CN102964582A - Segmented copolymer, preparation method thereof and hydrogel - Google Patents
Segmented copolymer, preparation method thereof and hydrogel Download PDFInfo
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- CN102964582A CN102964582A CN2012105127743A CN201210512774A CN102964582A CN 102964582 A CN102964582 A CN 102964582A CN 2012105127743 A CN2012105127743 A CN 2012105127743A CN 201210512774 A CN201210512774 A CN 201210512774A CN 102964582 A CN102964582 A CN 102964582A
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Abstract
The invention provides a segmented copolymer which comprises a segment A with a structure shown in a formula (I) or a formula (II) and a segment B with a structure shown in a formula (III) or a formula (IV). A laevo-configuration segmented copolymer and a dextro-configuration segmented copolymer are mixed in a water-based medium, and can be gradually transformed into a three-dimensional compound hydrogel material from a solution. Because the segment with the structure shown in the formula (III) or the formula (IV) contains an aniline oligomer segment, the segment B has a intermolecular pi-pi acting force and conjugated pi electrons have conductivity, the prepared segmented copolymer and the hydrogel have better electrochemical response characteristics; and meanwhile, the segment A is extremely dissolved in water, a packaged micelle formed by the segment A and the segment B under a certain linkage quantity can be dissolved in water. Therefore, the segmented copolymer and hydrogel provided by the invention have better water-solubility.
Description
Technical field
The present invention relates to field of biomedical polymer materials, relate in particular to a kind of segmented copolymer, its preparation method and hydrogel.
Background technology
Injection aquagel is the polymkeric substance with cross-linked network structure that a class can absorb and possess large quantity of moisture, such material can carry out crosslinked based on physical force, compound such as hydrophobic interaction, static, three-dimensional compound, hydrogen bond action etc., can also carry out crosslinked based on chemical reaction, such as the mode such as Michael addition, photo-crosslinking, cycloaddition, oxidative coupling, enzyme be crosslinked, and then generation solution-gel conversion, therefore at aspects such as regenerative medicine and medicine controlled releasings widely purposes being arranged, is the new research direction of biomedical materials field in recent years.Because it has good fluidity, easy to use, the characteristics such as the residence time is long, the surface of a wound is little, the similar tissue of performance, and it has preferably perviousness to low molecule solute, good biocompatibility and circulation ratio are preferably arranged, synthetic easily, thereby paid close attention to widely.
Injection aquagel can make the medicine of embedding stablize in the controlled arrival body fluid, and by medicine is mixed with polymers soln, in-situ injection forms the control release that gel reaches medicine in body again.Electroactive material, such as conductive polymers because its more easy advantage such as synthetic, cheap also is applied to the medicine controlled releasing field preferably.Wherein, have electroactive aniline oligomer and with the pH variation reversible doping can occur, electrochemical doping can occur with the redox-potential variation, cause the variation of polymer materials packaging assembly, and then have embedding, discharge the ability of medicine and bioactive molecules aspect, this is so that it can be applied to the medicine controlled releasing field.Simultaneously, all transmit relevant with electronics based on the organism internal reaction, and cell is to the susceptibility of electrical signal, by introducing adhesion, growth, differentiation, the apoptosis that electroactive material can regulating cell, therefore having electroactive conductive polymers has larger advantage in medicine controlled releasing, field of tissue engineering technology.
Prior art discloses multiple injection aquagel, such as the block copolymer hydrogel of polyoxyethylene glycol and PLLA, can realize the reversible change of colloidal sol and gel when temperature variation; The segmented copolymer that polyoxyethylene-polyoxytrimethylene polymkeric substance and polyalanine form also can form injectable gel under finite concentration.But the injection aquagel of prior art preparation does not all have electroactive.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of segmented copolymer, its preparation method and hydrogel, and the segmented copolymer for preparing and hydrogel not only have good water-soluble, and have good electrochemical response characteristic.
The invention provides a kind of segmented copolymer, comprise the have formula A block of (I) or formula (II) structure and the B block with formula (III) or formula IV structure:
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
Preferably, in described formula (III) or the formula IV, x is selected from 3 or 4.
Preferably, to account for the mass percent of described segmented copolymer be 10% ~ 50% to described B block.
