CN106750334B - Amphiphilic tadpole-shaped block copolymer and preparation method thereof - Google Patents

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

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CN106750334B
CN106750334B CN201611119644.8A CN201611119644A CN106750334B CN 106750334 B CN106750334 B CN 106750334B CN 201611119644 A CN201611119644 A CN 201611119644A CN 106750334 B CN106750334 B CN 106750334B
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毕韵梅
李�杰
杨耀宗
唐刚
马永翠
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Abstract

An amphiphilic tadpole-shaped block copolymer and a preparation method thereof, belonging to the technical field of high polymer material preparation. Firstly, preparing aliphatic polyester with alpha, omega-double-end sulfydryl and poly (N-vinyl caprolactam) with end alkynyl, and then preparing an amphiphilic tadpole-shaped block copolymer I through sulfydryl-alkyne click reaction of the aliphatic polyester with alpha, omega-double-end sulfydryl and the poly (N-vinyl caprolactam) with end alkynyl; preparing four-arm star polyester with terminal sulfydryl and poly (N-vinyl caprolactam) with terminal alkynyl, and preparing the amphiphilic bis-tadpole-shaped block copolymer II through sulfydryl-alkyne click reaction of the four-arm star polyester with terminal sulfydryl and the poly (N-vinyl caprolactam) with terminal alkynyl. The sulfydryl-alkyne reaction without copper catalysis is used for preparing the tadpole-shaped block copolymer, so that the problem of product pollution caused by the use of a copper catalyst is solved; the obtained product is pure and easy to purify, the reaction condition is easy to realize, the safety is realized, and the reaction efficiency is high; the product integrates amphipathy, temperature responsiveness, biodegradability and biocompatibility, and has wide application prospect in the field of biomedicine.

Description

Amphiphilic tadpole-shaped block copolymer and preparation method thereof
Technical Field
The invention belongs to the technical field of high polymer material preparation, and particularly relates to an amphiphilic tadpole-shaped block copolymer taking a ring-shaped aliphatic polyester as a head and linear poly (N-vinyl caprolactam) as a tail, an amphiphilic bis-tadpole-shaped block copolymer formed by sharing one carbon atom by two ring-shaped aliphatic polyesters and two single tadpole-shaped block copolymers taking the ring-shaped aliphatic polyester as the head and the linear poly (N-vinyl caprolactam) as the tail, and a preparation method thereof.
Background
Cyclic polymers, including mono-and polycyclic polymers, are a class of polymers having a particular topology, with particular properties different from those of linear and branched polymers. The ring topology is also one of the structures widely existing in nature, and the research of molecular biology and biochemistry finds that some ring biological macromolecules, such as ring oligosaccharides, ring DNA, ring polypeptides, ring polysaccharides and some microorganisms with ring morphology, also exist in organisms. Therefore, the research on the cyclic structure polymer not only can obtain new materials, but also is helpful for exploring the mysteries of life. Tadpole polymers are a special class of cyclic polymers, also known as cyclo-linear polymers, consisting of one ring and one (or more) linear polymer(s). The tadpole-shaped polymer combines the excellent performances of the annular polymer and the linear polymer into a whole, particularly, the amphiphilic tadpole-shaped block copolymer with both hydrophilicity and lipophilicity is a unique polymer with a special structure, different components and solution self-assembly performance, and has wide application prospects in the fields of materials science, supramolecule and self-assembly, biological medicine and the like. However, due to difficulties in synthesis, there are few reports on studies on tadpole-shaped block copolymers.
Currently, there are three main methods for synthesizing tadpole polymers: (1) at very dilute concentrations, there is an intramolecular ring closure reaction of the diblock copolymer with two groups that can react, one at one end of the block and the other at the juncture of the two blocks. (2) Firstly, a ring polymer with functional groups is synthesized, and then the ring polymer is obtained by coupling with a polymer chain or initiating the polymerization of small molecule monomers. (3) Two end groups on the linear polymer respectively generate intermolecular cyclization reaction with two end groups of the Y-shaped polymer. In recent years, Click chemistry (Click chemistry) is introduced into the synthesis of tadpole-shaped polymers, so that the synthesis efficiency of the tadpole-shaped polymers is greatly improved. At present, click chemistry applied to tadpole-shaped polymer synthesis is mainly a classical Cu (I) catalyzed azide-alkyne 1, 3-dipolar cycloaddition reaction (CuAAC), but Cu (I) is used as a catalyst, so that heavy metal copper is remained in a product, and the application of the product in the fields of biological high molecular materials, drug carriers and the like is limited to a great extent.
The sulfydryl-alkyne reaction is a sulfydryl-based copper-free catalytic green click reaction, raw materials are easy to obtain, a triple-bond polymerization monomer can perform click reaction with two sulfydryl compound molecules, the reaction efficiency is high, more importantly, the reaction can be performed simply and efficiently only by utilizing heating or illumination conditions to generate free radicals, the problem of product pollution caused by the use of a copper catalyst is avoided, and the method has an important application value in the synthesis of biomedical materials. At present, the sulfydryl-alkyne click reaction is mainly used for preparing functional polymers such as dendritic polymers, hyperbranched polymers, reticular polymers and the like, and no research report about the application of the sulfydryl-alkyne reaction to the preparation of the amphiphilic tadpole-shaped block copolymer is found in literature retrieval.
Aliphatic Polyester (PE) such as poly (-caprolactone), polyglycolide and polylactic acid is an important synthetic medical high polymer material, has good biocompatibility and biodegradability, and is widely applied in the field of biomedicine. Poly (N-vinyl caprolactam) (PNVCL) is a temperature responsive water soluble polymer with a Low Critical Solution Temperature (LCST) in the physiological temperature range (32 ℃ to 40 ℃) and good biocompatibility. The copolymer of PE and PNVCL has temperature responsiveness, biodegradability and amphipathy, can be self-assembled into biodegradable nano-micelle with temperature responsiveness in aqueous solution, and has important application value in the aspects of controlled release and targeted release of drugs. At present, the research on the copolymer of PE and PNVCL focuses on the linear copolymer, and the literature search shows no research report on the amphiphilic tadpole-shaped block copolymer of aliphatic Polyester (PE) and poly (N-vinyl caprolactam) (PNVCL).
Disclosure of Invention
The invention aims to provide an amphiphilic tadpole-shaped block copolymer taking a ring-shaped aliphatic polyester as a head and linear poly (N-vinyl caprolactam) as a tail, an amphiphilic bis-tadpole-shaped block copolymer formed by using two tadpole-shaped block copolymers taking the ring-shaped aliphatic polyester as the head and linear poly (N-vinyl caprolactam) as the tail and sharing one carbon atom by two ring-shaped aliphatic polyesters, and a preparation method thereof.
The invention provides a tadpole-shaped block copolymer, wherein one is an amphiphilic mono-tadpole-shaped block copolymer (c-PE) -b-PNVCL, the other is an amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL, and the molecular structures of the tadpole-shaped block copolymers are respectively as follows:
Figure BDA0001174014580000031
(c-PE)-b-PNVCL，
Figure BDA0001174014580000032
PNVCL-b-(c-PE)-(c-PE)-b-PNVCL，
m in formulas (c-PE) -b-PNVCL and PNVCL-b- (c-PE) - (c-PE) -b-PNVCL is selected from the group consisting of:
Figure BDA0001174014580000033
in the formula (c-PE) -b-PNVCL, n is 20-40, m is 40-100,
in the formula PNVCL-b- (c-PE) - (c-PE) -b-PNVCL, n is 10-20, and m is 40-100.
