CN108484921A - The preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc - Google Patents

The preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc Download PDF

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CN108484921A
CN108484921A CN201810311840.8A CN201810311840A CN108484921A CN 108484921 A CN108484921 A CN 108484921A CN 201810311840 A CN201810311840 A CN 201810311840A CN 108484921 A CN108484921 A CN 108484921A
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pnvcl
pvac
preparation
thf
crude product
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张国林
周丹
蘧广剑
吴秋华
刘学
矣杰
宋溪明
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Liaoning University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • C08G81/021—Block or graft polymers containing only sequences of polymers of C08C or C08F
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F118/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an acyloxy radical of a saturated carboxylic acid, of carbonic acid or of a haloformic acid
    • C08F118/02—Esters of monocarboxylic acids
    • C08F118/04—Vinyl esters
    • C08F118/08—Vinyl acetate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F126/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
    • C08F126/06—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2438/00—Living radical polymerisation
    • C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]

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Abstract

The present invention discloses a kind of preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL b PVAc.With vinylacetate (VAc) for monomer, with azodiisobutyronitrile (AIBN) for initiator, O (2 Azidoethyl) S benzyls dithiocarbonates (AEBDC) is RAFT reagents, synthesizes end azido polyvinyl acetate (PVAc N3)；With N caprolactams (NVCL) for monomer, AIBN is initiator, and thioacetic acid is chain-transferring agent, poly- N caprolactam (PNVCL ≡) of the synthesis with alkynes end group.By PVAc N3PNVCL b PVAc target products are synthesized by click chemistry method with PNVCL ≡.The present invention provides a kind of simple universality methods preparing Thermo-sensitive amphiphilic block copolymer.

Description

The preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc
Technical field
The invention belongs to the field of chemical synthesis, more particularly to a kind of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc Preparation method.
Background technology
Amphipathic nature block polymer can be self-assembly of a variety of supramolecular aggregation structures, including core-in water environment Shell structure spherical micelle, vermiculate glues, polymer vesicle etc..In addition, the amphiphilic block copolymer with stimulating responsive is certainly The micellar structure formed is assembled, for external environment condition, such as temperature, pH, ionic strength, illumination, the variation of pressure etc. can The physical arrangement or form for accordingly changing itself can be applied to drug conveying and genetic engineering etc..Therefore, it stimulates in recent years The research of amphiphilic block copolymer is responded by more and more extensive concern.
Responsive to temperature type polymer refers to that the generation of its structural property accordingly changes when ambient temperature changes One kind of stimuli responsive polymers.When temperature reaches a certain critical value, the minor change of temperature will cause polymer chain Swelling occurs or collapses, polymer chain shows hydrophilic/hydrophobic balance, realizes from random coil to the transformation for rolling up sphere.
PNVCL have hydrophily and temperature-responsive, can be dissolved in cold water, when heated can occurred conformation suddenly change Become, collapse, until forming precipitation, reaches close and distant water balance.In this sense, the minimum Critical Solutions of PNVCL in water Temperature (LCST) is 32 DEG C or so, in Physiological temperatures range, therefore is had extensively in medicine, biomaterial and household chemicals General application prospect.
Polyvinyl acetate is a kind of important chemical raw material, and the polyvinyl acetate as chewing gum base is to people Body is nontoxic.
Click chemistry (Click chemistry) is proposed first by chemist's summer Price (K B Sharpless) One synthesis concept, refers to the splicing by junior unit, quickly completes the chemical synthesis of various molecules.It highlights by carbon- Chemical synthesis new method based on heteroatomic bond (C-X-C) synthesis, and a variety of tools are simply and efficiently synthesized by click-reaction There is the molecule of labyrinth.
Invention content
The invention aims to overcome many harsh items for preparing Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc Part, to obtain a kind of method with universality.
To achieve the goals above, the technical solution adopted by the present invention is：
The preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc, includes the following steps：
1) with nitrine ethyl alcohol (N3CH2CH2OH), carbon disulfide (CS2) and benzyl bromide (PhBr) be raw material, synthesized intermediate Body 1 (AEBDC)；
2) it with azodiisobutyronitrile (AIBN) for initiator, under the regulation and control of intermediate 1 (AEBDC) chain-transferring agent, realizes Vinylacetate (VAc) RAFT polymerization, obtains the 2 (PVAc-N of intermediate of end azido3)；
3) with azodiisobutyronitrile (AIBN) for initiator, thioacetic acid (HSCH2COOH it is) chain-transferring agent, by common The method of free radical has synthesized the intermediate 3 (PNVCL- ≡) of end alkynyl radical；
4) pass through 2 (PVAc-N of intermediate3) and the click of intermediate 3 (PNVCL- ≡) synthesize to obtain target product (PNVCL-b-PVAc)。
5) target product (PNVCL-b-PVAc) is dissolved in THF and ultra-pure water is being added dropwise, removed THF and just obtain PNVCL- B-PVAc micellas.
