CN102408561A

CN102408561A - Segmented copolymer and its preparation method, and temperature sensitive type hydrogel

Info

Publication number: CN102408561A
Application number: CN2011103597383A
Authority: CN
Inventors: 贺超良; 成一龙; 肖春生; 丁建勋; 任凯旋; 庄秀丽; 陈学思
Original assignee: Changchun Institute of Applied Chemistry of CAS
Current assignee: Changzhou Institute of Energy Storage Materials & Devices
Priority date: 2011-11-14
Filing date: 2011-11-14
Publication date: 2012-04-11
Anticipated expiration: 2031-11-14
Also published as: CN102408561B

Abstract

The invention provides a segmented copolymer and a preparation method thereof, and a temperature sensitive type hydrogel. The segmented copolymer comprises a first segment formed by terminal aminated polyethylene glycol or terminal aminated polyethylene glycol monomethyl ether and a second segment formed by the poly (gamma-alkyl-L-glutamate), the side chain of the second segment contains alkyl substituent, segmented copolymers with different substituent side chains can be obtained by adjusting the types, structures or length of the carbon chain of substituent on the side chain, thereby the phase transition temperature of the formed temperature sensitive hydrogel can be adjusted, and the adjusting means of phase transition behaviors of the temperature sensitive type hydrogel are expanded, the segmented copolymer is in favor of further application of the temperature sensitive type hydrogel. The temperature sensitive type hydrogel has long degradation period, and is in favor of performing long drug effectiveness on the lesion location, the degradation products are amino acid and polyethylene glycol, and can be directly eliminated out of the body through kidney.

Description

A kind of segmented copolymer, its preparation method and temperature sensitive type water gel

Technical field

The present invention relates to a kind of polyamino acid technical field, relate in particular to a kind of segmented copolymer, its preparation method and temperature sensitive type water gel.

Background technology

Slowly released and controlled-drug delivery system is meant that the non-in vivo constant speed of medicine ground discharges lentamente from preparation, thus one type of new drug delivery system of prolong drug action time.With respect to traditional pharmaceutical prepn, slowly released and controlled-drug delivery system has that dosage is few, the medication number of times is few, curative effect is high, medicine is to characteristics such as the toxic side effect of normal cell tissue is little, becomes the popular research topic of pharmaceutical field over nearly 20 years.

Temperature sensitive type water gel has unique solution-gel conversion characteristic; Control its transformation temperature and body temperature coupling; Can obtain temperature sensitive injectable type hydrogel: when being lower than body temperature; Temperature sensitive injectable type hydrogel exists with solution state, can mix with medicines such as medicine, polypeptide, protein, cell or biologically active substance; After being injected into inside of human body; Because variation of temperature, solution undergoes phase transition rapidly, forms hydrogel; In the process that forms hydrogel; The medicine or the biologically active substance that are blended in wherein are embedded in hydrogel inside, and the degraded through diffusion or hydrogel self slowly discharges then, thereby reach the purpose of long-acting slow-release.This type hydrogel has good fluidity, and is easy to use, and the residence time is long; Slow, the persistent characteristics of release; And it has perviousness preferably to low molecule solute, and good biocompatibility and circulation ratio are preferably arranged, and synthesizes easily; Therefore be widely used in biomedical sector in recent years, especially the application in the slowly released and controlled-drug delivery system of protein and polypeptide drug has caused the concern of numerous pharmaceutical researchers.In addition, this type temperature sensitive type water gel is suitable for the wound of random shape owing to be low viscosity solution before the injection, and, can not cause new wound in the injection process, be easy to accepted by the patient, therefore also can be used as the timbering material of internal in-situ tissue culture.

But polymkeric substance formation temperature sensitive hydrogel becomes one of hot research in recent years.Wherein, The aqueous solution of polyoxyethylene-polyoxytrimethylene condenses (also claiming Poloxamer, Prist) can be used as temperature sensitive injectable type hydrogel, and it is one type of maximum polymkeric substance as temperature sensitive type water gel of research at present; But it can only exist a couple of days promptly to be diluted by body fluid in vivo; Can't realize continuing medication for a long time, and Prist can not biological degradation, this has just limited it in the intravital application of people; Subsequently, a kind of polyoxyethylene glycol and the hydrogel (Jeong B, the Bae YH that gather (L-lactic acid) segmented copolymer have been developed; Lee DS, et al.Biodegradable block copolymers as injectable drug-delivery systems [J] .Nature, 1997; 388:860～862.), it can be by biological degradation, but degraded product is micromolecular compounds such as lactic acid; The lactic acid of local excessive concentrations can cause inflammation, healthy unfavorable to human body; Along with going deep into of research, the researchist has prepared polyoxyethylene-polyoxytrimethylene again and has gathered L-Ala or gather L-Ala and the hydrogel of phenylalanine(Phe) random copolymers (Macromalecule, 2008; 41:8204～8209, Biomacromolecules, 2009; 10:2476～2481.), the biodegradable product of this type hydrogel is an amino acid, and human body is had no injury; But; The segmented copolymer that forms hydrogel can only be regulated the transformation behavior of hydrogel through the molecular weight that one-sided change gathers L-Ala block or polyphenylalanine, and controllability is more single, is unfavorable for the further application of temperature sensitive type water gel.

Summary of the invention

The object of the present invention is to provide a kind of segmented copolymer, its preparation method and temperature sensitive type water gel; The temperature sensitive type water gel that segmented copolymer provided by the invention forms has higher adjustable space; Expanded regulating measure, helped the further application of temperature sensitive type water gel the temperature sensitive type water gel transformation behavior.

