CN103709410A - Acid-sensitive amphiphilic segmented copolymer, self-assembled micelles thereof and applications - Google Patents

Acid-sensitive amphiphilic segmented copolymer, self-assembled micelles thereof and applications Download PDF

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CN103709410A
CN103709410A CN201310643667.9A CN201310643667A CN103709410A CN 103709410 A CN103709410 A CN 103709410A CN 201310643667 A CN201310643667 A CN 201310643667A CN 103709410 A CN103709410 A CN 103709410A
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CN103709410B (en
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沈玉梅
龚兵
朱方霞
魏晓飞
邵志峰
杨晴来
刘亚智
胡蔚
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Shanghai Jiaotong University
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Abstract

The invention discloses an acid-sensitive amphiphilic segmented copolymer, self-assembled micelles thereof and applications. The structural formula is shown in the formula (I), wherein, n is an arbitrary integer between 1-300, m is an arbitrary integer between 1-100, R has structures shown in the formulas (II), (III), (IV), (V) or (VI), wherein t is equal to 1 or 2. The raw materials for synthesis of the compound are simple and easily available, the synthetic processes are all routine reactions, the reaction conditions are mild, and large-scale preparation can be achieved. Micelles formed through self-assembly of the segmented copolymers can be used as drug delivery carriers.

Description

Acid-sensitive amphipathic segmented copolymer and self-organization micella thereof, purposes
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of acid-sensitive amphipathic segmented copolymer and self-organization micella thereof, purposes.
Background technology
PH value normally and in pathological tissue is differentiated, such as the pH value (approximately 6.8) of tumour and inflammation tissue is all low than blood and healthy tissues (approximately 7.4).Although the endocytosis passage of cell starts all the physiological environment close to 7.4, at endoenzyme body, pH reduces to 5.5～6.0, and when arriving lysosome, pH also can be even lower, and only has 4.5～5.0.Therefore, sour responsive type reactive system has started to be used widely in medicament transport carrier.To be insoluble in the cancer therapy drug parcel of water or load to solvability, transformation period and the targeting that can effectively improve medicine on suitable polymkeric substance.
Amphiphilic Block Copolymer Micelles is by having wetting ability fragment and hydrophobicity fragment forms, a kind of self-assembled structures of spontaneous formation in the aqueous solution, the hydrophobic block of polymkeric substance consists of the kernel of micella in water hydrophobic interaction, hydrophilic block forms the shell of micella in the surrounding of micella kernel.From the angle of medicine controlled releasing, amphipathic micella has unique advantage, as little in particle diameter, and good biocompatibility is stable under physiological condition, can stop the interaction of medicine and protein and cell.Block copolymer micelle can be used as the pharmaceutical carriers such as insoluble antitumour drug, depressor, antimicrobial drug, gene therapy medicine to insoluble drug effective solubilization, has been subject to extensive concern.With it, as antineoplastic drug carrier, can not only improve curative effect, reduce toxic side effect, can also effectively improve the multidrug resistance (MDR) of antitumor drug.Therefore block copolymer micelle has vast potential for future development as insoluble anti-tumor medicament carrier.
Based on this thinking, the research of relevant block polymer support material is in recent years very hot, as diblock AB superpolymer, and three block ABA superpolymer, and multi-arm type, star-like AnBm superpolymer etc.The superpolymer particularly with amphipathic nature, is self-assembled into the nanoparticle into micellar structure under certain condition in solution, centre is hydrophobic core, around hydrophilic shell, if insoluble chemical compound can stably be distributed in hydrophobic core, just can be by effective solubilization.Except micellar structure, Amphipathilic block polymer can also be used to stabilization of solid nanoparticle and emulsion etc., because its structure is clear and definite, purity is high, generally there is the micelle-forming concentration lower than small molecules tensio-active agent, so in body, application toxicity is less, is considered to one of comparatively desirable material of medicament nano-preparation.
The kind of amphipathic nature block polymer is a lot, but is limited to the requirements such as biocompatibility, can be for the limited amount of pharmacy.Application clinically at present or the wetting ability block of studying have amino acids, PEG class, and hydrophobicity block has poly(lactic acid) (PLA) class.Ideal situation should be for specific one or a compounds structure, is its custom-made by size preparation material, and the structure of material, composition, molecular weight etc. is carried out to screening and the optimization of system, could the most effectively set up stable drug molecule dispersion system.
Wherein, the amphipathic nature block polymer of acid-sensitive sense is studied and should a large class material with the most use.Conventionally, they utilize " protonation " to make uncharged hydrophobic section in multipolymer become hydrophilic under low pH value, thereby stimulate, self-assembly systems is unstable even to disintegrate.As pharmaceutical carrier, the responsive copolymer micelle of pH is considered to the ideal carrier of antitumor drug target administration, this analog copolymer of studying at present, the methods of chemosynthesis that adopt are carried out structural modification to it more, in its molecular structure, introduce the group of pH sensitivity, increase the susceptibility that it changes pH in body.Generally with ionizable functional group on main chain, side chain or side chain.When the pH of medium value changes, can accept proton or discharge proton.In aqueous media, they can generate polyelectrolyte, mainly comprise two classes: weak poly-acid and weak poly-alkali.Typical poly-acid discharges proton under neutrality or alkaline condition, as polyacrylic acid (PAA) or polymethyl acrylic acid.Typical poly-alkali, as poly-[methacrylic acid-2-(N, N-dimethylamino) ethyl ester] (PDMAEMA), side group is with substituted-amino, thereby can obtain proton under neutrality or acidic conditions.This self-assembly system unstable or disintegrate can promote greatly by the release of carrying medicament, in target area or the fixed point of particular organization discharge and provide one well to select.And tumour cell and inflammation organize a fainter sour environment, can make medicine discharge from sensitivity to acid carrier.
THP trtrahydropyranyl ether and tetrahydrofuran base ether are the ethylidene ether structures of a class acid labile, under acidic conditions, can effectively rupture, in our previous work, the Chinese patent that number of patent application is 201110331659.1 has been reported the synthetic of such connector element and the application in the synthetic order-checking of DNA.Number of patent application is that 201210442960.4 Chinese patent has reported that such connector element can be used for amphipathic nature block polymer, but emphasis remains the synthetic of connector element, just for two examples the purposes of such connector element is described.Number of patent application is that 201310205811.0 Chinese patent has been reported the preparation of such connector element for the synthetic and micella of amphipathic nature block polymer.
Connector element in the present invention is simple and easy to get, can be directly with this connector element, hydrophilic segment and hydrophobic fragment be coupled together to formation acid-sensitive amphipathic segmented copolymer, the self-assembled micelle of this based block copolymer can be used for medicament transport carrier and realizes medicine controlled releasing, slowly-releasing.Compare with other connector elements, such connector element is more amenable for use with synthetic acid-sensitive amphipathic segmented copolymer.
Summary of the invention
The object of the invention is to wetting ability based on polyoxyethylene glycol and the hydrophobic thinking of poly(lactic acid), a kind of acid-sensitive amphipathic segmented copolymer and self-organization micella thereof, purposes are provided.The micella being formed by such Self-Assembling of Block Copolymer can be used for medicament transport carrier.
The object of the invention is to be achieved through the following technical solutions:
First aspect, the present invention relates to a kind of acid-sensitive amphipathic segmented copolymer, and its structural formula is shown in formula (I):
Figure BDA0000428776940000031
wherein, n is any one integer in 1～300, and m is any one integer in 1～100, R be formula (II), (III), (IV), (V) or (VI) shown in structure:
Figure BDA0000428776940000032
Figure BDA0000428776940000033
wherein, t=1 or 2.
When preferably, n, m are different, be 1.
Second aspect, the present invention relates to a kind of preparation method of aforesaid acid-sensitive amphipathic segmented copolymer, and described method comprises the steps:
A, compd A
Figure BDA0000428776940000034
under the effect of Amberlyst A-15, react and obtain compd B with PEG (polyoxyethylene glycol)
Figure BDA0000428776940000035
F, compd B, under 10% palladium carbon catalysis, pass into hydrogen, obtain Compound C
Figure BDA0000428776940000036
G, Compound C are under the catalysis of HATU (2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester) and DIPEA (DIPEA), with PLA (poly(lactic acid))
Figure BDA0000428776940000037
reaction, obtains described acid-sensitive amphipathic segmented copolymer.
Preferably, when R is structure shown in formula (II), described compd A
Figure BDA0000428776940000038
be prepared by a method comprising the following steps and obtain:
A, compound 2
Figure BDA0000428776940000039
compound 10
Figure BDA00004287769400000310
or compound 17
Figure BDA00004287769400000311
under the effect of triethylamine and DMAP (lutidine), react with TsCl (p-methyl benzene sulfonic chloride), obtain compound 3 compound 11
Figure BDA00004287769400000313
or compound 18
Figure BDA00004287769400000314
C, compound 3,11 or 18 are at K 2cO 3under the effect of (salt of wormwood), react and obtain compound 4 with 4-nitrophenols
Figure BDA0000428776940000041
compound 12 or compound 19
D, compound 4 are at N 2under (nitrogen) condition, react with DIBAL-H (diisobutyl aluminium hydride), obtain compound 5:
Figure BDA0000428776940000044
Or compound 12 or 19 reacts with dilute hydrochloric acid and obtains compound 13 or compound 20
Figure BDA0000428776940000046
Described compound 5,13,20 is the compd A of R while being formula (II).
Preferably, 4-pentenoic acid reacts under the effect of formic acid solution and hydrogen peroxide, after being spin-dried for, with the reacting of concentrated hydrochloric acid and methyl alcohol, obtains described compound 2.
