CN102532531B

CN102532531B - Polyamino acid block copolymer and preparation method thereof

Info

Publication number: CN102532531B
Application number: CN201110343619.9A
Authority: CN
Inventors: 庄秀丽; 丁建勋; 栗迪; 汤朝晖; 陈学思
Original assignee: Changchun Institute of Applied Chemistry of CAS
Current assignee: Changzhou Institute of Energy Storage Materials & Devices
Priority date: 2011-11-03
Filing date: 2011-11-03
Publication date: 2014-03-26
Anticipated expiration: 2031-11-03
Also published as: CN102532531A

Abstract

The invention provides a polyamino acid block copolymer and a preparation method thereof, belonging to the technical field of polyamino acid. The polyamino acid block copolymer has the structure of formula (I) or the structure of formula (II), wherein R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaromatics, acylamino, carboxyl, amino, sulfydryl or guanidyl; n is the degree of polymerization, and n is more than or equal to 20 and is less than or equal to 1000; and m is the degree of polymerization, and m is more than or equal to 2 and is less than or equal to 350. The preparation method of the polyamino acid block copolymer comprises the step of subjecting a compound with the structure of formula (III) or the structure of formula (IV) and an amino acid monomer to react in an organic solvent so as to obtain the polyamino acid block copolymer with the structure of formula (I) or the structure of formula (II). According to the polyamino acid block copolymer and the preparation method thereof, one methoxy polyethylene glycol or polyethylene glycol chain of the polyamino acid block copolymer comprises two or four polyamino acid chains, so that the polyamino acid block copolymer has the advantages of abundant topology structures, high hydrophobic block content and short hydrophobic blocks, and an inner core of a formed micelle is smaller.

Description

Polyamino acid block copolymer and preparation method thereof

Technical field

The present invention relates to polyamino acid technical field, relate in particular to polyamino acid block copolymer and preparation method thereof.

Background technology

Polyamino acid has the character similar to natural polypeptides, be a kind of to organism nontoxic without immunogenicity, there is the novel high polymer material of good biocompatibility, and can finally be degraded to micromolecular amino acid and be absorbed by the body by the hydrolysis in body or enzyme digestion reaction.So polyamino acid is at biomedical sector, as: bioseparation, organizational project, gene therapy and medicine are controlled the aspects such as release and are with a wide range of applications.But most of polyamino acid is lyophobic dust, and its application is subject to certain restrictions.

By introduce second component in polyamino acid, to prepare multipolymer be one of important channel of improving polyamino acid performance, as introduced polyoxyethylene glycol, poly glycol monomethyl ether, aliphatic polyester, the materials such as polyethers.Wherein, polyoxyethylene glycol or poly glycol monomethyl ether are not only water-soluble but also be dissolved in organic solvent, have good biocompatibility, anticoagulant property, and nontoxicity and hypoimmunity, be widely used in biomedicine field.The end group of polyoxyethylene glycol or poly glycol monomethyl ether can further be modified, and low-molecular-weight polyoxyethylene glycol or poly glycol monomethyl ether can excrete by kidney.In addition, the selectable molecular weight ranges of polyoxyethylene glycol or poly glycol monomethyl ether is wider, by drug administration of the United States Federal (FDA) authentication, can be used for human body.Therefore, polyoxyethylene glycol or poly glycol monomethyl ether are often introduced into and prepare polyamino acid multipolymer as second component.

Prior art discloses polyamino acid block copolymer of multiple polyoxyethylene glycol or poly glycol monomethyl ether and preparation method thereof.As Bioconjugate Chemistry (Vol.7, p144～149,1996) and Macromolecules (Vol.31, p6071～6076,1998) a kind of polyethylene glycol-Methionin segmented copolymer is disclosed respectively, and studied its character and biocompatibility in solution, this segmented copolymer can be self-assembled into micella in water, can be used as the solid support material of medicament slow release; Macromolecules (Vol.29, p3227～3231,1996) and Journal of Polymer Science-Part A:Polymer Chemistry (Vol.36, p2949～2959,1998) disclose respectively a kind of PEG-PASP segmented copolymer, and studied its SOLUTION PROPERTIES.The patent of the applications such as Chen Xuesi (Chinese patent 03121397.9) discloses a kind of polyoxyethylene glycol-aliphatic polyester-polyamino acid terpolymer.In above-mentioned paper and patent, disclosed polyethylene glycol-amino acid block copolymer or poly glycol monomethyl ether-polyamino acid block copolymer are linear two blocks or triblock copolymer.The polyoxyethylene glycol of this linearity or the polyamino acid block copolymer of poly glycol monomethyl ether are widely studied and are applied to biomedicine field.But the polyamino acid block copolymer with linear structure contains longer hydrophobic block, the micella kernel of formation is larger, and the poor stability in the aqueous solution is unfavorable for its application in drug conveying.

Summary of the invention

In view of this, the technical problem to be solved in the present invention is to provide a kind of polyamino acid block copolymer, and in polyamino acid block copolymer provided by the invention, hydrophobic block content is high, hydrophobic block is short, and the micella kernel of formation is less.

The invention provides a kind of polyamino acid block copolymer with formula (I) structure or formula (II) structure,

Wherein, R is hydrogen, alkyl, substituted alkyl, aromatic base, substituted aromatic base, aromatic heterocycle, amide group, carboxyl, amino, sulfydryl or guanidine radicals;

N is the polymerization degree, 2≤n≤350;

M is the polymerization degree, 20≤m≤1000.

Preferably, R is CH ₂cH (CH ₃) ₂, CH ₂ph, CH ₂cH ₂cOOH or CH ₂cH ₂cH ₂cH ₂nH ₂.

Preferably, 5≤n≤300.

Preferably, 200≤m≤950.

The present invention also provides a kind of preparation method of described polyamino acid block copolymer, comprising:

The compound with formula (III) structure or formula (IV) structure reacts in organic solvent with amino acid monomer, the polyamino acid block copolymer of obtain having formula (I) structure or formula (II) structure;

Wherein, m is the polymerization degree, 20≤m≤1000.

