CN106750334A - Amphipathic tadpole-shaped block copolymer and preparation method thereof - Google Patents

Amphipathic tadpole-shaped block copolymer and preparation method thereof Download PDF

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CN106750334A
CN106750334A CN201611119644.8A CN201611119644A CN106750334A CN 106750334 A CN106750334 A CN 106750334A CN 201611119644 A CN201611119644 A CN 201611119644A CN 106750334 A CN106750334 A CN 106750334A
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pnvcl
alknyl
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CN106750334B (en
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毕韵梅
李�杰
杨耀宗
唐刚
马永翠
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Yunnan Normal University
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Abstract

Amphipathic tadpole-shaped block copolymer and preparation method thereof, belongs to field of polymer material preparing technology.First prepare with α, the aliphatic polyester and poly- (N caprolactams) with terminal acetylene of the double terminal sulfhydryl groups of ω, then the sulfydryl alkynes click-reaction for passing through the two, it is made amphipathic single tadpole-shaped block copolymer I；The four arm star polyesters with terminal sulfhydryl group and poly- (N caprolactams) with terminal acetylene, then the sulfydryl alkynes click-reaction for passing through the two are prepared, amphipathic couple of tadpole-shaped block copolymer II is made.Sulfydryl alkyne reaction without copper catalysis is used to prepare tadpole-shaped block copolymer, product pollution problem caused by the use because of copper catalyst is overcome；Products therefrom is pure, and easy purification, reaction condition is easily realized, safety, reaction efficiency is high；Product integrates amphipathic, temperature-responsive, biodegradable and biocompatibility, has broad prospect of application in biomedicine field.

Description

Amphipathic tadpole-shaped block copolymer and preparation method thereof
Technical field
The invention belongs to field of polymer material preparing technology, and in particular to one kind with cyclic aliphatic polyester as head, it is linear Poly- (N- caprolactams) is amphipathic single tadpole-shaped block copolymer and one kind two of tail with cyclic aliphatic polyester For head, linear poly- (N- caprolactams) for single tadpole-shaped block copolymer of tail is total to by two cyclic aliphatic polyester Amphipathic pair of tadpole-shaped block copolymer formed with a carbon atom and preparation method thereof.
Background technology
Cyclic polymer includes monocyclic and polycyclic polymers, is the polymer that a class has special topological structure, with not It is same as linear and branched polymer special nature.Ring topology is also one of structure for being widely present in nature, point Sub- biology and biochemical research find to there is also some annular large biological molecules in vivo, and such as annular is oligomeric Sugar, annular DNA, circular polypeptides, annular polysaccharide and some microorganisms with annular form.Therefore, to cyclic structure polymer Research can not only obtain new material, additionally aid and probe the mystery of life.Tadpole-shaped polymer is that a class is particularly ring-shaped Polymer, also referred to as annular-line polymer, are made up of a ring and (or multiple) line polymer.Tadpole-shaped is polymerized The excellent properties of thing combination annular polymeric and line polymer are in one, especially while having hydrophily and oil loving two Parent's property tadpole-shaped block copolymer is a kind of distinct polymer for having special construction, different component and solution self assembly performance concurrently, Had broad application prospects in the field such as materialogy, supermolecule and self assembly and biological medicine.But due to the difficulty in synthesis, Research report on tadpole-shaped block copolymer is less.
At present, the method for synthesis tadpole-shaped polymer mainly has three kinds：(1) under the dilute concentration of pole, can be anti-containing two The group answered, one end, an intramolecular cyclization for another diblock copolymer on the binding site of two blocks in block Reaction.(2) first synthesis one carries the annular polymeric of functional group, is then coupled or initiation small molecule monomer by with polymer chain Polymerization is obtained.(3) between two end groups of gamma-form polymer there is intermolecular cyclization in two end groups on line polymer respectively Reaction.In recent years, click chemistry (Click chemistry) was introduced in tadpole-shaped Macroscopic single crystal, was substantially increased The combined coefficient of tadpole-shaped polymer.At present, the click chemistry for being applied to tadpole-shaped Macroscopic single crystal is mainly the Cu (I) of classics Lower nitrine-the alkynes 1 of catalysis, 3- Dipolar Cycloadditions (CuAAC), but due to having used Cu (I) as catalyst so that in product Heavy metal copper can be remained, so as to greatly limit its answering in the field such as bioabsorbable polymer material and pharmaceutical carrier With.
Sulfydryl-alkyne reaction is a kind of green click-reaction without copper catalysis based on sulfydryl, and not only raw material is easy to get, one three Key polymerized monomer can occur click-reaction with two sulfhydryl compound molecules, and reaction efficiency is high, and what is more important only needs profit Free radical is produced with heating or illumination condition can be such that reaction simply and efficiently carries out, it is thus also avoided that because of the use of copper catalyst Caused by product pollution problem, in the synthesis of bio-medical material have important application value.At present, sulfydryl-alkynes point Reaction is hit mainly for the preparation of the functional polymers such as dendritic, dissaving polymer and network polymers, literature search Have no the research report for being applied to prepare amphipathic tadpole-shaped block copolymer about sulfydryl-alkyne reaction.
The aliphatic polyester such as poly- (6-caprolactone), PGA, PLA (PE) are the important synthesis of medical high scores of a class Sub- material, with good biocompatibility and biodegradability, is widely applied in biomedicine field.Poly- (N- Caprolactam) (PNVCL) be the water-soluble polymer with temperature-responsive, its lower critical solution temperature (LCST) exists In the range of physiological temp (32 DEG C~40 DEG C), and with good biocompatibility.The copolymer of PE and PNVCL has temperature sound concurrently Ying Xing, biodegradability and amphipathic, can be in aqueous that the biodegradable with temperature-responsive is received with self assembly Rice glue beam, has important application value in terms of drug controlled release and Targeting delivery.At present, being total on PE and PNVCL Polymers research focus mostly in linear copolymer aspect, literature search have no relevant aliphatic polyester (PE) and it is poly- (N- vinyl oneself Lactams) (PNVCL) amphipathic tadpole-shaped block copolymer research report.
The content of the invention
It is an object of the invention to provide one kind with cyclic aliphatic polyester as head, linear poly- (N- caprolactams) be Amphipathic single tadpole-shaped block copolymer of tail and it is a kind of two with cyclic aliphatic polyester as head, it is linear it is poly- (N- vinyl oneself Lactams) share the amphiphilic that a carbon atom is formed for single tadpole-shaped block copolymer of tail passes through two cyclic aliphatic polyester Property double tadpole-shaped block copolymers and preparation method thereof.
The tadpole-shaped block copolymer that the present invention is provided, one kind is amphipathic single tadpole-shaped block copolymer (c-PE)-b- PNVCL, another kind is amphipathic couple of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c-PE)-b-PNVCL, its molecule knot Structure is as follows respectively：
(c-PE)-b-PNVCL,
PNVCL-b- (c-PE)-(c-PE)-b-PNVCL,
M is selected from formula (c-PE)-b-PNVCL and PNVCL-b- (c-PE)-(c-PE)-b-PNVCL：
N=20~40 in formula (c-PE)-b-PNVCL, m=40~100,
N=10~20, m=40~100 in formula PNVCL-b- (c-PE)-(c-PE)-b-PNVCL.