Preferably, described compound 10 is prepare as follows and obtain:
A, diethyl malonate are under the effect of sodium hydride, bromo-1 with 2-, and the reaction of 1-glycol dimethyl ether, obtains compound 8
B, compound 8 react with Lithium Aluminium Hydride, obtain compound 9
Figure BDA0000428776940000048
C, compound 9 react with camphorsulfonic acid pyridinium salt, obtain described compound 10
Figure BDA0000428776940000049
Preferably, described compound 17 is prepare as follows and obtain:
A, methyl-formiate, under the effect of sodium hydride, after reacting, then react with hydrogenchloride/methyl alcohol and have obtained compound 16 with gamma-butyrolactone
Figure BDA00004287769400000410
B, compound 16 react with Lithium Aluminium Hydride, obtain compound 17
Figure BDA00004287769400000411
Preferably, R be formula (III), (IV), (V) or (VI) shown in during structure, described compd A
Figure BDA0000428776940000051
be prepared by a method comprising the following steps and obtain:
A, compound a AcO-R-OH react with salt of wormwood, obtain compound b HO-R-OH;
B, compound b, under the effect of triethylamine and DMAP, react with TsCl, obtain compound c Ts-R-OH;
C, compound c are at K 2cO 3effect under, react with 4-nitrophenols, obtain described compd A.
Preferably, described compound a is that the preparation of method by comprising following steps obtains:
A, ethylene glycol, under the effect of the vitriol oil, obtain compound 37 with acetic acidreaction
Figure BDA0000428776940000052
B, compound 37, under the effect of PPTS, react and obtain compound 38 with 2-methoxyl group propylene, 4-methoxybenzaldehyde or 4-methoxy-1- naphthalene formaldehyde
Figure BDA0000428776940000053
compound 44
Figure BDA0000428776940000054
or 50
Figure BDA0000428776940000055
Or:
A, pimelinketone or cyclopentanone, under the effect of pTSA, react with trimethyl orthoformate, obtain compound 23 or 30
Figure BDA0000428776940000057
Under the effect of B, compound 23 or 30 toluenesulphonic acidss and 5A molecular sieve, react with ethylene glycol acetate, obtain compound 24
Figure BDA0000428776940000058
or 31
Figure BDA0000428776940000059
Described compound 38,44,50,24,31 is described compound a.
The third aspect, the present invention relates to a kind of Amphiphilic Block Copolymer Micelles, described micella be prepare by the following method and: aforesaid acid-sensitive amphipathic segmented copolymer is dissolved in and in polar solvent, forms solution A; Described solution A is slowly added dropwise in the water of stirring and makes it form micro emulsion ball, pack the aqueous phase solution of described formation micro emulsion ball into dialysis tubing and appear polar solvent, obtain.In amphipathic nature block polymer prepared by the present invention, contain acid-sensitive sense connector element, therefore, its micella of preparing has sensitivity to acid.
Preferably, in described solution A, be dissolved with hydrophobic drug.
Preferably, described hydrophobic drug is Azythromycin, taxol, Elemenum or camptothecine.Described dialysis tubing molecular weight is 0.2KD.
Preferably, described polar solvent is DMSO (dimethyl sulfoxide (DMSO)), DMF (DMF) or THF (tetrahydrofuran (THF)); Described water is pure water, PBS damping fluid or physiological saline.
Fourth aspect, the present invention relates to the purposes of a kind of above-mentioned Amphiphilic Block Copolymer Micelles in preparing anti-cancer medicament carrier.Described micella is stablized, nontoxicity, and size distribution is even, can penetration cell, thus the hydrophobic anticancer drug that micella enters cancer cells and discharges parcel is killed cancer cells.
The hydrophobic anticancer drug of preferably, wrapping up in described anti-cancer medicament carrier is Azythromycin, taxol, Elemenum or camptothecine.
Compared with prior art, the present invention has following beneficial effect:
1, such compou nd synthesis raw material is simple and easy to get, and building-up process is popular response, and reaction conditions is gentle, can prepare in a large number.
2, this compounds can form micella under certain condition, and the micella being formed by such Self-Assembling of Block Copolymer can be used for medicament transport carrier.
3, the block copolymer micelle size that prepared by the present invention is even, have good stability, blank micella is to normal cell (NIH313 cell) toxicological harmless effect, carrier micelle can effectively discharge wrapped up medicine under acidic conditions, thereby carrier micelle can effectively enter cancer cells and in cancer cells, discharge medicine and kills cancer cells (take HeLa cell as example).
Accompanying drawing explanation
By reading the detailed description of non-limiting example being done with reference to the following drawings, it is more obvious that other features, objects and advantages of the present invention will become:
Fig. 1 is the synthesis path figure of amphipathic nature block polymer 1a;
Fig. 2 is the synthesis path figure of amphipathic nature block polymer 1b;
Fig. 3 is the synthesis path figure of amphipathic nature block polymer 1c;
Fig. 4 is the synthesis path figure of amphipathic nature block polymer 1d;
Fig. 5 is the synthesis path figure of amphipathic nature block polymer 1e;
Fig. 6 is the synthesis path figure of amphipathic nature block polymer 1f;
Fig. 7 is the synthesis path figure of amphipathic nature block polymer 1g;
Fig. 8 is the synthesis path figure of amphipathic nature block polymer 1h;
Fig. 9 is GPC figure, and wherein A:a is PLA 1000, b is 7 (n=43, PEG 1900), c is 1a (PLA 1000-PEG 1900); B:a is PLA 3000, b is 7 (n=43, PEG 1900), c is 1a (PLA 3000-PEG 1900); C:a is PLA 3000, b is 7 (n=114, PEG 5000), c is 1a (PLA 3000-PEG 5000); D:a is PLA 5000, b is 7 (n=114, PEG 5000), c is 1a (PLA 5000-PEG 5000);
Figure 10 is the size distribution figure of blank micella;
Figure 11 is the size distribution figure of carrier micelle;
Figure 12 is projection Electronic Speculum (TEM) photo of blank micella and carrier micelle, and wherein, figure A is PLA 3000-PEG 5000micella, figure B is PLA 5000-PEG 5000micella;
Figure 13 is micella stability test result, and wherein, figure A is PLA 3000-PEG 5000micella stability test result; Figure B is PLA 5000-PEG 5000micella stability test result;
Figure 14 is micellar concentration and fluorescence intensity I 1/ I 3graph of a relation, wherein A is PLA 1000-PEG 1900micellar concentration and fluorescence intensity I 1/ I 3graph of a relation, B is PLA 3000-PEG 1900micellar concentration and fluorescence intensity I 1/ I 3graph of a relation, C is PEG 1900-PLA 5000micellar concentration and fluorescence intensity I 1/ I 3graph of a relation, D is PLA 5000-PEG 5000micellar concentration and fluorescence intensity I 1/ I 3graph of a relation;
Figure 15 is the vitro drug release graphic representation of carrier micelle PLA5000-PEG5000;
Figure 16 is the cytotoxicity experiment that mtt assay is measured blank micella;
Figure 17 is the cytotoxicity that the two Coloration experiments of AO/EB are measured blank micella;
Figure 18 is the interior release graphics of the cell of carrier micelle PEG5000-PLA5000.
Embodiment
Below in conjunction with specific embodiments and the drawings, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
The present invention's raw material, reagent used is commercially available AR, CP level.
Gained intermediate product of the present invention and final product adopt NMR, IR, and GPC etc. characterize.
embodiment 1, amphipathic nature block polymer 1a's is synthetic
As shown in Figure 1, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1a:
(1) compound 2 is synthetic:
Described concrete steps are: the hydrogen peroxide of the formic acid solution of 20mL88% and 7.7mL30% is added in reaction flask, after being warming up to the formic acid solution that then 50 ℃ of stirrings be dissolved in 5.0096g4-pentenoic acid (50mmol) 10mL88%, be slowly added drop-wise to again (15min drips off) in reaction flask, stopped reaction after continuation is stirred 10h at 50 ℃, after being spin-dried for, reaction solution adds 0.35mL concentrated hydrochloric acid and 17mL methyl alcohol, at room temperature stir stopped reaction after 4h, revolve solution and obtain sterling yellow liquid 5.8g, productive rate 100%.
1H?NMR(CDCl 3，400MHz)：δ4.65-4.56(m，1H)，3.89-3.81(m，1H)，3.65-3.57(m，1H)，2.65-2.45(m，2H)，2.30-2.18(m，1H)，2.18-2.06(m，1H).
(2) compound 3 is synthetic:
Described concrete steps are: 6.6g compound 2 (56.9mmol) is dissolved in 80mL DCM, add 10mL triethylamine, 560mg DMAP (4.6mmol) and 10.86g TsCl (56.9mmol), under normal temperature, stir stopped reaction after 4h, organic phase washes with water successively, saturated common salt is washed, anhydrous sodium sulfate drying, revolves desolventizing and obtains brown color solid.Column chromatography separated (PE:DCM=2:1,1:2), obtains pure products 13.5g, productive rate 87.7%.
1H?NMR(CDCl 3，400MHz)：δ7.78(d，J＝8.4Hz，2H)，7.36(d，J＝8.4Hz，2H)，4.72-4.65(m，1H)，4.21-4.11(m，2H)，2.64-2.48(m，2H)，2.45(s，3H)，2.40-2.30(m，1H)，2.17-2.07(m，1H).
(3) compound 4 is synthetic:
Described concrete steps are: by 9.057g compound 3 (33.5mmol) and 5.09g K 2cO 3(36.8mmol) add in single port bottle, take after 6.65g4-nitrophenols (47.8mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 7.67g sterling, productive rate 95.8%.
1H?NMR(CDCl 3，400MHz)：δ8.13(d，J＝7.2Hz，2H)，6.94(d，J＝7.2Hz，2H)，4.94-4.86(m，1H)，4.31-4.26(m，1H)，4.19-4.13(m，1H)，2.73-2.54(m，2H)，2.49-2.39(m，1H)，2.29-2.19(m，1H).
(4) compound 5 is synthetic:
Described concrete steps are: take 6g compound 4 (25.3mmol) and add in dry reaction flask, and after taking out, taking a breath, N 2under gas protection, add 40mL DCM, at-78 ℃, slowly drip 20mL diisobutyl aluminium hydride (DIBAL-H) (1.5M, 30mmol), after reaction 4h, stopped reaction.Organic phase washes with water successively, saturated common salt is washed, anhydrous sodium sulfate drying, revolves desolventizing and obtains brown color solid 4.1g, and productive rate is 67%.