The preparation method, the step 1) are specially：
1.1) sodium azide (NaN is taken3), 2- ethyl alcohol (ClCH2CH2OH it) is dissolved in flask with ultra-pure water, 70 DEG C of oil baths are anti- It answers 96 hours, is extracted with ether, upper solution dries 12h with anhydrous magnesium sulfate, and revolving removes ether, obtains nitrine ethyl alcohol (N3CH2CH2OH)；
1.2) nitrine ethyl alcohol (N is taken3CH2CH2OH it) is dissolved in after 4h is stirred at room temperature in dimethyl sulfoxide (DMSO) (DMSO), is added dropwise Carbon disulfide (CS2), after being stirred overnight at room temperature, benzyl bromide (PhBr) is added, reaction mixture is poured into ice water by the reaction was continued 5h In.It is extracted with ether, is washed with distilled water organic phase, is finally dried with anhydrous magnesium sulfate.It is concentrated to give crude product, crude product passes through Chromatography obtains final product weak yellow liquid intermediate 1 (AEBDC).
The preparation method, the step 1.1) is as the raw material NaN for preparing nitrine ethyl alcohol3And ClCH2CH2The object of OH The ratio between amount of matter is 1:0.4-0.6, preferably 1:0.5.For synthesizing O- (2- Azidoethyls)-S- benzyl dithiocarbonates Raw material nitrine ethyl alcohol, CS2It is 1 with the ratio between the amount of substance of benzyl bromide：1-2:1, preferably 1:1.5:1.
The preparation method, the step 2) are specially：Take azodiisobutyronitrile (AIBN), O- (2- azido second Base)-S- benzyls dithiocarbonates (AEBDC) is in flask, addition vinylacetate (VAc), after leading to nitrogen 30min, nitrogen Protect lower 80 DEG C of oil baths reaction for 24 hours.Gained crude product is dissolved with tetrahydrofuran (THF), and (THF/ n-hexanes are precipitated in n-hexane =1:8), repeated multiple times precipitation.Gained sediment is dried in vacuum overnight, repeats above-mentioned dissolving precipitation process 2~3 times, finally Obtain 2 (PVAc-N of intermediate product3).The mass ratio of described AIBN, AEBDC and VAc are 1:5:100.
The preparation method, the step 3) include the following steps：
3.1) it takes N- caprolactams (NVCL), azodiisobutyronitrile (AIBN) in reaction bulb, dioxy six is added Ring leads to N under room temperature2After 30min, thioacetic acid (HSCH is added2COOH), after 68 DEG C of oil bath reaction 12h, reaction mixture is rotated It removes solvent and obtains crude product.Crude product dichloromethane (CH2Cl2) dissolve, it is precipitated in the n-hexane being slowly dropped to, stands 2h It is filtered after hour, 25 DEG C of vacuum drying of obtained solid are for 24 hours.It repeats dissolving precipitation operation 2~3 times, finally obtains the poly- N- second of end carboxyl Alkenyl caprolactam (PNVCL-COOH).
3.2) end carboxyl poly-N-vinylcaprolactam (PNVCL-COOH) is taken, to dimethylamino naphthyridine (DMAP), 2- first Base -3- butyne-2-alcohols and N, N '-Dicyclohexylcarbodiimide (DCC), are placed in a reaction flask, and dichloromethane dissolving is then added, Logical N230min, normal-temperature reaction for 24 hours after, revolving remove solvent obtain crude product.Crude product is dissolved with ethyl acetate, freezing is stood 24h.Insoluble matter is filtered off, colourless transparent solution is obtained, which is slowly dropped to n-hexane precipitation, is filtered, obtained solid vacuum It is dried overnight.Then above-mentioned dissolving precipitation operation is repeated twice.Finally obtain intermediate product 3.
The ratio between amount of substance of described step 3.1) NVCL, AIBN and thioacetic acid is 30:0.2-0.4:1；It is preferred that 30: 0.33:1.The ratio between amount of substance of step 3.2) PNVCL-COOH, DMAP, 2- methyl -3- butyne-2-alcohols and DCC is 3.5 ~4:1:18~24:4.
The preparation method, the step 4) are specially：Take PNVCL- ≡, PVAc-N3In reaction bulb, THF is added Dissolving, separately weighs cupric sulfate pentahydrate (CuSO4·5H2O), sodium ascorbate is added in reaction bulb, and it is ultrapure that 4~5 drops are slowly added dropwise Water makes CuSO4·5H2O and sodium ascorbate dissolve, and after stirring at normal temperature 48h, revolving removes solvent and obtains crude product.THF is taken to dissolve Crude product is slowly dropped in ether and precipitates, and sediment is dried overnight after filtering in 25 DEG C of vacuum drying chambers, obtains product.
Step 4) PNVCL- ≡, PVAc-N3、CuSO4·5H2The ratio between amount of substance of O and sodium ascorbate be 5~ 6:5~6:1:6.