The invention provides a kind of segmented copolymer, comprise have formula first block of (I) or formula (II) structure and second block with formula (III) structure:

Wherein, R is the alkyl that contains 10 following carbon atoms;

M is the polymerization degree, 10≤m≤227;

N is the polymerization degree, 10≤n≤226;

Q is the polymerization degree, 3≤q≤150.

Preferably, said R is methyl, ethyl, n-propyl, sec.-propyl or normal-butyl.

Preferably, to account for the weight percentage of said segmented copolymer be 25%～70% to said second block.

The invention provides a kind of preparation method of segmented copolymer, may further comprise the steps:

The amidized polyoxyethylene glycol of end and the γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtain segmented copolymer;

Wherein, m is the polymerization degree, 10≤m≤227;

N is the polymerization degree, 10≤n≤226.

Preferably, said have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the amidized polyoxyethylene glycol of end of formula V structure and the mol ratio of γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride is 1: (5～120).

Preferably, said γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride prepares according to following method:

L-L-glutamic acid and alcohol compound generation esterification obtain γ-didodecyl l glutamic acid ester;

Said γ-didodecyl l glutamic acid ester carries out condensation reaction with two (trichloromethyl) carbonic ethers, obtains γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride.

Preferably, said alcohol compound is methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol.

The invention provides a kind of temperature sensitive type water gel, comprise described segmented copolymer of technique scheme and solvent.

Preferably, said solvent is water, saline water, buffered soln, tissue culture medium or body fluid.

Preferably, the massfraction of said segmented copolymer is 2%～30%.

Segmented copolymer provided by the invention comprises the amidized polyoxyethylene glycol of end or holds amidized poly glycol monomethyl ether first block that forms and second block that gathers (γ-didodecyl l glutamic acid ester) formation.First block and second block of said segmented copolymer all have different degree of polymerization, can obtain the segmented copolymer of different molecular weight, thereby form the temperature sensitive type water gel with different transformation temperatures; And second block of segmented copolymer provided by the invention; Promptly gather on the side chain of (γ-didodecyl l glutamic acid ester) and contain alkyl substituent; Can be through regulating factors such as substituent kind, structure, carbon chain lengths on the side chain; Obtain containing the segmented copolymer of different substituents side chain, thereby can regulate the transformation temperature of the temperature sensitive type water gel of its formation; Moreover; The ratio of gathering (γ-didodecyl l glutamic acid ester) in the segmented copolymer provided by the invention is different; Can be gathered (γ-didodecyl l glutamic acid ester) different segmented copolymer of content, thus the transformation temperature that can regulate the temperature sensitive type water gel of its formation.Segmented copolymer provided by the invention has multiple regulating measure, and the controllability of the feasible temperature sensitive type water gel that forms is better, has expanded the regulating measure to the temperature sensitive type water gel transformation behavior, helps temperature sensitive type water gel and further uses.

Temperature sensitive type water gel provided by the invention has excellent biological compatibility and biological degradability; Its degradation cycle was 10 week～15 weeks; Help medicine in more permanent its drug effect of performance of diseased region; And the product that obtains of degraded is amino acid and polyoxyethylene glycol, can directly get rid of external, harmless through kidney.Experimental result shows that the gelation process of temperature sensitive type water gel provided by the invention is reversible, and transformation temperature can be used as pharmaceutical carrier or timbering material near body temperature.In addition, the present invention will hold amidized polyoxyethylene glycol or hold amidized poly glycol monomethyl ether and gather (γ-didodecyl l glutamic acid ester) copolymerization, can obtain segmented copolymer, and the preparation method is simple to operate, and raw material is simple and easy to, and reaction conditions is gentle.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 11 preparations;

Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 12 preparations;

Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 13 preparations;

Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 14 preparations;

Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 15 preparations;

The temperature variant phasor of block copolymer solution of the different concns that Fig. 6 obtains for the embodiment of the invention 41;

The temperature variant phasor of block copolymer solution of the different concns that Fig. 7 obtains for the embodiment of the invention 42;

The temperature variant phasor of block copolymer solution of the different concns that Fig. 8 obtains for the embodiment of the invention 43;

The temperature variant phasor of block copolymer solution of the different concns that Fig. 9 obtains for the embodiment of the invention 44;

The temperature variant phasor of block copolymer solution of the different concns that Figure 10 obtains for the embodiment of the invention 45;

The temperature variant phasor of block copolymer solution of the different concns that Figure 11 obtains for the embodiment of the invention 46.

Embodiment

Wherein, R is the alkyl that contains 10 following carbon atoms, is preferably the alkyl of 5 following carbon atoms, more preferably methyl, ethyl, n-propyl, sec.-propyl or normal-butyl;

M is the polymerization degree, and 10≤m≤227 are preferably 20≤m≤185, more preferably 30≤m≤115;

N is the polymerization degree, and 10≤n≤226 are preferably 20≤n≤180, more preferably 30≤n≤112;

Q is the polymerization degree, and 3≤q≤150 are preferably 5≤q≤105; 8≤q≤92 more preferably.

Wherein, m is the polymerization degree, 10≤m≤227;

N is the polymerization degree, 10≤n≤226.

Among the present invention, the said amidized polyoxyethylene glycol of end that has the amidized poly glycol monomethyl ether of end of formula (IV) structure or have a formula V structure is preferably according to following method preparation:

Poly glycol monomethyl ether or polyoxyethylene glycol and triethylamine, Methanesulfonyl chloride generation esterification obtain methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester;

Said methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester and ammoniacal liquor carry out ammonolysis reaction, obtain having formula amidized poly glycol monomethyl ether of end of (IV) structure or the amidized polyoxyethylene glycol of end with formula V structure.