First, the preparation method of amphipathic single tadpole-shaped block copolymer is as follows：
1st, preparing has α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
A. prepare with α, the polyester X-M-X of ω-bis- end xanthic acid ester groups, described polyester is polycaprolactone, the friendship of poly- second Any one in ester, poly- D-ALPHA-Hydroxypropionic acid, poly (l-lactic acid) and PDLLA.The step is prior art, and a kind of method is：By existing There is technology (for example to can refer to document Mishra AK, Vishwakarma N K, Patel V K, Biswas C S, Paira T K,Mandal T K,Maiti P,Ray B.Colloid Polym.Sci.,2014,292(6):1405-1418), first, with Stannous octoate is catalyst, and ethylene glycol is initiator, triggers the ring-opening polymerisation of lactone or lactide, and preparing has α, ω-bis- ends The polyester HO-M-OH of hydroxyl.Again with triethylamine as acid binding agent, reacted with HO-M-OH and 2 bromo propionyl bromide, preparing has α, ω- The polyester Br-M-Br of double end bromines.Finally, in the presence of pyridine, with Br-M-Br and O- ethoxy-dithioformic acid nak responses, had There are α, the polyester X-M-X of ω-bis- end xanthic acid ester groups.Described lactone and lactide be 6-caprolactone, glycolide, D- lactides, Any one in L- lactides and DL- lactides.
B. prepare with α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
X-M-X, n-butylamine, tributylphosphine, dichloromethane, wherein tributylphosphine, X-M-X and just are added in reaction vessel The amount ratio of the material of butylamine is 1:8000~10000:16000~30000, dissolved with the X-M- of 70~90mg in every mL dichloromethane X, 1~3h of stirring reaction, most handy dry reaction vessel carry out above-mentioned reaction.Crude product must have after being co-precipitated, drying The polyester HS-M-SH of α, ω-bis- terminal sulfhydryl groups.The molecular structure of HS-M-SH is as follows：
M is selected from formula：
N=20~40 in formula.
2nd, poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, by N, N- diethyl-S- α, α '-methyl-carbithionic acid thiocarbamate DTCA and dicyclohexyl carbon Imidodicarbonic diamide DCC is dissolved in dichloromethane, is dissolved with the amount ratio of the material of 20~50mg DTCA, DTCA and DCC per mL dichloromethane 1:1~1.5；At 0~5 DEG C, the dichloromethane solution of propilolic alcohol and dimethylamino naphthyridine DMAP is added dropwise, propilolic alcohol and DMAP's The amount ratio of material is 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, the dichloromethane solution of DTCA and DCC with The volume ratio of the dichloromethane solution of propilolic alcohol and DMAP is 1~3:1, drip off, react 1~2h, room temperature reaction 24 at 0~5 DEG C ~28h；Isolate and purify crude product and the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is obtained. The molecular structure of alknyl-CTA is as follows：
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Alknyl-CTA, N- caprolactam NVCL and azodiisobutyronitrile AIBN are added in reaction vessel, The mass ratio of alknyl-CTA, NVCL and AIBN is 5~8:300~330:1, vacuumize, after inflated with nitrogen, then vacuumize, then Be polymerized 12~16h at 65~75 DEG C, crude product through co-precipitation, dialysis, dry must have terminal acetylene poly- (N- vinyl is in oneself Acid amides) alknyl-PNVCL；The molecular structure of alknyl-PNVCL is as follows：
M=40~100 in formula.
3rd, amphipathic single tadpole-shaped block copolymer (c-PE)-b-PNVCL is prepared
Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl-PNVCL of 25~30mg in the DMF per mL, is taken out It is stand-by after vacuum, inflated with nitrogen.The HS-PE-SH that step 1b is obtained is dissolved in DMF, dissolved with 10~15mg's in the DMF per mL HS-PE-SH, vacuumizes, after inflated with nitrogen, stand-by.The DMF of 1.3~1.8L is added in reaction vessel, drum nitrogen deoxidation is added AIBN, dissolved with 15~25mg AIBN in every LDMF.75~85 DEG C are warming up to, and under nitrogen protection, with 90~120 μ L/ The speed of 10min adds the DMF solution of above-mentioned HS-PE-SH and the DMF solution of alknyl-PNVCL, described HS-PE-SH simultaneously DMF solution, the DMF solution of alknyl-PNVCL and AIBN DMF solution volume ratio be 1:1~1.5:1300~1800. Add, continue to react 10~15h.Crude product is through co-precipitation, dry amphipathic single tadpole-shaped block copolymer (c-PE)-b- PNVCL。
The preparation method of optimization is as follows：
1st, preparing has α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
A. with stannous octoate as catalyst, ethylene glycol is initiator, triggers the ring-opening polymerisation of lactone or lactide, preparation to have The polyester HO-M-OH of α, ω-bis- terminal hydroxyls.Again with triethylamine as acid binding agent, reacted with HO-M-OH and 2 bromo propionyl bromide, system It is standby that there is α, the polyester Br-M-Br of ω-bis- end bromines.Finally, in the presence of pyridine, with Br-M-Br and O- ehtyl potassium xanthates Reaction, preparing has α, the polyester X-M-X of ω-bis- end xanthic acid ester groups.Described lactone and lactide are 6-caprolactone, second friendship Any one in ester, D- lactides, L- lactides and DL- lactides.
B. prepare with α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
X-M-X, n-butylamine, tributylphosphine, dichloromethane, wherein tributylphosphine, X-M-X and just are added in reaction vessel The amount ratio of the material of butylamine is 1:8000~10000:16000~30000, dissolved with the X-M- of 70~90mg in every mL dichloromethane X, 1~3h of stirring reaction, most handy dry reaction vessel carry out above-mentioned reaction.Crude product is co-precipitated 2~5 times with petroleum ether, Drying at room temperature obtains HS-M-SH.
2nd, poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, DTCA and DCC are dissolved in dichloromethane, per mL dichloromethane dissolved with 20~50mg DTCA, DTCA and The amount ratio of the material of DCC is 1:1~1.5；At 0~5 DEG C and under stirring, the dichloromethane solution of propilolic alcohol and DMAP, third is added dropwise The amount ratio of the material of alkynol and DMAP is 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, the two of DTCA and DCC Chloromethanes solution is 1~3 with the volume ratio of propilolic alcohol and the dichloromethane solution of DMAP:1, drip off, 0~5 DEG C of 1~2h of reaction, 24~28h of room temperature reaction；Most handy dry reaction vessel carries out above-mentioned reaction.Filtering, vacuum distillation filtrate, residue second Refiltered after ether dissolving, steam ether, separated crude product and alknyl-CTA is obtained.
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Alknyl-CTA, NVCL and AIBN are added in reaction vessel, the mass ratio of alknyl-CTA, NVCL and AIBN is 5~8:300~330:1, vacuumize, after inflated with nitrogen 3~6 times, then vacuumize 30~40min, then it is polymerized 12 at 65~75 DEG C ~16h.Crude product THF dissolves, and is co-precipitated 2~5 times with petroleum ether, collects precipitation.It is put into after precipitation is distilled into water dissolves Molecular cut off be 3500 bag filter in dialyse 3~6 days, decompression steam water after, be vacuum dried to obtain alknyl-PNVCL.