The preparation method, the step 5) are specially：Weigh PNVCL30-b-PVAc25It is dissolved in THF, it is completely molten It is slowly added dropwise into ultra-pure water after solution, rotary evaporation removes THF, and obtained solution is moved to constant volume in 50mL volumetric flasks, is obtained dense Degree is the micellar solution of 1.00mg/mL, is stood overnight.The PNVCL-b-PVAc, THF, ultra-pure water mass ratio be 10:1:8.
Target product Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc prepared by method using the present invention is nanometer Micellar structure, it is that polyvinyl acetate is a kind of environmental-friendly that side has hydrophily and temperature-responsive, the other side for PNVCL , hydrophobic, the polymer of bio-compatible.
The beneficial effects of the invention are as follows：
Vinyl Acetate Monomer free radical is very active, and chain tra nsfer easily occurs in common free radical bulk polymerisation process And chain termination reaction, and easily there is sudden and violent poly- phenomenon so that polymerisation is uncontrollable, and molecular weight distribution is wider, uses RAFT herein Method realizes the controllable polymerization of VAc.
The present invention provides a kind of Thermo-sensitive amphiphilic poly-N-vinylcaprolactam/polyvinyl acetate (PNVCL-b-PVAc) The preparation method of block copolymer is with vinylacetate (VAc) for monomer, with azodiisobutyronitrile (AIBN) for initiator, O- (2- Azidoethyls)-S- benzyls dithiocarbonates (AEBDC) is RAFT reagents, synthesizes end azido polyvinyl acetate (PVAc-N3)；With N- caprolactams (NVCL) for monomer, AIBN is initiator, and thioacetic acid is chain-transferring agent, synthesis Poly-N-vinylcaprolactam (PNVCL- ≡) with alkynes end group.By PVAc-N3Pass through click chemistry method with PNVCL- ≡ Synthesize PNVCL-b-PVAc target products.The present invention provides a kind of simple universalities preparing Thermo-sensitive amphiphilic block copolymer Method.
The present invention prepares PAVc from the point of view of building-up process, by RAFT methods, and conventional free radical polymerize PNVCL, finally by Click chemistry makes two segments combine, easy to operate, and there is universality, nuclear-magnetism and infrared spectrum to characterize the knot of block polymer Structure illustrates the feasibility of the method.
This micellar material being made of PNVCL-b-PAVc, wherein side are with temperature sensitivity and hydrophilic PNVCL, the other side are hydrophobic PAVc, using this characteristic of material, pass through the control to temperature, the sides control PNVCL Wellability, and then realize containing and discharging for drug, while there is PNVCL biocompatibility, PAVc to have biodegradation Property, to organism nonhazardous, so this material has good application prospect in fields such as drug controlled deliveries.
Description of the drawings
Fig. 1 a nitrine ethyl alcohol infrared spectrograms.
Fig. 1 b nitrine ethyl alcohol1H-NMR schemes (CDCl3, δ ppm).
The infrared spectrogram of Fig. 2 a chain-transferring agents AEBDC.
Fig. 2 b chain-transferring agents AEBDC's1H-NMR schemes (CDCl3, δ ppm).
Fig. 3 a PVAc-N3Infrared spectrogram.
Fig. 3 b PVAc-N3's1H-NMR schemes (CDCl3, δ ppm).
The infrared spectrogram of Fig. 4 a PNVCL-COOH (a) and PNVCL- ≡ (b).
Fig. 4 b PNVCL-COOH's1H-NMR schemes (CDCl3, δ ppm).
Fig. 4 c PNVCL- ≡'s1H NMR scheme (CDCl3, δ ppm).
Fig. 5 a PNVCL- ≡ (a), PVAc-N3(b) and the infrared spectrogram of PNVCL-b-PVAc (c).
Fig. 5 b PNVCL-b-PVAc's1H-NMR schemes (CDCl3, δ ppm).
The GPC elution curve figures of Fig. 5 c polymer.
Fig. 6 a PNVCL30-b-PVAc25Copolymer micelle grain size distribution.
Fig. 6 b PNVCL30-b-PVAc45Copolymer micelle grain size distribution.
Fig. 6 c PNVCL30-b-PVAc60 copolymer micelle grain size distributions.
Fig. 7 PNVCL-b-PVAc aqueous solution micella transmission electron microscope shape appearance figures.
Fig. 8 a various concentrations PNVCL30-b-PVAc25Aqueous solution light transmittance varies with temperature curve (λ=500nm).
Fig. 8 b various concentrations PNVCL30-b-PVAc45Aqueous solution light transmittance varies with temperature curve (λ=500nm).
Fig. 8 c various concentrations PNVCL30-b-PVAc60Aqueous solution light transmittance varies with temperature curve (λ=500nm).