At first, poly glycol monomethyl ether or polyoxyethylene glycol and the methylbenzene azeotropic continued that dewaters is removed toluene, to wherein adding organic solvent, obtain poly glycol monomethyl ether or polyglycol solution again.Wherein, The number-average molecular weight of said poly glycol monomethyl ether or polyoxyethylene glycol is 550～10000, is preferably 1000～8000, more preferably 1500～5000; Said organic solvent is preferably methylene dichloride; The quality of said poly glycol monomethyl ether or polyoxyethylene glycol is preferably 1g with the volume of organic solvent ratio: (1～20) mL, more preferably 1g: (3～18) mL most preferably is 1g: (5～15) mL.

In poly glycol monomethyl ether that obtains or polyglycol solution, add triethylamine and Methanesulfonyl chloride, carry out esterification, obtain methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester.Wherein, the mol ratio of said triethylamine and poly glycol monomethyl ether is preferably (1～10): 1, more preferably (3～8): 1, most preferably be (4～7): 1; The mol ratio of said triethylamine and polyoxyethylene glycol is preferably (2～20): 1, more preferably (5～18): 1, most preferably be (8～14): 1; The mol ratio of said triethylamine and Methanesulfonyl chloride is preferably (1～10): (10～30), more preferably (3～8): (18～26) most preferably are (4～7): (15～24).

The present invention is preferably under-10 ℃～10 ℃, anhydrous condition; More preferably under-8 ℃～8 ℃, most preferably be under-5 ℃～5 ℃, in said poly glycol monomethyl ether or polyglycol solution, add triethylamine; Drip Methanesulfonyl chloride simultaneously; In the mixing solutions that obtains, said poly glycol monomethyl ether or polyoxyethylene glycol and triethylamine, Methanesulfonyl chloride carry out esterification, obtain methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester.Preferred reaction is 0.5 hour～4 hours under said temperature, more preferably 1 hour～3.5 hours, most preferably is 1.5 hours～2.5 hours; Preferably be warming up to 12 ℃～40 ℃ then; More preferably 18 ℃～35 ℃, most preferably be 15 ℃～28 ℃, preferably under agitation condition, continue reaction 10 hours～72 hours; More preferably 15 hours～60 hours, most preferably be 20 hours～48 hours.

After esterification finished, with the reacting liquid filtering that obtains, the elimination throw out was after filtrating concentrates; Preferably use the ether sedimentation, and then filter, wash, preferably under 10 ℃～40 ℃ temperature, carry out vacuum-drying; More preferably 15 ℃～38 ℃, most preferably be 20 ℃～30 ℃, be preferably 15 hours said time of drying～35 hours; More preferably 18 hours～30 hours, most preferably be 22 hours～28 hours, obtain methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester.

The methylsulphonic acid poly glycol monomethyl ether ester that obtains or methylsulphonic acid macrogol ester and ammonium chloride are dissolved in the ammoniacal liquor; The quality of wherein said methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester, the quality of ammonium chloride and the volume ratio of ammoniacal liquor are preferably 1g: (0.2～3.5) g: (30～70) mL; 1g more preferably: (0.5～3) g: (35～55) mL most preferably is 1g: (1～1.8) g: (40～50) mL.

In ammoniacal liquor, said methylsulphonic acid poly glycol monomethyl ether ester or methylsulphonic acid macrogol ester carry out ammonolysis reaction, obtain having formula amidized poly glycol monomethyl ether of end of (IV) structure or the amidized polyoxyethylene glycol of end with formula V structure.The temperature of said aminating reaction is preferably 10 ℃～40 ℃, and more preferably 15 ℃～35 ℃, most preferably be 20 ℃～30 ℃, the said aminating reaction time is preferably 40 hours～and 100 hours, more preferably 50 hours～85 hours, most preferably be 60 hours～75 hours.

After ammonolysis reaction is accomplished, with the reaction solution that obtains preferably with dichloromethane extraction, then with sodium chloride aqueous solution washing, anhydrous sodium sulfate drying, the filtrating that obtains is concentrated; Use the ether sedimentation then, the sediment that obtains is filtered, washs, preferably under 10 ℃～40 ℃ temperature, carry out vacuum-drying; More preferably 15 ℃～35 ℃; Most preferably be 20 ℃～30 ℃, be preferably 15 hours said time of drying～35 hours, more preferably 18 hours～30 hours; Most preferably be 20 hours～28 hours, obtain having formula amidized poly glycol monomethyl ether of end of (IV) structure or the amidized polyoxyethylene glycol of end with (V) structure.

Among the present invention, said γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride is preferably according to following method preparation:

At first L-L-glutamic acid is mixed with alcohol compound and stirs, and under agitation condition to wherein dripping the vitriol oil, the vitriol oil exist and stirring condition under, L-L-glutamic acid and alcohol compound carry out esterification, obtain γ-didodecyl l glutamic acid ester.Said alcohol compound is preferably methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol; The mol ratio of said L-L-glutamic acid and alcohol compound is preferably 1: (0.8～8); More preferably 1: (1.5～6) most preferably are 1: (3～4), and the mol ratio of the said L-L-glutamic acid and the vitriol oil is preferably 1: (0.5～5); More preferably 1: (0.8～3) most preferably is 1: (1.2～2).Said L-L-glutamic acid and alcohol compound blended temperature are preferably 0 ℃～30 ℃, more preferably 2 ℃～20 ℃, most preferably are 3 ℃～15 ℃; The temperature of said esterification is preferably 20 ℃～50 ℃; More preferably 25 ℃～45 ℃, most preferably be 28 ℃～40 ℃, said reaction time of esterification is preferably 5 hours～and 35 hours; More preferably 7 hours～33 hours, most preferably be 10 hours～30 hours.