Preferably, the compound that has formula (III) structure or formula (IV) structure is prepared in accordance with the following methods:

Compound and amino shielded phenylalanine, the acetone with formula (V) structure or formula (VI) structure contract 2,2 '-bis-(methylol) propionic anhydrides and DMAP react, and obtain having the compound of formula (III) structure or formula (IV) structure after deprotection;

Wherein, m is the polymerization degree, 20≤m≤1000.

Preferably, described in, there is the compound of formula (V) structure and the mol ratio of amino shielded phenylalanine is 1: 5～1: 10.

The mol ratio preferably, with formula (VI) structural compounds and amino shielded phenylalanine is 1: 10～1: 20.

The compound preferably, with formula (V) structure or formula (VI) structure is prepared in accordance with the following methods:

Poly glycol monomethyl ether or polyoxyethylene glycol and acetone contracting 2,2 '-bis-(methylol) propionic anhydride, DMAP and methyl alcohol react in organic solvent, generate the compound with formula (V) structure or formula (VI) structure after deprotection.

Compared with prior art, polyamino acid block copolymer provided by the invention has connected many hydrophobic polyamino acid chains by 1 hydrophilic poly glycol monomethyl ether or polyglycol chain: have in the polyamino acid block copolymer of formula (I) structure, article 1, poly glycol monomethyl ether chain connects 2 polyamino acid chains, article 2, polyamino acid chain is distributed in poly glycol monomethyl ether chain one end, forms a kind of y-type structure; Have in the polyamino acid block copolymer of formula (II) structure, 1 polyglycol chain connects 4 polyamino acid chains, and polyamino acid chain is distributed in the both sides of polyglycol chain, forms a kind of dumbbell shape structure.Because polyamino acid chain is as having important functional group, can deliver and discharge medicine, so the polyamino acid chain carrying in polyamino acid block copolymer is more, its biological function having is stronger.Segmented copolymer provided by the invention can carry 2 or 4 polyamino acid chains, there is abundant topological framework, in the situation that with linear polyethylene glycol-amino acid block copolymer or poly glycol monomethyl ether-polyamino acid block copolymer, to have identical molecular composition identical, the hydrophobic block containing is relatively short, and the micella kernel of formation is less; In the identical situation of the hydrophobic flakes segment length of the polyethylene glycol-amino acid block copolymer with linear or poly glycol monomethyl ether-polyamino acid block copolymer, the Drug loading capacity of polyamino acid block copolymer provided by the invention is stronger.

Accompanying drawing explanation

Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram with formula (V) structural compounds that the embodiment of the present invention 1 obtains;

Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram with formula (VI) structural compounds that the embodiment of the present invention 2 obtains;

Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram with formula (III) structural compounds that the embodiment of the present invention 3 obtains;

Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram with formula (IV) structural compounds that the embodiment of the present invention 4 obtains;

Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of the poly glycol monomethyl ether with formula (I) structure that obtains of the embodiment of the present invention 6-poly-(D, L-Leu);

Fig. 6 is the infrared spectrum of the product that obtains of the embodiment of the present invention 3 and embodiment 6.

Embodiment

The invention discloses a kind of polyamino acid block copolymer with formula (I) structure or formula (II) structure,

Wherein, R is hydrogen, alkyl, substituted alkyl, aromatic base, substituted aromatic base, aromatic heterocycle, amide group, carboxyl, amino, sulfydryl or guanidine radicals; Be preferably CH ₂cH (CH ₃) ₂, CH ₂ph, CH ₂cH ₂cOOH or CH ₂cH ₂cH ₂cH ₂nH ₂.

N is the polymerization degree, and 2≤n≤350 are preferred, 5≤n≤300.

M is the polymerization degree, and 20≤m≤1000 are preferred, 200≤m≤950.

The present invention also provides a kind of preparation method of polyamino acid block copolymer:

Wherein, m is the polymerization degree, and 20≤m≤1000, are preferably, 200≤m≤950.

It is raw material that the compound of (III) structure that has formula or formula (IV) structure is take in the present invention, after dewatering, reacts with amino acid monomer with methylbenzene azeotropic.The present invention, is preferably under anhydrous and oxygen-free condition and carries out without particular restriction reaction conditions.Described organic solvent is preferably the mixture of DMF and Isosorbide-5-Nitrae-dioxane, and the volume ratio of DMF and Isosorbide-5-Nitrae-dioxane is preferably 4～6: 1.Reaction times is preferably 36～60h, more preferably 45～50h.There is formula (III) structure or the compound of formula (IV) structure and the temperature of reaction of amino acid monomer and there is no special requirement, be preferably room temperature.Described amino acid monomer is carboxylic acid anhydride in amino acid-N-; it can be carboxylic acid anhydride in the amino acid-N-with protecting group; also can be for not with carboxylic acid anhydride in the amino acid-N-of protecting group; be preferably D, carboxylic acid anhydride in carboxylic acid anhydride, the interior carboxylic acid anhydride of γ-phenmethyl-Pidolidone ester-N-, the interior carboxylic acid anhydride of L-Phe-N-or ε-carbobenzoxy-(Cbz)-1B-N-in L-Leu ester-N-.

After completion of the reaction, process the polyamino acid block copolymer of (I) structure that obtains having formula or formula (II) structure, described processing comprises after reacted mixing liquid is concentrated uses ether sedimentation.When described amino acid monomer be with the amino acid-N-of phenmethyl in during carboxylic acid anhydride, preferably the polyamino acid block copolymer obtaining is carried out to deprotection, the present invention is not particularly limited the method for described deprotection, preferably according to following steps, carries out:

Polyamino acid block copolymer is dissolved with dichloro acetic acid at 20～30 ℃; under agitation condition, adding hydrogen bromide mass content is 30%～35% hydrogen bromide and the mixing solutions of Glacial acetic acid; the mol ratio of hydrogen bromide and phenmethyl is preferably 1: 3～and 5; at 20～30 ℃, react 0.5～2h; products therefrom ether sedimentation; 20～30 ℃ of vacuum-drying 20～30h after filtration washing, obtain the polyamino acid block copolymer of deprotection.

