84.3 |
| 2 | 0.3 | 8928 | 0.30 | 83.5 |
In the last table, Mn
1Be the number-average molecular weight of POLYACTIC ACID, m
1Be the quality of VISOSE, m
2Quality for POLYACTIC ACID.
Embodiment 54～56: VISOSE-b-gathers the preparation of (γ-phenmethyl-L-glutamate) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 30000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 2 preparations respectively is 5793,9516; 14334 end group azide gather (γ-phenmethyl-L-glutamate) 0.038g (0.000067mol), 0.063g (0.0000067mol), 0.10g (0.0000067mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (γ-phenmethyl-L-glutamate) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 20.
Table 20 VISOSE-b-gathers (γ-phenmethyl-L-glutamate) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 5793 | 0.038 | 85.2 |
| 2 | 0.3 | 9516 | 0.063 | 84.5 |
| 3 | 0.3 | 14334 | 0.100 | 83.3 |
In the last table, Mn
1For gathering the number-average molecular weight of (γ-phenmethyl-L-glutamate), m
1Be the quality of VISOSE, m
2For gathering the quality of (γ-phenmethyl-L-glutamate).
Embodiment 57～59: VISOSE-b-gathers the preparation of (γ-phenmethyl-L-glutamate) segmented copolymer
The number-average molecular weight that takes by weighing 3 parts of 0.3g embodiment, 1 preparation respectively is 60000 Terminal Acetylenes base VISOSE, and the number-average molecular weight that adds embodiment 2 preparations respectively is 5793,9516; 14334 end group azide gather (γ-phenmethyl-L-glutamate) 0.019g (0.00000333mol), 0.032g (0.00000333mol), 0.048g (0.00000333mol) put into the peace bottle; Use the 30mL dmso solution; Add 10 μ L sodium cyanoborohydride parts, use the liquefied ammonia freeze thawing then three times, when second time freeze thawing, add 7.2mg respectively; 7.2mg, the 7.2mg cuprous bromide.After freeze thawing finished, under 40 ℃ of agitation conditions, Click reacted 72h.After reaction finishes,, continue to change water, with the product freeze-drying, promptly obtain VISOSE-b-and gather (γ-phenmethyl-L-glutamate) segmented copolymer after the dialysis to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.The result joins table 21.
Table 21 VISOSE-b-gathers (γ-phenmethyl-L-glutamate) segmented copolymer
| Experiment numbers | m 1(g) | Mn 1(g?mol -1) | m 2(g) | Reaction yield (%) |
| 1 | 0.3 | 5793 | 0.019 | 85.8 |
| 2 | 0.3 | 9516 | 0.032 | 83.9 |
| 3 | 0.3 | 14334 | 0.048 | 84.7 |
In the last table, Mn
1For gathering the number-average molecular weight of (γ-phenmethyl-L-glutamate), m
1Be the quality of VISOSE, m
2For gathering the quality of (γ-phenmethyl-L-glutamate).
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (3)
1. VISOSE base amphipathic nature block polymer is characterized in that, hydrophilic segment is a VISOSE in the described VISOSE base amphipathic nature block polymer, and hydrophobic segment is polyamino acid or aliphatic polyester.VISOSE base amphipathic nature block polymer is to be obtained through highly active click reaction with end group azide polyamino acid or end group azide polyester respectively by Terminal Acetylenes base VISOSE.The number-average molecular weight scope of said VISOSE is 6000-60000, and polyamino acid segmental number-average molecular weight is 3000-10000, and the number-average molecular weight of polyester segment is 3000-10000.
2. VISOSE base amphipathic nature block polymer as claimed in claim 1; It is characterized in that described polyamino acid comprises and gathers (γ-phenmethyl-L-glutamate), gathers (β-phenmethyl-L-aspartate), gathers (ε-carbobenzoxy-(Cbz)-L-Methionin), gathers (O-benzyl-L-Serine), gathers (L-phenylalanine(Phe)), gathers (L-L-Ala), gathers (L-leucine); Described polyester comprises POLYACTIC ACID and gathers (6-caprolactone).
3. the preparation method of VISOSE base amphipathic nature block polymer as claimed in claim 1 is characterized in that, step and reaction conditions are following:
(1) preparation of Terminal Acetylenes base VISOSE
VISOSE is dissolved in acetic acid/sodium acetate buffer solution of pH=5, adds propargylamine and sodium cyanoborohydride under the whipped state successively, wherein, the mol ratio of described VISOSE, propargylamine, sodium cyanoborohydride is 1: 10: 10,50 ℃ of reaction 96h.After reaction finishes, with the reaction product 96h that dialyses, continue to change water to remove water miscible small-molecule substance with the 3500Da dialysis tubing.With the product freeze-drying, promptly get Terminal Acetylenes base VISOSE after the dialysis.