After the esterification of L-L-glutamic acid and alcohol compound is accomplished, the reaction solution that preferably neutralizes and obtain with triethylamine and alcoholic acid mixing solutions, then that the mixing solutions that obtains is centrifugal, recrystallization, drying obtain γ-didodecyl l glutamic acid ester.Among the present invention; Said triethylamine and alcoholic acid volume ratio are preferably 1: (0.5～1.5); More preferably 1: (0.7～1.3) most preferably is 1: (0.8～1.2), and the mol ratio of the said triethylamine and the vitriol oil is preferably (1～3): 1; More preferably (1.5～2.8): 1, most preferably be (1.8～2.2): 1.

After obtaining γ-didodecyl l glutamic acid ester; Preferably under anhydrous condition; With the said γ of organic solvent dissolution-didodecyl l glutamic acid ester and two (trichloromethyl) carbonic ethers; In organic solvent, γ-didodecyl l glutamic acid ester carries out condensation reaction with two (trichloromethyl) carbonic ethers, obtains γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride.Said γ-didodecyl l glutamic acid ester is preferably 1 with the mol ratio of two (trichloromethyl) carbonic ethers: (0.1～1.2), and more preferably 1: (0.3～1) most preferably is 1: (0.5～0.8); Said organic solvent is preferably THF; Said γ-didodecyl l glutamic acid ester is preferably 10 ℃～40 ℃ with two (trichloromethyl) temperature when carbonic ether mixes, and more preferably 15 ℃～35 ℃, most preferably is 20 ℃～30 ℃; Said temperature of reaction is preferably 30 ℃～80 ℃; More preferably 35 ℃～70 ℃, most preferably be 40 ℃～60 ℃, said condensation reaction time is preferably 0.1 hour～and 5 hours; More preferably 0.15 hour～3 hours, more preferably 0.2 hour～2 hours.

Condensation reaction is preferably used the sherwood oil sedimentation with the reaction solution that obtains after finishing, and the sediment that obtains is separated, and then with the separated product washing, recrystallization, the drying that obtain, obtains γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride.

In the present invention; The amidized polyoxyethylene glycol of end and the γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure; Obtain segmented copolymer, specifically may further comprise the steps:

The amidized polyoxyethylene glycol of end that will have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have a formula V structure is dissolved in first organic solvent, obtains first solution;

γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride is dissolved in second organic solvent, obtains second solution;

First solution that obtains is mixed with second solution; The said amidized polyoxyethylene glycol of end and the γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that has the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtains segmented copolymer.

Among the present invention; Said amidized polyoxyethylene glycol of end and the dry toluene azeotropic water removing continued that has the amidized poly glycol monomethyl ether of end of formula (IV) structure or have a formula V structure removed toluene; Then it is dissolved in first organic solvent; Obtain first solution, the present invention does not have particular restriction to the concentration of said first solution.Said first organic solvent is preferably N, dinethylformamide, DMAC N,N or trichloromethane, N more preferably, dinethylformamide.Said quality and the volume ratio of dry toluene that has the amidized poly glycol monomethyl ether of end of formula (IV) structure or have an amidized polyoxyethylene glycol of end of formula V structure is preferably 1g: (10mL～50mL); 1g more preferably: (15mL～45mL); Most preferably be 1g: (25mL～35mL), said azeotropic temperature is preferably 110 ℃～150 ℃, more preferably 115 ℃～140 ℃; Most preferably be 125 ℃～135 ℃; The said azeotropic time is preferably 1 hour～and 3 hours, more preferably 1.5 hours～2.5 hours, most preferably be 1.8 hours～2.2 hours.

Said γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride is dissolved in second organic solvent, obtains second solution, the present invention does not have particular restriction to the concentration of said second solution.Said second organic solvent is preferably N, dinethylformamide, DMAC N,N or trichloromethane, N more preferably, dinethylformamide.

After obtaining first solution and second solution; Under nitrogen atmosphere; Said first solution is mixed with second solution and constantly stirring; In the mixing solutions that obtains, the said amidized polyoxyethylene glycol of end and the γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride polymerization reaction take place that has the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the formula V structure obtains segmented copolymer.Said have the amidized polyoxyethylene glycol of end of formula (IV) structure or have the amidized poly glycol monomethyl ether of end of formula V structure and the mol ratio of γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride is 1: (5～120); Be preferably 1: (10～100), more preferably 1: (15～90).Said polymeric reaction temperature is preferably 15 ℃～45 ℃, and more preferably 20 ℃～40 ℃, more preferably 25 ℃～35 ℃, said polymerization reaction time is preferably 20 hours～and 80 hours, more preferably 24 hours～72 hours, most preferably be 30 hours～70 hours.

After polyreaction finishes; Preferably with the method for decompressing and extracting the organic solvent in the reaction solution that obtains is drained, the solid with dissolved in chloroform obtains carries out sedimentation with ether then; Sediment to obtaining carries out suction filtration, washing, vacuum-drying, obtains segmented copolymer.

In the segmented copolymer that the present invention obtains, the weight percentage that said second block accounts for said segmented copolymer is preferably 25%～70%, and more preferably 30%～65%, most preferably be 35%～60%.

The invention provides a kind of temperature sensitive type water gel, comprise described segmented copolymer of technique scheme and solvent.Said solvent is preferably water, saline water, buffered soln, tissue culture medium or body fluid, and more preferably buffered soln or saline water most preferably are buffered soln.In said temperature sensitive type water gel, the massfraction of said segmented copolymer is preferably 2%～30%, and more preferably 4%～20%, most preferably be 5%～15%.