When described amino acid monomer be with the amino acid-N-of carbobenzoxy-(Cbz) in during carboxylic acid anhydride, preferably the polyamino acid block copolymer obtaining is carried out to deprotection, the present invention is not particularly limited the method for described deprotection, preferably according to following steps, carries out:

Polyamino acid block copolymer is dissolved with trifluoroacetic acid at 20～30 ℃; under agitation condition, adding hydrogen bromide mass content is 30%～35% hydrogen bromide and the mixing solutions of Glacial acetic acid; the mol ratio of hydrogen bromide and carbobenzoxy-(Cbz) is preferably 1: 3～and 5; at 20～30 ℃, react 0.5～2h; products therefrom ether sedimentation; 20～30 ℃ of vacuum-drying 20～30h after filtration washing, obtain the polyamino acid block copolymer of deprotection.

The compound in the present invention with formula (III) structure or formula (IV) structure can cause carboxylic acid anhydride ring-opening polymerization in amino acid-N-and obtain polyamino acid block copolymer.The mol ratio by control with carboxylic acid anhydride in primary amine groups in the compound of formula (III) structure or formula (IV) structure and amino acid-N-is the number-average molecular weight of adjustable polyamino acid, the number-average molecular weight of described polyamino acid can reach 1000～50000, thereby expands the application of polyamino acid block copolymer.

The present invention is not particularly limited the described source with the compound of formula (III) structure or formula (IV) structure, can buy and obtain by market, also can prepare according to method well known to those skilled in the art, be preferably preparation in accordance with the following methods:

The present invention has in the compound process of formula (III) structure or formula (IV) structure in preparation; take (V) structure that there is formula or (VI) compound and the amino shielded phenylalanine of structure are raw material; after dewatering with methylbenzene azeotropic, use organic solvent dissolution; then with acetone contracting 2; 2 '-bis-(methylol) propionic anhydrides and DMAP react, and obtain amino shielded intermediate product.

Described organic solvent is preferably methylene dichloride.There is formula (V) structure or (VI) compound, amino shielded phenylalanine of structure and the reaction times of acetone contracting 2,2 '-bis-(methylol) propionic anhydrides and DMAP are preferably 36～60h, 45～50h more preferably.Described reaction does not have special requirement to temperature of reaction, is preferably room temperature.Described there is the compound of formula (V) structure and the mol ratio of amino shielded phenylalanine be preferably 1: 5～1: 10, more preferably 1: 8～1: 10; The described mol ratio with formula (VI) structural compounds and amino shielded phenylalanine is preferably 1: 10～and 1: 20, more preferably 1: 15～1: 20.

Obtain, after amino shielded intermediate product, preferably in accordance with the following methods it being carried out to deprotection: reacted mixing liquid is filtered, filter N, N-dichloro urethanum, concentrated, use ether sedimentation, obtain white solid; With the diethyl ether solution of hydrogenchloride, dissolve described white solid, concentrated, then with the compound of ether sedimentation (III) structure that obtains thering is formula or formula (IV) structure.

The present invention to have formula (V) structure or (VI) the compound source of structure be not particularly limited, can be bought by market, also can prepare according to method well known to those skilled in the art, be preferably preparation in accordance with the following methods:

Described preparation has formula (V) structure or (VI) in the compound reaction process of structure, take poly glycol monomethyl ether or polyoxyethylene glycol as raw material, first be dissolved in described organic solvent, described organic solvent is preferably the mixing solutions of methylene dichloride and pyridine, then with acetone contracting 2,2 '-bis-(methylol) propionic anhydrides and DMAP reaction are spent the night, then add methyl alcohol to continue reaction, and the time of reacting with methyl alcohol is preferably 4～6h.Temperature of reaction does not have special requirement, is preferably room temperature.

React and obtain after intermediate product with methyl alcohol; preferably in accordance with the following methods it is carried out to deprotection: the ether sedimentation of reacted mixture; after vacuum-drying, be dissolved in again methyl alcohol; add ion exchange resin; 50～60 ℃ of reactions; after end, filter ion exchange resin, filtrate obtains generating the compound with formula (V) structure or formula (VI) structure with ether sedimentation.

In order to further illustrate the present invention, below in conjunction with embodiment, polyamino acid block copolymer with formula (I) structure or formula (II) structure provided by the invention and preparation method thereof is described in detail.

Mn represents number-average molecular weight, by ¹h NMR measures and obtains.The product quality that reaction yield=the actual product quality/theory obtaining obtains.The mean polymerisation degree that DP is the polyamino acid block copolymer that drawn by number-average molecular weight.A/I is carboxylic acid anhydride monomer and the molar ratio with the compound of formula (III) structure or formula (IV) structure in amino acid-N-.

The preparation of the compound with formula (V) structure of embodiment 1 different number-average molecular weights

Taking respectively 10g number-average molecular weight is 1000g.mol ^-1(0.01mol), 20000g.mol ^-1(0.0005mol), 40000g.mol ^-1(0.00025mol) poly glycol monomethyl ether, be dissolved in respectively in the methylene dichloride of 60mL and the mixing solutions of pyridine, the volume ratio of methylene dichloride and pyridine is 90: 10, add respectively at ambient temperature 9.91g (0.03mol), 0.50g (0.0015mol), the acetone contracting 2 of 0.25g (0.00075mol), 2 '-bis-(methylol) propionic anhydrides and 1.10g (0.009mol), 0.055g (0.00045mol), the DMAP of 0.027g (0.000225mol) reacts and spends the night under stirrer stirs.Add methyl alcohol continue to stir 5h, reaction finishes after product ether sedimentation, and vacuum-drying 24h at 25 ℃, obtains the compound with formula (V) structure that condensation of acetone is protected.