1H?NMR(CDCl 3，400MHz)：δ8.21-8.16(m，2H)，7.01-6.95(m，2H)，5.65-5.55(m，1H)，4.67-4.60(m，1H)，4.16-4.13(m，1H)，4.10-4.00(m，1H)，2.32-2.03(m，2H)，2.02-1.76(m，2H).
(5) compound 6 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 686mg compound 5 (2.87mmol), 8.5g PEG5000 (1.7mmol) and 600mg Amberlyst A-15 and be dissolved in 60mL toluene, at 100 ℃, reflux after 4h and add 370mg and 480mg A-15, the continuation 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.1g compared with sterling, productive rate 23.7%.
1H?NMR(CDCl 3，400MHz)：δ8.21-8.17(m，2H)，7.02-6.96(m，2H)，5.25-5.22(m，0.5H)，5.19-5.16(m，0.5H)，4.51-4.45(m，1H)，4.16-4.06(m，2H)，3.89-3.43(m，435H)，3.37(s，3H)，2.12-1.96(m，4H).
(6) compound 7 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.12g compound 6 (n=114, PEG 5000) and 430mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid.
1H?NMR(CDCl 3，400MHz)：δ6.88-6.70(m，4H)，5.22-5.10(m，1H)，4.45-4.36(m，1H)，3.97-3.85(m，2H)，3.89-3.40(m，403H)，3.35(s，3H)，2.17-1.91(m，4H).
(7) compound 1a (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA5000 (0.057mmol) and the 44mgHATU (0.116mmol) that 290mg one end are connected with to Succinic anhydried are dissolved in 5mL DMF; under nitrogen protection; under condition of ice bath, add 0.03mL DIPEA (0.176mmol), stir 0.5h at 0 ℃.By 136mg compound 7 (n=114, PEG 5000) (0.026mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid, productive rate 11%.
1H?NMR(CDCl 3，400MHz)：δ7.55-7.36(m，2H)，6.86-6.26(m，2H)，5.35-5.26(m，1H)，5.22-5.05(m，31H)，3.99-3.86(m，2H)，3.84-3.40(m，412H)，3.37(s，3H)，2.80-2.50(m，4H)，2.21-1.79(m，4H)，1.64-1.40(m，94H).
embodiment 2, amphipathic nature block polymer 1b's is synthetic
As shown in Figure 2, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1b:
(1) compound 8 is synthetic:
Get 2.70g60% sodium hydride (67.5mmol), add 50mL DMF, vigorous stirring.Add 9.00g (56.2mmol) diethyl malonate, then add 10.39g2-bromo-1,1-glycol dimethyl ether (61.8mmol), 100 ℃ are stirred 12 hours.Stopped reaction, adds 50mL water, uses 100mL dichloromethane extraction.100mL saturated common salt water washing for organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, obtains 12.80g pale yellow oily liquid body.With 200-300 order silica gel column chromatography (PE:EA=5:1), obtain colourless liquid 5.60g, productive rate 40%.
1H?NMR(400MHz，CDCl 3)：δ4.42(t，J＝5.6Hz，1H)，4.20(q，J＝7.2Hz，4H)，3.48(t，J＝5.6Hz，1H)，3.33(s，6H)，2.23-2.19(m，2H)，1.27(t，J＝7.2Hz.6H).
(2) compound 9 is synthetic:
Get 2.20g compound 8 (8.86mmol), add 10mL ether, add 20mL Lithium Aluminium Hydride (20mmol) (1.0M in THF).Stirring at room 2 hours.Add ethyl acetate cancellation reaction, add water, by ethyl acetate, repeatedly extract, use anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent obtains weak yellow liquid 1.02g, productive rate 70%.
1H?NMR(400MHz，CDCl 3)：δ4.51(t，J＝5.6Hz，1H)，3.77-3.65(m，4H)，3.36(s，6H)，2.86(s，2H)，1.93-1.86(m，1H)，1.71-1.68(m，2H).
(3) compound 10 is synthetic:
Get 272mg compound 9 (1.66mmol), add 3mL methylene dichloride to dissolve, add 0.22M camphorsulfonic acid pyridinium salt dichloromethane solution.Stir 18 hours.Stopped reaction, pressure reducing and steaming solvent.With 200-300 order silica gel column chromatography (DCM:CH 3oH=20:1), obtain weak yellow liquid 188mg, productive rate 85%.
1H?NMR(400MHz，CDCl 3)：δ5.09-5.07(m，0.23H)，5.02-4.98(m，0.77H)，4.05-3.92(m，1H)，3.71-3.49(m，3H)，3.33-3.30(m，3H)，2.62-2.54(m，0.77H)，2.52-2.46(m，0.23H)，2.21-2.13(m，0.46H)，2.00-1.95(m，0.77H)，1.75-1.70(m，0.77H).
(4) compound 11 is synthetic:
Described concrete steps are: 6.1g compound 10 (46mmol) is dissolved in 80mL DCM, add 10mL triethylamine, 560mg DMAP (4.6mmol) and 8.8g TsCl (46mmol), under normal temperature, stir stopped reaction after 4h, organic phase washes with water successively, saturated common salt is washed, anhydrous sodium sulfate drying, revolves desolventizing and obtains brown color solid.Column chromatography separated (PE:DCM=2:1,1:2), obtains pure products 11.2g, productive rate 85%.
1H?NMR(CDCl 3，400MHz)：δ7.77(d，J＝8.4Hz，2H)，7.35(d，J＝8.4Hz，2H)，5.02-5.00(m，1H)，4.07-3.96(m，1H)，3.75-3.47(m，2H)，3.42-3.35(m，1H)，3.32(m，3H)，2.74-2.67(m，0.5H)，2.60-2.52(m，0.5H)，2.45(s，3H)，2.24-2.13(m，0.5H)，2.02-1.96(m，0.5H)，1.74-1.60(m，1H).
(5) compound 12 is synthetic:
Described concrete steps are: by 7.15g compound 11 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 5.91g sterling, productive rate 93.4%.
1H?NMR(400MHz，CDCl 3)：δ8.21-8.16(m，2H)，7.01-6.95(m，2H)，5.02-5.00(m，1H)，4.17-3.99(m，1H)，3.75-3.63(m，1H)，3.66-3.55(m，1H)，3.49-3.45(m，1H)，3.32(m，3H)，2.74-2.67(m，0.5H)，2.60-2.52(m，0.5H)，2.24-2.13(m，0.5H)，2.02-1.96(m，0.5H)，1.74-1.68(m，0.5H)，1.66-1.60(m，0.5H).
(6) compound 13 is synthetic:
Described concrete steps are: get 581mg compound 12 (2.3mmol), add 10mL1,4-dioxane, adds 10mL dilute hydrochloric acid (concentration is 0.1M).React two days.Use dichloromethane extraction reaction solution, anhydrous magnesium sulfate drying, pressure reducing and steaming solvent.200-300 order silica gel column chromatography separating purification (PE:EA=5:1) for resistates, obtains faint yellow solid 445mg, productive rate 81%.
1H?NMR(400MHz，CDCl 3)：δ8.21-8.16(m，2H)，7.01-6.95(m，2H)，5.44-5.43(m，0.5H)，5.43-5.40(m，0.5H)，4.26-4.18(m，0.42H)，4.11-4.05(m，0.58H)，3.94-3.89(m，0.58H)，3.79-3.73(m，0.42H)，3.58-3.51(m，1.16H)，3.47-3.38(m，0.84H)，2.81-2.74(m，0.42H)，2.59-2.54(m，0.58H)，2.26-2.19(m，0.58H)，2.04-1.98(m，0.42H)，1.77-1.73(m，1H).
(7) compound 14 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 813mg compound 13 (3.4mmol), 8.5g PEG 5000(1.7mmol) be dissolved in 60mL toluene with 600mg Amberlyst A-15, at 100 ℃, reflux after 4h and add 300mg and 480mg A-15, the continuation 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.5g compared with sterling, productive rate 28.2%.
1H?NMR(CDCl 3，400MHz)：δ8.20-8.17(m，2H)，7.02-6.96(m，2H)，5.42-5.35(m，0.5H)，5.34-5.26(m，0.5H)，4.27-4.12(m，1H)，4.05-3.92(m，1H)，3.87-3.69(m，2H)，3.89-3.43(m，432H)，3.37(s，3H)，2.23-2.01(m，2H)，1.99-1.90(m，1H).
(8) compound 15 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.12g compound 14 (n=114, PEG 5000) and 430mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid 1.92g, productive rate 91.4%.
1H?NMR(CDCl 3，400MHz)：δ6.89-6.72(m，4H)，5.44-5.27(m，1H)，4.26-4.11(m，1H)，4.07-3.94(m，1H)，3.87-3.69(m，2H)，3.85-3.42(m，432H)，3.35(s，3H)，2.23-2.01(m，2H)，1.93-1.79(m，1H).
(9) compound 1b (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mgHATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 156mg compound 15 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 37mg, productive rate 12%.
1H?NMR(CDCl 3，400MHz)：δ7.55-7.36(m，2H)，6.86-6.26(m，2H)，5.43-5.31(m，1H)，5.20-5.05(m，32H)，4.26-4.11(m，1H)，4.07-3.94(m，1H)，3.87-3.69(m，2H)，3.84-3.40(m，412H)，3.37(s，3H)，2.80-2.24(m，4H)，2.23-2.01(m，2H)，1.93-1.79(m，1H)，1.64-1.40(m，96H).
embodiment 3, amphipathic nature block polymer 1c's is synthetic
As shown in Figure 3, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1c:
(1) compound 16 is synthetic:
Described concrete steps are: get 400mg60% sodium hydride (10mmol), add 10mL ether, vigorous stirring.Add 600mg methyl-formiate (10mmol), add 860mg gamma-butyrolactone (10mmol), stir 20h.Stopped reaction, filters reactant normal hexane, ether washing leaching cake.In filter cake, add 3mL dissolve with methanol, add 4mL hydrogenchloride/methanol solution, stir 1h.With the neutralization of 1M sodium hydrate methanol solution, remove by filter insolubles, filtrate is concentrated.With 200-300 order silica gel column chromatography separating purification (PE:EA=5:1), obtain colourless liquid 780mg, productive rate 48%.Nucleus magnetic resonance shows two diastereomers.
cis-16： 1H?NMR(400MHz，CDCl 3)：δ5.09(d，J＝5.1Hz，1H)，4.07-3.97(m，1H)，3.95-3.88(m，1H)，3.70(s，3H)，3.31(s，3H)，3.12-3.01(m，1H)，2.23-2.16(m，2H).trans-16： 1H?NMR(400MHz，CDCl 3，distinctive?peaks)：δ5.17(s，1H)，3.34(s，3H)，2.52-2.38(m，1H)，2.08-1.97(m，1H).