In the present invention, after said segmented copolymer and solvent, obtain temperature sensitive type water gel.

At first prepare said block copolymer solution, the block copolymer solution that obtains is positioned in the water bath with thermostatic control, the formation temperature sensitive hydrogel.The mass concentration of said block copolymer solution is preferably 2%～30%, and more preferably 4%～20%, most preferably be 5%～15%; Said thermostat temperature is preferably 25 ℃～45 ℃; More preferably 30 ℃～40 ℃, most preferably be 35 ℃～38 ℃, be preferably 1 minute said storage period～20 minutes; More preferably 5 minutes～15 minutes, most preferably be 8 minutes～12 minutes.

After obtaining temperature sensitive type water gel; The transformation behavior of the temperature sensitive type water gel that the segmented copolymer that contains different side groups is formed is tested; The result shows; Its transformation temperature changes with the difference of side group, is that the transformation temperature of the temperature sensitive type water gel that forms of the segmented copolymer of methyl is 30 ℃～45 ℃ like side group, and side group is that the transformation temperature of the temperature sensitive type water gel that forms of the segmented copolymer of ethyl is 16 ℃～38 ℃; Side group is that the transformation temperature of the temperature sensitive type water gel that forms of the segmented copolymer of n-propyl is 46 ℃～58 ℃; Side group is that the transformation temperature of the temperature sensitive type water gel that forms of the segmented copolymer of sec.-propyl is 43 ℃～62 ℃, and side group is that the transformation temperature of the temperature sensitive type water gel that forms of the segmented copolymer of normal-butyl is 48 ℃～66 ℃, the kind of side group that therefore can be through regulating segmented copolymer; Structure, factors such as the length of carbochain are regulated the transformation behavior of the temperature sensitive type water gel of its formation.

The present invention adopts following method that the degradation property of said temperature sensitive type water gel is tested:

The segmented copolymer that technique scheme is obtained is dissolved in the buffered soln, obtains block copolymer solution.Said buffered soln is preferably phosphate buffer soln, and the pH of said buffered soln is preferably 5.5～8.5, and more preferably 6.0～8.0, most preferably be 6.5～7.5.The block copolymer solution that obtains was preferably placed 10 minutes in water bath with thermostatic control, and the temperature of said water bath with thermostatic control is preferably 30 ℃～45 ℃, more preferably 35 ℃～40 ℃, obtains block copolymer hydrogel.Then preferably with in the said block copolymer hydrogel of the slow adding of the said buffered soln of 3mL; Preferably said block copolymer hydrogel is positioned in 30 ℃～45 ℃ the constant-temperature shaking case, more preferably 35 ℃～40 ℃, was preferably for 1 week～20 week said storage period; 5 week～18 weeks more preferably; Most preferably be for 10 week～16 weeks,, adopt weighting method and gel permeation chromatography to analyze; The result shows that the degradation cycle of the temperature sensitive type water gel that said segmented copolymer forms was 10 week～15 weeks, and degraded product is polyoxyethylene glycol and L-L-glutamic acid.

First block and second block of segmented copolymer provided by the invention all have different degree of polymerization, obtain the segmented copolymer of different molecular weight, thereby form the temperature sensitive type water gel with different transformation temperatures; And second block of segmented copolymer provided by the invention; Promptly gather on the side chain of (γ-didodecyl l glutamic acid ester) and contain alkyl substituent; Can be through regulating substituent kind, structure, carbon chain lengths etc.; Obtain containing the segmented copolymer of different substituents side chain, thereby can regulate the transformation temperature of the temperature sensitive type water gel of its formation; Moreover; The ratio difference of gathering second block of (γ-didodecyl l glutamic acid ester) formation in the segmented copolymer provided by the invention; Gathered (γ-didodecyl l glutamic acid ester) different segmented copolymer of content, thus the transformation temperature that can regulate the temperature sensitive type water gel of its formation.Segmented copolymer provided by the invention has multiple regulating measure, and the controllability of the feasible temperature sensitive type water gel that forms is better, has enlarged the regulation range of temperature sensitive type water gel transformation behavior, helps the further application of temperature sensitive type water gel.In addition, method provided by the invention is simple to operate, and raw material is simple and easy to, and reaction conditions is gentle.

In order to further specify the present invention, segmented copolymer provided by the invention, its preparation method and temperature sensitive type water gel are described in detail below in conjunction with embodiment.

Embodiment 1

With 2.2g, number-average molecular weight is that 550 amidized poly glycol monomethyl ether of end and 60mL dry toluene dewater at 130 ℃ of following azeotropic 2h, then the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 3.74g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, said first solution is mixed stirring reaction 24h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 71%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 715, accounts for 56.5% of segmented copolymer gross weight.

Embodiment 2

With 2.2g, number-average molecular weight be 550 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.02g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 24h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 68%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 785, accounts for 58.8% of segmented copolymer gross weight.

Embodiment 3

With 2.2g, number-average molecular weight be 550 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.3g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 24h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 65%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 855, accounts for 60.9% of segmented copolymer gross weight.

Embodiment 4

With 2.2g, number-average molecular weight be 550 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.3g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 24h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 71%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 855, accounts for 60.9% of segmented copolymer gross weight.

Embodiment 5

With 2.2g, number-average molecular weight be 550 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 3.74g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 24h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 68%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 925, accounts for 62.7% of segmented copolymer gross weight.

Embodiment 6

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 1.122g is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 74%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 715, accounts for 26.3% of segmented copolymer gross weight.

Embodiment 7

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 1.206g is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 65%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 785, accounts for 28.2% of segmented copolymer gross weight.

Embodiment 8

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 1.29g is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 69%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 855, accounts for 29.9% of segmented copolymer gross weight.