The compound with formula (V) structure that takes respectively condensation of acetone protection described in 5g, is dissolved in respectively in 200mL methyl alcohol, adds Dowex 50WX2 resin, reaction at 55 ℃ until ¹³till C nucleus magnetic resonance monitoring acetone protection base peak disappears, filter resin, filtrate is used ether sedimentation, the compound of (V) structure that obtains having formula.

To in the present embodiment, test 2 obtain described in there is formula (V) structure compound carry out nuclear magnetic resonance spectroscopy, result is referring to Fig. 1, Fig. 1 is for having the hydrogen nuclear magnetic resonance spectrogram of formula (V) structural compounds, as shown in Figure 1, the methyl peak that place, chemical shift δ=1.2ppm left and right is hydroxyl side on chain, place, δ=2.3ppm left and right is hydroxyl peak, and place, δ=3.3ppm left and right is methoxy base peak, and all the other characteristic peaks and polyoxyethylene glycol methylene peak are overlapping.Hence one can see that, and the compound that embodiment 1 obtains has formula (V) structure.Each walks the number-average molecular weight of products therefrom and reaction yield in Table 1.

Table 1 respectively walks number-average molecular weight and the reaction yield of products therefrom

In table 1, Mn ₁for the number-average molecular weight of the compound with formula (V) structure of condensation of acetone protection, the productive rate that reaction yield 1 is reacted for the first step; Mn ₂for having the number-average molecular weight of the compound of formula (V) structure, reaction yield 2 is the productive rate of second step reaction.

The preparation of the compound with formula (VI) structure of embodiment 2 different number-average molecular weights

Taking respectively 10g number-average molecular weight is 1000g.mol ^-1(0.01mol), 20000g.mol ^-1(0.0005mol), 40000g.mol ^-1(0.00025mol) polyoxyethylene glycol, be dissolved in respectively in the methylene dichloride of 60mL and the mixing solutions of pyridine, the volume ratio of methylene dichloride and pyridine is 90: 10, add respectively at ambient temperature 19.82g (0.06mol), 0.99g (0.003mol), the acetone contracting 2 of 0.50g (0.0015mol), 2 '-bis-(methylol) propionic anhydrides and 2.20g (0.018mol), 0.11g (0.0009mol), the DMAP of 0.055g (0.00045mol) reacts and spends the night under stirrer stirs.Add methyl alcohol continue to stir 5h, reaction finishes after product ether sedimentation, and vacuum-drying 24h at 25 ℃, obtains the compound with formula (VI) structure that acetonide is protected.

The compound with formula (VI) structure that takes respectively condensation of acetone protection described in 5g, is dissolved in respectively in 200mL methyl alcohol, adds Dowex 50WX2 resin, reaction at 55 ℃ until ¹³till C NMR monitoring acetone protection base peak disappears, filter resin, filtrate is used ether sedimentation, the compound of (VI) structure that obtains having formula.

To in the present embodiment, test 2 obtain described in there is formula (VI) structure compound carry out nuclear magnetic resonance spectroscopy, result is referring to Fig. 2, Fig. 2 is for having the hydrogen nuclear magnetic resonance spectrogram of formula (VI) structural compounds, as shown in Figure 2, the methyl peak that place, δ=1.2ppm left and right is hydroxyl side on chain, place, δ=2.5ppm left and right is hydroxyl peak, and all the other characteristic peaks and polyoxyethylene glycol methylene peak are overlapping.As can be seen here, the compound that embodiment 2 obtains has formula (VI) structure.Each walks the number-average molecular weight of products therefrom and reaction yield in Table 2.

Table 2 respectively walks number-average molecular weight and the reaction yield of products therefrom

In table 2, Mn ₁number-average molecular weight for the compound with formula (VI) structure of condensation of acetone protection; Reaction yield 1 is the productive rate of the first step reaction; Mn ₂for thering is the number-average molecular weight of the compound of formula (VI) structure; Reaction yield 2 is the productive rate of second step reaction.

Embodiment 3 has the preparation of the compound of formula (III) structure

Take respectively in 8g embodiment 1 and test 1,2,3 compounds with formula (V) structure that obtain, with 19.00g (0.07mol), 1.05g (3.96 * 10 respectively ^-3mol), 0.53g (2 * 10 ^-3mol) after the phenylalanine that tertbutyloxycarbonyl is protected mixes, as in dry ampulla, after dewatering, with methylene dichloride, dissolve with methylbenzene azeotropic, add respectively 14.77g (0.065mol), 0.82g (3.63 * 10 ^-3mol), 0.41g (1.8 * 10 ^-3mol) acetone contracting 2,2 '-bis-(methylol) propionic anhydrides and 0.44g (3.6 * 10 ^-3mol), 0.024g (1.97 * 10 ^-4mol), 0.012g (9.8 * 10 ^-5mol) DMAP, under stirring, stirrer reacts 48h, filter out N, N-dichloro urethanum, concentration of reaction solution, ether sedimentation, obtain white solid, with the diethyl ether solution of hydrogenchloride, dissolve, stir 4h, reaction finishes rear concentration of reaction solution, with the compound of ether sedimentation (III) structure that obtains having formula.

To test the compound with formula (III) structure prepared by 2 compounds with formula (V) structure that obtain in embodiment 1, carry out nuclear magnetic resonance spectroscopy, result is referring to Fig. 3, Fig. 3 is for having the hydrogen nuclear magnetic resonance spectrogram of formula (III) structural compounds, as shown in Figure 3, δ=3.3ppm left and right is methyl peak in methoxyl group, δ=2.5ppm is terminal amino group peak, phenyl ring peak and CDCl ₃solvent peak is overlapping.As can be seen here, the compound that embodiment 3 obtains has formula (III) structure.The number-average molecular weight Mn of products therefrom and reaction yield are in Table 3.