The present invention also provides a kind of preparation method of segmented copolymer, comprising:
A) polyoxyethylene glycol or poly glycol monomethyl ether and rac-Lactide, catalyst mix are carried out ring-opening polymerization, obtain the segmented copolymer intermediate, and described rac-Lactide is left-handed-rac-Lactide or dextrorotation-rac-Lactide;
B) with steps A) segmented copolymer intermediate and the coupling reagent that obtains and the compound with formula (V) structure, condensation reaction occurs, obtain segmented copolymer;
Wherein,
X is the polymerization degree, 2≤x≤5.
Preferably, the mol ratio of described polyoxyethylene glycol or poly glycol monomethyl ether and rac-Lactide is 1:1 ~ 45.
Preferably, the segmented copolymer intermediate that described steps A) obtains and described mass ratio with compound of formula (V) structure are 1:0.01 ~ 1.
Preferably, described catalyzer is stannous octoate, and described coupling reagent is selected from N, any one or a few in N-carbodicyclo hexylimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and the 4-dimethylamino pyridine.
Preferably, described steps A) in, the temperature of described ring-opening polymerization is 100 ℃ ~ 150 ℃, the time of described ring-opening polymerization is 12h ~ 48h.
Preferably, described step B) in, the temperature of described condensation reaction is 0 ℃ ~ 60 ℃, the time of described condensation reaction is 24h ~ 72h.
The present invention also provides a kind of hydrogel, comprises aqueous medium and three-dimensional compound segmented copolymer, and described aqueous medium is selected from any one or a few in water, physiological saline, buffered soln, tissue culture medium or the body fluid; The compound segmented copolymer of described solid is formed with the second segmented copolymer that formula IV forms by the first segmented copolymer and the formula (I) that formula (I) and formula (III) form; The first segmented copolymer and the formula (II) that are perhaps formed by formula (II) and formula (III) form with the second segmented copolymer that formula IV forms;
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
Preferably, the first segmented copolymer of described formula (I) and formula (III) formation and described formula (I) are 0.5 ~ 1.5:1 with the ratio of the number-average molecular weight of the second segmented copolymer of formula IV formation; The first segmented copolymer that described formula (II) and formula (III) form and described formula (II) are 0.5 ~ 1.5:1 with the ratio of the number-average molecular weight of the second segmented copolymer of formula IV formation.
Preferably, described x is selected from 3 or 4.
Segmented copolymer provided by the invention comprises the have formula A block of (I) or formula (II) structure and the B block with formula (III) or formula IV structure.Contain the aniline oligomer fragment owing to have the B block of formula (III) or formula IV structure, itself have Intermolecularπ πinteraction power, the π-electron of conjugation has electroconductibility, and therefore, the segmented copolymer for preparing has good electrochemical response characteristic; Simultaneously, because A and the formed micella of B block of certain chain number ratio are water-soluble, therefore, segmented copolymer provided by the invention also has good water-soluble.The segmented copolymer of the laevo-oonfiguration of the present invention preparation is mixed in aqueous medium with the segmented copolymer of dextrorotation configuration, can be changed by solution gradually and form three-dimensional compound water congealing glue material, the character such as that the hydrogel that obtains has is electroactive, water-soluble, degradable, injectable can be used as pharmaceutical carrier or timbering material etc. and are applied to biomedical materials field.
Description of drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer that obtains in the embodiment of the invention 8;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 70 preparations;
Fig. 3 is the dynamic mechanical test figure of the hydrogel that forms of the segmented copolymers of the embodiment of the invention 58 and 82 preparations;
Fig. 4 is the uv-absorbing figure of the segmented copolymer of the embodiment of the invention 114 preparations;
Fig. 5 is the uv-absorbing figure of the segmented copolymer of the embodiment of the invention 144 preparations.
Embodiment
The invention provides a kind of segmented copolymer, comprise the have formula A block of (I) or formula (II) structure and the B block with formula (III) or formula IV structure:
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
Contain the aniline oligomer fragment owing to have the B block of formula (III) or formula IV structure, itself has Intermolecularπ πinteraction power, the π-electron of conjugation has electroconductibility, and therefore, the segmented copolymer for preparing and hydrogel have good electrochemical response characteristic; Simultaneously, A block and the formed micella of B block of certain chain number ratio are water-soluble, and therefore, segmented copolymer provided by the invention and hydrogel also have good water-soluble.