Embodiment 9

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 1.29g is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 70%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 855, accounts for 29.9% of segmented copolymer gross weight.

Embodiment 10

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 1.374g is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 70%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 925, accounts for 31.6% of segmented copolymer gross weight.

Embodiment 11

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 2.805g is dissolved in 30mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy; Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 11 preparations; Experimental result shows that the productive rate of said segmented copolymer is 61%, wherein; The number-average molecular weight of gathering (γ-methyl-L-glutamate) is 1716, accounts for 46.2% of segmented copolymer gross weight.

Embodiment 12

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 3.015g is dissolved in 30mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy; Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 12 preparations; Experimental result shows that the productive rate of said segmented copolymer is 69%, wherein; The number-average molecular weight of gathering (γ-ethyl-L-glutamate) is 1884, accounts for 48.5% of segmented copolymer gross weight.

Embodiment 13

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 2.58g is dissolved in 30mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy; Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 13 preparations; Experimental result shows that the productive rate of said segmented copolymer is 66%, wherein; The number-average molecular weight of gathering (γ-n-propyl-L-glutamate) is 1710, accounts for 46.1% of segmented copolymer gross weight.

Embodiment 14

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 2.58g is dissolved in 30mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy; Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 14 preparations; Experimental result shows that the productive rate of said segmented copolymer is 70%, wherein; The number-average molecular weight of gathering (γ-sec.-propyl-L-glutamate) is 1710, accounts for 46.1% of segmented copolymer gross weight.

Embodiment 15

With the 2g number-average molecular weight be 2000 the amidized poly glycol monomethyl ether of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 20mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 2.748g is dissolved in 30mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy; Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 15 preparations; Experimental result shows that the productive rate of said segmented copolymer is 64%, wherein; The number-average molecular weight of gathering (γ-normal-butyl-L-glutamate) is 1665, accounts for 45.4% of segmented copolymer gross weight.

Embodiment 16

With 5g, number-average molecular weight be 5000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 2.805g is dissolved in 30mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 71%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 1430, accounts for 26.3% of segmented copolymer gross weight.

Embodiment 17

With 5g, number-average molecular weight be 5000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.02g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 65%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 2512, accounts for 33.4% of segmented copolymer gross weight.

Embodiment 18

With 5g, number-average molecular weight be 5000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.3g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 69%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 2736, accounts for 35.4% of segmented copolymer gross weight.

Embodiment 19

With 5g, number-average molecular weight be 5000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.3g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 64%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 2565, accounts for 33.9% of segmented copolymer gross weight.

Embodiment 20

With 5g, number-average molecular weight be 5000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 4.58g is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 67%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 2775, accounts for the 35.7%. of segmented copolymer gross weight

Embodiment 21

With 2g, number-average molecular weight be 2000 the amidized polyoxyethylene glycol of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 3.74g is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-methyl-L-glutamate)-polyethylene glycol-(γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 70%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 1716, accounts for 46.2% of segmented copolymer gross weight.

Embodiment 22

With 2g, number-average molecular weight be 2000 the amidized polyoxyethylene glycol of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; 4.02g γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-ethyl-L-glutamate)-polyethylene glycol-(γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 64%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 1884, accounts for 48.5% of segmented copolymer gross weight.

Embodiment 23

With 2g, number-average molecular weight be 2000 the amidized polyoxyethylene glycol of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; 4.3g γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-n-propyl-L-glutamate)-polyethylene glycol-(γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 69%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 2223, accounts for 52.6% of segmented copolymer gross weight.

Embodiment 24

With 2g, number-average molecular weight be 2000 the amidized polyoxyethylene glycol of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; 4.3g γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride is dissolved in 40mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-sec.-propyl-L-glutamate)-polyethylene glycol-(γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 69%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 2394, accounts for 54.5% of segmented copolymer gross weight.

Embodiment 25

With 2g, number-average molecular weight be 2000 the amidized polyoxyethylene glycol of end and 60mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; 4.58g γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-normal-butyl-L-glutamate)-polyethylene glycol-(γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 67%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 2220, accounts for 52.6% of segmented copolymer gross weight.

Embodiment 26

With 5g, number-average molecular weight be 5000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 5.61g is dissolved in 60mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-methyl-L-glutamate)-polyethylene glycol-(γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 72%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 3003, accounts for 37.5% of segmented copolymer gross weight.

Embodiment 27

With 5g, number-average molecular weight be 5000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 6.03g is dissolved in 60mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-ethyl-L-glutamate)-polyethylene glycol-(γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 69%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 3768, accounts for 43.0% of segmented copolymer gross weight.

Embodiment 28

With 5g, number-average molecular weight be 5000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 6.45g is dissolved in 70mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-n-propyl-L-glutamate)-polyethylene glycol-(γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 76%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 3762, accounts for 42.9% of segmented copolymer gross weight.

Embodiment 29

With 5g, number-average molecular weight be 5000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 6.45g is dissolved in 70mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-sec.-propyl-L-glutamate)-polyethylene glycol-(γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 76%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 4104, accounts for 45.1% of segmented copolymer gross weight.

Embodiment 30

With 5g, number-average molecular weight be 5000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 6.87g is dissolved in 70mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-normal-butyl-L-glutamate)-polyethylene glycol-(γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 70%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 3700, accounts for 42.5% of segmented copolymer gross weight.

Embodiment 31

With 5g, number-average molecular weight be 10000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 7.48g is dissolved in 70mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 61%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 10153, accounts for 50.4% of segmented copolymer gross weight.

Embodiment 32

With 5g, number-average molecular weight be 10000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 8.04g is dissolved in 80mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 63%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 10833, accounts for 51.9% of segmented copolymer gross weight.