(2) compound 17 is synthetic:
Described concrete steps are: get 400mg compound 16 (2.5mmol), add 5mL ether, add 2.5mL Lithium Aluminium Hydride.Reflux 2 hours.Add ethyl acetate cancellation reaction, add 20mL water, by ethyl acetate, repeatedly extract, use anhydrous magnesium sulfate drying.Remove solvent under reduced pressure and obtain colourless liquid 300mg, productive rate 91%.
cis-17： 1H?NMR(400MHz，CDCl 3)：δ4.96(d，J＝4.8Hz，1H)，4.00-3.82(m，2H)，3.74-3.66(m，2H)，3.35(s，3H)，2.38-2.28(m，1H)，1.99(s，1H)，1.94-1.87(m，2H).trans-17： 1H?NMR(400MHz，CDCl 3，distinctive?peaks)：δ4.86(s，1H)，3.60-3.50(m，2H)，3.33(s，3H)，2.13-2.04(m，1H)，1.60-1.52(m，1H).
(3) compound 18 is synthetic:
Described concrete steps are: 3.04g compound 17 (23mmol) is dissolved in 50mL DCM, add 4.5mL triethylamine, 280mg DMAP (2.3mmol) and 4.39g TsCl (23mmol), under normal temperature, stir stopped reaction after 4h, organic phase washes with water successively, saturated common salt is washed, anhydrous sodium sulfate drying, revolves desolventizing and obtains brown color solid.Column chromatography separated (PE:DCM=2:1,1:2), obtains pure products 5.9g, productive rate 89.7%.
1H?NMR(CDCl 3，400MHz)：δ7.77(d，J＝8.4Hz，2H)，7.35(d，J＝8.4Hz，2H)，4.72-4.65(m，1H)，4.21-4.11(m，2H)，3.32(m，3H)，2.64-2.48(m，2H)，2.45(s，3H)，2.40-2.30(m，1H)，2.17-2.07(m，1H).
(4) compound 19 is synthetic:
Described concrete steps are: by 7.15g compound 18 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 5.82g sterling, productive rate 91.9%.
cis-19： 1H?NMR(400MHz，CDCl 3)：δ8.20-8.14(m，2H)，7.01-6.96(m，2H)，4.92(d，J＝4.5Hz，1H)，4.12-3.93(m，2H)，3.80-3.74(m，1H)，3.62-3.57(m，1H)，3.33(s，3H)，2.53-2.40(m，1H)，2.16-1.98(m，1H)，1.70-1.60(m，1H).trans-19： 1H?NMR(400MHz，CDCl 3，distinetive?peaks)：δ4.85(s，1H)，3.39-3.36(m，2H)，3.34(s，3H).
(5) compound 20 is synthetic:
Described concrete steps are: get 581mg compound 19 (2.3mmol), add 10mL1,4-dioxane, adds 10mL dilute hydrochloric acid (concentration is 0.1M).React two days.Use dichloromethane extraction reaction solution, anhydrous magnesium sulfate drying, pressure reducing and steaming solvent.200-300 order silica gel column chromatography separating purification (PE:EA=5:1) for resistates, obtains faint yellow solid 390mg, productive rate 71%.
cis-20： 1H?NMR(400MHz，CDCl 3)：δ8.20-8.14(m，2H)，7.01-6.96(m，2H)，5.44(t，J＝3.6Hz，1H)，4.25-3.98(m，2H)，3.92-3.86(m，1H)，3.80-3.70(m，1H)，2.59-2.45(m，1H)，2.26-2.03(m，1H)，1.76-1.65(m，1H).trans-20： 1H?NMR(400MHz，CDCl 3，distinctive?peaks)：δ5.37(s，1H)，4.03(q，J＝8Hz，1H)，3.42-3.34(m，2H)，3.10(s，1H)，2.52-2.44(m，1H)，2.21-2.12(m，1H)，1.66-1.58(m，1H).
(6) compound 21 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 813mg compound 20 (3.4mmol), 8.5g PEG 5000(1.7mmol) be dissolved in 60mL toluene with 600mg Amberlyst A-15, at 100 ℃, reflux after 4h and add 300mg and 480mg A-15, the continuation 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.3g compared with sterling, productive rate 26%.
cis-21： 1H?NMR(400MHz，CDCl 3)：δ8.23-8.15(m，2H)，7.03-6.96(m，2H)，5.07(d，J＝4.4Hz，1H)，4.23-4.10(m，2H)，3.85-3.78(m，2H)，3.75-3.42(m，422H)，3.35(s，3H)，2.68-2.52(m，1H)，2.27-2.05(m，1H)，1.80-1.70(m，1H).trans-21： 1H?NMR(400MHz，CDCl 3，distinctive?peaks)：δ5.03(s，1H)，3.97-3.85(m，1H)，3.80-3.74(m，1H)，3.38(s，1H)，3.36(s，1H)，2.58-2.49(m，1H)，2.17-2.09(m，1H)，1.61-1.52(m，1H).
(7) compound 22 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.12g compound 21 (n=114, PEG 5000) and 430mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid 1.90g, productive rate 90.4%.
cis-22： 1H?NMR(400MHz，CDCl 3)：δ6.88-6.72(m，4H)，5.09(d，J＝4.4Hz，1H)，4.23-4.10(m，2H)，3.85-3.78(m，2H)，3.75-3.42(m，422H)，3.35(s，3H)，2.68-2.52(m，1H)，2.27-2.05(m，1H)，1.80-1.70(m，1H).trans-22： 1H?NMR(400MHz，CDCl 3，distinctive?peaks)：δ5.05(s，1H)，3.97-3.85(m，1H)，3.80-3.74(m，1H)，3.38(s，1H)，3.36(s，1H)，2.58-2.49(m，1H)，2.17-2.09(m，1H)，1.61-1.52(m，1H).
(8) compound 1c (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mgHATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 156mg compound 22 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 35mg, productive rate 11.3%.
cis-1c： 1H?NMR(400MHz，CDCl 3)：δ6.88-6.72(m，4H)，5.20-5.05(m，32H)，5.09(d，J＝4.4Hz，1H)，4.23-4.10(m，2H)，3.85-3.78(m，2H)，3.75-3.42(m，422H)，3.35(s，3H)，2.68-2.52(m，1H)，2.27-2.05(m，1H)，1.80-1.70(m，1H)，1.64-1.40(m，96H).trans-1c： 1H?NMR(400MHz，CDCl 3，distinctive?peaks)：δ5.05(s，1H)，3.97-3.85(m，1H)，3.80-3.74(m，1H)，3.38(s，1H)，3.36(s，1H)，2.58-2.49(m，1H)，2.17-2.09(m，1H)，1.61-1.52(m，1H).
embodiment 4, amphipathic nature block polymer 1d's is synthetic
As shown in Figure 4, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1d:
(1) compound 23 is synthetic:
Described concrete steps are: take pimelinketone (30g, 0.31mol) and trimethyl orthoformate (39g, 0.37mol) in single port bottle, add pTSA (0.57g, 0.003mol) stirring at room 2h, separated with fractional column, methyl-formiate, methyl alcohol are first separated, and are then trimethyl orthoformates, collect the cut of 125-138 ℃, for target product, obtain 16.7g, productive rate 48%.
1H?NMR(400MHz，CDCl 3)：δ4.61(t，1H，J＝3.6Hz)，3.50(s，3H)，2.07-2.03(m，4H)，1.70-1.64(m，2H)，1.59-1.51(m，2H).
(2) compound 24 is synthetic:
Described concrete steps are: ethylene glycol acetate (5.22g, 50.2mmol) is dissolved in the anhydrous THF of 75mL, adds successively tosic acid (477mg, 2.5mmol) and 5A molecular sieve (23.75g) and at room temperature stir 15min.Then add compound 2.25g compound 23 (20.1mmol) and at room temperature stir 48h.Add 475mg NaHCO 3cancellation react and stir 10min after filter, after filtrate revolving removed, column chromatography separated (PE:EA=6:1), column chromatography obtains faint yellow oily matter 2.1g, productive rate 46%.
1H?NMR(400MHz，CDCl 3)：δ4.21(t，4H，J＝4.8Hz)，3.64(t，4H，J＝4.8Hz)，2.07(s，6H)，1.66(m，4H)，1.59(m，4H)，1.51(m，2H).
(3) compound 25 is synthetic:
Described concrete steps are: 2g compound 24 (6.94mmol) is dissolved in 20mL methyl alcohol, add 2.886g salt of wormwood (20.9mmol) and 1mL water, and at room temperature stir 15h, with diatomite filtration, and by methanol wash, revolve to desolventize and with methylene dichloride, dissolve afterwards, filter and be spin-dried for to obtain faint yellow oily matter 1.38g, productive rate 97.4%.
1H?NMR(400MHz，CDCl 3)：δ3.75(t，4H，J＝4Hz)，3.58(t，4H，J＝4.8Hz)，2.35(bs，2H)，1.69(m，4H)，1.52(m，4H)，1.43(m，2H).
(4) compound 26 is synthetic:
Described concrete steps are: 1.36g compound 25 (6.69mmol) is dissolved in 15mL DCM and is stirred, add 0.775mL EtN under ice bath 3, more dropwise add under 425mg TsCl (2.23mmol) room temperature being dissolved in 5ml DCM and stir and spend the night.Revolve to desolventize with PE:EA=2:1 column chromatography and obtain 460mg, productive rate 57%.