Firstly, the preparation method of the amphiphilic tadpole-shaped block copolymer comprises the following steps:
1. preparation of polyesters HS-M-SH having alpha, omega-double-terminal mercapto groups
a. Preparing polyester X-M-X with alpha, omega-double terminal xanthate group, wherein the polyester is any one of polycaprolactone, polyglycolide, poly D-lactic acid, poly L-lactic acid and poly DL-lactic acid. The steps are the prior art, and one method is as follows: polyesters HO-M-OH having alpha, omega-double terminal hydroxyl groups are prepared according to the prior art (see, for example, Mishra AK, Vishwakarma N K, Patel V K, Biswas C S, Paira TK, Mandal T K, Maiti P, Ray B. colloid Polymer. Sci.,2014,292(6):1405-1418) by first initiating the ring-opening polymerization of lactones or lactides using stannous octoate as catalyst and ethylene glycol as initiator. And then triethylamine is used as an acid-binding agent, HO-M-OH and 2-bromopropionyl bromide react to prepare polyester Br-M-Br with alpha, omega-double-end bromine. Finally, in the presence of pyridine, Br-M-Br and potassium O-ethylxanthate are reacted to obtain the polyester X-M-X with alpha, omega-double terminal xanthate groups. The lactone and lactide are any one of caprolactone, glycolide, D-lactide, L-lactide and DL-lactide.
b. Preparation of polyesters HS-M-SH having alpha, omega-double-terminal mercapto groups
Adding X-M-X, n-butylamine, tributylphosphine and dichloromethane into a reaction vessel, wherein the mass ratio of the tributylphosphine to the X-M-X to the n-butylamine is 1: 8000-10000: 16000-30000, and 70-90 mg of the X-M-X is dissolved in every mL of dichloromethane, stirring and reacting for 1-3 h, and preferably carrying out the reaction in a dry reaction vessel. And co-precipitating and drying the crude product to obtain the polyester HS-M-SH with alpha, omega-double-end sulfydryl. The molecular structure of HS-M-SH is as follows:
Figure BDA0001174014580000041
wherein M is selected from:
Figure BDA0001174014580000042
wherein n is 20 to 40.
2. Preparation of Poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving N, N-diethyl-S- α' -dithiocarbamic acid thiocarbamate DTCA and dicyclohexylcarbodiimide DCC in dichloromethane, wherein each mL of dichloromethane is dissolved with 20-50 mg of DTCA, the mass ratio of DTCA to DCC is 1: 1-1.5, dropwise adding a dichloromethane solution of propiolic alcohol and dimethylaminopyridine DMAP at 0-5 ℃, the mass ratio of propiolic alcohol to DMAP is 1.5-2: 1, each mL of dichloromethane is dissolved with 20-40 mg of propiolic alcohol, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, completely dropping, reacting at 0-5 ℃ for 1-2 h, and reacting at room temperature for 24-28 h, separating and purifying a crude product to obtain a thiocarbamate alkyl-CTA-chain transfer agent with terminal alkynyl, wherein the molecular structure of alkyl-CTA-CTA is as follows:
Figure BDA0001174014580000051
b. preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, N-vinyl caprolactam NVCL and azobisisobutyronitrile AIBN into a reaction vessel, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing, filling nitrogen, vacuumizing again, polymerizing for 12-16 h at 65-75 ℃, and coprecipitating, dialyzing and drying a crude product to obtain poly (N-vinyl caprolactam) alkyl-PNVCL with terminal alkynyl; the molecular structure of alkyl-PNVCL is as follows:
Figure BDA0001174014580000052
wherein m is 40 to 100.
3. Preparation of amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL
Dissolving alkyl-PNVCL in DMF, wherein 25-30 mg of alkyl-PNVCL is dissolved in each mL of DMF, and vacuumizing and filling nitrogen for later use. And (3) dissolving the HS-PE-SH obtained in the step (1 b) in DMF, dissolving 10-15 mg of HS-PE-SH in each mL of DMF, vacuumizing, and filling nitrogen for later use. Adding 1.3-1.8L of DMF into a reaction vessel, blowing nitrogen for deoxidation, and adding AIBN, wherein 15-25 mg of AIBN is dissolved in each LDMF. Heating to 75-85 ℃, and simultaneously adding the DMF solution of the HS-PE-SH and the DMF solution of the alkyl-PNVCL at the speed of 90-120 mu L/10min under the protection of nitrogen, wherein the volume ratio of the DMF solution of the HS-PE-SH to the DMF solution of the alkyl-PNVCL to the DMF solution of AIBN is 1: 1-1.5: 1300-1800. And after the addition, continuously reacting for 10-15 h. And co-precipitating and drying the crude product to obtain the amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL.
The optimized preparation method comprises the following steps:
1. preparation of polyesters HS-M-SH having alpha, omega-double-terminal mercapto groups
a. The polyester HO-M-OH with alpha, omega-double terminal hydroxyl is prepared by initiating ring-opening polymerization of lactone or lactide by using stannous octoate as a catalyst and ethylene glycol as an initiator. And then triethylamine is used as an acid-binding agent, HO-M-OH and 2-bromopropionyl bromide react to prepare polyester Br-M-Br with alpha, omega-double-end bromine. Finally, the polyester X-M-X with alpha, omega-double terminal xanthate groups is prepared by reacting Br-M-Br with potassium O-ethylxanthate in the presence of pyridine. The lactone and lactide are any one of caprolactone, glycolide, D-lactide, L-lactide and DL-lactide.
b. Preparation of polyesters HS-M-SH having alpha, omega-double-terminal mercapto groups
Adding X-M-X, n-butylamine, tributylphosphine and dichloromethane into a reaction vessel, wherein the mass ratio of the tributylphosphine to the X-M-X to the n-butylamine is 1: 8000-10000: 16000-30000, and 70-90 mg of the X-M-X is dissolved in every mL of dichloromethane, stirring and reacting for 1-3 h, and preferably carrying out the reaction in a dry reaction vessel. And coprecipitating the crude product with petroleum ether for 2-5 times, and drying at room temperature to obtain HS-M-SH.
2. Preparation of Poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving DTCA and DCC in dichloromethane, wherein 20-50 mg of DTCA is dissolved in each mL of dichloromethane, and the mass ratio of DTCA to DCC is 1: 1-1.5; dropwise adding a dichloromethane solution of propiolic alcohol and DMAP under stirring at 0-5 ℃, wherein the mass ratio of the propiolic alcohol to the DMAP is 1.5-2: 1, 20-40 mg of propiolic alcohol is dissolved in every mL of dichloromethane, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, reacting for 1-2 h at 0-5 ℃, and reacting for 24-28 h at room temperature; preferably, the reaction is carried out in a dry reaction vessel. Filtering, distilling the filtrate under reduced pressure, dissolving the residue with diethyl ether, filtering again, distilling out the diethyl ether, and separating the crude product to obtain alkyl-CTA.
b. Preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, NVCL and AIBN into a reaction vessel, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing and charging nitrogen for 3-6 times, vacuumizing for 30-40 min, and polymerizing for 12-16 h at 65-75 ℃. And dissolving the crude product by using THF, coprecipitating for 2-5 times by using petroleum ether, and collecting precipitate. Dissolving the precipitate with distilled water, putting the precipitate into a dialysis bag with the molecular weight cutoff of 3500, dialyzing for 3-6 days, evaporating water under reduced pressure, and drying in vacuum to obtain alkyl-PNVCL.