Segmented copolymer provided by the invention, comprise the have formula A block of (I) or formula (II) structure and the B block with formula (III) or formula IV structure, preferably, formula (I) and formula (III) form poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide segmented copolymer of BAB block configuration, formula (I) and formula IV form poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide segmented copolymer of BAB block configuration, formula (II) and formula (III) form the poly glycol monomethyl ether of AB block configuration-poly-(L) rac-Lactide segmented copolymer, and formula (II) and formula IV form the poly glycol monomethyl ether of AB block configuration-poly-(D) rac-Lactide segmented copolymer.
Wherein, described n is the polymerization degree, and is preferred, and 23≤n≤500 are preferred, 30≤n≤450; Described m is the polymerization degree, and is preferred, and 3≤m≤90 are preferred, 10≤m≤80; Described x is the polymerization degree, and is preferred, 2≤x≤5, and preferred, x is 3 or 4.
The mass percent that described B block accounts for described segmented copolymer is preferably 10% ~ 50%.
The number-average molecular weight of described A block is preferably 1000 ~ 22000, and more preferably 1500 ~ 20000; The number-average molecular weight of described B block is preferably 200 ~ 8000, and more preferably 200 ~ 6500.
The segmented copolymer of laevo-oonfiguration is mixed in aqueous medium with the segmented copolymer of dextrorotation configuration, can prepare and have electroactive three-dimensional compound water congealing glue material.
The present invention also provides a kind of preparation method of segmented copolymer, may further comprise the steps:
A) polyoxyethylene glycol or poly glycol monomethyl ether and rac-Lactide, catalyst mix are carried out ring-opening polymerization, obtain the segmented copolymer intermediate, and described rac-Lactide is left-handed-rac-Lactide or dextrorotation-rac-Lactide;
B) with steps A) segmented copolymer intermediate and the coupling reagent that obtains and the compound with formula (V) structure, condensation reaction occurs, obtain segmented copolymer;
Wherein,
X is the polymerization degree, 2≤x≤5.
Preferably, x is 3 or 4.
At first, with polyoxyethylene glycol or poly glycol monomethyl ether and rac-Lactide, catalyst mix, carry out ring-opening polymerization.
Among the present invention, described polyoxyethylene glycol or poly glycol monomethyl ether are as the initiator of rac-Lactide ring-opening polymerization, its number-average molecular weight is preferably 1000 ~ 22000, and the present invention there is no particular requirement to source and the purity of described polyoxyethylene glycol and poly glycol monomethyl ether, can be for generally commercially available.The present invention to described left-handed-source of rac-Lactide or dextrorotation-rac-Lactide (hereinafter to be referred as (L/D) rac-Lactide) there is no particular requirement, can be for generally commercially available.Described catalyzer is preferably stannous octoate, and the present invention there is no particular requirement to the source of described stannous octoate, can be for generally commercially available.Among the present invention, described polyoxyethylene glycol or poly glycol monomethyl ether and (L/D) mol ratio of rac-Lactide be preferably 1:1 ~ 45,1:2 ~ 30 more preferably; Described catalyzer is preferably 0.001 ~ 0.05:1 with (L/D) mass ratio of rac-Lactide, more preferably 0.005 ~ 0.03:1.The present invention preferably carries out ring-opening polymerization in organic solvent, the present invention there is no particular restriction to described organic solvent, can dissolve described polyoxyethylene glycol or poly glycol monomethyl ether and (L/D) rac-Lactide, catalyzer get final product, be preferably any one or two kinds in toluene and the benzene.The present invention preferably carries out under the anhydrous and oxygen-free condition, and described anhydrous and oxygen-free condition optimization is nitrogen or argon shield.