The number-average molecular weight of table 3 products therefrom and reaction yield

Embodiment 4 has the preparation of the compound of formula (IV) structure

Take respectively the compound with formula (VI) structure that the experiment 1,2,3 in 8g embodiment 2 obtains, with 34.40g (0.13mol), 2.09g (7.8 * 10 respectively ^-3mol), 1.05g (3.96 * 10 ^-3mol) phenylalanine of tertbutyloxycarbonyl protection mix after as in dry ampulla, with methylene dichloride, dissolve after adding methylbenzene azeotropic to dewater, then add respectively 26.74g (0.12mol), 1.63g (7.2 * 10 ^-3mol), 0.82g (3.63 * 10 ^-3mol) acetone contracting 2,2 '-bis-(methylol) propionic anhydrides and 0.44g (3.6 * 10 ^-3mol), 0.024g (1.97 * 10 ^-4mol), 0.012g (9.8 * 10 ^-5mol) DMAP, under stirring, stirrer reacts 48h,, filter out N, N-dichloro urethanum, concentration of reaction solution, ether sedimentation, obtains white solid, with the diethyl ether solution of hydrogenchloride, dissolve, stir 4h, reaction finishes rear concentration of reaction solution, with the compound of ether sedimentation (IV) structure that obtains having formula.

To test the compound with formula (IV) structure prepared by 2 compounds with formula (VI) structure that obtain in embodiment 2, carry out nuclear magnetic resonance spectroscopy, result is referring to Fig. 4, Fig. 4 is for having the hydrogen nuclear magnetic resonance spectrogram of formula (IV) structural compounds, as shown in Figure 4, δ=2.7ppm left and right is amino peak, phenyl ring peak and CDCl ₃solvent peak is overlapping.As can be seen here, the compound that embodiment 4 obtains has formula (IV) structure.The number-average molecular weight of products therefrom and reaction yield are in Table 4.

The number-average molecular weight of table 4 products therefrom and reaction yield

The preparation of carboxylic acid anhydride in embodiment 5 amino acid-N-

Take respectively 20g D, L-Leu (131g.mol ^-1, 0.15mol), Pidolidone benzyl ester (237g.mol ^-1, 0.17mol), L-Phe (165g.mol ^-1, 0.12mol) and ε-carbobenzoxy-(Cbz)-1B (264g.mol ^-1, 0.14mol), put into respectively 4 dry reaction flasks, in these 4 reaction flasks, all add 200ml tetrahydrofuran (THF) and 15g triphosgene, under the condition of logical nitrogen, 55 ℃ are stirred to system solution clarification.By the reaction mixture obtaining, with after normal hexane sedimentation, with acetic acid ethyl dissolution, frozen water is washed once, with sodium bicarbonate, wash once, once, anhydrous magnesium sulfate drying spends the night in frozen water after backwashing again, filter siccative, drain solvent, after recrystallization, obtain respectively D, carboxylic acid anhydride in carboxylic acid anhydride, the interior carboxylic acid anhydride of γ-phenmethyl-Pidolidone ester-N-, the interior carboxylic acid anhydride of L-Phe-N-, γ-phenmethyl-Pidolidone ester-N-in L-Leu-N-, productive rate is respectively 80.1%, 79.5%, 81.4%, 80.6%.

Embodiment 6 has the preparation of poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer (n=5) of formula (I) structure

Add respectively 2g embodiment 3 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 2.30g, 0.15g, the D of 0.078g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively 28mL, 1.6mL, the N that 0.8mL is dry, dinethylformamide solubilizing reaction thing, under room temperature, react after 48h, use ether sedimentation, vacuum-drying 24h at 25 ℃, the poly glycol monomethyl ether of (I) structure that obtains thering is formula-poly-(D, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 5.

Poly glycol monomethyl ether-poly-(the D preparing test 2 compounds with formula (III) structure that obtain in embodiment 3, L-Leu) segmented copolymer carries out nuclear magnetic resonance spectroscopy, result is referring to Fig. 5, Fig. 5 is for having the poly glycol monomethyl ether-poly-(D of formula (I) structure, L-Leu) hydrogen nuclear magnetic resonance spectrogram, as shown in Figure 5, δ=7ppm is for having phenyl ring characteristic peak in the compound of formula (III) structure, δ=4～5ppm is the methyne peak of phenylalanine in chain, the methyne peak and the methylene peak that with polyoxyethylene glycol be connected adjacent with carbonyl in leucine unit, δ=1.5ppm left and right is methyne peak adjacent with methyl in leucine unit.As can be seen here, the product that embodiment 6 obtains is poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer with formula (I) structure.The product that embodiment 6 and embodiment 3 are obtained carries out Infrared spectroscopy, result is referring to Fig. 6, Fig. 6 is the infrared spectrum of the product of embodiment 3 and embodiment 6, wherein a tests 2 compounds with formula (III) structure that obtain in embodiment 3, b is for testing 2 poly glycol monomethyl ethers with formula (I) structure that obtain-poly-(D in enforcement 6, L-Leu), in b at 1750cm ^-1the carbonylic stretching vibration intensity at place is strengthened showing that polyamino acid block copolymer successfully synthesizes.The number-average molecular weight of products therefrom and reaction yield are in Table 5.

The number-average molecular weight of table 5 products therefrom and reaction yield

In table 5, Mn ₁for thering is the number-average molecular weight of the compound of formula (III) structure; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer knot of formula (I) structure.

Embodiment 7 has the preparation of polyethylene glycol-(D, the L-Leu) segmented copolymer (n=5) of formula (II) structure

Add respectively 2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 4.25g, 0.31g, the D of 0.16g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 51mL, 3mL, the N that 1.6mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(the D of (II) structure that obtains thering is formula, L-Leu) segmented copolymer, wherein the amino acid whose polymerization degree is 5.The number-average molecular weight of products therefrom and reaction yield are in Table 6.

The number-average molecular weight of table 6 products therefrom and reaction yield

In table 6, Mn ₁for thering is the number-average molecular weight of the compound of formula (IV) structure; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure.