3. Preparation of amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL
Dissolving alkyl-PNVCL in DMF, wherein 25-30 mg of alkyl-PNVCL is dissolved in each mL of DMF, vacuumizing, and filling nitrogen for 2-5 times for later use. Dissolving HS-PE-SH in DMF, wherein 10-15 mg of HS-PE-SH is dissolved in each mL of DMF, vacuumizing, and filling nitrogen for 2-5 times for later use. Adding 1.3-1.8L of DMF into a reaction container, deoxidizing by blowing nitrogen for 1-3 h, and adding AIBN, wherein 15-25 mg of AIBN is dissolved in each LDMF. Heating to 75-85 ℃, and simultaneously adding the DMF solution of the HS-PE-SH and the DMF solution of the alkyl-PNVCL at the speed of 90-120 mu L/10min under the protection of nitrogen, wherein the volume ratio of the DMF solution of the HS-PE-SH to the DMF solution of the alkyl-PNVCL to the DMF solution of AIBN is 1: 1-1.5: 1300-1800. And (3) after the addition, continuing the reaction for 10-15 h, cooling to room temperature, evaporating the solvent under reduced pressure, and coprecipitating with diethyl ether to obtain a crude product. The crude product is substituted by CH2Cl2After dissolving, coprecipitating with petroleum ether, collecting precipitate, and drying at room temperature to obtain the amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL.
Secondly, the preparation method of the amphiphilic tadpole-shaped block copolymer comprises the following steps:
1. preparation of a four-armed Star polyester Star- (PE-SH) having four terminal thiol groups4
a. Preparation of a four-armed Star polyester Star- (PE-Y) having four terminal xanthate groups4The polyester is any one of polycaprolactone, polyglycolide, poly D-lactic acid, poly L-lactic acid and poly DL-lactic acid. This step is prior art and one method is according to the prior art (see for example the documents Lijie, Yangzuanzong, Liulingqi et al, Guangzhou Chemicals 2014,42(6):1-4), first of all, the ring-opening polymerization of lactones or lactides is initiated with pentaerythritol under the catalysis of stannous octoate to give the four-armed Star polyester Star- (PE-OH) having four terminal hydroxyl groups4The lactone and the lactide are any one of caprolactone, glycolide, D-lactide, L-lactide and DL-lactide; then reacts with 2-bromopropionyl bromide in the presence of triethylamine to obtain four-arm Star polyester Star- (PE-Br) with four terminal bromides4(ii) a Then reacting with potassium O-ethyl xanthate in the presence of pyridine to obtain four-arm Star polyester Star- (P) with four terminal xanthate groupsE-Y)4。
b. Preparation of a four-armed Star polyester Star- (PE-SH) having four terminal thiol groups4
Mixing Star- (PE-Y)4Dissolving in dichloromethane, adding n-butylamine and tributylphosphine, wherein 70-90 mg of Star- (PE-Y) is dissolved in every mL of dichloromethane4The mass ratio of tributyl phosphine, X-M-X and N-butylamine is 1: 8000-10000: 40000-80000, and N2Stirring and reacting for 1-3 h under protection, coprecipitating and drying to obtain Star- (PE-SH)4。Star-(PE-SH)4The molecular structure of (a) is as follows:
Figure BDA0001174014580000081
wherein M is selected from:
Figure BDA0001174014580000082
wherein n is 10 to 20.
2. Preparation of Poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving N, N-diethyl-S- α' -dithioacetic acid thiocarbamate DTCA and dicyclohexylcarbodiimide DCC in dichloromethane, wherein each mL of dichloromethane is dissolved with 20-50 mg of DTCA, the mass ratio of DTCA to DCC is 1: 1-1.5, dropwise adding a dichloromethane solution of propiolic alcohol and dimethylaminopyridine DMAP at 0-5 ℃, the mass ratio of propiolic alcohol to DMAP is 1.5-2: 1, each mL of dichloromethane is dissolved with 20-40 mg of propiolic alcohol, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, completely dropping, reacting at 0-5 ℃ for 1-2 h, and reacting at room temperature for 24-28 h, and separating and purifying a crude product to obtain alkyl-CTA, wherein the molecular structure of alkyl-CTA is as follows:
Figure BDA0001174014580000083
b. preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, NVCL and AIBN into a reaction container, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing, filling nitrogen, vacuumizing again, polymerizing for 12-16 h at 65-75 ℃, and coprecipitating, dialyzing and drying a crude product to obtain alkyl-PNVCL; the molecular structure of alkyl-PNVCL is as follows:
Figure BDA0001174014580000091
wherein m is 40 to 100.
3. Preparation of amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL
Mixing Star- (PE-SH)4Dissolving in DMF, wherein 6-10 mg of Star- (PE-SH) is dissolved in each mL of DMF4Vacuumizing, and filling nitrogen for later use. And dissolving alkyl-PNVCL in DMF, wherein 50-80 mg of alkyl-PNVCL is dissolved in each mL of DMF, and vacuumizing and filling nitrogen for later use. Adding 1.3-1.8 LDMF into a reaction container, deoxidizing by blowing nitrogen, and adding AIBN, wherein 15-25 mg of AIBN is dissolved in each LDMF. Heating to 75-85 ℃, and adding the Star- (PE-SH) at the same time at the speed of 90-120 mu L/10min under the protection of nitrogen4And a solution of alkyl-PNVCL in DMF, Star- (PE-SH)4The volume ratio of the DMF solution of the alkyl-PNVCL to the DMF solution of the AIBN is 1: 1-1.5: 1300-1800. And after the addition, continuously reacting for 10-15 h, and coprecipitating and drying the crude product to obtain the amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL.
The procedures of coprecipitation, dialysis, drying and the like in the steps are the same as the conventional technology.
The optimized preparation method comprises the following steps:
1. preparation of a four-armed Star polyester Star- (PE-SH) having four terminal thiol groups4
a. Preparation of a four-armed Star polyester Star- (PE-Y) having four terminal xanthate groups4
Under the catalysis of stannous octoate, using seasonPentetiol initiates ring-opening polymerization of the lactone or lactide to give a four-armed Star polyester Star- (PE-OH) having four terminal hydroxyl groups4The lactone and the lactide are any one of caprolactone, glycolide, D-lactide, L-lactide and DL-lactide; then reacts with 2-bromopropionyl bromide in the presence of triethylamine to obtain four-arm Star polyester Star- (PE-Br) with four terminal bromides4(ii) a Then reacting with potassium O-ethyl xanthate in the presence of pyridine to obtain Star- (PE-Y)4。
b. Preparation of a four-armed Star polyester Star- (PE-SH) having four terminal thiol groups4
Mixing Star- (PE-Y)4Dissolving in dichloromethane, adding n-butylamine and tributylphosphine, wherein 70-90 mg of Star- (PE-Y) is dissolved in every mL of dichloromethane4The mass ratio of tributylphosphine, X-M-X and n-butylamine is 1: 8000-10000: 40000-80000, stirring and reacting for 1-3 h, and coprecipitating for 3-5 times by using petroleum ether. Collecting the precipitate, and drying at room temperature to obtain Star- (PE-SH)4。
2. Preparation of Poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving DTCA and DCC in dichloromethane, wherein 20-50 mg of DTCA is dissolved in each mL of dichloromethane, and the mass ratio of DTCA to DCC is 1: 1-1.5; dropwise adding a dichloromethane solution of propiolic alcohol and DMAP under stirring at 0-5 ℃, wherein the mass ratio of the propiolic alcohol to the DMAP is 1.5-2: 1, 20-40 mg of propiolic alcohol is dissolved in every mL of dichloromethane, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, reacting for 1-2 h at 0-5 ℃, and reacting for 24-28 h at room temperature; preferably, the reaction is carried out in a dry reaction vessel. Filtering, distilling the filtrate under reduced pressure, dissolving the residue with diethyl ether, filtering again, distilling out the diethyl ether, and separating the crude product to obtain alkyl-CTA.
b. Preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, NVCL and AIBN into a reaction vessel, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing and charging nitrogen for 3-6 times, vacuumizing for 30-40 min, and polymerizing for 12-16 h at 65-75 ℃. And dissolving the crude product by using THF, coprecipitating for 2-5 times by using petroleum ether, and collecting precipitate. Dissolving the precipitate with distilled water, putting the precipitate into a dialysis bag with the molecular weight cutoff of 3500, dialyzing for 3-6 days, evaporating water under reduced pressure, and drying in vacuum to obtain alkyl-PNVCL.