1H?NMR(400MHz，CDCl 3)：δ7.79(d，2H，J＝8.4Hz)，7.33(d，2H，J＝8.4Hz)，4.15(t，2H，J＝4.8Hz)，3.71-3.66(m，2H)，3.62(t，2H，J＝4.8Hz)，3.46(t，2H，J＝4.8Hz)，2.44(s，3H)，1.60-1.57(m，4H)，1.46-1.34(m，6H).
(5) compound 27 is synthetic:
Described concrete steps are: by 8.61g compound 26 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 70mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 6.82g sterling, productive rate 87.5%.
1H?NMR(400MHz，CDCl 3)：δ8.19-8.13(m，2H)，7.09-6.99(m，2H)，4.15(t，2H，J＝4.8Hz)，3.71-3.66(m，2H)，3.62(t，2H，J＝4.8Hz)，3.46(t，2H，J＝4.8Hz)，1.60-1.57(m，4H)，1.46-1.34(m，6H).
(6) compound 28 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 1.06g compound 27 (3.4mmol), 8.5g PEG 5000(1.7mmol) and 800mg Amberlyst A-15 be dissolved in 60mL toluene, the 15h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.7g compared with sterling, productive rate 30%.
1H?NMR(400MHz，CDCl 3)：δ8.19-8.13(m，2H)，7.09-6.99(m，2H)，4.15-4.09(m，2H)，3.89-3.43(m，432H)，3.37(s，3H)，1.67-1.57(m，4H)，1.49-1.39(m，6H).
(7) 29 (n=114, PEG5000's) is synthetic:
Described concrete steps are: 2.10g compound 28 (n=114, PEG5000) and 420mg10%Pd/C are dissolved in 80mL methyl alcohol, and hydrogen pours down, stopped reaction stir 12h at 35 ℃ after, reacting liquid filtering, is spin-dried for to obtain lilac solid 1.92g, productive rate 91.7%.
1H?NMR(400MHz，CDCl 3)：δ6.95-6.78(m，4H)，4.15-4.09(m，2H)，3.89-3.43(m，438H)，3.34(s，3H)，1.67-1.57(m，4H)，1.49-1.39(m，6H).
(8) compound 1d (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mgHATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 158mg compound 29 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 38mg, productive rate 12%.
1H?NMR(CDCl 3，400MHz)：δ7.55-7.36(m，2H)，6.86-6.26(m，2H)，5.20-5.05(m，32H)，4.15-4.09(m，2H)，3.89-3.43(m，438H)，3.33(s，3H)，2.80-2.42(m，4H)，1.67-1.57(m，4H)，1.52-1.45(m，6H).
embodiment 5, amphipathic nature block polymer 1e's is synthetic
As shown in Figure 5, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1e:
(1) compound 30 is synthetic:
Described concrete steps are: take 26g cyclopentanone (0.309mol) and 39.36g trimethyl orthoformate (0.371mol) in single port bottle, under ice bath conditional, add 0.588g pTSA (3.09mmol) to stir after 20min, stirring at room 2h, separated with fractional column, methyl-formiate, methyl alcohol are first separated, and are then trimethyl orthoformates, collect the cut of 106-114 ℃, for target product, obtain 16.7g, productive rate 55%.
1H?NMR(400MHz，CDCl 3)：δ4.46-4.44(m，1H)，3.59(s，3H)，2.35-2.28(m，4H)，1.92-1.83(m，2H)
(2) compound 31 is synthetic:
Described concrete steps are: 5.5g ethylene glycol acetate (52.88mol) is dissolved in the anhydrous THF of 55mL, and add according to this 0.664g PPTS (2.64mmol) and 22.5g5A molecular sieve and 2.748g compound 30 (28.41mmol), at room temperature stir 48h.Add 668mg NaHCO 3cancellation react and stir 10min after filter, filtrate is revolved and with PE:EA=7:1 column chromatography, is obtained oily matter 3.7g, productive rate 51% except rear.
1H?NMR(400MHz，CDCl 3)：δ4.22-4.19(t，4H，J＝4.8Hz)，3.67-3.65(t，4H，J＝4.8Hz)，2.07(s，6H)，1.79(m，4H)，1.69(m，4H).
(3) compound 32 is synthetic:
Described concrete steps are: 2g compound 31 (7.3mmol) is dissolved in 20mL methyl alcohol, add 3.023g salt of wormwood (21.3mmol) and 1.023mL water, and at room temperature stir 3h, with diatomite filtration, and by methanol wash, revolve to desolventize and with methylene dichloride, dissolve afterwards, filter and be spin-dried for to obtain oily matter 720mg. 1H?NMR(400MHz，CDCl 3)：δppm3.75-3.71(m，4H)，3.61-3.58(m，4H)，1.84-1.77(m，4H)，1.71-1.65(m，4H)
(4) compound 33 is synthetic:
Described concrete steps are: 720mg compound 32 (3.79mmol) is dissolved in 8mL DCM and is stirred, add 0.35mL EtN under ice bath 3, more dropwise add under 255mg TsCl (1.26mmol) room temperature being dissolved in 2mL DCM and stir and spend the night.Revolve to desolventize with PE:EA=3:1 column chromatography and obtain 244mg, productive rate 56%.
1H?NMR(400MHz，CDCl 3)：δ7.79(d，2H，J＝8.4Hz)，7.33(d，2H，J＝8.4Hz)，4.15(t，2H，J＝4.8Hz)，3.71-3.66(m，2H)，3.64(t，2H，J＝4.8Hz)，3.48(t，2H，J＝4.8Hz)，2.44(s，3H)，1.77-1.70(m，4H)，1.66-1.60(m，4H).
(5) compound 34 is synthetic:
Described concrete steps are: by 8.61g compound 33 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 6.95g sterling, productive rate 89.3%.
1H?NMR(400MHz，CDCl 3)：δ8.20-8.14(m，2H)，7.01-6.96(m，2H)，4.16(t，2H，J＝4.8Hz)，3.73-3.67(m，2H)，3.66(t，2H，J＝4.8Hz)，3.49(t，2H，J＝4.8Hz)，1.77-1.71(m，4H)，1.68-1.62(m，4H).
(6) compound 35 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 1.06g compound 34 (3.4mmol), 8.5g PEG 5000(1.7mmol) and 800mg Amberlyst A-15 be dissolved in 60mL toluene, the 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.9g compared with sterling, productive rate 32.2%.
1H?NMR(400MHz，CDCl 3)：δ8.20-8.14(m，2H)，7.01-6.96(m，2H)，4.22-4.15(m，2H)，3.78-3.41(m，435H)，3.35(s，3H)，1.79-1.70(m，4H)，1.68-1.60(m，4H).
(7) compound 36 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.40g compound 35 (n=114, PEG 5000) and 480mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid 2.13g, productive rate 89.1%.
1H?NMR(400MHz，CDCl 3)：δ6.88-6.72(m，4H)，4.21-4.16(m，2H)，3.78-3.41(m，435H)，3.35(s，3H)，1.79-1.70(m，4H)，1.68-1.60(m，4H).
(8) compound 1e (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mg HATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 158mg compound 36 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mL DMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 59mg, productive rate 19%.
1H?NMR(400MHz，CDCl 3)：δ6.86-6.71(m，4H)，5.19-5.06(m，33H)，4.20-4.12(m，2H)，3.78-3.41(m，435H)，3.35(s，3H)，2.80-2.48(m，4H)，1.79-1.70(m，4H)，1.68-1.60(m，4H)，1.60-1.40(m100H).
embodiment 6, amphipathic nature block polymer 1f's is synthetic
As shown in Figure 6, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1f:
(1) compound 37 is synthetic:
Described concrete steps are: take 18.61g ethylene glycol (300mmol) and 6g acetic acid (99.9mmol) stirs in 100mL single port bottle, drip the 0.112mL vitriol oil in reaction, at 25 ℃, stir 24h, adding 17mL saturated sodium bicarbonate solution to stir spends the night, in reaction, add 12mL water and extract with methylene dichloride 50 * 8, organic layer is with after anhydrous sodium sulfate drying, revolves to desolventize with DCM:MeOH=30:1 column chromatography to obtain sterling 6.3g.Productive rate 60.6%.
1H?NMR(400MHz，CDCl3)：δ4.20(t，2H，J＝4.8Hz)，3.82(t，2H，J＝4.8Hz)，2.09(s，3H)，1.93(s，1H).
(2) compound 38 is synthetic:
Described concrete steps are: 6.3g compound 37 (60.6mmol) is added in 150mL single port bottle, add the anhydrous THF of 87mL and 0.725g PPTS (2.89mmol) to stir 15min, add 28.8g5A molecular sieve to stir 15min, add 2.4mL2-methoxyl group propylene (25.9mmol) at room temperature to stir 48h, add potassium carbonate powder to make to be neutral, filtration is revolved filtrate and is obtained crude product 7.3g, and PE:EA=3:1 column chromatography for separation obtains sterling 3.8g.Productive rate 59.4%.
1H?NMR(400MHz，CDCl3)：δ4.20(t，4H，J＝4.8Hz)，3.66(t，4H，J＝4.8Hz)，2.08(s，6H)，1.38(s，6H).
(3) compound 39 is synthetic:
Described concrete steps are: get 2g compound 38 (8.06mmol) in 100mL single port bottle, add 20mL methyl alcohol to stir, add 3.339g salt of wormwood (24.19mmol) and 1mL water to stir and spend the night at 25 ℃, by reaction solution diatomite filtration, filtrate is spin-dried for, with methylene dichloride dissolution filter, is spin-dried for to obtain product 1.23g.Productive rate 93.2%.
1H?NMR(400MHz，CDCl3)：δ3.72(t，4H，J＝4.4Hz)，3.58(t，4H，J＝4.8Hz)，2.57(bs，2H)，1.41(s，6H).
(4) compound 40 is synthetic:
Described concrete steps are: 1g compound 39 (6.098mmol) is dissolved in 7.5mL DCM and is stirred, add 0.43mL EtN under ice bath 3, more dropwise add under 0.291g TsCl (1.524mmol) room temperature being dissolved in 1.5mL DCM and stir and spend the night.Revolve to desolventize with PE:EA=2.5:1 column chromatography and cross post, obtain sterling 380mg.Productive rate 78.4%.