3rd, amphipathic single tadpole-shaped block copolymer (c-PE)-b-PNVCL is prepared
Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl-PNVCL of 25~30mg in the DMF per mL, is taken out It is stand-by after vacuum, inflated with nitrogen 2~5 times.HS-PE-SH is dissolved in DMF, dissolved with the HS- of 10~15mg in the DMF per mL PE-SH, vacuumizes, after inflated with nitrogen 2~5 times, stand-by.The DMF of 1.3~1.8L is added in reaction vessel, through the bulging nitrogen of 1~3h Qi exhaustion oxygen, adds AIBN, dissolved with 15~25mg AIBN in every LDMF.75~85 DEG C are warming up to, and under nitrogen protection, with 90 The speed of~120 μ L/10min adds the DMF solution of above-mentioned HS-PE-SH and the DMF solution of alknyl-PNVCL simultaneously, described The volume ratio of the DMF solution of the DMF solution of HS-PE-SH, the DMF solution of alknyl-PNVCL and AIBN is 1:1~1.5:1300 ~1800.Add, continue to react 10~15h, be cooled to room temperature, decompression steams solvent, crude product is co-precipitated to obtain with ether.It is thick to produce Thing CH2Cl2After dissolving, it is co-precipitated with petroleum ether, collects precipitation, drying at room temperature obtains amphipathic single tadpole-shaped block copolymer (c- PE)-b-PNVCL。
2nd, the preparation method of amphipathic pair of tadpole-shaped block copolymer is as follows：
1st, four arm star polyesters Star- (PE-SH) with four terminal sulfhydryl groups are prepared4
A. prepare with four four arm star polyesters Star- (PE-Y) of end xanthic acid ester group4, described polyester is to gather oneself Any one in lactone, PGA, poly- D-ALPHA-Hydroxypropionic acid, poly (l-lactic acid) and PDLLA.The step is prior art, a kind of Method is that (for example can refer to the Chemical Industry in Guangzhou such as document Li Jie, Yang Yaozong, Liu Lingqi, 2014,42 (6) by prior art:1-4), First, under stannous octoate catalysis, the ring-opening polymerisation of lactone or lactide is triggered with pentaerythrite, obtains that there are four terminal hydroxyls Four arm star polyesters Star- (PE-OH)4, described lactone and lactide are 6-caprolactone, glycolide, D- lactides, L- lactides With any one in DL- lactides；Obtain that there is four end bromines with 2 bromo propionyl bromide reaction in the presence of triethylamine again Four arm star polyesters Star- (PE-Br)4；Obtained with four ends with O- ethoxy-dithioformic acid nak responses in the presence of pyridine again Four arm star polyesters Star- (PE-Y) of xanthic acid ester group4。
B. prepare with four four arm star polyesters Star- (PE-SH) of terminal sulfhydryl group4
By Star- (PE-Y)4Be dissolved in dichloromethane, add n-butylamine, tributylphosphine, in the dichloromethane per mL dissolved with 70~90mg Star- (PE-Y)4, the amount ratio of the material of tributylphosphine, X-M-X and n-butylamine is 1:8000~10000:40000 ~80000, N2Under protection, after 1~3h of stirring reaction, through co-precipitation, dry Star- (PE-SH)4。Star-(PE-SH)4's Molecular structure is as follows：
M is selected from formula：
N=10~20 in formula.
2nd, poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, by N, N- diethyl-S- α, α '-methyl-carbithionic acid thiocarbamate DTCA and dicyclohexyl carbon Imidodicarbonic diamide DCC is dissolved in dichloromethane, is dissolved with the amount ratio of the material of 20~50mg DTCA, DTCA and DCC per mL dichloromethane 1:1~1.5；At 0~5 DEG C, the dichloromethane solution of propilolic alcohol and dimethylamino naphthyridine DMAP is added dropwise, propilolic alcohol and DMAP's The amount ratio of material is 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, the dichloromethane solution of DTCA and DCC with The volume ratio of the dichloromethane solution of propilolic alcohol and DMAP is 1~3:1, drip off, 0~5 DEG C of 1~2h of reaction, room temperature reaction 24~ 28h；Isolate and purify crude product and alknyl-CTA is obtained.The molecular structure of alknyl-CTA is as follows：
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Alknyl-CTA, NVCL and AIBN are added in reaction vessel, the mass ratio of alknyl-CTA, NVCL and AIBN is 5~8:300~330:1, vacuumize, after inflated with nitrogen, then vacuumize, be then polymerized 12~16h at 65~75 DEG C, and crude product is through altogether Precipitation, dialysis, dry alknyl-PNVCL；The molecular structure of alknyl-PNVCL is as follows：
M=40~100 in formula.
3rd, amphipathic pair of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c-PE)-b-PNVCL is prepared
By Star- (PE-SH)4DMF is dissolved in, dissolved with the Star- (PE-SH) of 6~10mg in the DMF per mL4, take out true It is stand-by after empty, inflated with nitrogen.Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl- of 50~80mg in the DMF of every mL PNVCL, vacuumizes, after inflated with nitrogen, stand-by.1.3~1.8LDMF is added in reaction vessel, through drum nitrogen deoxidation, is added AIBN, dissolved with 15~25mg AIBN in every LDMF.75~85 DEG C are warming up to, and under nitrogen protection, with 90~120 μ L/ The speed of 10min adds above-mentioned Star- (PE-SH) simultaneously4DMF solution and alknyl-PNVCL DMF solution, Star- (PE-SH)4DMF solution, the DMF solution of alknyl-PNVCL and AIBN DMF solution volume ratio be 1:1~1.5:1300 ~1800.Add, continue to react 10~15h, crude product is through co-precipitation, dry amphipathic pair of tadpole-shaped block copolymer PNVCL-b-(c-PE)-(c-PE)-b-PNVCL。
The same routine techniques of the operations such as co-precipitation, dialysis, drying in above-mentioned steps.
The preparation method of optimization is as follows：
1st, four arm star polyesters Star- (PE-SH) with four terminal sulfhydryl groups are prepared4
A. prepare with four four arm star polyesters Star- (PE-Y) of end xanthic acid ester group4
Under stannous octoate catalysis, the ring-opening polymerisation of lactone or lactide is triggered with pentaerythrite, obtain that there are four ends Four arm star polyesters Star- (PE-OH) of hydroxyl4, described lactone and lactide are 6-caprolactone, glycolide, D- lactides, L- third Any one in lactide and DL- lactides；Obtain that there are four ends with 2 bromo propionyl bromide reaction in the presence of triethylamine again Four arm star polyesters Star- (PE-Br) of bromine4；Again Star- (PE- are obtained in the presence of pyridine with O- ethoxy-dithioformic acid nak responses Y)4。
B. prepare with four four arm star polyesters Star- (PE-SH) of terminal sulfhydryl group4
By Star- (PE-Y)4Be dissolved in dichloromethane, add n-butylamine, tributylphosphine, in the dichloromethane per mL dissolved with 70~90mg Star- (PE-Y)4, the amount ratio of the material of tributylphosphine, X-M-X and n-butylamine is 1:8000~10000:40000 ~80000, after 1~3h of stirring reaction, it is co-precipitated 3~5 times with petroleum ether.Precipitation is collected, drying at room temperature obtains Star- (PE-SH )4。
2nd, poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, DTCA and DCC are dissolved in dichloromethane, per mL dichloromethane dissolved with 20~50mg DTCA, DTCA and The amount ratio of the material of DCC is 1:1~1.5；At 0~5 DEG C and under stirring, the dichloromethane solution of propilolic alcohol and DMAP, third is added dropwise The amount ratio of the material of alkynol and DMAP is 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, the two of DTCA and DCC Chloromethanes solution is 1~3 with the volume ratio of propilolic alcohol and the dichloromethane solution of DMAP:1, drip off, 0~5 DEG C of 1~2h of reaction, 24~28h of room temperature reaction；Most handy dry reaction vessel carries out above-mentioned reaction.Filtering, vacuum distillation filtrate, residue second Refiltered after ether dissolving, steam ether, separated crude product and alknyl-CTA is obtained.