Embodiment 33

With 5g, number-average molecular weight be 10000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 8.6g is dissolved in 80mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 66%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 11457, accounts for 53.4% of segmented copolymer gross weight.

Embodiment 34

With 5g, number-average molecular weight be 10000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 8.6g is dissolved in 80mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 68%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 11970, accounts for 54.5% of segmented copolymer gross weight.

Embodiment 35

With 5g, number-average molecular weight be 10000 the amidized poly glycol monomethyl ether of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 9.16g is dissolved in 90mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide is dissolved in the solid that obtains in the chloroform then, carries out sedimentation with ether again, and suction filtration after the drying, obtains poly glycol monomethyl ether-gather (γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 61%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 12210, accounts for 55.0% of segmented copolymer gross weight.

Embodiment 36

With 5g, number-average molecular weight be 10000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-methyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 11.22g is dissolved in 100mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-methyl-L-glutamate)-polyethylene glycol-(γ-methyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 80%, and the number-average molecular weight of wherein, gathering (γ-methyl-L-glutamate) is 17160, accounts for 63.2% of segmented copolymer gross weight.

Embodiment 37

With 5g, number-average molecular weight be 10000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-ethyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 12.06g is dissolved in 100mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-ethyl-L-glutamate)-polyethylene glycol-(γ-ethyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 73%, and the number-average molecular weight of wherein, gathering (γ-ethyl-L-glutamate) is 18369, accounts for 64.8% of segmented copolymer gross weight.

Embodiment 38

With 5g, number-average molecular weight be 10000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-n-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 12.9g is dissolved in 100mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-n-propyl-L-glutamate)-polyethylene glycol-(γ-n-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 73%, and the number-average molecular weight of wherein, gathering (γ-n-propyl-L-glutamate) is 19665, accounts for 66.3% of segmented copolymer gross weight.

Embodiment 39

With 5g, number-average molecular weight be 10000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-sec.-propyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 12.9g is dissolved in 100mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-sec.-propyl-L-glutamate)-polyethylene glycol-(γ-sec.-propyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 73%, and the number-average molecular weight of wherein, gathering (γ-sec.-propyl-L-glutamate) is 20000, accounts for 66.7% of segmented copolymer gross weight.

Embodiment 40

With 5g, number-average molecular weight be 10000 the amidized polyoxyethylene glycol of end and 100mL dry toluene behind 130 ℃ of following azeotropic water removing 2h, the remaining toluene of decompressing and extracting; The solid that obtains is dissolved in 50mL exsiccant N, in the dinethylformamide, obtains first solution; γ-normal-butyl-L-glutamate-N-carboxylic acid inner-acid anhydride of 13.74g is dissolved in 100mL exsiccant N, in the dinethylformamide, obtains second solution; In nitrogen atmosphere, first solution is mixed stirring reaction 72h under room temperature, nitrogen protection condition with second solution; After reaction finishes, decompressing and extracting N, dinethylformamide; Then the solid that obtains is dissolved in the chloroform, carries out sedimentation, suction filtration with ether again; After the drying, gathered (γ-normal-butyl-L-glutamate)-polyethylene glycol-(γ-normal-butyl-L-glutamate) segmented copolymer.

Segmented copolymer to obtaining carries out nuclear magnetic resonance spectroscopy, and experimental result shows that the productive rate of said segmented copolymer is 73%, and the number-average molecular weight of wherein, gathering (γ-normal-butyl-L-glutamate) is 21460, accounts for 68.2% of segmented copolymer gross weight.

Embodiment 41

It is 5%～20% phosphate buffer solution that the segmented copolymer of embodiment 7 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃～80 ℃ and changes, and when being inverted with tubule, not taking place in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min.

The result is referring to Fig. 6, and the temperature variant phasor of block copolymer solution of the different concns that Fig. 6 obtains for the embodiment of the invention 41 is in Fig. 6; Regional Representative's solution of straight line below, Regional Representative's gel of straight line top can be known by Fig. 6; This gelation process is a reversible; When block copolymer solution concentration was 15%～20%, it was 30 ℃～40 ℃ by the temperature that solution forms hydrogel, can under body temperature, form hydrogel; Therefore can be used as injectable sexual type gel, use as pharmaceutical carrier or timbering material.

Embodiment 42

It is 3%～12% phosphate buffer solution that the segmented copolymer of the embodiment of the invention 11 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃～80 ℃ and changes, and when being inverted with tubule, not taking place in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min.

The result is referring to Fig. 7, the temperature variant phasor of block copolymer solution of the different concns that Fig. 7 obtains for the embodiment of the invention 11.Can know that by Fig. 7 when block copolymer solution concentration was 6%～12%, it was 30 ℃～40 ℃ by the temperature that solution forms hydrogel, can under body temperature, form hydrogel, therefore can be used as injectable sexual type gel, use as pharmaceutical carrier or timbering material.

Embodiment 43

It is 3%～12% phosphate buffer solution that the segmented copolymer of the embodiment of the invention 12 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃～80 ℃ and changes, and when being inverted with tubule, not taking place in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min.

The result is referring to Fig. 8, the temperature variant phasor of block copolymer solution of the different concns that Fig. 8 obtains for the embodiment of the invention 12.Can know that by Fig. 8 gelation can take place this block copolymer solution, and this gelation process is a reversible; Because this block copolymer solution forms the temperature of gel near body temperature, therefore can be used as the injectable type hydrogel, use as pharmaceutical carrier or timbering material.

Embodiment 44

It is 9%～20% phosphate buffer solution that the segmented copolymer of the embodiment of the invention 13 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃～80 ℃ and changes, and when being inverted with tubule, not taking place in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min.