3. Preparation of amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL
Mixing Star- (PE-SH)4Dissolving in DMF, wherein 6-10 mg of Star- (PE-SH) is dissolved in each mL of DMF4Vacuumizing, and filling nitrogen for 2-5 times for later use. Dissolving alkyl-PNVCL in DMF, wherein 50-80 mg of alkyl-PNVCL is dissolved in each mL of DMF, vacuumizing, and filling nitrogen for 2-5 times for later use. Adding 1.3-1.8L of DMF into a reaction container, deoxidizing by using nitrogen for 1-3 h, and adding AIBN, wherein 15-25 mg of AIBN is dissolved in each L of DMF. Heating to 75-85 ℃, and adding the Star- (PE-SH) at the same time at the speed of 90-120 mu L/10min under the protection of nitrogen4And a solution of alkyl-PNVCL in DMF, Star- (PE-SH)4The volume ratio of the DMF solution of the alkyl-PNVCL to the DMF solution of the AIBN is 1: 1-1.5: 1300-1800. And after the addition, continuously reacting for 10-15 h. Preferably, the reaction is carried out in a dry reaction vessel. Cooling to room temperature, decompressing and distilling off the solvent, and coprecipitating by ether to obtain a crude product. And dissolving the crude product by using dichloromethane, then carrying out coprecipitation by using petroleum ether, collecting the precipitate, and drying at room temperature to obtain the amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL.
The procedures of filtering, reduced pressure distillation, column chromatography, vacuum drying and the like in the steps are the same as the conventional technology.
In the invention, the prepared amphiphilic tadpole-shaped block copolymer and amphiphilic tadpole-shaped block copolymer have definite structures and can pass through1HNMR, IR, GPC and MALDI-TOF MS were subjected to detailed characterization.
The invention has the beneficial effects that: at present, most of click chemistry used for tadpole-shaped polymer synthesis is azide-alkyne 1, 3-dipolar cycloaddition reaction (CuAAC) under catalysis of Cu (I), Cu (I) has cytotoxicity as a catalyst, the application in organisms needs to be reduced, the reaction conditions required for preparing Cu (I) are complex, and Cu (I) is difficult to remove in product purification, so that product pollution is caused; in addition, the reaction involves an azide compound, which has a certain risk. The mercapto-based copper-free catalytic mercapto-alkyne reaction is used for preparing the mono-tadpole-shaped block copolymer and the bis-tadpole-shaped block copolymer of the aliphatic polyester and the poly (N-vinyl caprolactam), the problem that Cu (I) in CuAAC reaction has biotoxicity and is not beneficial to the application of the reaction to the fields of preparation of drug carriers and the like is solved, and the product is pure and easy to purify. And the reaction conditions are easy to realize, safe and high in reaction efficiency. The tadpole-shaped block copolymer and the tadpole-shaped block copolymer prepared by the invention take a biodegradable annular aliphatic polyester as a head and take a water-soluble and temperature-responsive poly (N-vinyl caprolactam) as a tail, integrate amphipathy, temperature responsiveness, biodegradability and biocompatibility, can be self-assembled into a biodegradable nano micelle with temperature responsiveness in an aqueous solution, and have wide application prospects in the aspects of drug controlled release and targeted release.
Drawings
FIG. 1 shows the IR spectrum of (c-PCL) -b-PNVCL obtained in example five.
FIG. 2 is a GPC curve of (c-PCL) -b-PNVCL obtained in example five.
FIG. 3 is the NMR spectrum of PNVCL-b- (c-PCL) - (c-PCL) -b-PNVCL obtained in example eleven (C-PCL)1HNMR)。
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited thereto.
The first embodiment is as follows:
0.28g of ethylene glycol, 29.2. mu.L of stannous octoate and 20mL of caprolactone (-CL) were added to a dry Schlenk flask, and the mixture was placed in an oil bath at 100 ℃ for stirring reaction for 14 hours after being evacuated and charged with nitrogen for a plurality of times. After cooling, 10mL of ethanol was added and the mixture was filtered to obtain the crude product. The crude product is dissolved by a small amount of THF, and coprecipitated by n-hexane for 3 times to obtain polycaprolactone (HO-PCL-OH) with alpha, omega-double-end hydroxyl.
4.5g of HO-PCL-OH are taken outIn a three-necked flask, 50mL CH was added2Cl2And 1.77mL of triethylamine were added to the ice-water bath, 5mL of CH containing 1.06mL 2-bromopropionyl bromide (BPB)2Cl2The solution is dripped off and reacted for 48 hours at room temperature. Filtering, adding 100mLCH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24h, filtering, distilling off the solvent, dissolving the residue with THF, coprecipitating with n-hexane, and drying at room temperature to obtain polycaprolactone (Br-PCL-Br) with α, omega-double-end bromine.
2.0g of Br-PCL-Br, 1.31g O-potassium ethylxanthate and 100mLCH were added to a dry two-necked flask2Cl2After stirring and dissolving, 30mL of CH containing 9mL of pyridine was added2Cl2The solution was reacted at room temperature for 24 hours. Filtering, adding 100mLCH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24h, filtering, distilling off the solvent, dissolving the residue with THF, coprecipitating with n-hexane, and drying at room temperature to obtain the polycaprolactone (X-PCL-X) with α, omega-double-end xanthate groups with the yield of 83%.
Example two:
0.42g X-PCL-X was placed in a dry reaction flask, and 5mL CH was added2Cl2Dissolving it, N2Under protection, 14.6mg of n-butylamine and trace tributylphosphine are added, stirring and reaction are carried out for 2h, after the reaction is finished, petroleum ether is used for coprecipitation for 3 times, precipitate is collected and dried at room temperature to obtain polycaprolactone (HS-PCL-SH) with α omega-double-end sulfydryl, and the yield is 70%.
Example three:
N2under protection, 1.13g DTCA, 1.0g DCC were dissolved in 40mL CH2Cl2Placing in an ice-water bath, slowly adding dropwise 20mL of CH dissolved with 0.5g of propiolic alcohol and 60mg of DMAP2Cl2The solution is dripped off, and the reaction is carried out for 1h in an ice-water bath and 24h at room temperature. Filtering, concentrating the filtrate, dissolving the residue with diethyl ether, filtering, and evaporating diethyl ether to obtain crude product. The crude product is separated by silica gel column chromatography (V)Petroleum ether∶VEthyl acetate20:1) yield thiocarbamate chain transfer agent (alkyl-CTA) with terminal alkyne group in 70% yield.
Example four:
80mg of alkyl-CTA, 3.8g of NVCL and 12mg of AIBN are added into a dry polymerization bottle, vacuum pumping and nitrogen filling are carried out for multiple times, then vacuum pumping is carried out for 30min, and then the reaction bottle is put into an oil bath at 70 ℃ for polymerization for 14 h. The product was dissolved in a small amount of THF, coprecipitated with petroleum ether 3 times, and the precipitate was collected. Dissolving the precipitate with water, dialyzing for 3 days, evaporating water under reduced pressure, and vacuum drying to obtain poly (N-vinyl caprolactam) (alkyl-PNVCL) with terminal alkynyl.