Specific implementation mode
The preparation of 1 Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc1 of embodiment
Including：
(1) with nitrine ethyl alcohol (N3CH2CH2OH), carbon disulfide (CS2) and benzyl bromide (PhBr) be Material synthesis intermediate 1 (AEBDC).Concrete operation step is as follows：
(1.1) synthesis of nitrine ethyl alcohol：NaN is weighed respectively332.528g (0.5mol), ClCH2CH2OH 19.989g (0.248mol) is added the ultrapure water dissolutions of 100ml, obtains pale pink solution in 250ml round-bottomed flasks.It is reacted in 70 DEG C of oil baths It after 96h, is extracted with ether (75mL × 3), upper solution is added anhydrous magnesium sulfate and dries 12h.It is outstanding that ether is evaporated off, it obtains colourless Bright product 12.78g, yield 59%.Shown in synthetic route figure below：
(1.2) conjunction of 1 O- of intermediate (2- Azidoethyls)-S- benzyl dithiocarbonates RAFT reagents (AEBDC) At：Nitrine ethyl alcohol 4.380g (50mmol) is weighed, is dissolved in 30mL DMSO, is added into the round-bottomed flask of 250mL, is then added Enter prepared NaOH aqueous solutions 30mL (NaOH containing 2g) in advance, after 4h is stirred at room temperature, 4.53mL (75mmol) is added dropwise CS2, after being stirred overnight at room temperature, benzyl bromide 5.94mL (50mmol), the reaction was continued 5h is added, reaction mixture is poured into ice water In.(3 × 50mL) is extracted with ether, organic phase is washed with distilled water, is finally dried with anhydrous magnesium sulfate.It is concentrated to give crude product 13.890g, crude product obtain final product intermediate 1 (AEBDC) 4.262g by chromatography, are weak yellow liquid, yield 33.7%.Synthetic route is as follows：
(2) it with azodiisobutyronitrile (AIBN) for initiator, under the regulation and control of intermediate 1 (AEBDC) chain-transferring agent, realizes Vinylacetate (VAc) RAFT polymerization, obtains the 2 (PVAc1-N of intermediate of end azido3).Concrete operation step is as follows：
AIBN 0.1952g are weighed, 22mL VAc are added in 100mL reagent bottles in AEBDC 0.912g, lead to nitrogen 30min Afterwards, the lower 80 DEG C of oil baths of nitrogen protection are reacted for 24 hours.Gained crude product 50mL THF dissolve, and are precipitated in 400mL n-hexanes (n-hexane=1 THF/:8), repeated multiple times precipitation.Gained sediment is dried in vacuum overnight, above-mentioned dissolving precipitation process 2 is repeated ~3 times, finally obtain 2 (PVAc1-N of intermediate product3).Synthetic route is as follows：
(3) with azodiisobutyronitrile (AIBN) for initiator, thioacetic acid (HSCH2COOH it is) chain-transferring agent, by general The method of logical free radical has synthesized the intermediate 3 (PNVCL- ≡) of end alkynyl radical.Concrete operation step is as follows：
(3.1) synthesis of end carboxyl poly-N-vinylcaprolactam (PNVCL-COOH)：Weigh NVCL 20.8785g (150 Mmol), AIBN 0.2737g (1.67mmol) are added 100mL dioxane, lead to N under room temperature in the reaction bulb of 250mL2 After 30min, the thioacetic acid of 0.4615g (5mmol) is added, after 12h are reacted in 68 DEG C of oil baths, revolving reaction mixture removes solvent Obtain crude product.Crude product 60mL dichloromethane dissolves, and is slowly dropped in the n-hexane of 500mL and precipitates, after standing 2h hours It filters, 25 DEG C of vacuum drying of obtained solid are for 24 hours.It repeats dissolving precipitation operation 2~3 times, finally obtains the poly- N- second of 17.237g end carboxyls Alkenyl caprolactam (PNVCL-COOH), white powder, yield 82.6%.Synthetic route is as follows：
(3.2) synthesis of 3 end alkynyl radical poly-N-vinylcaprolactam of intermediate product (PNVCL- ≡)：Weigh 10.0025g (2.40mmol) PNVCL-COOH, 0.082g (0.67mmol) is to dimethylamino naphthyridine (DMAP), 1.020g (12.12mmol) 2- methyl -3- butyne-2-alcohols, 0.553g (2.68mmol) N, N '-Dicyclohexylcarbodiimide (DCC), are placed in the anti-of 250mL It answers in bottle, the dissolving of 150mL dichloromethane is then added, leads to N230min, normal-temperature reaction for 24 hours after, revolving removes solvent and obtains and slightly produces Object.Crude product is dissolved with 50mL ethyl acetate, freezing is stood for 24 hours.Insoluble matter is filtered off, colourless transparent solution is obtained, which is delayed The slow n-hexane precipitation for being added drop-wise to 500mL, filters, obtained solid is dried in vacuum overnight.Then above-mentioned dissolving precipitation operation is repeated Twice.Finally obtain intermediate product 3, white powder, 8.25 g, yield 82.5%.Synthetic route is as follows：
(4) pass through 2 (PVAc-N of intermediate3) and the click of intermediate 3 (PNVCL- ≡) synthesize to obtain target product (PNVCL-b-PVAc).Concrete operation step is as follows：Weigh PNVCL- ≡ 0.228g (0.55mmol), PVAc- N3 0.225g (0.56mmol) is added 25mL THF dissolvings, separately weighs cupric sulfate pentahydrate (CuSO in 100mL reaction bulbs4·5H2O)0.0256g (0.1mmol), sodium ascorbate 0.1192g (0.6mmol) are added in reaction bulb, and 4~5 drop ultra-pure waters are slowly added dropwise, make CuSO4·5H2O and sodium ascorbate dissolve, and after stirring at normal temperature 48h, revolving removes solvent and obtains crude product.10mL THF are taken to dissolve Crude product is slowly dropped in the ether of 100mL and precipitates, and sediment is dried overnight after filtering in 25 DEG C of vacuum drying chambers.Weight Multiple above-mentioned dissolving precipitation operation three times, obtains final product block copolymer PNVCL-b-PVAc, 0.156g, yield 34.4%.Synthesis Route is as follows：