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Alknyl-CTA, NVCL and AIBN are added in reaction vessel, the mass ratio of alknyl-CTA, NVCL and AIBN is 5~8:300~330:1, vacuumize, after inflated with nitrogen 3~6 times, then vacuumize 30~40min, then it is polymerized 12 at 65~75 DEG C ~16h.Crude product THF dissolves, and is co-precipitated 2~5 times with petroleum ether, collects precipitation.It is put into after precipitation is distilled into water dissolves Molecular cut off be 3500 bag filter in dialyse 3~6 days, decompression steam water after, be vacuum dried to obtain alknyl-PNVCL.
3rd, amphipathic pair of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c-PE)-b-PNVCL is prepared
By Star- (PE-SH)4DMF is dissolved in, dissolved with the Star- (PE-SH) of 6~10mg in the DMF per mL4, take out true It is stand-by after empty, inflated with nitrogen 2~5 times.Alknyl-PNVCL is dissolved in DMF, dissolved with 50~80mg's in the DMF of every mL Alknyl-PNVCL, vacuumizes, after inflated with nitrogen 2~5 times, stand-by.1.3~1.8L DMF are added in reaction vessel, through 1~3h Bulging nitrogen deoxidation, add AIBN, per L DMF in dissolved with 15~25mg AIBN.75~85 DEG C are warming up to, and in nitrogen protection Under, above-mentioned Star- (PE-SH) is added with the speed of 90~120 μ L/10min simultaneously4DMF solution and alknyl-PNVCL DMF solution, Star- (PE-SH)4The volume ratio of DMF solution of DMF solution, the DMF solution of alknyl-PNVCL and AIBN be 1:1~1.5:1300~1800.Add, continue to react 10~15h.Most handy dry reaction vessel carries out above-mentioned reaction.It is cold But to room temperature, decompression steams solvent, and crude product is co-precipitated to obtain with ether.It is common with petroleum ether after crude product is dissolved with dichloromethane Precipitation, collects precipitation, and drying at room temperature obtains amphipathic pair of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c-PE)-b- PNVCL。
The same routine techniques of the operations such as filtering, vacuum distillation, column chromatography, vacuum drying in above-mentioned steps.
In the present invention, prepared amphipathic single tadpole-shaped block copolymer and amphipathic pair of tadpole-shaped block copolymer knot Structure clearly, can pass through1HNMR, IR, GPC and MALDI-TOF MS carry out detailed characterizations.
Beneficial effects of the present invention：Click chemistry mostly Cu (I) catalysis for being presently used for tadpole-shaped Macroscopic single crystal is lower folded Nitrogen-alkynes 1,3- Dipolar Cycloadditions (CuAAC), Cu (I) has cytotoxicity as catalyst, it is necessary to reduce in vivo Application, and reaction condition required for preparing Cu (I) is more complicated, and Cu (I) is difficult to remove in purification of products, causes product dirty Dye；Furthermore it is related to azido compound in reaction, with certain danger.The present invention by based on sulfydryl without copper catalysis sulfydryl- Alkyne reaction is used to prepare single tadpole-shaped block copolymer and double tadpole-shapeds of aliphatic polyester and poly- (N- caprolactams) Block copolymer, Cu (I) has bio-toxicity and is unfavorable for the reactive applications to pharmaceutical carrier system in overcoming CuAAC reactions The problem in the field such as standby, products pure, easy purification.And reaction condition is easily realized, safety, reaction efficiency is high.It is prepared by the present invention Single tadpole-shaped block copolymer and double tadpole-shaped block copolymers with biodegradable cyclic aliphatic polyester as head, have Poly- (the N- vinyl oneself in base acid amides) of water-soluble and temperature-responsive is tail, collects amphipathic, temperature-responsive, biodegradable Property and biocompatibility in one, can be in aqueous the Biodegradable nanometer glue with temperature-responsive with self assembly Beam, has broad application prospects in terms of drug controlled release and Targeting delivery.
Brief description of the drawings
Fig. 1 is the infrared spectrum (IR) of the gained of embodiment five (c-PCL)-b-PNVCL.
Fig. 2 is the GPC curves of the gained of embodiment five (c-PCL)-b-PNVCL.
Fig. 3 is the proton nmr spectra of the gained PNVCL-b- (c-PCL) of embodiment 11-(c-PCL)-b-PNVCL (1HNMR)。
Specific embodiment
The present invention is described in further detail with embodiment below, but present disclosure is not limited thereto.
Embodiment one：
Added in dry Schlenk flasks 0.28g ethylene glycol, 29.2 μ L stannous octoates, 20mL 6-caprolactones (ε- CL), vacuumize, inflated with nitrogen it is multiple after be placed in stirring reaction 14h in 100 DEG C of oil bath.10mL ethanol is added after cooling, is filtered Crude product.Crude product is dissolved with a small amount of THF, is co-precipitated 3 times with n-hexane, is obtained with α, the polycaprolactone of ω-bis- terminal hydroxyls (HO-PCL-OH)。
Take 4.5g HO-PCL-OH to be placed in three-necked bottle, add 50mL CH2Cl2With 1.77mL triethylamines, in ice-water bath, plus Enter CHs of the 5mL dissolved with 1.06mL2- bromopropionyl bromides (BPB)2Cl2Solution, drips off, room temperature reaction 48h.Filtering, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution Wash successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steam solvent, residue THF dissolves, coprecipitated with n-hexane Form sediment, drying at room temperature is obtained with α, the polycaprolactone (Br-PCL-Br) of ω-bis- end bromines.
2.0g Br-PCL-Br, 1.31g O- ehtyl potassium xanthates and 100mLCH are added in dry two neck bottle2Cl2, After stirring is allowed to dissolving, the CH for adding 30mL to contain 9mL pyridines2Cl2Solution, room temperature reaction 24h.Filtering, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution Wash successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steam solvent, residue THF dissolves, coprecipitated with n-hexane Form sediment, drying at room temperature is obtained with α, the polycaprolactone (X-PCL-X) of ω-bis- end xanthic acid ester groups, yield 83%.
Embodiment two：
Take 0.42g X-PCL-X to be placed in dry reaction bulb, add 5mL CH2Cl2It is allowed to dissolve, N2Under protection, add 14.6mg n-butylamines and micro tributylphosphine, stirring reaction 2h.After reaction terminates, it is co-precipitated 3 times with petroleum ether.Collect precipitation, Drying at room temperature must have α, the polycaprolactone (HS-PCL-SH) of ω-bis- terminal sulfhydryl groups, yield 70%.
Embodiment three：
N2Under protection, by 1.13g DTCA, 1.0g DCC are dissolved in 40mL CH2Cl2, it is placed in ice-water bath, it is slowly added dropwise 20mL is dissolved with 0.5g propilolic alcohols, the CH of 60mg DMAP2Cl2Solution, is dripped off, and 1h, room temperature reaction 24h are reacted in ice-water bath.Filtering, After filtrate concentration, residue ether dissolution, filtering boils off ether and obtains crude product.Crude on silica gel column chromatography for separation (VPetroleum ether ∶VEthyl acetate=20:1) must have the thiocarbamate chain-transferring agent (alknyl-CTA) of terminal acetylene, yield 70%.