Example five:
0.12g of HS-PCL-SH is dissolved in 10mLDMF, and the mixture is vacuumized and filled with nitrogen for 3 times for later use. In another dry reaction flask, 0.28g alkyl-PNVCL was added, 10mL DMF was added, and the mixture was evacuated and purged with nitrogen 3 times, and then used. 1.5LDMF was added to a 2L round bottom flask, deoxygenated over 2h of nitrogen sparge, 30mg AIBN was added, then the temperature was raised to 80 ℃ and the solutions in both reaction flasks were added simultaneously to the flask via a micro-syringe at a rate of 100. mu.L/10 min under nitrogen blanket. After the addition, the reaction was continued for 12 hours. After the reaction is finished, cooling to room temperature, decompressing and distilling off the solvent, and coprecipitating by ether to obtain a crude product. The crude product is substituted by CH2Cl2After dissolution, petroleum ether is used for coprecipitation, precipitates are collected and dried at room temperature to obtain the tadpole-shaped block copolymer (c-PCL) -b-PNVCL with the yield of 70%. The product is processed by1HNMR, IR, GPC and MALDI-TOF MS detect the structure, molecular weight and molecular weight distribution, and prove that the target product is obtained.
The structural formula of the target product is as follows:
Figure BDA0001174014580000131
example six:
essentially the same as example one, except that D, L-lactide (DLLA) was used in place of-caprolactone (-CL): 0.28g of ethylene glycol, 29.2. mu.L of stannous octoate, 25.9g D, L-lactide (DLLA) were added to a dry Schlenk flask, and the mixture was placed in an oil bath at 130 ℃ for stirring and reacting for 5 hours after vacuum evacuation and nitrogen gas filling. After cooling, 10mL of ethanol was added and the mixture was filtered to obtain the crude product. The crude product was dissolved in a small amount of THF and co-precipitated 3 times with n-hexane to give poly (DL-lactic acid) (HO-PDLLA-OH) having α, ω -double terminal hydroxyl groups.
4.2g of HO-PDLLA-OH was placed in a three-necked flask, 50mL of CH was added2Cl2And 1.77mL of triethylamine were added under ice-water bath 5mL of CH containing 1.06mL of 2-bromopropionyl bromide (BPB)2Cl2The solution is dripped off and reacted for 48 hours at room temperature. Filtering, adding 100mL CH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24h, filtering, distilling off solvent, dissolving the residue with THF, coprecipitating with n-hexane, and drying at room temperature to obtain poly (DL-lactic acid) (Br-PDLLA-Br) with α omega-double-end bromine.
Into a dry two-necked flask was added 1.9g of Br-PDLLA-Br, 1.31g O-potassium ethylxanthate and 100mL CH2Cl2After stirring and dissolving, 30mL of CH containing 9mL of pyridine was added2Cl2The solution was reacted at room temperature for 24 hours. Filtering, adding 100mL CH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24h, filtering, distilling off solvent, dissolving residue with THF, coprecipitating with n-hexane, and drying at room temperature to obtain poly (DL-lactic acid) (X-PDLLA-X) with α, omega-double terminal xanthate group with yield of 85%.
Example seven:
the difference is that X-PDLLA-X is used to replace X-PCL-X: placing 0.41g X-PDLLA-X into a dry reaction flask, adding 5mL CH2Cl2Dissolving it, N2Under protection, 14.6mg of n-butylamine and a trace amount of tributylphosphine are added, stirring is carried out for 2h, after the reaction is finished, coprecipitation is carried out for 3 times by using petroleum ether, precipitate is collected and dried at room temperature to obtain poly (DL-lactic acid) (HS-PDLLA-SH) with α omega-double-end sulfydryl, and the yield is 68%.
Example eight:
is basically the same asExample V, except that HS-PDLLA-SH is used instead of HS-PCL-SH: 0.11g of HS-PDLLA-SH is dissolved in 10mL of DMF, and the mixture is vacuumized and charged with nitrogen for 3 times for later use. In another dry reaction flask, 0.28g alkyl-PNVCL was added, 10mL DMF was added, and the mixture was evacuated and purged with nitrogen 3 times, and then used. 1.5L of DMF was added to a 2L round bottom flask, deoxygenated over 2h of nitrogen bubbling, 30mg of AIBN was added, then the temperature was raised to 80 ℃ and the solutions in both reaction flasks were added simultaneously to the flask by a micro-syringe at a rate of 100. mu.L/10 min under nitrogen protection. After the addition, the reaction was continued for 12 hours. After the reaction is finished, cooling to room temperature, decompressing and distilling off the solvent, and coprecipitating by ether to obtain a crude product. The crude product is substituted by CH2Cl2After dissolution, petroleum ether is used for coprecipitation, precipitates are collected and dried at room temperature to obtain the tadpole-shaped block copolymer (c-PDLLA) -b-PNVCL with the yield of 72 percent. The product is processed by1HNMR, IR, GPC and MALDI-TOF MS detect the structure, molecular weight and molecular weight distribution, and prove that the target product is obtained.
The structural formula of the target product is as follows:
Figure BDA0001174014580000151
example nine:
0.61g of pentaerythritol, 29.2. mu.L of stannous octoate and 20mL of caprolactone (-CL) were added to a dry Schlenk flask, and the mixture was placed in an oil bath at 100 ℃ for stirring and reacting for 14 hours after being evacuated and charged with nitrogen for a plurality of times. After cooling, 10mL of ethanol was added and the mixture was filtered to obtain the crude product. Dissolving the crude product with a small amount of THF, and coprecipitating with n-hexane for 3 times to obtain four-arm Star-shaped polycaprolactone Star- (PCL-OH) with four terminal hydroxyl groups4. Take 4.5g Star- (PCL-OH)4Put into a three-necked flask, and 50mL of CH is added2Cl2And 1.77mL of triethylamine, 10mL of CH containing 1.59mL of 2-bromopropionyl bromide dissolved therein was placed in an ice-water bath2Cl2The solution is slowly dripped into the solution, and the reaction is carried out for 72 hours at room temperature after the dripping is finished. Filtering, adding 100mL CH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24h, filtering, evaporating the solvent,dissolving the residue with THF, coprecipitating with n-hexane, and drying at room temperature to obtain four-arm Star-shaped polyester Star- (PCL-Br) with four terminal bromides4. 2.0g of Star- (PCL-Br) was added to a dry two-necked flask41.31g O-Potassium ethylxanthate and 100mL CH2Cl2After stirring and dissolving, 30mL of CH containing 9mL of pyridine was added2Cl2The solution was reacted at room temperature for 36 hours. Filtering, adding 100mL CH into the filtrate2Cl2After dilution, the organic phase was washed sequentially with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), 1.0M NaCl (3 × 50mL) and anhydrous MgSO4Drying for 24h, filtering, distilling off solvent, dissolving the residue with THF, co-precipitating with n-hexane, and drying at room temperature to obtain four-arm Star-shaped polycaprolactone Star- (PCL-Y) with four terminal xanthate groups4The yield was 85%.
Example ten:
0.42g of Star- (PCL-Y) is taken4Put into a dry reaction flask and add 5mL CH2Cl2Dissolving it, N232.9mg of n-butylamine and a trace of tributylphosphine were added under protection and stirred for 2 h. After the reaction, coprecipitation was carried out 3 times with petroleum ether. Collecting the precipitate, and drying at room temperature to obtain four-arm Star-shaped polycaprolactone Star- (PCL-SH) with four terminal sulfydryl groups4Yield 78%.