(5) target product (PNVCL-b-PVAc) is dissolved in THF and ultra-pure water is being added dropwise, removed THF and just obtain PNVCL- B-PVAc micellas.Specially：Weigh PNVCL30-b-PVAc2550mg dissolves in 5mLTHF, be slowly added dropwise after being completely dissolved to In 40mL ultra-pure waters, 27 DEG C of rotary evaporations remove THF, and obtained solution is moved to constant volume in 50mL volumetric flasks, is obtained a concentration of The micellar solution of 1.00mg/mL, stands overnight.
Testing result
Fig. 1 a are nitrine ethyl alcohol infrared spectrogram, 2105cm-1Place is-N3Characteristic absorption peak, 3396cm-1Place is alcoholic extract hydroxyl group Characteristic absorption peak.Fig. 1 b be nitrine ethyl alcohol nucleus magnetic hydrogen spectrum figure, wherein chemical shift 3.77ppm locate triplet for and-OH phases The proton peak b of methylene even；Triplet is the proton peak a for the methylene being connected with azido at 3.46ppm；2.35ppm place The unimodal proton peak c for hydroxyl.And occur without other impurity peaks.Complex chart 1a and Fig. 1 b, it was demonstrated that successfully synthesize nitrine second Alcohol.
Fig. 2 a are the infrared spectrogram of chain-transferring agent AEBDC, 2102cm-1Place is-N3Characteristic absorption peak；760cm-1With 696cm-1The bimodal characteristic absorption peak for monosubstituted phenyl ring at place.Fig. 2 b are the nucleus magnetic hydrogen spectrum figure of chain-transferring agent AEBDC, wherein changing It is the proton peak a on the methylene being connected with nitrine at displacement study 3.61ppm；It is on the methylene being connected with oxygen at 4.05ppm Proton peak b；It is the proton peak c on the methylene being connected with phenyl ring at 4.64ppm；For on phenyl ring at 7.26~7.29ppm Proton peak d o-, m-, in contraposition.Complex chart 2a and Fig. 2 b, it was demonstrated that successfully synthesize chain-transferring agent AEBDC.
Fig. 3 a are PVAc-N3Infrared spectrogram, 2104cm-1Place is the characteristic absorption peak of end group nitrine, 1743cm-1Place is The stretching vibration absworption peak of side chain ester carbonyl group.Fig. 3 b are PVAc-N3Nucleus magnetic hydrogen spectrum figure, be at wherein chemical shift 1.75ppm The proton peak g for the methyl being connected with carbonyl；It is the proton peak c of PVAc segmental repeat unit methylenes at 2.03ppm； The methene proton peak e being connected with phenyl ring for the polymer P VAc end of the chains at 2.59ppm；Asia at 3.73ppm to be connected with nitrine Methyl proton peak a；It is the methene proton peak b adjacent with the methylene that nitrine is connected at 4.69ppm；It is at 4.86ppm and second The connected methine protons peak d of acyloxy；It is the proton peak f on phenyl ring at 7.17ppm.Complex chart 3a, 3b are it is found that vinyl acetate Ester is successfully made RAFT polymerizations, has obtained polymer P VAc-N3。
The infrared spectrogram of Fig. 4 a PNVCL-COOH (a) and PNVCL- ≡ (b), in b curves Central Plains a curves 1732cm-1 Locate carboxylic carbonylic stretching vibration peak to disappear, while 2090cm-1Locate appearance-C ≡ C- stretching vibrations, preliminary proof generates 2- methyl- 3- butine 2- alcohol esters.Fig. 4 b are the nucleus magnetic hydrogen spectrum figure of PNVCL-COOH.For on PNVCL main chains at wherein chemical shift 4.40ppm The methine protons peak a being connected directly with N atoms；Asia at chemical shift 3.22ppm to be connected with carbonyl on caprolactam ring Methyl proton peak f；Methene proton peak c at chemical shift 2.74ppm to be connected with carboxyl；Chemical shift 2.35~ Methene proton peak d at 2.49ppm to be connected with N atoms on caprolactam ring；It is at 1.24~1.68ppm of chemical shift Other methene proton peaks e on methene proton peak b and caprolactam on main chain.Fig. 4 c are the nucleus magnetic hydrogen spectrum figure of PNVCL- ≡. Methine protons peak a at wherein 4.05~4.75ppm of chemical shift to be connected directly with N atoms on PNVCL main chains；Chemical potential Move the methene proton peak f to be connected with carbonyl on caprolactam ring at 3.23~3.60ppm；It is at chemical shift 2.76ppm The methene proton peak c being connected with carboxyl；Methylene at chemical shift 2.49ppm to be connected with N atoms on caprolactam ring Proton peak d；It is alkynyl proton peak at chemical shift 2.06ppm；It is methylene on main chain at 1.26~1.70ppm of chemical shift Other methene proton peaks e on proton peak b and caprolactam；It is the characteristic peak of solvent hexane at chemical shift 0.87ppm. Complex chart 4a, Fig. 4 b and Fig. 4 c can prove to successfully synthesize PNVCL- ≡.