Embodiment 8 has the preparation of poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer (n=25) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 11.52g, 0.77g, the D of 0.39g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 110mL, 8mL, the N that 4mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, the poly glycol monomethyl ether of (I) structure that obtains thering is formula-poly-(D, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 25.The number-average molecular weight of products therefrom and reaction yield are in Table 7.

The number-average molecular weight of table 7 products therefrom and reaction yield

In table 7, Mn ₁for thering is the number-average molecular weight of the compound of formula (III) structure; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure.

Embodiment 9 has the preparation of polyethylene glycol-(D, the L-Leu) segmented copolymer (n=25) of formula (II) structure

Add respectively 2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 21.23g, 1.53g, the D of 0.76g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 210mL, 16mL, the N that 8mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(the D of (II) structure that obtains thering is formula, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 25.The number-average molecular weight of products therefrom and reaction yield are in Table 8.

The number-average molecular weight of table 8 products therefrom and reaction yield

In table 8, Mn ₁for thering is the number-average molecular weight of the compound of formula (IV) structure; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure.

Embodiment 10 has the preparation of poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer (n=50) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 23.04g, 1.54g, the D of 0.78g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 230mL, 16mL, the N that 8mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, (I) structure that obtains thering is formula-poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 50.The number-average molecular weight of products therefrom and reaction yield are in Table 9.

The number-average molecular weight of table 9 products therefrom and reaction yield

In table 9, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure.

Embodiment 11 has the preparation of polyethylene glycol-(D, the L-Leu) segmented copolymer (n=50) of formula (II) structure

In the reaction flask that 3 dry bands prop up mouthful, adding respectively 2g number-average molecular weight is to test 1 in embodiment 4, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 42.46g, 3.07g, the D of 1.55g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 400mL, 30mL, the N that 16mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(the D of (II) structure that obtains thering is formula, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 50.The number-average molecular weight of products therefrom and reaction yield are in Table 10.

The number-average molecular weight of table 10 products therefrom and reaction yield

In table 10, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure.

Embodiment 12 has the preparation of poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer (n=100) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 4.61g, 0.31g, the D of 0.156g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 46mL, 3.2mL, the N that 1.6mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, the poly glycol monomethyl ether of (I) structure that obtains thering is formula-poly-(D, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 50.The number-average molecular weight of products therefrom and reaction yield are in Table 11.

The number-average molecular weight of table 11 products therefrom and reaction yield

In table 11, Mn ₁for thering is the number-average molecular weight of the chemical combination of formula (III) structure; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure.

Embodiment 13 has the preparation of polyethylene glycol-(D, the L-Leu) segmented copolymer (n=100) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 8.49g, 0.61g, the D of 0.31g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 85mL, 6mL, the N that 3mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(the D of (II) structure that obtains thering is formula, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 100.The number-average molecular weight of products therefrom and reaction yield are in Table 12.

The number-average molecular weight of table 12 products therefrom and reaction yield

In table 12, Mn ₁for thering is the number-average molecular weight of the compound of formula (IV) structure; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure.

Embodiment 14 has the preparation of poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer (n=200) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, under anhydrous and oxygen-free condition, add respectively 9.21g, 0.62g, the D of 0.31g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 92mL, 6mL, the N that 3mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, the poly glycol monomethyl ether of (I) structure that obtains thering is formula-poly-(D, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 200.The number-average molecular weight of products therefrom and reaction yield are in Table 13.

The number-average molecular weight of table 13 products therefrom and reaction yield

In table 13, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure.

Embodiment 15 has the preparation of polyethylene glycol-(D, the L-Leu) segmented copolymer (n=200) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 16.98g, 1.23g, the D of 0.62g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 170mL, 12mL, the N that 6mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(the D of (II) structure that obtains thering is formula, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 200.The number-average molecular weight of products therefrom and reaction yield are in Table 14.

The number-average molecular weight of table 14 products therefrom and reaction yield

In table 14, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure.

Embodiment 16 has the preparation of poly glycol monomethyl ether-poly-(D, the L-Leu) segmented copolymer (n=300) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 13.82g, 0.93g, the D of 0.47g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 140mL, 9mL, the N that 5mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, the poly glycol monomethyl ether of (I) structure that obtains thering is formula-poly-(D, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 300.The number-average molecular weight of products therefrom and reaction yield are in Table 15.

The number-average molecular weight of table 15 products therefrom and reaction yield

In table 15, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(D, L-Leu) segmented copolymer of formula (I) structure.

Embodiment 17 has the preparation of polyethylene glycol-(D, the L-Leu) segmented copolymer (n=300) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 25.48g, 1.84g, the D of 0.93g embodiment 5 preparations, carboxylic acid anhydride monomer in L-Leu-N-, use respectively again 250mL, 18mL, the N that 9mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(the D of (II) structure that obtains thering is formula, L-Leu) segmented copolymer, the amino acid whose polymerization degree is 300.The number-average molecular weight of products therefrom and reaction yield are in Table 16.

The number-average molecular weight of table 16 products therefrom and reaction yield

In table 16, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(D, the L-Leu) segmented copolymer of formula (II) structure.

Embodiment 18 has the preparation of poly glycol monomethyl ether-PLGA segmented copolymer (n=5) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 4.26g, 0.28g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.14g embodiment 5 preparations, use respectively again 43mL, 3mL, the N that 1.5mL is dry, dinethylformamide solubilizing reaction thing, after at room temperature reacting 48h, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLGA segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 5.

Described poly glycol monomethyl ether-PLGA segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 4ml, 2ml, 2ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; after ether sedimentation, filter; washing; vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 17.

The number-average molecular weight of table 17 products therefrom and reaction yield

In table 17, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure.

Embodiment 19 has the preparation of polyethylene glycol-(Pidolidone) segmented copolymer (n=5) of formula (II) structure

Add respectively 2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 7.84g, 0.57g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.29g embodiment 5 preparations, use respectively again 78mL, 6mL, the N that 3mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(Pidolidone) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 5.