1H?NMR(400MHz，CDCl3)：δ7.79(d，2H，J＝8.0Hz)，7.34(d，2H，J＝8.0Hz)，4.14(t，2H，J＝4.8Hz)，3.69-3.62(m，4H)，3.50-3.47(m，2H)，2.44(s，3H)，1.31(s，6H).
(5) compound 41 is synthetic:
Described concrete steps are: by 7.96g compound 40 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 6.38g sterling, productive rate 89.4%.
1H?NMR(400MHz，CDCl 3)：δ8.21-8.16(m，2H)，7.01-6.95(m，2H)，4.28(t，2H，J＝4.8Hz)，3.75-3.64(m，4H)，3.52-3.47(m，2H)，1.31(s，6H).
(6) compound 42 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 970mg compound 41 (3.4mmol), 8.5g PEG 5000(1.7mmol) and 800mg Amberlyst A-15 be dissolved in 60mL toluene, the 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.7g compared with sterling, productive rate 30%.
1H?NMR(CDCl 3，400MHz)：δ8.21-8.17(m，2H)，7.02-6.96(m，2H)，4.31-4.25(m，2H)，3.89-3.43(m，437H)，3.37(s，3H)，1.32(s，6H).
(7) compound 43 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.6g compound 42 (n=114, PEG 5000) and 520mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid 2.32g, productive rate 89.7%.
1H?NMR(CDCl 3，400MHz)：δ6.89-6.71(m，4H)，4.31-4.25(m，2H)，3.89-3.43(m，438H)，3.37(s，3H)，1.32(s，6H).
(8) compound 1f (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mgHATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 157mg compound 43 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 64mg, productive rate 20.7%.
1H?NMR(CDCl 3，400MHz)：δ7.55-7.36(m，2H)，6.86-6.26(m，2H)，5.20-5.06(m，32H)，4.31-4.25(m，2H)，3.89-3.43(m，438H)，3.37(s，3H)，1.64-1.40(m，96H)，1.32(s，6H).
embodiment 7, amphipathic nature block polymer 1g's is synthetic
As shown in Figure 7, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1g:
(1) compound 44 is synthetic:
Described concrete steps are: 2.72g compound 37 (20mmol) is placed in to single port bottle, under ice bath, add 0.656g pTSA (3.45mmol) and 10.4g4A molecular sieve to stir after ten minutes, after adding 912mg4-methoxybenzaldehyde (6.7mmol) to stir 4d, add 3mL TEA, filter, and wash with EA, PE:EA:TEA=8:1:1 column chromatography obtains 1.6g, productive rate 73%.
1H?NMR(400MHz，CDCl3)：δ7.37(d，2H，J＝8.8Hz)，6.87(d，2H，J＝8.8Hz)，5.61(s，1H)，4.25-4.21(m，4H)，3.79(s，3H)，3.73-3.63(m，4H)，2.07-2.05(m，6H).
(2) compound 45 is synthetic:
Described concrete steps are: take 600mg compound 45 (1.84mmol) in single port bottle, be dissolved in 5.26mL methyl alcohol, and add 762mg K 2cO 3(5.52mmol) and 0.263mL water under room temperature, stir and spend the night, filter after being spin-dried for solvent and be again dissolved in DCM and filter, revolve after desolventizing to obtain 434mg, productive rate 97.5%.
1H?NMR(400MHz，CDCl3)：δ7.38(d，2H，J＝8.8Hz)，6.90(d，2H，J＝8.8Hz)，5.55(s，1H)，3.81(s，3H)，3.78-3.74(m，4H)，3.69-3.66(m，4H).
(3) compound 46 is synthetic:
Described concrete steps are: take 420mg compound 45 (1.74mmol) in single port bottle, add 6mL DCM to dissolve and be placed in ice bath, add 293mg TEA (2.9mmol) to stir, 111mg TsCl (0.58mmol) is dissolved in 2mL DCM and joins in reaction and stir and spend the night, after revolving and desolventizing, PE:EA:TEA=2:1:0.1 column chromatography obtains 122mg, productive rate 53%.
1H?NMR(400MHz，MeOD)：δ7.77(d，2H，J＝8.0Hz)，7.40(d，2H，J＝8.0Hz)，7.30(d，2H，J＝8.4Hz)，6.88(d，2H，J＝8.4Hz)，5.49(s，1H)，4.18-4.09(m，2H)，3.80(s，3H)，3.66-3.46(m，6H)，2.44(s，3H).
(4) compound 47 is synthetic:
Described concrete steps are: by 9.91g compound 46 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 8.2g sterling, productive rate 90%.
1H?NMR(400MHz，CDCl 3)：δ8.21-8.16(m，2H)，7.31(d，2H，J＝8.4Hz)，7.01-6.95(m，2H)，6.89(d，2H，J＝8.4Hz)，5.48(s，1H)，4.16-4.09(m，2H)，3.81(s，3H)，3.67-3.48(m，6H).
(5) compound 48 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 1.24g compound 47 (3.4mmol), 8.5g PEG 5000(1.7mmol) and 600mg Amberlyst A-15 be dissolved in 60mL toluene, the 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.56g compared with sterling, productive rate 28.2%.
1H?NMR(CDCl 3，400MHz)：δ8.20-8.17(m，2H)，7.02-6.96(m，4H)，6.90(d，2H，J＝8.4Hz)，5.49(s，1H)，4.16-4.10(m，2H)，3.89-3.43(m，438H)，3.35(s，3H).
(6) compound 49 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.5g compound 48 (n=114, PEG 5000) and 500mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid 2.28g, productive rate 91.7%.
1H?NMR(CDCl 3，400MHz)：δ7.02-6.96(m，2H)，6.93-6.90(m，2H)，6.89-6.72(m，4H)，5.48(s，1H)，4.16-4.12(m，2H)，3.89-3.43(m，438H)，3.34(s，3H).
(7) compound 1g (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mgHATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 163mg compound 49 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 62mg, productive rate 19.9%.
1H?NMR(CDCl 3，400MHz)：δ7.55-7.36(m，2H)，7.02-6.96(m，2H)，6.93-6.90(m，2H)，6.86-6.26(m，2H)，5.49(s，1H)，5.19-5.06(m，32H)，4.17-4.10(m，2H)，3.89-3.43(m，438H)，3.34(s，3H)，2.80-2.24(m，4H)，1.64-1.40(m，96H).
embodiment 8, amphipathic nature block polymer 1h's is synthetic
As shown in Figure 8, synthesis step is as follows for the synthetic route schematic diagram of amphipathic nature block polymer 1h:
(1) compound 50 is synthetic:
Described concrete steps are: take 61.69g5A molecular sieve in single port bottle, add the anhydrous THF of 120mL, after adding successively 8.936g compound 37 (85.92mmol) and 0.613g pTSA (3.22mmol) to stir 10min, add the rear 48h of stirring of 5.33g4-methoxy-1-naphthalene formaldehyde (28.64mmol), in backward reaction solution, add TEA to be neutral, filter, filtrate is washed with EA, revolve desolventize rear PE:EA=6:1 column chromatography (2%TEA) product 2.5g, productive rate 23.2%.
1H?NMR(400MHz，MeOD)：δ8.26-8.20(m，2H)，7.66(d，2H，J＝8.0Hz)，7.54-7.44(m，2H)，6.68(d，1H，J＝8.0Hz)，6.07(s，1H)，4.23-4.19(m，4H)，4.01(s，3H)，3.75(t，2H，J＝4.8Hz)，1.94(s，6H).
(2) compound 51 is synthetic:
Described concrete steps are: take 2.4g compound 50 (6.38mmol) in single port bottle, be dissolved in 19mL methyl alcohol, and add 2.643g K 2cO 3(19.15mmol) and 0.95mL water under room temperature, stir, filter after being spin-dried for solvent and be again dissolved in DCM and filter, revolve after desolventizing to obtain 1.85g, productive rate 99.1%.
1H?NMR(400MHz，MeOD)：δ8.30-8.23(m，2H)，7.72(d，1H，J＝8.0Hz)，7.52-7.44(m，2H)，6.88(d，1H，J＝8.0Hz)，6.08(s，1H)，4.01(s，3H)，3.69-3.30(m，8H).
(3) compound 52 is synthetic:
Described concrete steps are: take 1.8g compound 51 (6.16mmol) in single port bottle, add 23mL DCM to dissolve and be placed in ice bath, add 1.43mL TEA (10.28mmol) to stir, 392mg TsCl (2.06mmol) is dissolved in 2mL DCM and joins in reaction and stir and spend the night, after revolving and desolventizing, PE:EA=2:1 (2%TEA) column chromatography obtains 540mg, productive rate 58.7%.
1H?NMR(400MHz，MeOD)：δ8.27-8.24(m，1H)，8.17-8.13(m，1H)，7.65(d，2H，J＝8.0Hz)，7.59(d，1H，J＝8.0Hz)，7.52-7.43(m，2H)，7.25(d，2H，J＝8.0Hz)，6.84(d，1H，J＝8.0Hz)，5.97(s，1H)，4.18-4.12(m，2H)，4.02(s，3H)，3.74-3.63(m，4H)，3.56-3.53(m，2H)，2.36(s，3H).
(4) compound 53 is synthetic:
Described concrete steps are: by 11.16g compound 52 (25mmol) and 3.81g K 2cO 3(27.5mmol) add in single port bottle, take after 4.18g4-nitrophenols (30mmol) is dissolved in 60mL DMF and add in single port bottle, after taking out, taking a breath, at N 2under protection, reaction flask is inserted in the oil bath of 80 ℃ and stir, after reaction 5h, stopped reaction, DCM extraction, organic phase washes twice, saturated common salt washing twice, anhydrous Na SO successively with water 4dry, revolve the yellow solid of desolventizing, column chromatography separation obtains 9.1g sterling, productive rate 88%.