Fig. 5 a are PNVCL- ≡ (a), PVAc-N3(b) and the infrared spectrogram of PNVCL-b-PVAc (c).In curve a 1632cm-1Locate the 1739cm in the stretching vibration peak and curve b of amidocarbonylation-1Locate the stretching vibration peak of acetyl carbonyl all in song Occur in line c, and 2013cm in curve a-1Locate 2107cm in alkynyl stretching vibration peak and curve b-1Locate azido stretching vibration Peak all disappears in curve c, can tentatively judge the successful synthesis of block copolymer PNVCL-b-PVAc.Fig. 5 b are PNVCL- The nucleus magnetic hydrogen spectrum figure of b-PVAc.It is the methine protons peak f in triazole ring at wherein chemical shift 7.6ppm； 7.33ppm、 It is respectively proton peak n1, n2, n3 on phenyl ring at 7.20ppm, 6.93ppm；It is the secondary first on main chain in PVAc segments at 4.88ppm Base proton peak b；It is the methine protons peak i on main chain in PNVCL segments at 4.39ppm；It is and three at 3.75~3.77ppm The methene proton peak d nitrogen-atoms of azoles ring connected methene proton peak e and be connected with oxygen；It is PVAc segments at 3.48ppm Methene proton peak c on main chain；Methylene at 3.10~3.24ppm to be connected with carbonyl on PNVCL segment caprolactam rings The base proton peak p and methene proton peak h being connected with carbonyl, sulphur atom；For on PNVCL segment caprolactam rings at 2.52ppm The methene proton peak k being connected with nitrogen-atoms；At 1.99~2.04ppm on PVAc segment side chains methyl proton peak q and with The connected methene proton peak a of phenyl ring；For in the methene proton peak j and oneself on PNVCL segment main chains at 1.46~1.84ppm Methene proton peak m on amide ring；It is the methyl proton peak g on the tertiary carbon being connected with triazole ring at chemical shift 1.21ppm.Figure 5c is the GPC elution curve figures of PNVCL and PNVCL-b-PVAc.As can be seen from the figure polymer molecular weight distribution is in single flat Sliding curve, occurs without other impurity peaks.Complex chart 5a, Fig. 5 b and Fig. 5 c can prove to successfully synthesize amphiphilic block copolymer Object PNVCL-b-PVAc.
Fig. 6 a, 6b, 6c are respectively the PNVCL of 0.5mg/mL30-b-PVAc25、PNVCL30-b-PVAc45And PNVCL30-b- PVAc60The average particle size distribution figure of micellar aqueous solution.From the graph, it is apparent that grain size is all at Unimodal Distribution, and with The average grain diameter of the increase of block copolymer hydrophobic chain segment, micella increases.
Fig. 7 is the PNVCL-b-PVAc aqueous solution micella transmission electron microscope shape appearance figures of different polymerization degree, and wherein a figures are PNVCL30-b-PVAc25, b figures are PNVCL30-b-PVAc45, c figures are PNVCL30-b-PVAc60.It can from above-mentioned electron microscope Go out, PNVCL-b-PVAc aqueous solution micella patterns all show ball-type.Micella grain size is respectively 100nm, 125nm and 230nm, Substantially it is consistent with the micella average grain diameter numerical value that DLS is measured, but tem observation is micellar solution dry state micella after water evaporation Pattern, since the evaporation of water causes micella to collapse, tem observation to micella grain size compared to the numerical value that DLS is measured It is less than normal.