(2) preparation of end group azide polyamino acid
Carboxylic acid anhydride in amino acid-N-is dissolved in anhydrous N, in the dinethylformamide, under the stirrer whipped state, adds the nitrine propylamine, wherein, the ratio of the mole of carboxylic acid anhydride is 1: 30～70 in nitrine propylamine and the amino acid-N-.25 ℃ of stirring reaction 72h.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, washing obtains throw out.25 ℃ of vacuum-drying 24h promptly obtain the polyamino acid of end group azide.
(3) preparation of end group azide polyester
A. the preparation of differing mol weight polyester
The aliphatics cyclic monomer is dissolved in the toluene, adds stannous octoate and Virahol, the mol ratio of cyclic monomer, stannous octoate is 1: 1000, and the mol ratio of cyclic monomer and Virahol is that 1: 20～70,120 ℃ stirrers stir reaction 24h down.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, wash and obtain throw out, 25 ℃ of vacuum-drying 24h promptly get the polyester of different number-average molecular weights.
B. the preparation of methyl sulphonyl polyester
Polyester is dissolved with anhydrous methylene chloride, and stirrer stirs down and adds triethylamine, slowly drips Methanesulfonyl chloride with tap funnel then, and wherein, the mol ratio of described polyester, triethylamine, Methanesulfonyl chloride is 1: 10: 10.Under the condition of ice bath, continue stirring reaction 24h.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, washing obtains throw out, and 25 ℃ of vacuum-drying 24h promptly obtain the methyl sulphonyl polyester.
C. the preparation of end group azide polyester
The methyl sulphonyl polyester that b is obtained dissolves with THF, adds sodiumazide then, and wherein, the mol ratio of described methyl sulphonyl polyester, sodiumazide is 1: 10.40 ℃ of lasting stirring reaction 24h.After reaction finishes, with the ether sedimentation of 10 times of reaction solution volumes, filter, washing obtains throw out, and 25 ℃ of vacuum-drying 24h promptly obtain end group azide polyester.
(4) preparation of VISOSE base Amphipathilic block polymer
A. the preparation of VISOSE-b-polyamino acid Amphipathilic block polymer
Terminal Acetylenes base VISOSE and end group azide polyamino acid are dissolved in the DMSO 99.8MIN., and stirrer stirs and to add the part pentamethyl-diethylenetriamine down, uses the liquefied ammonia freeze thawing then three times, when second time freeze thawing, adds cuprous bromide.Wherein, the mol ratio of VISOSE, azide polyamino acid, pentamethyl-diethylenetriamine, cuprous bromide is 1.5: 1: 1.5: 1.5.After freeze thawing finishes, 40 ℃ of click reaction 72h.After reaction finishes,, continue to change water to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.With the product freeze-drying, promptly get VISOSE-b-polyamino acid amphipathic nature block polymer after the dialysis.