1H?NMR(400MHz，CDCl 3)：δ8.27-8.24(m，1H)，8.21-8.17(m，2H)，8.17-8.13(m，1H)，7.59(d，1H，J＝8.0Hz)，7.52-7.43(m，2H)，7.02-6.95(m，2H)，6.84(d，1H，J＝8.0Hz)，5.98(s，1H)，4.19-4.12(m，2H)，4.01(s，3H)，3.75-3.62(m，4H)，3.56-3.51(m，2H).
(5) compound 54 (n=114, PEG 5000) synthetic:
Described concrete steps are: take 1.41g compound 53 (3.4mmol), 8.5g PEG 5000(1.7mmol) and 600mg Amberlyst A-15 be dissolved in 60mL toluene, the 10h stopped reaction that refluxes at 100 ℃, reaction solution diatomite filtration is removed A-15, after being spin-dried for to yellow solid.Column chromatography separation obtains 2.43g compared with sterling, productive rate 26.6%.
1H?NMR(400MHz，CDCl 3)：δ8.27-8.24(m，1H)，8.21-8.16(m，2H)，8.17-8.13(m，1H)，7.59(d，1H，J＝8.0Hz)，7.52-7.43(m，2H)，7.01-6.95(m，2H)，6.84(d，1H，J＝8.0Hz)，5.98(s，1H)，4.19-4.12(m，2H)，4.03(s，3H)，3.87-3.42(m，438H)，3.36(s，3H).
(6) compound 55 (n=114, PEG 5000) synthetic:
Described concrete steps are: by 2.5g compound 54 (n=114, PEG 5000) and 500mg10%Pd/C be dissolved in 80mL methyl alcohol, hydrogen pours down, at 35 ℃, stir 12h after stopped reaction, reacting liquid filtering, is spin-dried for to obtain lilac solid 2.29g, productive rate 92.1%.
1H?NMR(CDCl 3，400MHz)：δ8.28-8.25(m，1H)，8.18-8.13(m，1H)，7.60(d，1H，J＝8.0Hz)，7.52-7.43(m，2H)，6.89-6.72(m，5H)，5.99(s，1H)，4.19-4.12(m，2H)，4.03(s，3H)，3.87-3.42(m，438H)，3.36(s，3H).
(7) compound 1h (PLA 5000-PEG 5000) synthetic:
Described concrete steps are: the PLA that 306mg one end is connected with to Succinic anhydried 5000(0.06mmol) and 45.6mg HATU (0.12mmol) be dissolved in 6mL DMF, under nitrogen protection, under condition of ice bath, add 0.031mL DIPEA (0.18mmol), stir 0.5h at 0 ℃.By 161mg compound 55 (n=114, PEG 5000) (0.03mmol) add in reaction flask and remove ice bath after being dissolved in 3mLDMF, make reaction stir at normal temperatures stopped reaction after 24h, reaction solution is washed successively, saturated common salt washing, anhydrous sodium sulfate drying, revolves desolventizing and obtains yellow liquid.Revolve column chromatography (DCM:CH after desolventizing 3oH=50:1,40:1,20:1), obtained light yellow solid 56mg, productive rate 17.9%.
1H?NMR(CDCl 3，400MHz)：δ8.27-8.23(m，1H)，8.18-8.13(m，1H)，7.61(d，1H，J＝8.0Hz)，7.55-7.36(m，4H)，6.86-6.31(m，3H)，5.97(s，1H)，5.21-5.03(m，34H)，4.19-4.12(m，2H)，4.01(s，3H)，3.87-3.42(m，438H)，3.34(s，3H)，2.80-2.24(m，4H)，1.64-1.42(m，102H).
the mensuration of embodiment 9, block copolymer amount
Adopt GPC method to measure the molecular weight of the segmented copolymer PLA-PEG making in above embodiment; Instrument: Agilent1260 type gel permeation chromatograph, the gel chromatographic columns of GPC post: 7.5 * 300mm, 10 μ m, solvent: tetrahydrofuran (THF), flow velocity: 1.0mL/min, column temperature: 35 ℃, standard specimen: polystyrene.As shown in Figure 9, the test data of each polymkeric substance is as shown in table 1 below for the GPC graph of molecular weight distribution of each polymkeric substance.
The molecular weight of each polymkeric substance of table 1 and range of molecular weight distributions
Polymer Mn Mw D
PLA1000 957 1742 1.82
PLA3000 1224 3430 2.80
PLA5000 3701 5989 1.62
7(n＝43，PEG1900) 1964 2030 1.03
7(n＝114，PEG5000) 4521 4993 1.10
1a(PLA1000-PEG1900) 2794 3136 1.12
1a(PLA3000-PEG1900) 3587 4215 1.17
1a(PLA3000-PEG5000) 7782 8404 1.08
1a(PLA5000-PEG5000) 10798 13304 1.23
1b(PLA 5000-PEG 5000) 11340 14011 1.26
1c(PLA 5000-PEG 5000) 10967 13524 1.23
1d(PLA 5000-PEG 5000) 11003 13985 1.27
1e(PLA 5000-PEG 5000) 11431 14013 1.23
1f(PLA 5000-PEG 5000) 10967 13679 1.25
1g(PLA 5000-PEG 5000) 10524 13501 1.28
1h(PLA 5000-PEG 5000) 10376 13412 1.29
the system of embodiment 10, micella each with sign
The preparation of 10.1 blank micellas
Accurately take the segmented copolymer of 10mg synthesized, be dissolved in 1mL DMSO (also can be DMF or THF), segmented copolymer DMF solution is slowly splashed in the pure water (also can be PBS buffered soln or physiological saline) that 8mL stirs (10min/mL), after stirring 60min, proceed in dialysis tubing, with pure water dialysis 48 hours, 4h changes water once, gives DMSO, obtains self-assembled micelle.
The preparation of 10.2 carrier micelles
Accurately taking the segmented copolymer of 10mg synthesized and 1mg DOX.HCI and dissolve in 2mL DMSO (also can be DMF or THF), (can be Azythromycin, taxol, Elemenum or camptothecine containing medicine after adding 20 μ l triethylamines to stir 30min; What in the present embodiment, adopt is Azythromycin) the segmented copolymer DMSO solution of synthesized slowly splash in the pure water (also can be PBS buffered soln or physiological saline) that 8mL stirs (10min/mL), after stirring 60min, proceed in dialysis tubing, with pure water dialysis 48 hours, 4h changes water once, give DMSO, obtain self-assembly carrier micelle.
The mensuration of 10.3 micella size distribution
Get 1mL micella, insert laser particle analyzer and measure particle diameter, measure temperature: 25 ℃ of starting time 3 min, LASER Light Source: He-Ne laser, wavelength is 633nm.As shown in figure 10, as shown in figure 11, particle size data is as shown in table 2 for the size distribution figure of carrier micelle for the size distribution figure of blank micella.In table 2, institute's column data is mainly the data of copolymer 1 a, for copolymer 1 b, c, 1d, 1e, 1f, 1g, 1h, has also obtained similar result by the method for same formation micella, and the particle diameter after these all micelle medicine carryings is all large than the particle diameter of blank micella, and the micella after medicine carrying is all greater than 100nm, be less than 200nm, the micella of this size has EPR effect, is to be applicable to very much medicine carrying.
The measured value of table 2 micella particle diameter
Figure BDA0000428776940000261
The morphology characterization of 10.4 polymer micelles
Copper mesh is placed in the watch-glass that is covered with filter paper, gets approximately 20 μ L micellar solutions and drip on copper mesh, the solvent on copper mesh naturally volatilizes after being substantially evaporated completely under room temperature, and micella is fixed on after grid, with its pattern of transmission electron microscopy observation.Electromicroscopic photograph as shown in figure 12; As shown in Figure 12: the micella size that transmission electron microscope records and distribution record result with particle size analyzer and be consistent, PLA in blank micella 3000-PEG 5000, PLA 5000-PEG 5000particle size dispersion is more even.For copolymer 1 b, c, 1d, 1e, 1f, 1g, 1h, has also obtained similar result, all can form micella particle of uniform size.
The stability test of 10.5 blank micellas
Get blank micella that 2mL prepares in the centrifuge tube of 5mL, the variation of compartment timing micella particle diameter, until particle diameter generation considerable change illustrates that micella changes.Particle diameter test result is as shown in figure 13: as shown in Figure 13: when hydrophobic fragment ratio one regularly, hydrophilic segment ratio increases, be conducive to disperse in water, micella stability reduces, regularly, hydrophobic fragment ratio is larger, is conducive to form stable inner core for hydrophilic segment one, micella becomes more stable, wherein micella PLA 5000-PEG 5000more stable.For copolymer 1 b, c, 1d, 1e, 1f, 1g, 1h micella, under neutrallty condition, has good stability equally.
The mensuration of 10.6 minimum aggregate concentration CMC
The pyrene of take is measured CMC value as near fluorescent molecular probe (fluorescence emission spectrum of pyrene solution has 5 fluorescence peaks, respectively 373,379,384,394,480nm), gets the EP pipe of 10 10ml, adds 100 μ l6.4 * 10 in every arm -3pyrene/acetone soln of mM, after acetone volatilization is dry, adds respectively different concns (concentration range: 0.5mg/mL, 0.25mg/mL, 0.1mg/mL, 0.05mg/mL, 0.025mg/mL, 5 * 10 in every arm -3mg/mL, 1 * 10 -3mg/mL, 0.25 * 10 -3mg/mL, 0.05 * 10 -3mg/mL, 0 * 10 -3mg/mL) micellar solution 2ml, stirs 12h and measures respectively fluorescence intensity under room temperature.The excitation wavelength of fluorescent scanning is 334nm, excites slit to be set to 5.0nm, and transmitting slit is set to 2.0nm, and sweep velocity is 300nm/min.Take micellar concentration as X-coordinate, fluorescence intensity I 1/ I 3(I 1corresponding fluorescent emission wavelength X 1for 373nm; I 3corresponding fluorescent emission wavelength X 3for 384nm) ratio be that ordinate zou is done graphic representation, by fluorescence intensity I 1/ I 3the hop point that increases progressively of ratio determine minimum aggregate concentration CMC.To the graph of a relation of fluorescence intensity ratio as shown in figure 14, test data is as shown in table 3 for micellar concentration.