Fig. 8 a, 8b, 8c are respectively the PNVCL of various concentration30-b-PVAc25、PNVCL30-b-PVAc45And PNVCL30- b- PVAc60Micellar aqueous solution light transmittance varies with temperature curve.It can be seen that after temperature is increased to the LCST of polymer, after The light transmittance of high-temperature aqueous solutions of polymers of continuing rising declines, this is because hydrogen of the high temperature between polymer and aqueous solvent Key, polymer is precipitated from water phase occurs phase transfer, thus light transmittance reduces.And with the degree of polymerization of hydrophobic chain segment PVAc Increase, the light transmittance of solution reduces, this is because the increase of hydrophobic segment, micelle inner core increases, the light transmittance of micellar solution With regard to reducing.
The preparation of 2 Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc2 of embodiment
Including：
(1) with embodiment 1.
(2) end azido PVAc (PVAc2-N3) synthesis:
AIBN 0.1952g are weighed, 17mL VAc are added in 100mL reagent bottles in AEBDC 0.912g, lead to nitrogen 30 After min, the lower 80 DEG C of oil baths reaction of nitrogen protection is for 24 hours.Gained crude product 50mL THF dissolve, and are precipitated in 400mL n-hexanes (n-hexane=1 THF/:8), repeated multiple times precipitation.Gained sediment is dried in vacuum overnight, above-mentioned dissolving precipitation process 2 is repeated ~3 times, finally obtain PVAc2-N3。
(3) with embodiment 1.
(4) with embodiment 1.
(5) with embodiment 1.
The preparation of 3 Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc3 of embodiment
(1) with embodiment 1.
(2) end azido PVAc (PVAc3-N3) synthesis:
AIBN 0.1952g are weighed, 27mL VAc are added in 100mL reagent bottles in AEBDC 0.912g, lead to nitrogen 30 After min, the lower 80 DEG C of oil baths reaction of nitrogen protection is for 24 hours.Gained crude product 50mL THF dissolve, and are precipitated in 400mL n-hexanes (n-hexane=1 THF/:8), repeated multiple times precipitation.Gained sediment is dried in vacuum overnight, above-mentioned dissolving precipitation process 2 is repeated ~3 times, finally obtain PVAc3-N3。
(3) with embodiment 1.
(4) with embodiment 1.
(5) with embodiment 1.
From the point of view of building-up process, VAc is polymerize with RAFT radical polymerizations, then uses click chemistry and PNVCL chains Section combines, and mild condition is easily operated, has universality.Infrared and nuclear-magnetism is illustrated according to each cloth compound synthesis success is shown The feasibility of the method.This Thermo-sensitive amphiphilic block copolymer being made of PNVCL-b-PVAc, since it is quick with temperature Perception, biocompatibility and biological degradability have good application prospect in fields such as drug controlled deliveries.

Claims (10)

1. the preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc, which is characterized in that include the following steps：
1) with nitrine ethyl alcohol (N3CH2CH2OH), carbon disulfide (CS2) and benzyl bromide (PhBr) be raw material, synthetic intermediate 1 (AEBDC)；
2) with azodiisobutyronitrile (AIBN) for initiator, under the regulation and control of intermediate 1 (AEBDC) chain-transferring agent, acetic acid is realized Vinyl acetate (VAc) RAFT polymerize, and obtains the 2 (PVAc-N of intermediate of end azido3)；
3) with azodiisobutyronitrile (AIBN) for initiator, thioacetic acid (HSCH2COOH it is) chain-transferring agent, by common free The intermediate 3 (PNVCL- ≡) of the method synthesis end alkynyl radical of base；
4) pass through 2 (PVAc-N of intermediate3) and the click of intermediate 3 (PNVCL- ≡) synthesize to obtain target product (PNVCL-b- PVAc)。
5) target product (PNVCL-b-PVAc) is dissolved in THF and ultra-pure water is being added dropwise, removed THF and obtain PNVCL-b-PVAc glue Beam.
2. preparation method as described in claim 1, which is characterized in that the step 1) is specially：
1.1) sodium azide (NaN is taken3), ethylene chlorhydrin (ClCH2CH2OH it) is dissolved in flask with ultra-pure water, 70 DEG C of oil bath reactions It 96 hours, is extracted with ether, upper solution dries 12h with anhydrous magnesium sulfate, and revolving removes ether, obtains nitrine ethyl alcohol (N3CH2CH2OH)；
1.2) nitrine ethyl alcohol (N is taken3CH2CH2OH it) is dissolved in after 4h is stirred at room temperature in dimethyl sulfoxide (DMSO) (DMSO), two sulphur is added dropwise Change carbon (CS2), after being stirred overnight at room temperature, benzyl bromide (PhBr) is added, the reaction was continued 5h pours into reaction mixture in ice water, It is extracted with ether, is washed with distilled water organic phase, is finally dried with anhydrous magnesium sulfate, be concentrated to give crude product, crude product passes through color Spectrum column purification obtains final product weak yellow liquid intermediate 1 (AEBDC).