Example IV：
80mg alknyl-CTA, 3.8g NVCL and 12mg AIBN are added in dry polymerization bottle, is vacuumized, nitrogen charging 30min is vacuumized after gas is multiple again, reaction bulb is then put into the 14h that is polymerized in 70 DEG C of oil bath.Product is dissolved with a small amount of THF, It is co-precipitated 3 times with petroleum ether, collects precipitation.To be dialysed 3 days after precipitation water dissolves, after decompression steams water, being vacuum dried to have Have poly- (N- caprolactams) (alknyl-PNVCL) of terminal acetylene.
Embodiment five：
Take 0.12g HS-PCL-SH and be dissolved in 10mLDMF, vacuumize, after inflated with nitrogen 3 times, it is stand-by.In another dry reaction 0.28g alknyl-PNVCL are added in bottle, and 10mL DMF is added, vacuumized, after inflated with nitrogen 3 times, it is stand-by.Burnt in 2L round bottoms Bottle adds 1.5LDMF, through the bulging nitrogen deoxidation of 2h, adds 30mg AIBN, then heats to 80 DEG C, and under nitrogen protection, leads to Cross micro syringe with the speed of 100 μ L/10min by the solution in two reaction bulbs while being added in flask.Charging is finished, after Continuous reaction 12h.Reaction is cooled to room temperature after terminating, decompression steams solvent, crude product is co-precipitated to obtain with ether.Crude product is used CH2Cl2After dissolving, it is co-precipitated with petroleum ether, collects precipitation, drying at room temperature obtains single tadpole-shaped block copolymer (c-PCL)-b- PNVCL, yield 70%.Product is passed through1HNMR, IR, GPC and MALDI-TOF MS detect its structure, molecular weight and molecular weight distribution, Proof obtains target product.
The structural formula of target product：
Embodiment six：
Basic to be a difference in that and use D with embodiment one, L- lactides (DLLA) replace 6-caprolactone (ε-CL)：In drying Schlenk flasks in add 0.28g ethylene glycol, 29.2 μ L stannous octoates, 25.9g D, L- lactide (DLLA), vacuumize, Stirring reaction 5h in 130 DEG C of oil bath is placed in after inflated with nitrogen is multiple.10mL ethanol is added after cooling, crude product is filtered to obtain.It is thick to produce Thing is dissolved with a small amount of THF, is co-precipitated 3 times with n-hexane, is obtained with α, poly- (the DL-LACTIC ACID) (HO- of ω-bis- terminal hydroxyls PDLLA-OH)。
Take 4.2g HO-PDLLA-OH to be placed in three-necked bottle, add 50mL CH2Cl2With 1.77mL triethylamines, under ice-water bath, 5mL is added dissolved with the CH of 1.06mL 2 bromo propionyl bromides (BPB)2Cl2Solution, drips off, room temperature reaction 48h.Filtering, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution is washed successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steam solvent, residue THF dissolves, with just Hexane is co-precipitated, and drying at room temperature is obtained with α, poly- (DL-LACTIC ACID) (Br-PDLLA-Br) of ω-bis- end bromines.
1.9g Br-PDLLA-Br, 1.31g O- ehtyl potassium xanthates and 100mL are added in dry two neck bottle CH2Cl2, after stirring is allowed to dissolving, the CH for adding 30mL to contain 9mL pyridines2Cl2Solution, room temperature reaction 24h.Filtering, filtrate adds Enter 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution is washed successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steam solvent, residue THF dissolves, with just Hexane is co-precipitated, and drying at room temperature is obtained with α, poly- (DL-LACTIC ACID) (X-PDLLA-X) of ω-bis- end xanthic acid ester groups, yield 85%.
Embodiment seven：
Substantially with embodiment two, to be a difference in that and replace X-PCL-X with X-PDLLA-X：0.41g X-PDLLA-X are taken to be placed in In dry reaction bulb, 5mL CH are added2Cl2It is allowed to dissolve, N2Under protection, 14.6mg n-butylamines and micro tributylphosphine are added, Stirring 2h.After reaction terminates, it is co-precipitated 3 times with petroleum ether.Precipitation is collected, drying at room temperature there must be α, ω-bis- terminal sulfhydryl groups Poly- (DL-LACTIC ACID) (HS-PDLLA-SH), yield 68%.
Embodiment eight：
Substantially with embodiment five, to be a difference in that and replace HS-PCL-SH with HS-PDLLA-SH：Take 0.11g HS-PDLLA- SH is dissolved in 10mL DMF, vacuumizes, after inflated with nitrogen 3 times, stand-by.0.28g alknyl- are added in another dry reaction bulb PNVCL, and add 10mL DMF, vacuumizes, after inflated with nitrogen 3 times, stand-by.1.5L DMF are added in 2L round-bottomed flasks, through 2h's Drum nitrogen deoxidation, adds 30mg AIBN, then heats to 80 DEG C, and under nitrogen protection, by micro syringe with 100 μ L/ Simultaneously be added in flask solution in two reaction bulbs by the speed of 10min.Charging is finished, and continues to react 12h.After reaction terminates Room temperature is cooled to, decompression steams solvent, crude product is co-precipitated to obtain with ether.Crude product CH2Cl2It is coprecipitated with petroleum ether after dissolving Form sediment, collect precipitation, drying at room temperature obtains single tadpole-shaped block copolymer (c-PDLLA)-b-PNVCL, yield 72%.Product is passed through1HNMR, IR, GPC and MALDI-TOF MS detect its structure, molecular weight and molecular weight distribution, it was demonstrated that obtain target product.
The structural formula of target product：
Embodiment nine：
Added in dry Schlenk flasks 0.61g pentaerythrites, 29.2 μ L stannous octoates, 20mL 6-caprolactones (ε- CL), vacuumize, inflated with nitrogen it is multiple after be placed in stirring reaction 14h in 100 DEG C of oil bath.10mL ethanol is added after cooling, is filtered Crude product.Crude product is dissolved with a small amount of THF, is co-precipitated 3 times with n-hexane, is obtained the four arm stars with four terminal hydroxyls and is gathered oneself Lactone Star- (PCL-OH)4.Take 4.5g Star- (PCL-OH)4It is placed in three-necked bottle, adds 50mL CH2Cl2With 1.77mL tri- Ethamine, under ice-water bath, by 10mL dissolved with 1.59mL 2 bromo propionyl bromides CH2Cl2Solution is slowly dropped into above-mentioned solution, is dripped off, Room temperature reaction 72h.Filtering, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution are washed successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steamed molten Agent, residue THF is dissolved, and is co-precipitated with n-hexane, and drying at room temperature is obtained with four four arm star polyesters of end bromine Star-(PCL-Br)4.2.0g Star- (PCL-Br) is added in dry two neck bottle4, 1.31g O- ehtyl potassium xanthates and 100mL CH2Cl2, after stirring is allowed to dissolving, addition contains the CH of 9mL pyridines containing 30mL2Cl2Solution, room temperature reaction 36h.Cross Filter, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution is washed successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steam solvent, residue THF Dissolving, is co-precipitated with n-hexane, and drying at room temperature must have four four arm star polycaprolactone Star- of end xanthic acid ester group (PCL-Y)4, yield 85%.