The minimum aggregate concentration CMC of table 3 micella value
Polymer PLA 1000-PEG 1900 PLA 3000-PEG 1900 PLA 3000-PEG 5000 PLA 5000-PEG 5000
CMC(mg/ml) 0.0349 0.0295 0.0200 0.0177
Polymer 1b 1d 1e 1g
CMC(mg/ml) 0.0171 0.0180 0.0179 0.0187
The release in vitro of 10.7 micellas and pH susceptibility are investigated
By dialysis method, prepare Zorubicin copolymer micelle, accurate draw 2 parts of each 2.5mL of carrier micelle in dialysis tubing, be placed in respectively the release medium of 200mL pH7.4 and pH5.0, constant temperature stirs at 37 ℃, rotating speed 30rmin -1regularly take out release medium 2.5mL, supplement isopyknic fresh release medium simultaneously. with spectrophotofluorometer, at excitation wavelength 485nm place, mensuration emission wavelength is that the absorption value at 590nm place calculates the medicament contg in release medium, calculates cumulative release degree and also draws release profiles.Calculation formula is as follows:
E r = V e Σ 1 n - 1 C i + V 0 C n m drug
Er in formula: the cumulative release amount of medicine DOX, %; The displaced volume of Ve:PBS (2.5mL); V0: the volume (200mL) that discharges liquid PBS; Ci: the concentration (mg/mL) that discharges liquid Chinese medicine during the i time displacement sampling; m drug: for the quality (mg) of the carrier micelle DOX that discharges; N: the number of times of displacement PBS.Shown in drug release curve Figure 15; As can be seen from Figure 15: carrier micelle can discharge the medicine of parcel lentamente, under acidic conditions, can accelerate the rate of release of medicine and the burst size of increase medicine simultaneously.And new synthetic micella 1a, 1e, 1f, 1g, 1h all has release rate faster, that is to say that these several micellas are more responsive to acid.In addition, and take the segmented copolymer that six-ring is connector element and compare, the segmented copolymer that the five-ring of usining is connector element is better as carrier micelle releasing effect.
the cell experiment of embodiment 11, micella
One, the cytotoxicity experiment of blank micella
1, mtt assay
The NIH3T3 cell of taking the logarithm vegetative period, in 96 Zhong Banmei holes, hole, planting into cell count is 1 * 10 4individual, add 200 μ LDMEM to cultivate 24h, removing substratum adds the blank micellar solution of DMEM (every group of concentration is established 4 holes) of 200 μ L different concns to cultivate 24h, remove the blank micellar solution of DMEM, PBS damping fluid is careful to be cleaned three times, adds the MTT water culture 4h of 100 μ LDMEM and 20 μ L5mg.mL-1 to form crystallization, then removes solution, add 200 μ LDMSO dissolving crystallized, at absorbing wavelength 490nm, sentence microplate reader and measure its absorbancy.Experimental result as shown in figure 16; As shown in Figure 16: in the survival rate major part of tested micellar concentration scope inner cell, more than 90%, illustrate that polymer micelle is to normal cell toxicological harmless effect.Copolymer 1 b, c, 1d, 1e, 1f, 1g, 1h micella is very little for the same toxicity of NIH3T3 cell.There is very similarly experimental result with 1a micella.
2, the two Coloration experiments of AO/EB
In each hole of 6 orifice plates, plant into 5 * 10 5individual NIH3T3 cell, adds 1mL DMEM to cultivate 24h, removes substratum and adds 1mL to contain polymer concentration 1000 μ g.mL -1dMEM micellar solution, cultivate 24h, remove substratum PBS and clean three times, then add 100 μ l PBS and two staining reagent AO/EB staining agent (5 μ g.mL -1) cultivation 10min, fluorescence microscopy Microscopic observation dead cell and viable cell situation.Observations as shown in figure 17; As shown in Figure 17: as can be seen from the figure the survival rate of cell is confirmed mutually in more than 90% MTT experimental result.Copolymer 1 b, c, 1d, 1e, 1f, 1g, 1h micella is very little for the same toxicity of NIH3T3 cell, and the survival rate of cell is all greater than 90%.
Two, carrier micelle cell experiment
Fluorescence microscopy is measured cell endocytic and the interior release experiment of cell of carrier micelle
The Hela cell of taking the logarithm vegetative period is planted into cell count 2 * 10 in each hole of six hollow plates 6individual, cultivate 24h, add weakly acidic solution to cultivate 2h, using the hole of acid adding not as blank, then in each hole, add the DOX micella substratum of 9ug/mL, each processes 0.5h, the fixing 30min of 4% formaldehyde solution after 1.0h, the DAPI 10min that dyes, fluorescence microscopy Microscopic observation (excitation wavelength 486nm, emission wavelength 596nm).Result as shown in figure 18; As shown in Figure 18: under the identical treatment time, add weak acid and be conducive to promote that micella enters cell interior, and reach nucleus, along with entering nuclear carrier micelle, the prolongation of time increases, cancer cells micella under weak acid effect is destroyed makes medicine start to discharge, solutions of weak acidity can further promote micella to destroy and the drug release that makes parcel out.Acid-sensitive sense copolymer 1 b, c, 1d, 1e, 1f, 1g, 1h micella, in tumor tissues, all can effectively discharge the medicine of parcel.Have very similarly experimental result with 1a micella, the speed just discharging is different.
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or modification within the scope of the claims, and this does not affect flesh and blood of the present invention.

Claims (10)

1. an acid-sensitive amphipathic segmented copolymer, its structural formula is shown in formula (I): wherein, n is any one integer in 1～300, and m is any one integer in 1～100, R be formula (II), (III), (IV), (V) or (VI) shown in structure:
Figure FDA0000428776930000012
Figure FDA0000428776930000013
wherein, t=1 or 2.
2. a preparation method for acid-sensitive amphipathic segmented copolymer as claimed in claim 1, is characterized in that, described method comprises the steps:
A, compd A
Figure FDA0000428776930000014
under the effect of Amberlyst A-15, react and obtain compd B with PEG
Figure FDA0000428776930000015
F, compd B, under 10% palladium carbon catalysis, pass into hydrogen, obtain Compound C
Figure FDA0000428776930000016
G, Compound C are under the catalysis of HATU and DIPEA, with PLA
Figure FDA0000428776930000017
reaction, obtains described acid-sensitive amphipathic segmented copolymer.
3. the preparation method of acid-sensitive amphipathic segmented copolymer as claimed in claim 2, is characterized in that, when R is structure shown in formula (II), and described compd A
Figure FDA0000428776930000018
be prepared by a method comprising the following steps and obtain:
A, compound 2
Figure FDA0000428776930000019
compound 10
Figure FDA00004287769300000110
or compound 17
Figure FDA00004287769300000111
under the effect of triethylamine and DMAP, react with TsCl, obtain compound 3 compound 11
Figure FDA00004287769300000113
or compound 18
Figure FDA00004287769300000114
C, compound 3,11 or 18 are at K 2cO 3effect under, react and obtain compound 4 with 4-nitrophenols
Figure FDA0000428776930000021
compound 12 or compound 19
D, compound 4 are at N 2under condition, react with DIBAL-H, obtain compound 5:
Figure FDA0000428776930000024
Or compound 12 or 19 reacts with dilute hydrochloric acid and obtains compound 13
Figure FDA0000428776930000025
or compound 20
Figure FDA0000428776930000026
Described compound 5,13,20 is the compd A of R while being formula (II).
4. the preparation method of acid-sensitive amphipathic segmented copolymer as claimed in claim 2, is characterized in that, R be formula (III), (IV), (V) or (VI) shown in during structure, described compd A
Figure FDA0000428776930000027
be prepared by a method comprising the following steps and obtain:
A, compound a AcO-R-OH react with salt of wormwood, obtain compound b HO-R-OH;
B, compound b, under the effect of triethylamine and DMAP, react with TsCl, obtain compound c Ts-R-OH;
C, compound c are at K 2cO 3effect under, react with 4-nitrophenols, obtain described compd A.
5. the preparation method of acid-sensitive amphipathic segmented copolymer as claimed in claim 4, is characterized in that, described compound a is that the method preparation by comprising following steps obtains:
A, ethylene glycol, under the effect of the vitriol oil, obtain compound 37 with acetic acidreaction
Figure FDA0000428776930000028
B, compound 37, under the effect of PPTS, react and obtain compound 38 with 2-methoxyl group propylene, 4-methoxybenzaldehyde or 4-methoxy-1-naphthalene formaldehyde
Figure FDA0000428776930000029
compound 44
Figure FDA00004287769300000210
or 50
Or:
A, pimelinketone or cyclopentanone, under the effect of pTSA, react with trimethyl orthoformate, obtain compound 23
Figure FDA0000428776930000031
or 30
Figure FDA0000428776930000032
Under the effect of B, compound 23 or 30 toluenesulphonic acidss and 5A molecular sieve, react with ethylene glycol acetate, obtain compound 24
Figure FDA0000428776930000033
or 31
Figure FDA0000428776930000034
Described compound 38,44,50,24,31 is described compound a.
6. an Amphiphilic Block Copolymer Micelles, is characterized in that, described micella be prepare by the following method and: acid-sensitive amphipathic segmented copolymer as claimed in claim 1 is dissolved in and in polar solvent, forms solution A; Described solution A is slowly added dropwise in the water of stirring and makes it form micro emulsion ball, pack the aqueous phase solution of described formation micro emulsion ball into dialysis tubing and appear polar solvent, obtain.
7. Amphiphilic Block Copolymer Micelles as claimed in claim 6, is characterized in that, in described solution A, is dissolved with hydrophobic drug.
8. Amphiphilic Block Copolymer Micelles as claimed in claim 6, is characterized in that, described polar solvent is DMSO, DMF or THF; Described water is pure water, PBS damping fluid or physiological saline.
9. an Amphiphilic Block Copolymer Micelles as claimed in claim 6 purposes in preparing anti-cancer medicament carrier.
10. purposes as claimed in claim 9, is characterized in that, the hydrophobic anticancer drug of wrapping up in described anti-cancer medicament carrier is Azythromycin, taxol, Elemenum or camptothecine.
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