Concrete, at first with toluene or benzene polyoxyethylene glycol or poly glycol monomethyl ether are carried out azeotropic water removing, then vacuum is removed toluene or benzene, and the condition optimization of described azeotropic water removing is 120 ℃ ~ 160 ℃ heated and stirred; Simultaneously, with ethyl acetate (L/D) rac-Lactide is carried out recrystallization and purify, then vacuum is removed ethyl acetate; Then the polyoxyethylene glycol after a certain amount of the dewatering or poly glycol monomethyl ether are mixed with (L/D) rac-Lactide behind the recrystallization, under the anhydrous and oxygen-free condition, the toluene or the benzole soln that add a certain amount of stannous octoate, the toluene of described stannous octoate or the concentration of benzole soln are preferably 0.02mmol/mL ~ 0.08mmol/mL, and then fill into a certain amount of toluene or benzene as solvent, carry out ring-opening polymerization, the condition optimization of described reaction is stirring reaction, the temperature of described ring-opening polymerization is preferably 100 ℃ ~ 150 ℃, more preferably 110 ℃ ~ 140 ℃; The time of described ring-opening polymerization is preferably 12h ~ 48h, more preferably 24h ~ 48h.The solvent of described reaction can be benzene or toluene, also can be the mixed solvent of benzene and toluene, and the present invention there is no particular restriction to this.
After reaction finishes, product is purified, preferably, with reaction solution ethanol/ether mixed solution sedimentation, suction filtration obtains solid, again solid is dissolved with chloroform, then use ethanol/ether mixed solution sedimentation, repeated multiple times, obtain the segmented copolymer intermediate after the vacuum-drying, namely gather (L/D) rac-Lactide-polyethylene glycol-(L/D) rac-Lactide segmented copolymer or poly glycol monomethyl ether-poly-(L/D) rac-Lactide segmented copolymer, its concrete structure is as follows:
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90.
After obtaining the segmented copolymer intermediate, with itself and coupling reagent with have the compound of formula (V) structure, condensation reaction occurs, wherein, described coupling reagent is preferably N, in N-carbodicyclo hexylimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and the 4-dimethylamino pyridine (DMAP) any one or a few, more preferably any one among EDC and the DMAP or two kinds.The present invention there is no particular requirement to the source of described coupling reagent, can be for generally commercially available.
The present invention there is no particular requirement to the source of the compound of described formula (V) structure, can be according to synthetic method preparation well known to those skilled in the art, and the present invention is in accordance with the following methods preparation preferably:
A, Isosorbide-5-Nitrae-p-phenylene diamine derivative that N is replaced react under the effect of oxygenant, obtain end group and are amino oligomer of phenylamine;
B, with the end group that obtains for amino oligomer of phenylamine and Succinic anhydried react, the compound of (V) structure that obtains having formula.
Condensation reaction occurs in the Isosorbide-5-Nitrae-p-phenylene diamine derivative who at first N is replaced under the effect of oxygenant, obtain end group and be amino oligomer of phenylamine.1 of described N replacement, the 4-p-phenylene diamine derivative is preferably N-phenyl-1,4-Ursol D, N-(4-anilino)-1,4-Ursol D and N, in N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D any one or a few, the present invention is to 1 of described N replacement, the source of 4-Ursol D there is no particular requirement, can be for generally commercially available.Described oxygenant is preferably ammonium persulphate, can be for generally commercially available.
Concrete, Isosorbide-5-Nitrae-p-phenylene diamine derivative that described N replaces preferably is dissolved in first in the mixing solutions of concentrated hydrochloric acid, organic solvent and water, described organic solvent be can be miscible with water organic solvent, the present invention is preferably acetone or DMF; Isosorbide-5-Nitrae-p-phenylene diamine derivative's that described N replaces quality and the volume ratio of concentrated hydrochloric acid, organic solvent and water are preferably 2g ~ 4g:10mL ~ 30mL:80mL ~ 120mL:10mL ~ 120mL.Then add oxygenant, Isosorbide-5-Nitrae-p-phenylene diamine derivative's that described oxygenant and N replace mass ratio is preferably 1:0.5 ~ 2; Described oxygenant preferably is dissolved in first the aqueous hydrochloric acid that concentration is 0.8mol/L ~ 1.5mol/L, be added dropwise to again 1 of described N replacement, carry out oxidizing reaction in 4-p-phenylene diamine derivative's the mixing solutions, described dropping is preferably carried out in ice-water bath, the time of described reaction is preferably 1h ~ 5h, the present invention there is no particular requirement to the temperature of described reaction, is preferably in the ice bath and reacts.After reaction finishes, filtration can obtain solid, described solid is 0.1mol/L ~ 0.8mol/L aqueous hydrochloric acid and washing with acetone with concentration successively preferably, after the filtration, carrying out contra-doping with 0.1mol/L ~ 0.6mol/L ammoniacal liquor processes, be washed at last neutral and drying, obtain end group and be amino oligomer of phenylamine.