Example eleven:
0.08g of Star- (PCL-SH)4Dissolving in 10mL DMF, vacuumizing, and introducing nitrogen for 3 times. In another dry reaction flask, 0.56g alkyl-PNVCL was added, 10mL DMF was added, and the mixture was evacuated and purged with nitrogen 3 times, and then used. 1.5L of DMF was added to a 2L round bottom flask, deoxygenated over 2h of nitrogen bubbling, 30mg of AIBN was added, then the temperature was raised to 80 ℃ and the solutions in both reaction flasks were added simultaneously to the flask by a micro-syringe at a rate of 100. mu.L/10 min under nitrogen protection. After the addition, the reaction was continued for 12 hours. The solvent was distilled off and the crude product was obtained by coprecipitation with diethyl ether. The crude product is substituted by CH2Cl2After dissolving, petroleum ether is used for coprecipitation, precipitate is collected and dried at room temperature to obtain the bis-tadpole-shaped block copolymer PNVCL-b- (c-PCL) - (c-PCL) -b-PNVCL with the yield of 67 percent. The product is processed by1HNMR, IR, GPC andMALDI-TOF MS detects the structure, molecular weight and molecular weight distribution of the target product, and proves that the target product is obtained.
The structural formula of the target product is as follows:
Figure BDA0001174014580000161
example twelve:
essentially the same as example nine, except that D, L-lactide (DLLA) was used in place of-caprolactone (-CL): 0.61g of pentaerythritol, 29.2. mu.L of stannous octoate, 25.9g D, L-lactide (DLLA) were added to a dry Schlenk flask, and the mixture was placed in an oil bath at 130 ℃ for stirring and reacting for 5 hours after vacuum evacuation and nitrogen gas filling. After cooling, 10mL of ethanol was added and the mixture was filtered to obtain the crude product. Dissolving the crude product with a small amount of THF, and coprecipitating with n-hexane for 3 times to obtain four-arm Star poly (DL-lactic acid) Star- (PDLLA-OH) with four terminal hydroxyl groups4. Taking 4.8g Star- (PDLLA-OH)4Put into a three-necked flask, and 50mL of CH is added2Cl2And 1.77mL of triethylamine, 10mL of CH containing 1.59mL of 2-bromopropionyl bromide dissolved therein was placed in an ice-water bath2Cl2The solution is slowly dripped into the solution, and the reaction is carried out for 72 hours at room temperature after the dripping is finished. Filtering, adding 100mL CH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24 hr, filtering, distilling off solvent, dissolving the residue with THF, co-precipitating with n-hexane, and drying at room temperature to obtain four-arm Star poly (DL-lactic acid) Star- (PDLLA-Br) with four terminal bromine4. 2.2g of Star- (PDLLA-Br) was added to a dry two-necked flask41.31g O-Potassium ethylxanthate and 100mL CH2Cl2After stirring and dissolving, 30mL of CH containing 9mL of pyridine was added2Cl2The solution was reacted at room temperature for 36 hours. Filtering, adding 100mL CH into the filtrate2Cl2After dilution, the organic phase was washed successively with 1.0M HCl (3 × 50mL), 1.0M NaOH (3 × 50mL), and 1.0M NaCl (3 × 50mL), respectively, and anhydrous MgSO4Drying for 24 hr, filtering, distilling off solvent, dissolving the residue with THF, coprecipitating with n-hexane, and drying at room temperature to obtain yellow pigment with four terminal endsOrthoester based four-armed Star poly (DL-lactic acid) Star- (PDLLA-Y)4Yield 83%.
Example thirteen:
basically, the same procedure is followed as in example ten except that Star- (PDLLA-Y) is used4Instead of Star- (PCL-Y)4: take 0.44gStar- (PDLLA-Y)4Put into a dry reaction flask and add 5mL CH2Cl2Dissolving it, N232.9mg of n-butylamine and a trace of tributylphosphine were added under protection and stirred for 2 h. After the reaction, coprecipitation was carried out 3 times with petroleum ether. Collecting the precipitate, and drying at room temperature to obtain four-arm Star poly (DL-lactic acid) Star- (PDLLA-SH) with four terminal sulfydryl groups4The yield was 80%.
Example fourteen:
basically, the same procedure is followed as in example ten, except that Star- (PDLLA-SH) is used4Instead of Star- (PCL-SH)4: taking 0.1gStar- (PDLLA-SH)4Dissolving in 10mL DMF, vacuumizing, and introducing nitrogen for 3 times. To another dry reaction flask was added 0.56g of alkyl-PNVCL and 10mL of DMF until use. 1.5L of DMF was added to a 2L round bottom flask, deoxygenated over 2h of nitrogen bubbling, 30mg of AIBN was added, then the temperature was raised to 80 ℃ and the solutions in both reaction flasks were added simultaneously to the flask by a micro-syringe at a rate of 100. mu.L/10 min under nitrogen protection. After the addition, the reaction was continued for 12 hours. The solvent was distilled off and the crude product was obtained by coprecipitation with diethyl ether. The crude product is substituted by CH2Cl2After dissolution, petroleum ether is used for coprecipitation, the precipitate is collected and dried at room temperature to obtain the bis-tadpole-shaped block copolymer PNVCL-b- (c-PDLLA) - (c-PDLLA) -b-PNVCL with the yield of 65 percent. The product is processed by1HNMR, IR, GPC and MALDI-TOF MS detect the structure, molecular weight and molecular weight distribution, and prove that the target product is obtained.
The structural formula of the target product is as follows:
Figure BDA0001174014580000181

Claims (5)

1. amphiphilic tadpole-shaped block copolymer is characterized in that:
one is amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL, the other is amphiphilic tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL, and the molecular structures are respectively as follows:
Figure FDA0002519814380000011
PNVCL-b-(c-PE)-(c-PE)-b-PNVCL，
m in the formula (c-PE) -b-PNVCL1Selected from:
Figure FDA0002519814380000012
m in formula PNVCL-b- (c-PE) - (c-PE) -b-PNVCL1Selected from:
Figure FDA0002519814380000013
m in formula PNVCL-b- (c-PE) - (c-PE) -b-PNVCL2Selected from:
Figure FDA0002519814380000021
in the formula (c-PE) -b-PNVCL, n is 20-40, m is 40-100,
in the formula PNVCL-b- (c-PE) - (c-PE) -b-PNVCL, n is 10-20, and m is 40-100.