Described polyethylene glycol-(Pidolidone) segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 6ml, 2ml, 2ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; after ether sedimentation, filter; washing; vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 18.

The number-average molecular weight of table 18 products therefrom and reaction yield

In table 18, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure.

Embodiment 20 has the preparation of poly glycol monomethyl ether-PLGA segmented copolymer (n=25) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 21.28g, 1.42g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.72g embodiment 5 preparations, use respectively again 210mL, 14mL, the N that 7mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLGA segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 25.

Described poly glycol monomethyl ether-PLGA segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 16ml, 3ml, 2ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; after ether sedimentation, filter; washing; vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 19.

The number-average molecular weight of table 19 products therefrom and reaction yield

In table 19, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure.

Embodiment 21 has the preparation of polyethylene glycol-(Pidolidone) segmented copolymer (n=25) of formula (II) structure

Add respectively 2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 39.22g, 2.83g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 1.43g embodiment 5 preparations, use respectively again 250mL, 16mL, the N that 8mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(Pidolidone) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 25.

Described polyethylene glycol-(Pidolidone) segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 30ml, 3ml, 2ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; after ether sedimentation, filter; washing; vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 20.

The number-average molecular weight of table 20 products therefrom and reaction yield

In table 20, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure.

Embodiment 22 has the preparation of poly glycol monomethyl ether-PLGA segmented copolymer (n=50) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 42.55g, 2.85g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 1.44g embodiment 5 preparations, use respectively again 420mL, 28mL, the N that 14mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLGA segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 50.

Described poly glycol monomethyl ether-PLGA segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 30ml, 4ml, 3ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 21.

The number-average molecular weight of table 21 products therefrom and reaction yield

In table 21, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure.

Embodiment 23 has the preparation of polyethylene glycol-(Pidolidone) segmented copolymer (n=50) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 7.84g, 0.57g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.29g embodiment 5 preparations, use respectively again 78mL, 5.8mL, the N that 3mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(Pidolidone) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 50.

Described polyethylene glycol-(Pidolidone) segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 56ml, 4ml, 3ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 22.

The number-average molecular weight of table 22 products therefrom and reaction yield

In table 22, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure.

Embodiment 24 has the preparation of poly glycol monomethyl ether-PLGA segmented copolymer (n=100) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 taking in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 8.51g, 0.57g, in γ-phenmethyl-Pidolidone ester-N-of 0.29g embodiment 5 preparations, carboxylic acid anhydride monomer is used respectively 85mL again, 6mL, the N that 3mL is dry, dinethylformamide solubilizing reaction thing, after at room temperature reacting 48h, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLGA segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 100.

Described poly glycol monomethyl ether-PLGA segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 3ml, 5ml, 3ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 23.

The number-average molecular weight of table 23 products therefrom and reaction yield

In table 23, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure.

Embodiment 25 has the preparation of polyethylene glycol-(Pidolidone) segmented copolymer (n=100) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 15.69g, 1.13g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.57g embodiment 5 preparations, use respectively again 157mL, 11mL, the N that 6mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(Pidolidone) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 100.

Described polyethylene glycol-(Pidolidone) segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 113ml, 9ml, 5ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 24.

The number-average molecular weight of table 24 products therefrom and reaction yield

In table 24, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure.

Embodiment 26 has the preparation of poly glycol monomethyl ether-PLGA segmented copolymer (n=200) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 17.02g, 1.14g, 0.57g γ embodiment 5 preparations-the interior carboxylic acid anhydride monomer of phenmethyl-Pidolidone ester-N-, use respectively again 170mL, 11mL, the N that 6mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLGA segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 200.

Described poly glycol monomethyl ether-PLGA segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 125ml, 8ml, 2ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 25.

The number-average molecular weight of table 25 products therefrom and reaction yield

In table 25, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure.

Embodiment 27 has the preparation of polyethylene glycol-(Pidolidone) segmented copolymer (n=200) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 31.37g, 2.27g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 1.15g embodiment 5 preparations, use respectively again 300mL, 23mL, the N that 11mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(Pidolidone) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 200.

Described polyethylene glycol-(Pidolidone) segmented copolymer (n=200) is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 226ml, 15ml, 9ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 26.

The number-average molecular weight of table 26 products therefrom and reaction yield

In table 26, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure.

Embodiment 28 has the preparation of poly glycol monomethyl ether-PLGA segmented copolymer (n=300) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 25.53g, 1.71g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.86g embodiment 5 preparations, use respectively again 250mL, 17mL, the N that 9mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLGA segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 300.

Described poly glycol monomethyl ether-PLGA segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 188ml, 12ml, 7ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 27.

The number-average molecular weight of table 27 products therefrom and reaction yield

In table 27, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLGA segmented copolymer of formula (I) structure.

Embodiment 29 has the preparation of polyethylene glycol-(Pidolidone) segmented copolymer (n=300) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 47.06g, 3.40g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 1.72g embodiment 5 preparations, use respectively again 450mL, 34mL, the N that 17mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(Pidolidone) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 300.

Described polyethylene glycol-(Pidolidone) segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 340ml, 22ml, 12ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 28.

The number-average molecular weight of table 28 products therefrom and reaction yield

In table 28, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(Pidolidone) segmented copolymer of formula (II) structure.

Embodiment 30 has the preparation of poly glycol monomethyl ether-poly-(L-Phe) segmented copolymer (n=50) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 2.80g, 0.188g, carboxylic acid anhydride monomer in the L-Phe-N-of 0.10g embodiment 5 preparations, use respectively again 28mL, 2mL, the N that 1mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, the poly glycol monomethyl ether of (I) structure that obtains thering is formula-poly-(L-Phe) segmented copolymer, the amino acid whose polymerization degree is 50.The number-average molecular weight of products therefrom and reaction yield are in Table 29.

The number-average molecular weight of table 29 products therefrom and reaction yield

In table 29, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-poly-(L-Phe) segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-poly-(L-Phe) segmented copolymer of formula (I) structure.