B. the preparation of VISOSE-b-polyester amphipathic nature block polymer
Terminal Acetylenes base VISOSE and end group azide polyester are dissolved in the DMSO 99.8MIN., and stirrer stirs and to add the part pentamethyl-diethylenetriamine down, uses the liquefied ammonia freeze thawing then three times, when second time freeze thawing, adds cuprous bromide.Wherein, the mol ratio of VISOSE, azide polyester, pentamethyl-diethylenetriamine, cuprous bromide is 1.5: 1: 1.5: 1.5.After freeze thawing finishes, click reaction 72h under 40 ℃ of stirrings.After reaction finishes,, continue to change water to remove water miscible small-molecule substance with 10000Da dialysis tubing dialysis 96h.With the product freeze-drying, promptly get VISOSE-b-polyester amphipathic nature block polymer after the dialysis.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977378A (en) * | 2012-12-24 | 2013-03-20 | 中山大学 | Amphipathic heparin-based block polymer and preparation method and application thereof |
| CN102977362A (en) * | 2012-11-28 | 2013-03-20 | 中国科学院长春应用化学研究所 | Poly-amino acid block copolymer, preparation method thereof and temperature-sensitive hydrogel |
| CN103204998A (en) * | 2013-04-23 | 2013-07-17 | 中山大学 | Amphipathic polysaccharide/polypeptide block polymer containing azobenzene group and preparation method and application of block polymer |
| CN104725632A (en) * | 2015-04-02 | 2015-06-24 | 中国科学院长春应用化学研究所 | Glucan-polyamino acid block copolymer and preparation method thereof, and drug-carrying micelle |
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| CN111196863A (en) * | 2016-12-16 | 2020-05-26 | 杜邦工业生物科学美国有限责任公司 | Amphiphilic polysaccharide derivatives and compositions containing the same |
| US11104747B2 (en) | 2015-11-05 | 2021-08-31 | Nutrition & Biosciences USA 4, Inc. | Dextran-poly alpha-1,3-glucan graft copolymers and synthesis methods thereof |
| CN113621139A (en) * | 2021-08-24 | 2021-11-09 | 濮阳市盛源石油化工（集团）有限公司 | Glucan-based amphiphilic block copolymer and preparation method thereof |
| US11732216B2 (en) | 2020-06-10 | 2023-08-22 | The Procter & Gamble Company | Laundry care or dish care composition comprising a poly alpha-1,6-glucan derivative |
| US11965147B2 (en) | 2020-06-10 | 2024-04-23 | The Procter & Gamble Company | Laundry care or dish care composition comprising a poly alpha-1,6-glucan derivative |
| JP7478394B2 (en) | 2018-06-11 | 2024-05-07 | ウニベルシダージ デ コインブラ | Photopolymerized biodegradable copolymer formulations for biomedical applications |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851306A (en) * | 2010-06-21 | 2010-10-06 | 哈尔滨工程大学 | Synthetic method of polystyrene macromolecular ligand |
-
2012
- 2012-03-21 CN CN201210075156.7A patent/CN102634033B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851306A (en) * | 2010-06-21 | 2010-10-06 | 哈尔滨工程大学 | Synthetic method of polystyrene macromolecular ligand |
Non-Patent Citations (1)
| Title |
|---|
| 张琦等: "β-(1-3)-D-葡聚糖可德胶化学改性的研究进展", 《高分子通报》 * |
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| CN104725632A (en) * | 2015-04-02 | 2015-06-24 | 中国科学院长春应用化学研究所 | Glucan-polyamino acid block copolymer and preparation method thereof, and drug-carrying micelle |
| CN104725632B (en) * | 2015-04-02 | 2017-11-14 | 中国科学院长春应用化学研究所 | A kind of glucan polyamino acid block copolymer and preparation method thereof and carrier micelle |
| US11104747B2 (en) | 2015-11-05 | 2021-08-31 | Nutrition & Biosciences USA 4, Inc. | Dextran-poly alpha-1,3-glucan graft copolymers and synthesis methods thereof |
| CN111196863B (en) * | 2016-12-16 | 2022-06-28 | 宝洁公司 | Amphiphilic polysaccharide derivatives and compositions containing the same |
| CN111196863A (en) * | 2016-12-16 | 2020-05-26 | 杜邦工业生物科学美国有限责任公司 | Amphiphilic polysaccharide derivatives and compositions containing the same |
| CN107397962B (en) * | 2017-07-06 | 2020-04-07 | 天津大学 | Glucan-g-poly (L-lysine) -VAPG nucleic acid vector and preparation method and application thereof |
| JP2021528127A (en) * | 2018-06-11 | 2021-10-21 | ウニベルシダージ デ コインブラＵｎｉｖｅｒｓｉｄａｄｅ Ｄｅ Ｃｏｉｍｂｒａ | Photopolymerized biodegradable copolymer formulation for biomedical applications |
| WO2019239266A1 (en) * | 2018-06-11 | 2019-12-19 | Universidade De Coimbra | Photopolymerized biodegradable copolymer formulations for biomedical applications |
| JP7478394B2 (en) | 2018-06-11 | 2024-05-07 | ウニベルシダージ デ コインブラ | Photopolymerized biodegradable copolymer formulations for biomedical applications |
| US11732216B2 (en) | 2020-06-10 | 2023-08-22 | The Procter & Gamble Company | Laundry care or dish care composition comprising a poly alpha-1,6-glucan derivative |
| US11965147B2 (en) | 2020-06-10 | 2024-04-23 | The Procter & Gamble Company | Laundry care or dish care composition comprising a poly alpha-1,6-glucan derivative |
| CN113621139A (en) * | 2021-08-24 | 2021-11-09 | 濮阳市盛源石油化工（集团）有限公司 | Glucan-based amphiphilic block copolymer and preparation method thereof |
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