Embodiment ten：
Take 0.42g Star- (PCL-Y)4It is placed in dry reaction bulb, adds 5mL CH2Cl2It is allowed to dissolve, N2Protection Under, 32.9mg n-butylamines and micro tributylphosphine are added, stir 2h.After reaction terminates, it is co-precipitated 3 times with petroleum ether.Collect heavy Form sediment, drying at room temperature there must be four four arms star polycaprolactone Star- (PCL-SH) of terminal sulfhydryl group4, yield 78%.
Embodiment 11：
Take 0.08g Star- (PCL-SH)4It is dissolved in 10mL DMF, it is stand-by after evacuated, inflated with nitrogen 3 times.In another dry 0.56g alknyl-PNVCL are added in dry reaction bulb, and 10mL DMF is added, it is stand-by after evacuated, inflated with nitrogen 3 times. 1.5L DMF are added in 2L round-bottomed flasks, through the bulging nitrogen deoxidation of 2h, 30mg AIBN is added, 80 DEG C are then heated to, and in nitrogen Under gas shielded, the solution in two reaction bulbs is added in flask simultaneously with the speed of 100 μ L/10min by micro syringe. Charging is finished, and continues to react 12h.Solvent is steamed, crude product is co-precipitated to obtain with ether.Crude product CH2Cl2After dissolving, oil is used Ether is co-precipitated, and collects precipitation, and drying at room temperature obtains double tadpole-shaped block copolymer PNVCL-b- (c-PCL)-(c-PCL)-b- PNVCL, yield 67%.Product is passed through1HNMR, IR, GPC and MALDI-TOF MS detect its structure, molecular weight and molecular weight distribution, Proof obtains target product.
The structural formula of target product：
Embodiment 12：
Basic to be a difference in that and use D with embodiment nine, L- lactides (DLLA) replace 6-caprolactone (ε-CL)：In drying Schlenk flasks in add 0.61g pentaerythrites, 29.2 μ L stannous octoates, 25.9g D, L- lactide (DLLA), take out true Stirring reaction 5h in 130 DEG C of oil bath is placed in after empty, inflated with nitrogen is multiple.10mL ethanol is added after cooling, crude product is filtered to obtain.Slightly Product is dissolved with a small amount of THF, is co-precipitated 3 times with n-hexane, obtains the four arm stars with four terminal hydroxyls poly- (DL-LACTIC ACID) Star-(PDLLA-OH)4.Take 4.8g Star- (PDLLA-OH)4It is placed in three-necked bottle, adds 50mL CH2Cl2With 1.77mL tri- Ethamine, under ice-water bath, by 10mL dissolved with 1.59mL 2 bromo propionyl bromides CH2Cl2Solution is slowly dropped into above-mentioned solution, is dripped off, Room temperature reaction 72h.Filtering, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution are washed successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steamed molten Agent, residue THF dissolves, and is co-precipitated with n-hexane, drying at room temperature, obtains poly- (the DL- breasts of four arm stars with four end bromines Acid) Star- (PDLLA-Br)4.2.2g Star- (PDLLA-Br) is added in dry two neck bottle4, 1.31g O- ethyl xanthan Sour potassium and 100mL CH2Cl2, after stirring is allowed to dissolving, addition contains the CH of 9mL pyridines containing 30mL2Cl2Solution, room temperature reaction 36h.Filtering, filtrate adds 100mL CH2Cl2After dilution, respectively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) solution is washed successively.The anhydrous MgSO of organic phase424h is dried, is filtered, steam solvent, Residue THF dissolves, and is co-precipitated with n-hexane, and drying at room temperature must have four four arm stars of end xanthic acid ester group to gather (DL-LACTIC ACID) Star- (PDLLA-Y)4, yield 83%.
Embodiment 13：
Substantially with embodiment ten, it is a difference in that with Star- (PDLLA-Y)4Instead of Star- (PCL-Y)4：Take 0.44g Star-(PDLLA-Y)4It is placed in dry reaction bulb, adds 5mL CH2Cl2It is allowed to dissolve, N2Under protection, 32.9mg is being added just Butylamine and micro tributylphosphine, stir 2h.After reaction terminates, it is co-precipitated 3 times with petroleum ether.Precipitation is collected, drying at room temperature must have There is poly- (DL-LACTIC ACID) Star- (PDLLA-SH) of four arm stars of four terminal sulfhydryl groups4, yield 80%.
Embodiment 14：
Substantially with embodiment ten, it is a difference in that with Star- (PDLLA-SH)4Instead of Star- (PCL-SH)4：Take 0.1g Star-(PDLLA-SH)4It is dissolved in 10mL DMF, it is stand-by after evacuated, inflated with nitrogen 3 times.Add in another dry reaction bulb Enter 0.56g alknyl-PNVCL, and add 10mL DMF, it is stand-by.1.5L DMF are added in 2L round-bottomed flasks, through the bulging nitrogen of 2h Qi exhaustion oxygen, adds 30mg AIBN, then heats to 80 DEG C, and under nitrogen protection, by micro syringe with 100 μ L/ Simultaneously be added in flask solution in two reaction bulbs by the speed of 10min.Charging is finished, and continues to react 12h.Steam solvent, Crude product is co-precipitated to obtain with ether.Crude product CH2Cl2After dissolving, it is co-precipitated with petroleum ether, collects precipitation, drying at room temperature obtains double Tadpole-shaped block copolymer PNVCL-b- (c-PDLLA)-(c-PDLLA)-b-PNVCL, yield 65%.Product is passed through1HNMR、IR、 GPC and MALDI-TOF MS detect its structure, molecular weight and molecular weight distribution, it was demonstrated that obtain target product.
The structural formula of target product：

Claims (5)

1. amphipathic tadpole-shaped block copolymer, it is characterised in that：
One kind is amphipathic single tadpole-shaped block copolymer (c-PE)-b-PNVCL, and another kind is total to for amphipathic pair of tadpole-shaped block Polymers PNVCL-b- (c-PE)-(c-PE)-b-PNVCL, molecular structure is as follows respectively：
M is selected from formula (c-PE)-b-PNVCL and PNVCL-b- (c-PE)-(c-PE)-b-PNVCL：
N=20~40 in formula (c-PE)-b-PNVCL, m=40~100,
N=10~20, m=40~100 in formula PNVCL-b- (c-PE)-(c-PE)-b-PNVCL.