3. preparation method as claimed in claim 2, which is characterized in that the step 1.1) is as the raw material for preparing nitrine ethyl alcohol NaN3And ClCH2CH2The ratio between amount of substance of OH is 1:0.4-0.6, preferably 1:0.5；The step 1.2) is used for synthetic intermediate 1 raw material nitrine ethyl alcohol, CS2It is 1 with the ratio between the amount of substance of benzyl bromide：1-2:1, preferably 1:1.5:1.
4. preparation method as described in claim 1, which is characterized in that the step 2) is specially：Take azodiisobutyronitrile (AIBN), vinylacetate (VAc) is added in flask in intermediate 1, and after leading to nitrogen 30min, the lower 80 DEG C of oil baths of nitrogen protection are anti- Should for 24 hours, gained crude product is dissolved with tetrahydrofuran (THF), and (n-hexane=1 THF/ is precipitated in n-hexane:8), repeated multiple times Precipitation.Gained sediment is dried in vacuum overnight, repeats above-mentioned dissolving precipitation process 2~3 times, finally obtains intermediate product 2 (PVAc-N3)。
5. preparation method as claimed in claim 4, which is characterized in that the mass ratio of the AIBN, intermediate 1 and VAc is 1:5:100。
6. preparation method as described in claim 1, which is characterized in that the step 3) includes the following steps：
3.1) it takes N- caprolactams (NVCL), azodiisobutyronitrile (AIBN) in reaction bulb, dioxane is added, often The lower logical N of temperature2After 30min, thioacetic acid (HSCH is added2COOH), after 68 DEG C of oil bath reaction 12h, revolving reaction mixture removes Solvent obtains crude product, crude product dichloromethane (CH2Cl2) dissolve, it is precipitated in the n-hexane being slowly dropped to, stands 2h hours After filter, the vacuum drying of 25 DEG C of obtained solid for 24 hours, repeats to dissolve precipitation operation 2~3 times, finally end carboxyl poly N-vinyl Caprolactam (PNVCL-COOH).
3.2) end carboxyl poly-N-vinylcaprolactam (PNVCL-COOH) is taken, to dimethylamino naphthyridine (DMAP), 2- methyl -3- Butyne-2-alcohol and N, N '-Dicyclohexylcarbodiimide (DCC), are placed in a reaction flask, and dichloromethane dissolving is then added, leads to N2 30min, normal-temperature reaction for 24 hours after, revolving remove solvent obtain crude product, with ethyl acetate dissolve crude product, freezing stand for 24 hours, filter Insoluble matter is removed, colourless transparent solution is obtained, which is slowly dropped to n-hexane precipitation, is filtered, obtained solid was dried in vacuo Then night repeats above-mentioned dissolving precipitation operation twice.Finally obtain intermediate product 3.
7. preparation method as claimed in claim 6, which is characterized in that described step 3.1) NVCL, AIBN and thioacetic acid The ratio between amount of substance is 30:0.2-0.4:1；It is preferred that 30:0.33:1.Step 3.2) PNVCL-COOH, DMAP, 2- methyl- The ratio between amount of substance of 3- butyne-2-alcohols and DCC is 3.5~4:1:18~24:4.
8. preparation method as described in claim 1, which is characterized in that the step 4) is specially：Take 3 (PNVCL- of intermediate ≡), 2 (PVAc-N of intermediate3) in reaction bulb, THF dissolvings are added, separately weigh cupric sulfate pentahydrate (CuSO4·5H2O), anti-ring Hematic acid sodium is added in reaction bulb, and 4~5 drop ultra-pure waters are slowly added dropwise, make CuSO4·5H2O and sodium ascorbate dissolving, stirring at normal temperature After 48h, revolving removes solvent and obtains crude product.It takes THF to dissolve crude product, is slowly dropped in ether and precipitates, after sediment filters It is dried overnight in 25 DEG C of vacuum drying chambers, obtains product.
9. preparation method as claimed in claim 8, which is characterized in that the step 4) intermediate 3 (PNVCL- ≡), intermediate 2(PVAc-N3)、CuSO4·5H2The ratio between amount of substance of O and sodium ascorbate is 5~6:5~6:1:6.
10. preparation method as described in claim 1, which is characterized in that the step 5) is specially：By target product (PNVCL-b-PVAc) it dissolves in THF, is slowly added dropwise into ultra-pure water after being completely dissolved, rotary evaporation removes THF, will obtain Solution move to constant volume in 50mL volumetric flasks, obtain the micellar solution of a concentration of 1.00mg/mL, stand overnight；
The PNVCL-b-PVAc, THF, ultra-pure water mass ratio be 10:1:8.
CN201810311840.8A 2018-04-09 2018-04-09 The preparation method of Thermo-sensitive amphiphilic block copolymer PNVCL-b-PVAc Pending CN108484921A (en)

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