The result is referring to Fig. 9, the temperature variant phasor of block copolymer solution of the different concns that Fig. 9 obtains for the embodiment of the invention 13.Can know that by Fig. 9 the solution of this segmented copolymer can form hydrogel when temperature raises, and this gelation process is a reversible; This block copolymer solution forms the temperature of gel near body temperature, therefore can be used as the injectable type hydrogel, uses as pharmaceutical carrier or timbering material.

Embodiment 45

It is 9%～25% phosphate buffer solution that the segmented copolymer of the embodiment of the invention 14 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃～80 ℃ and changes, and when being inverted with tubule, not taking place in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min.

The result is referring to Figure 10, the temperature variant phasor of block copolymer solution of the different concns that Figure 10 obtains for the embodiment of the invention 14.Can know that by Figure 10 the solution of this segmented copolymer can form hydrogel when temperature raises, and this gelation process is a reversible; This block copolymer solution forms the temperature of gel near body temperature, therefore can be used as the injectable type hydrogel, use as pharmaceutical carrier or timbering material,

Embodiment 46

It is 9%～25% phosphate buffer solution that the segmented copolymer of embodiment 15 preparation is mixed with mass concentration, adopts the tubule inverted type to observe its viscosity at 5 ℃～80 ℃ and changes, and when being inverted with tubule, not taking place in the 30s to flow is gelation.Balance 10min under each temperature, temperature rise rate are 2 ℃/min.

The result is referring to Figure 11, the temperature variant phasor of block copolymer solution of the different concns that Figure 11 obtains for the embodiment of the invention 46.Can know that by Figure 11 the solution of this segmented copolymer can form hydrogel when temperature raises, and this gelation process is a reversible; Therefore the capable temperature that becomes gel of this block copolymer solution can be used as the injectable type hydrogel near body temperature, as pharmaceutical carrier or timbering material application.

Embodiment 47

It is 6% PBS buffered soln that the segmented copolymer of the embodiment of the invention 12 preparation is mixed with mass concentration, and 0.5mL buffered soln is placed 10min in 37 ℃ constant-temperature shaking case, forms hydrogel; Then the said PBS solution of 3mL is joined in the above-mentioned hydrogel,, solution is taken out, adopt weighting method that sample is analyzed, add the new buffered soln of 3mL then in the time period of setting.Attached gel permeation chromatography (GPC) is analyzed sample simultaneously, and the result shows that the degradation cycle of said segmented copolymer was 12 weeks, and degraded product is polyoxyethylene glycol and L-L-glutamic acid.

Can know that by above embodiment segmented copolymer provided by the invention has different molecular weight, can regulate the transformation temperature of the temperature sensitive type water gel of its formation; And contain alkyl substituent on the side chain of segmented copolymer provided by the invention; Through regulating factors such as substituent kind, structure, carbon chain lengths; Obtain containing the segmented copolymer of different substituents side chain, thereby regulate the transformation behavior of the temperature sensitive type water gel of its formation; In addition; It is different to gather (γ-didodecyl l glutamic acid ester) content in the segmented copolymer provided by the invention; Obtain difference and gather the segmented copolymer of (γ-didodecyl l glutamic acid ester) content, thus the transformation behavior of the temperature sensitive type water gel that adjusting obtains, and segmented copolymer provided by the invention is better to the transformation behavior controllability of the temperature sensitive type water gel of its formation; Expanded regulating measure, helped temperature sensitive type water gel and further use the temperature sensitive type water gel transformation behavior.The gelling temperature of the temperature sensitive type water gel that segmented copolymer provided by the invention forms can be used as the injectable type hydrogel near body temperature, use as pharmaceutical carrier or timbering material.Temperature sensitive type water gel provided by the invention has excellent biological compatibility and biological degradability; Its degradation cycle was 10 week～15 weeks; Help medicine in long its drug effect of performance just of diseased region; Degraded product is polyoxyethylene glycol and L-L-glutamic acid, can directly get rid of external, harmless through kidney.

The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.

Claims

1. segmented copolymer comprises first block and second block with formula (III) structure of have formula (I) or formula (II) structure:

Wherein, R is the alkyl that contains 10 following carbon atoms;

M is the polymerization degree, 10≤m≤227;

N is the polymerization degree, 10≤n≤226;

Q is the polymerization degree, 3≤q≤150.

2. segmented copolymer according to claim 1 is characterized in that, said R is methyl, ethyl, n-propyl, sec.-propyl or normal-butyl.

3. segmented copolymer according to claim 1 is characterized in that, the weight percentage that said second block accounts for said segmented copolymer is 25%～70%.

4. the preparation method of a segmented copolymer may further comprise the steps:

Wherein, m is the polymerization degree, 10≤m≤227;

N is the polymerization degree, 10≤n≤226.

5. preparation method according to claim 4; It is characterized in that said have the amidized poly glycol monomethyl ether of end of formula (IV) structure or have the amidized polyoxyethylene glycol of end of formula V structure and the mol ratio of γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride is 1: (5～120).

6. preparation method according to claim 4 is characterized in that, said γ-didodecyl l glutamic acid ester-N-carboxylic acid inner-acid anhydride prepares according to following method:

7. preparation method according to claim 6 is characterized in that, said alcohol compound is methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol.

8. a temperature sensitive type water gel comprises any described segmented copolymer of claim 1～7 and solvent.

9. temperature sensitive type water gel according to claim 8 is characterized in that, said solvent is water, saline water, buffered soln, tissue culture medium or body fluid.

10. temperature sensitive type water gel according to claim 8 is characterized in that, the massfraction of said segmented copolymer is 2%～30%.