2. the preparation method of amphipathic single tadpole-shaped block copolymer as claimed in claim 1, it is characterised in that by following step Suddenly：
(1), preparing has α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
A. prepare with α, the polyester X-M-X of ω-bis- end xanthic acid ester groups, described polyester is polycaprolactone, PGA, gathers Any one in D-ALPHA-Hydroxypropionic acid, poly (l-lactic acid) and PDLLA；
B. prepare with α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
X-M-X, n-butylamine, tributylphosphine, wherein dichloromethane, tributylphosphine, X-M-X and n-butylamine are added in reaction vessel Mass ratio be 1:8000~10000:16000~30000, dissolved with the X-M-X of 70~90mg in every mL dichloromethane, stirring is anti- Answering 1~3h, crude product must have α, the molecule of the polyester HS-M-SH, HS-M-SH of ω-bis- terminal sulfhydryl groups after being co-precipitated, drying Structure is as follows：
M is selected from formula：
N=20~40 in formula；
(2) poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene, is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, by N, N- diethyl-S- α, α '-methyl-carbithionic acid thiocarbamate DTCA and the acyl of dicyclohexyl carbon two Imines DCC is dissolved in dichloromethane, and every mL dichloromethane is 1 dissolved with the mass ratio of 20~50mgDTCA, DTCA and DCC:1~1.5； At 0~5 DEG C, the dichloromethane solution of propilolic alcohol and dimethylamino naphthyridine DMAP is added dropwise, the mass ratio of propilolic alcohol and DMAP is 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, dichloromethane solution and propilolic alcohol and the DMAP of DTCA and DCC Dichloromethane solution volume ratio be 1~3:1, drip off, react 1~2h, 24~28h of room temperature reaction at 0~5 DEG C；Separate pure Change the molecule knot that crude product is obtained thiocarbamate chain-transferring agent alknyl-CTA, alknyl-CTA with terminal acetylene Structure is as follows：
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Alknyl-CTA, N- caprolactam NVCL and azodiisobutyronitrile AIBN, alknyl- are added in reaction vessel The mass ratio of CTA, NVCL and AIBN is 5~8:300~330:1, vacuumize, after inflated with nitrogen, then vacuumize, then 65~75 DEG C polymerization 12~16h, crude product through co-precipitation, dialysis, it is dry obtain have terminal acetylene poly- (N- caprolactams) alknyl-PNVCL；The molecular structure of alknyl-PNVCL is as follows：
M=40~100 in formula；
(3) amphipathic single tadpole-shaped block copolymer (c-PE)-b-PNVCL, is prepared
Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl-PNVCL of 25~30mg in the DMF per mL, vacuumize, It is stand-by after inflated with nitrogen；The HS-PE-SH that step 1b is obtained is dissolved in DMF, dissolved with the HS-PE- of 10~15mg in the DMF per mL SH, vacuumizes, after inflated with nitrogen, stand-by；The DMF of 1.3~1.8L is added in reaction vessel, drum nitrogen deoxidation adds AIBN, often Dissolved with 15~25mg AIBN in L DMF, 75~85 DEG C are warming up to, and under nitrogen protection, with the speed of 90~120 μ L/10min Spend and add the DMF solution of above-mentioned HS-PE-SH and the DMF solution of alknyl-PNVCL simultaneously, the DMF solution of described HS-PE-SH, The volume ratio of the DMF solution of alknyl-PNVCL and the DMF solution of AIBN is 1:1~1.5:1300~1800；Add, continue anti- Answer 10~15h, crude product is through co-precipitation, dry amphipathic single tadpole-shaped block copolymer (c-PE)-b-PNVCL.
3. the preparation method of amphipathic single tadpole-shaped block copolymer as claimed in claim 2, it is characterised in that by following step Suddenly：
(1) preparing has α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
A. with stannous octoate as catalyst, ethylene glycol is initiator, triggers the ring-opening polymerisation of lactone or lactide, and preparing has α, The polyester HO-M-OH of ω-bis- terminal hydroxyls；Again with triethylamine as acid binding agent, reacted with HO-M-OH and 2 bromo propionyl bromide, prepared With α, the polyester Br-M-Br of ω-bis- end bromines；Finally, it is anti-with Br-M-Br and O- ehtyl potassium xanthates in the presence of pyridine Should, preparing has α, the polyester X-M-X of ω-bis- end xanthic acid ester groups, described lactone and lactide be 6-caprolactone, glycolide, Any one in D- lactides, L- lactides and DL- lactides；
B. prepare with α, the polyester HS-M-SH of ω-bis- terminal sulfhydryl groups
X-M-X, n-butylamine, tributylphosphine, wherein dichloromethane, tributylphosphine, X-M-X and n-butylamine are added in reaction vessel Mass ratio be 1:8000~10000:16000~30000, dissolved with the X-M-X of 70~90mg in every mL dichloromethane, stirring is anti- 1~3h, crude product is answered to be co-precipitated 2~5 times with petroleum ether, drying at room temperature obtains HS-M-SH；
2nd, poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, DTCA and DCC are dissolved in dichloromethane, per mL dichloromethane dissolved with 20~50mgDTCA, DTCA and DCC Mass ratio is 1:1~1.5；At 0~5 DEG C and under stirring, the dichloromethane solution of propilolic alcohol and DMAP, propilolic alcohol and DMAP is added dropwise Material amount ratio be 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, the dichloromethane solution of DTCA and DCC It is 1~3 with the volume ratio of propilolic alcohol and the dichloromethane solution of DMAP:1, drip off, 0~5 DEG C of 1~2h of reaction, room temperature reaction 24 ~28h；Filtering, vacuum distillation filtrate refilters after residue ether dissolution, steams ether, separates crude product and is obtained alknyl-CTA；
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Add alknyl-CTA, NVCL and AIBN in reaction vessel, the mass ratio of alknyl-CTA, NVCL and AIBN for 5~ 8:300~330:1, vacuumize, after inflated with nitrogen 3~6 times, then vacuumize 30~40min, then it is polymerized 12 at 65~75 DEG C~ 16h；Crude product THF dissolves, and is co-precipitated 2~5 times with petroleum ether, collects precipitation；Cut being put into after precipitation distillation water dissolves Stay in the bag filter that molecular weight is 3500 and dialyse 3~6 days, after decompression steams water, be vacuum dried to obtain alknyl-PNVCL；
3rd, amphipathic single tadpole-shaped block copolymer (c-PE)-b-PNVCL is prepared
Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl-PNVCL of 25~30mg in the DMF per mL, vacuumize, It is stand-by after inflated with nitrogen 2~5 times；HS-PE-SH is dissolved in DMF, dissolved with the HS-PE- of 10~15mg in the DMF per mL SH, vacuumizes, after inflated with nitrogen 2~5 times, stand-by；The DMF of 1.3~1.8L is added in reaction vessel, through the bulging nitrogen of 1~3h Deoxidation, adds AIBN, dissolved with 15~25mg AIBN in every LDMF；75~85 DEG C are warming up to, and under nitrogen protection, with 90~ The speed of 120 μ L/10min adds the DMF solution of above-mentioned HS-PE-SH and the DMF solution of alknyl-PNVCL, described HS- simultaneously The volume ratio of the DMF solution of the DMF solution of PE-SH, the DMF solution of alknyl-PNVCL and AIBN is 1:1~1.5:1300~ 1800, add, continue to react 10~15h, room temperature is cooled to, decompression steams solvent, crude product is co-precipitated to obtain with ether；Crude product Use CH2Cl2After dissolving, it is co-precipitated with petroleum ether, collects precipitation, drying at room temperature obtains amphipathic single tadpole-shaped block copolymer (c- PE)-b-PNVCL。
4. the amphipathic pair of preparation method of tadpole-shaped block copolymer as claimed in claim 1, it is characterised in that by following step Suddenly：