2. The process for preparing the amphiphilic tadpole-shaped block copolymer according to claim 1, characterized by the steps of:
(1) preparing the polyester HS-PE-SH with alpha, omega-double-end sulfydryl
a. Preparing polyester X-PE-X with alpha, omega-double terminal xanthate groups, wherein the polyester is any one of polycaprolactone, polyglycolide, poly D-lactic acid, poly L-lactic acid and poly DL-lactic acid;
b. preparation of polyester HS-PE-SH having alpha, omega-double-terminal mercapto group
Adding X-PE-X, n-butylamine, tributylphosphine and dichloromethane into a reaction container, wherein the mass ratio of the tributylphosphine to the X-PE-X to the n-butylamine is 1: 8000-10000: 16000-30000, 70-90 mg of the X-PE-X is dissolved in every mL of dichloromethane, stirring for reacting for 1-3 h, coprecipitating and drying a crude product to obtain the polyester HS-PE-SH with alpha, omega-double-end sulfydryl, and the molecular structure of the HS-PE-SH is as follows:
Figure FDA0002519814380000022
in the formula M1Selected from:
Figure FDA0002519814380000023
in the formula M2Selected from:
Figure FDA0002519814380000024
(2) preparation of poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving N, N-diethyl-S- α' -dithiocarbamic acid thiocarbamate DTCA and dicyclohexylcarbodiimide DCC in dichloromethane, wherein each mL of dichloromethane is dissolved with 20-50 mg of DTCA, the mass ratio of DTCA to DCC is 1: 1-1.5, dropwise adding a dichloromethane solution of propiolic alcohol and dimethylaminopyridine DMAP at 0-5 ℃, the mass ratio of propiolic alcohol to DMAP is 1.5-2: 1, each mL of dichloromethane is dissolved with 20-40 mg of propiolic alcohol, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, completing dripping, reacting at 0-5 ℃ for 1-2 h, reacting at room temperature for 24-28 h, separating and purifying a crude product to obtain thiocarbamate alkyl-CTA with terminal alkynyl, and the molecular structure of alkyl-CTA is as follows:
Figure FDA0002519814380000031
b. preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, N-vinyl caprolactam NVCL and azobisisobutyronitrile AIBN into a reaction vessel, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing, filling nitrogen, vacuumizing again, polymerizing for 12-16 h at 65-75 ℃, and coprecipitating, dialyzing and drying a crude product to obtain poly (N-vinyl caprolactam) alkyl-PNVCL with terminal alkynyl; the molecular structure of alkyl-PNVCL is as follows:
Figure FDA0002519814380000032
wherein m is 40-100;
(3) preparation of amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL
Dissolving alkyl-PNVCL in DMF (dimethyl formamide), wherein 25-30 mg of alkyl-PNVCL is dissolved in each mL of DMF, and vacuumizing and filling nitrogen for later use; dissolving the HS-PE-SH obtained in the step 1b in DMF, dissolving 10-15 mg of HS-PE-SH in each mL of DMF, vacuumizing, and filling nitrogen for later use; adding 1.3-1.8L of DMF into a reaction container, carrying out nitrogen deoxidation, adding AIBN, dissolving 15-25 mg of AIBN in each L of DMF, heating to 75-85 ℃, and simultaneously adding the DMF solution of HS-PE-SH and the DMF solution of alkyl-PNVCL at the speed of 90-120 mu L/10min under the protection of nitrogen, wherein the volume ratio of the DMF solution of HS-PE-SH, the DMF solution of alkyl-PNVCL and the DMF solution of AIBN is 1: 1-1.5: 1300-1800; and after the addition, continuously reacting for 10-15 h, and coprecipitating and drying the crude product to obtain the amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL.
3. The process for preparing the amphiphilic tadpole-shaped block copolymer according to claim 2, characterized by the steps of:
(1) preparing the polyester HS-PE-SH with alpha, omega-double-end sulfydryl
a. Initiating ring-opening polymerization of lactone or lactide by using stannous octoate as a catalyst and ethylene glycol as an initiator to prepare polyester HO-PE-OH with alpha, omega-double-terminal hydroxyl; then triethylamine is used as an acid-binding agent, HO-PE-OH is used for reacting with 2-bromopropionyl bromide to prepare polyester Br-PE-Br with alpha, omega-double-end bromine; finally, reacting Br-PE-Br and potassium O-ethyl xanthate in the presence of pyridine to prepare polyester X-PE-X with alpha, omega-double terminal xanthate groups, wherein lactone and lactide are any one of caprolactone, glycolide, D-lactide, L-lactide and DL-lactide;
b. preparation of polyester HS-PE-SH having alpha, omega-double-terminal mercapto group
Adding X-PE-X, n-butylamine, tributylphosphine and dichloromethane into a reaction container, wherein the mass ratio of the tributylphosphine to the X-PE-X to the n-butylamine is 1: 8000-10000: 16000-30000, 70-90 mg of the X-PE-X is dissolved in every mL of dichloromethane, stirring and reacting for 1-3 h, coprecipitating a crude product with petroleum ether for 2-5 times, and drying at room temperature to obtain HS-PE-SH;
(2) preparation of poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving DTCA and DCC in dichloromethane, wherein 20-50 mg of DTCA is dissolved in each mL of dichloromethane, and the mass ratio of DTCA to DCC is 1: 1-1.5; dropwise adding a dichloromethane solution of propiolic alcohol and DMAP under stirring at 0-5 ℃, wherein the mass ratio of the propiolic alcohol to the DMAP is 1.5-2: 1, 20-40 mg of propiolic alcohol is dissolved in every mL of dichloromethane, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, reacting for 1-2 h at 0-5 ℃, and reacting for 24-28 h at room temperature; filtering, distilling the filtrate under reduced pressure, dissolving the residue with diethyl ether, filtering again, distilling out diethyl ether, and separating the crude product to obtain alkyl-CTA;
b. preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, NVCL and AIBN into a reaction vessel, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing and charging nitrogen for 3-6 times, vacuumizing for 30-40 min, and polymerizing for 12-16 h at 65-75 ℃; dissolving the crude product by using THF, coprecipitating for 2-5 times by using petroleum ether, and collecting precipitate; dissolving the precipitate with distilled water, putting the precipitate into a dialysis bag with the molecular weight cutoff of 3500, dialyzing for 3-6 days, evaporating water under reduced pressure, and drying in vacuum to obtain alkyl-PNVCL;
(3) preparation of amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL
Dissolving alkyl-PNVCL in DMF (dimethyl formamide), wherein 25-30 mg of alkyl-PNVCL is dissolved in each mL of DMF, vacuumizing, and filling nitrogen for 2-5 times for later use; dissolving HS-PE-SH in DMF, wherein 10-15 mg of HS-PE-SH is dissolved in each mL of DMF, vacuumizing, and filling nitrogen for 2-5 times for later use; adding 1.3-1.8L of DMF (dimethyl formamide) into a reaction container, deoxidizing by using nitrogen for 1-3 h, and adding AIBN (ethylene-propylene-diene-butadiene-styrene), wherein 15-25 mg of AIBN is dissolved in each L of DMF; heating to 75-85 ℃, simultaneously adding the DMF solution of HS-PE-SH and the DMF solution of alkyl-PNVCL at the speed of 90-120 mu L/10min under the protection of nitrogen, wherein the volume ratio of the DMF solution of HS-PE-SH to the DMF solution of alkyl-PNVCL to the DMF solution of AIBN is 1: 1-1.5: 1300-1800, continuing to react for 10-15 h, cooling to room temperature, evaporating the solvent under reduced pressure, and coprecipitating with diethyl ether to obtain a crude product; the crude product is substituted by CH2Cl2After dissolving, coprecipitating with petroleum ether, collecting precipitate, and drying at room temperature to obtain the amphiphilic tadpole-shaped block copolymer (c-PE) -b-PNVCL;
4. the process for preparing the amphiphilic bis-tadpole-shaped block copolymer according to claim 1, characterized by the steps of:
(1) preparation of four-armed Star polyester Star- (PE-SH) having four terminal mercapto groups4
a. Preparation of a four-armed Star polyester Star- (PE-Y) having four terminal xanthate groups4The polyester is any one of polycaprolactone, polyglycolide, poly D-lactic acid, poly L-lactic acid and poly DL-lactic acid;
b. preparation of a four-armed Star polyester Star- (PE-SH) having four terminal thiol groups4
Mixing Star- (PE-Y)4Dissolving in dichloromethane, adding n-butylamine and tributylphosphine, wherein 70-90 mg of Star- (PE-Y) is dissolved in every mL of dichloromethane4Tributyl phosphine, Star- (PE-Y)4And of n-butylamineThe quantity ratio is 1: 8000-10000: 40000-80000, N2Stirring and reacting for 1-3 h under protection, coprecipitating and drying to obtain Star- (PE-SH)4。Star-(PE-SH)4The molecular structure of (a) is as follows:
Figure FDA0002519814380000061
in the formula M1Selected from:
Figure FDA0002519814380000062
in the formula M2Selected from:
Figure FDA0002519814380000063
wherein n is 10-20;
(2) preparation of poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving N, N-diethyl-S- α' -dithioacetic acid thiocarbamate DTCA and dicyclohexylcarbodiimide DCC in dichloromethane, wherein each mL of dichloromethane is dissolved with 20-50 mg of DTCA, the mass ratio of DTCA to DCC is 1: 1-1.5, dropwise adding a dichloromethane solution of propiolic alcohol and dimethylaminopyridine DMAP at 0-5 ℃, the mass ratio of propiolic alcohol to DMAP is 1.5-2: 1, each mL of dichloromethane is dissolved with 20-40 mg of propiolic alcohol, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, completing dripping, reacting at 0-5 ℃ for 1-2 h, and reacting at room temperature for 24-28 h, and separating and purifying a crude product to obtain an alkyl-CTA, wherein the molecular structure of the alkyl-CTA is as follows:
Figure FDA0002519814380000064
b. preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, NVCL and AIBN into a reaction container, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing, filling nitrogen, vacuumizing again, polymerizing for 12-16 h at 65-75 ℃, and coprecipitating, dialyzing and drying a crude product to obtain alkyl-PNVCL; the molecular structure of alkyl-PNVCL is as follows:
Figure FDA0002519814380000071
wherein m is 40-100;
(3) preparing amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL
Mixing Star- (PE-SH)4Dissolving in DMF, wherein 6-10 mg of Star- (PE-SH) is dissolved in each mL of DMF4Vacuumizing and filling nitrogen for later use; dissolving alkyl-PNVCL in DMF, wherein 50-80 mg of alkyl-PNVCL is dissolved in each mL of DMF, and vacuumizing and filling nitrogen for later use; adding 1.3-1.8L of DMF into a reaction container, deoxidizing by blowing nitrogen, adding AIBN, dissolving 15-25 mg of AIBN in each LDMF, heating to 75-85 ℃, and simultaneously adding the Star- (PE-SH) at the speed of 90-120 mu L/10min under the protection of nitrogen4And a solution of alkyl-PNVCL in DMF, Star- (PE-SH)4The volume ratio of the DMF solution of the alkyl-PNVCL to the DMF solution of the AIBN is 1: 1-1.5: 1300-1800, the reaction is continued for 10-15 h after the addition is finished, and the crude product is subjected to coprecipitation and drying to obtain the amphiphilic tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL.
5. The process for preparing the amphiphilic bis-tadpole-shaped block copolymer according to claim 4, characterized by the steps of:
(1) preparation of four-armed Star polyester Star- (PE-SH) having four terminal mercapto groups4
a. Preparation of a four-armed Star polyester Star- (PE-Y) having four terminal xanthate groups4
Under the catalysis of stannous octoate, pentaerythritol is used for initiating the ring-opening polymerization of lactone or lactide to obtain the product with four terminalsHydroxyl four-arm Star polyester Star- (PE-OH)4The lactone and the lactide are any one of caprolactone, glycolide, D-lactide, L-lactide and DL-lactide; then reacts with 2-bromopropionyl bromide in the presence of triethylamine to obtain four-arm Star polyester Star- (PE-Br) with four terminal bromides4(ii) a Then reacting with potassium O-ethyl xanthate in the presence of pyridine to obtain Star- (PE-Y)4；
b. Preparation of a four-armed Star polyester Star- (PE-SH) having four terminal thiol groups4
Mixing Star- (PE-Y)4Dissolving in dichloromethane, adding n-butylamine and tributylphosphine, wherein 70-90 mg of Star- (PE-Y) is dissolved in every mL of dichloromethane4Tributyl phosphine, Star- (PE-Y)4The mass ratio of the n-butylamine to the n-butylamine is 1: 8000-10000: 40000-80000, stirring and reacting for 1-3 hours, and then coprecipitating for 3-5 times by using petroleum ether; collecting the precipitate, and drying at room temperature to obtain Star- (PE-SH)4；
(2) Preparation of poly (N-vinylcaprolactam) alkinyl-PNVCL with terminal alkynyl group
a. Preparation of a Thiourethane chain transfer agent alknyl-CTA with a terminal alkynyl group
N2Under protection, dissolving DTCA and DCC in dichloromethane, wherein 20-50 mg of DTCA is dissolved in each mL of dichloromethane, and the mass ratio of DTCA to DCC is 1: 1-1.5; dropwise adding a dichloromethane solution of propiolic alcohol and dimethylaminopyridine DMAP under stirring at 0-5 ℃, wherein the mass ratio of the propiolic alcohol to the DMAP is 1.5-2: 1, 20-40 mg of propiolic alcohol is dissolved in every mL of dichloromethane, the volume ratio of the dichloromethane solution of DTCA and DCC to the dichloromethane solution of propiolic alcohol and DMAP is 1-3: 1, reacting for 1-2 h at 0-5 ℃, and reacting for 24-28 h at room temperature; filtering, distilling the filtrate under reduced pressure, dissolving the residue with diethyl ether, filtering again, distilling out diethyl ether, and separating the crude product to obtain alkyl-CTA;
b. preparation of Poly (N-vinylcaprolactam) alkyl-PNVCL with terminal alkynyl group
Adding alkyl-CTA, NVCL and AIBN into a reaction vessel, wherein the mass ratio of alkyl-CTA to NVCL to AIBN is 5-8: 300-330: 1, vacuumizing and charging nitrogen for 3-6 times, vacuumizing for 30-40 min, and polymerizing for 12-16 h at 65-75 ℃; dissolving the crude product by using THF, coprecipitating for 2-5 times by using petroleum ether, and collecting precipitate; dissolving the precipitate with distilled water, putting the precipitate into a dialysis bag with the molecular weight cutoff of 3500, dialyzing for 3-6 days, evaporating water under reduced pressure, and drying in vacuum to obtain alkyl-PNVCL;
(3) preparing amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL
Mixing Star- (PE-SH)4Dissolving in DMF, wherein 6-10 mg of Star- (PE-SH) is dissolved in each mL of DMF4Vacuumizing, and filling nitrogen for 2-5 times for later use; dissolving alkyl-PNVCL in DMF, wherein 50-80 mg of alkyl-PNVCL is dissolved in each mL of DMF, and vacuumizing and filling nitrogen for 2-5 times for later use; adding 1.3-1.8L of DMF into a reaction container, deoxidizing by using nitrogen for 1-3 h, adding AIBN, wherein 15-25 mg of AIBN is dissolved in each L of DMF, heating to 75-85 ℃, and simultaneously adding the Star- (PE-SH) at the speed of 90-120 mu L/10min under the protection of nitrogen4And a solution of alkyl-PNVCL in DMF, Star- (PE-SH)4The volume ratio of the DMF solution of the alkyl-PNVCL to the DMF solution of the AIBN is 1: 1-1.5: 1300-1800; after the addition, continuing to react for 10-15 h, cooling to room temperature, evaporating the solvent under reduced pressure, and coprecipitating with diethyl ether to obtain a crude product; and dissolving the crude product by using dichloromethane, then carrying out coprecipitation by using petroleum ether, collecting the precipitate, and drying at room temperature to obtain the amphiphilic bis-tadpole-shaped block copolymer PNVCL-b- (c-PE) - (c-PE) -b-PNVCL.
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