Embodiment 31 has the preparation of polyethylene glycol-(L-Phe) segmented copolymer (n=50) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 5.17g, 0.37g, carboxylic acid anhydride monomer in the L-Phe-N-of 0.19g embodiment 5 preparations, use respectively again 52mL, 4mL, the N that 2mL is dry, dinethylformamide is molten, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(L-Phe) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 50.The number-average molecular weight of products therefrom and reaction yield are in Table 30.

The number-average molecular weight of table 30 products therefrom and reaction yield

In table 30, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(L-Phe) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(L-Phe) the block copolymer structure unit of formula (II) structure.

Embodiment 32 has the preparation of poly glycol monomethyl ether-PLL segmented copolymer (n=50) of formula (I) structure

In the reaction flask that 3 dry bands prop up mouthful, add respectively the experiment 1 in 0.2g embodiment 3, 2, 3 compounds with formula (III) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 3.86g, 0.26g, carboxylic acid anhydride monomer in the ε-carbobenzoxy-(Cbz)-1B-N-of 0.13g embodiment 5 preparations, use respectively again 39mL, 26mL, the N that 1.5mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, poly glycol monomethyl ether-PLL segmented copolymer of (I) structure that obtains thering is formula, the amino acid whose polymerization degree is 50.

Described poly glycol monomethyl ether-PLL segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 70ml, 6ml, 4ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 31.

The number-average molecular weight of table 31 products therefrom and reaction yield

In table 31, Mn ₁for thering is the number-average molecular weight of formula (III) structural compounds; Mn ₂for thering is the number-average molecular weight of poly glycol monomethyl ether-(1B) sour segmented copolymer of formula (I) structure; DP is for having the mean polymerisation degree of poly glycol monomethyl ether-PLL segmented copolymer of formula (I) structure.

Embodiment 33 has the preparation of polyethylene glycol-(1B) segmented copolymer (n=50) of formula (II) structure

Add respectively 0.2g embodiment 4 in the reaction flask that 3 dry bands prop up mouthful in, test 1, 2, 3 compounds with formula (IV) structure that obtain, dewater with 20mL methylbenzene azeotropic respectively, then under anhydrous and oxygen-free condition, add respectively 7.11g, 0.51g, carboxylic acid anhydride monomer in γ-phenmethyl-Pidolidone ester-N-of 0.26g embodiment 5 preparations, again respectively with dry 71mL, 5mL, the N that 3mL is dry, dinethylformamide solubilizing reaction thing, after reacting 48h under room temperature, use ether sedimentation, vacuum-drying 24h at 25 ℃, polyethylene glycol-(1B) segmented copolymer of (II) structure that obtains thering is formula, the amino acid whose polymerization degree is 50.

Described polyethylene glycol-(1B) segmented copolymer is dissolved with trifluoroacetic acid at 25 ℃; then under stirring, stirrer adds respectively the hbr/acetic acid mixing solutions that 127ml, 9ml, 5ml hydrogen bromide mass content are 33%; at 25 ℃, react 1h; ether sedimentation; filter; washing, vacuum-drying 24h at 25 ℃, obtains the polyamino acid block copolymer of deprotection.The number-average molecular weight of products therefrom and reaction yield are in Table 32.

The number-average molecular weight of table 32 products therefrom and reaction yield

In table 32, Mn ₁for thering is the number-average molecular weight of formula (IV) structural compounds; Mn ₂for thering is the number-average molecular weight of polyethylene glycol-(1B) segmented copolymer of formula (II) structure; DP is for having the mean polymerisation degree of polyethylene glycol-(1B) segmented copolymer of formula (II) structure.

The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims

1. a polyamino acid block copolymer, has formula (I) structure or formula (II) structure:

Wherein, R is hydrogen, alkyl, substituted alkyl, substituted aromatic base, amide group, carboxyl or amino;

N is the polymerization degree, 2≤n≤350;

M is the polymerization degree, 20≤m≤1000.

2. polyamino acid block copolymer according to claim 1, is characterized in that, described R is CH ₂cH (CH ₃) ₂, CH ₂ph, CH ₂cH ₂cOOH or CH ₂cH ₂cH ₂cH ₂nH ₂.

3. polyamino acid block copolymer according to claim 1, is characterized in that, 5≤n≤300.

4. polyamino acid block copolymer according to claim 1, is characterized in that, 200≤m≤950.

5. a preparation method for polyamino acid block copolymer described in claim 1～4 any one, comprising:

The compound with formula (III) structure or formula (IV) structure reacts in organic solvent with carboxylic acid anhydride in amino acid-N-, the polyamino acid block copolymer of obtain having formula (I) structure or formula (II) structure;

Wherein, m is the polymerization degree, 20≤m≤1000.

6. preparation method according to claim 5, is characterized in that, described organic solvent is the mixture of DMF and Isosorbide-5-Nitrae-dioxane.

7. preparation method according to claim 5, is characterized in that, described in there is formula (III) structure or formula (IV) structure compound prepare in accordance with the following methods:

Compound and amino shielded phenylalanine, the acetone with formula V structure or formula (VI) structure contract 2,2'-bis-(methylol) propionic anhydride and DMAP react, and obtain having the compound of formula (III) structure or formula (IV) structure after deprotection;

Wherein, m is the polymerization degree, 20≤m≤1000.

8. preparation method according to claim 7, is characterized in that, described in there is formula V structure or formula (VI) structure compound prepare in accordance with the following methods:

Poly glycol monomethyl ether or polyoxyethylene glycol and acetone contracting 2,2'-bis-(methylol) propionic anhydride, DMAP and methyl alcohol react in organic solvent, generate the compound with formula V structure or formula (VI) structure after deprotection.

9. preparation method according to claim 7, is characterized in that, described in there is the compound of formula V structure and the mol ratio of amino shielded phenylalanine is 1:5～1:10.

10. preparation method according to claim 7, is characterized in that, described in there is formula (VI) structural compounds and amino shielded phenylalanine mol ratio be 1:10～1:20.