(1) four arm star polyesters Star- (PE-SH) with four terminal sulfhydryl groups, are prepared4
A. prepare with four four arm star polyesters Star- (PE-Y) of end xanthic acid ester group4, described polyester be polycaprolactone, Any one in PGA, poly- D-ALPHA-Hydroxypropionic acid, poly (l-lactic acid) and PDLLA；
B. prepare with four four arm star polyesters Star- (PE-SH) of terminal sulfhydryl group4
By Star- (PE-Y)4Be dissolved in dichloromethane, add n-butylamine, tributylphosphine, in the dichloromethane per mL dissolved with 70~ 90mg Star-(PE-Y)4, the amount ratio of the material of tributylphosphine, X-M-X and n-butylamine is 1:8000~10000:40000~ 80000, N2Under protection, after 1~3h of stirring reaction, through co-precipitation, dry Star- (PE-SH)4。Star-(PE-SH)4Point Minor structure is as follows：
M is selected from formula：
N=10~20 in formula；
(2) poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene, is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, by N, N- diethyl-S- α, α '-methyl-carbithionic acid thiocarbamate DTCA and the acyl of dicyclohexyl carbon two Imines DCC is dissolved in dichloromethane, and every mL dichloromethane is 1 dissolved with the amount ratio of the material of 20~50mgDTCA, DTCA and DCC:1~ 1.5；At 0~5 DEG C, the quality of the dichloromethane solution of propilolic alcohol and dimethylamino naphthyridine DMAP, propilolic alcohol and DMAP is added dropwise Than being 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, the dichloromethane solution of DTCA and DCC and propilolic alcohol and The volume ratio of the dichloromethane solution of DMAP is 1~3:1, drip off, 0~5 DEG C of reaction 1~2h, 24~28h of room temperature reaction；Separate Purification of crude product is obtained alknyl-CTA.The molecular structure of alknyl-CTA is as follows：
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Add alknyl-CTA, NVCL and AIBN in reaction vessel, the mass ratio of alknyl-CTA, NVCL and AIBN for 5~ 8:300~330:1, vacuumize, after inflated with nitrogen, then vacuumize, be then polymerized 12~16h at 65~75 DEG C, and crude product is through coprecipitated Form sediment, dialysis, dry alknyl-PNVCL；The molecular structure of alknyl-PNVCL is as follows：
M=40~100 in formula；
3rd, amphipathic pair of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c-PE)-b-PNVCL is prepared
By Star- (PE-SH)4DMF is dissolved in, dissolved with the Star- (PE-SH) of 6~10mg in the DMF per mL4, vacuumize, fill It is stand-by after nitrogen；Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl-PNVCL of 50~80mg in the DMF of every mL, Vacuumize, after inflated with nitrogen, it is stand-by；1.3~1.8L DMF are added in reaction vessel, through drum nitrogen deoxidation, AIBN is added, often Dissolved with 15~25mg AIBN in LDMF, 75~85 DEG C are warming up to, and under nitrogen protection, with the speed of 90~120 μ L/10min Add above-mentioned Star- (PE-SH) simultaneously4DMF solution and alknyl-PNVCL DMF solution, Star- (PE-SH)4DMF it is molten The volume ratio of the DMF solution of liquid, the DMF solution of alknyl-PNVCL and AIBN is 1:1~1.5:1300~1800, add, after 10~15h of continuous reaction, crude product is through co-precipitation, dry amphipathic couple of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c- PE)-b-PNVCL。
5. the amphipathic pair of preparation method of tadpole-shaped block copolymer as claimed in claim 4, it is characterised in that by following step Suddenly：
(1) four arm star polyesters Star- (PE-SH) with four terminal sulfhydryl groups, are prepared4
A. prepare with four four arm star polyesters Star- (PE-Y) of end xanthic acid ester group4
Under stannous octoate catalysis, the ring-opening polymerisation of lactone or lactide is triggered with pentaerythrite, obtain that there are four terminal hydroxyls Four arm star polyesters Star- (PE-OH)4, described lactone and lactide are 6-caprolactone, glycolide, D- lactides, L- lactides With any one in DL- lactides；Obtain that there is four end bromines with 2 bromo propionyl bromide reaction in the presence of triethylamine again Four arm star polyesters Star- (PE-Br)4；Again Star- (PE-Y) is obtained in the presence of pyridine with O- ethoxy-dithioformic acid nak responses4；
B. prepare with four four arm star polyesters Star- (PE-SH) of terminal sulfhydryl group4
By Star- (PE-Y)4Be dissolved in dichloromethane, add n-butylamine, tributylphosphine, in the dichloromethane per mL dissolved with 70~ 90mg Star-(PE-Y)4, the amount ratio of the material of tributylphosphine, X-M-X and n-butylamine is 1:8000~10000:40000~ 80000, after 1~3h of stirring reaction, it is co-precipitated 3~5 times with petroleum ether；Precipitation is collected, drying at room temperature obtains Star- (PE-SH)4,
(2) poly- (N- caprolactams) alkynyl-PNVCL with terminal acetylene, is prepared
A. the thiocarbamate chain-transferring agent alknyl-CTA with terminal acetylene is prepared
N2Under protection, DTCA and DCC are dissolved in dichloromethane, per mL dichloromethane dissolved with 20~50mgDTCA, DTCA and DCC The amount ratio of material is 1:1~1.5；At 0~5 DEG C and under stirring, the dichloromethane of propilolic alcohol and dimethylamino naphthyridine DMAP is added dropwise The amount ratio of the material of solution, propilolic alcohol and DMAP is 1.5~2:1, per mL dichloromethane dissolved with 20~40mg propilolic alcohols, DTCA and The dichloromethane solution of DCC is 1~3 with the volume ratio of propilolic alcohol and the dichloromethane solution of DMAP:1, drip off, 0~5 DEG C of reaction 1~2h, 24~28h of room temperature reaction；Filtering, vacuum distillation filtrate refilters after residue ether dissolution, steams ether, point Alknyl-CTA is obtained from crude product；
B. poly- (N- ethene oneself in the base acid amides) alknyl-PNVCL with terminal acetylene is prepared
Add alknyl-CTA, NVCL and AIBN in reaction vessel, the mass ratio of alknyl-CTA, NVCL and AIBN for 5~ 8:300~330:1, vacuumize, after inflated with nitrogen 3~6 times, then vacuumize 30~40min, then it is polymerized 12 at 65~75 DEG C~ 16h；Crude product THF dissolves, and is co-precipitated 2~5 times with petroleum ether, collects precipitation；Cut being put into after precipitation distillation water dissolves Stay in the bag filter that molecular weight is 3500 and dialyse 3~6 days, after decompression steams water, be vacuum dried to obtain alknyl-PNVCL；
3rd, amphipathic pair of tadpole-shaped block copolymer PNVCL-b- (c-PE)-(c-PE)-b-PNVCL is prepared
By Star- (PE-SH)4DMF is dissolved in, dissolved with the Star- (PE-SH) of 6~10mg in the DMF per mL4, vacuumize, fill It is stand-by after nitrogen 2~5 times；Alknyl-PNVCL is dissolved in DMF, dissolved with the alknyl- of 50~80mg in the DMF of every mL PNVCL, vacuumizes, after inflated with nitrogen 2~5 times, stand-by；1.3~1.8L DMF are added in reaction vessel, through the bulging nitrogen of 1~3h Qi exhaustion oxygen, adds AIBN, dissolved with 15~25mg AIBN in every L DMF, is warming up to 75~85 DEG C, and under nitrogen protection, with 90 The speed of~120 μ L/10min adds above-mentioned Star- (PE-SH) simultaneously4DMF solution and alknyl-PNVCL DMF solution, Star-(PE-SH)4DMF solution, the DMF solution of alknyl-PNVCL and AIBN DMF solution volume ratio be 1:1~ 1.5:1300~1800；Add, continue to react 10~15h, be cooled to room temperature, decompression steams solvent, is co-precipitated slightly with ether Product；After crude product is dissolved with dichloromethane, it is co-precipitated with petroleum ether, collects precipitation, drying at room temperature obtains amphipathic pair of tadpole-shaped Block copolymer PNVCL-b- (c-PE)-(c-PE)-b-PNVCL.
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