After obtaining the oligomer of phenylamine of end group for amino, it is mixed, reacts with Succinic anhydried, preferred, first described end group is dissolved in the organic solvent for amino oligomer of phenylamine; Then, under the nitrogen protection Succinic anhydried is dissolved in the organic solvent; Then with the two mixing, stirring reaction.The present invention there is no particular requirement to described organic solvent, can dissolve described end group and get final product for amino oligomer of phenylamine and Succinic anhydried, and the present invention is preferably methylene dichloride; Described end group is that the oligomer of phenylamine of amino and the mol ratio of Succinic anhydried are preferably 1:5 ~ 15, more preferably 1:8 ~ 12; The time of described reaction is preferably 2h ~ 10h, more preferably 3h ~ 8h; The present invention there is no particular requirement to the temperature of described reaction, can be room temperature reaction; The present invention preferably reacts under nitrogen protection.After reaction finishes, preferred, the solid that obtains is used the methylene dichloride extracting in apparatus,Soxhlet's, then the compound of washing and drying (V) structure that obtains having formula.
Among the present invention, described compound with formula (V) structure is preferably following structure:
Formula (compound shown in the V-a) is in accordance with the following methods preparation preferably:
N-phenyl-Isosorbide-5-Nitrae-Ursol D is reacted under the oxygenant effect, obtain end group and be amino Tetraaniline;
With the end group that obtains for amino Tetraaniline and Succinic anhydried react, (the compound of structure of V-a) that obtains having formula.
At first N-phenyl-Isosorbide-5-Nitrae-Ursol D is reacted under the oxygenant effect, described oxygenant is preferably ammonium persulphate, can be for generally commercially available.Described N-phenyl-Isosorbide-5-Nitrae-Ursol D can be for generally commercially available.Concrete, described N-phenyl-Isosorbide-5-Nitrae-Ursol D preferably is dissolved in first in the mixing solutions of concentrated hydrochloric acid, organic solvent and water, described organic solvent be can be miscible with water organic solvent, the present invention is preferably acetone or DMF; The quality of described N-phenyl-Isosorbide-5-Nitrae-Ursol D and the volume ratio of concentrated hydrochloric acid, organic solvent and water are preferably 2g ~ 4g:10mL ~ 30mL:80mL ~ 120mL:10mL ~ 120mL.Then add oxygenant, the mass ratio of described oxygenant and N-phenyl-Isosorbide-5-Nitrae-Ursol D is preferably 1:0.5 ~ 2; Described oxygenant preferably is dissolved in first the aqueous hydrochloric acid that concentration is 0.8mol/L ~ 1.5mol/L, be added dropwise to again described N-phenyl-1, carry out oxidizing reaction in the mixing solutions of 4-Ursol D, described dropping is preferably carried out in ice-water bath, the time of described reaction is preferably 1h ~ 5h, the present invention there is no particular requirement to the temperature of described reaction, is preferably in the ice bath and reacts.After reaction finishes, filtration can obtain solid, described solid is 0.1mol/L ~ 0.8mol/L aqueous hydrochloric acid and washing with acetone with concentration successively preferably, after the filtration, carrying out contra-doping with 0.1mol/L ~ 0.6mol/L ammoniacal liquor processes, be washed at last neutral and drying, obtain end group and be amino Tetraaniline.
After obtaining the Tetraaniline of end group for amino, it is mixed, reacts with Succinic anhydried, preferred, first described end group is dissolved in the organic solvent for amino Tetraaniline; Then, under the nitrogen protection Succinic anhydried is dissolved in the organic solvent; Then with the two mixing, stirring reaction.The present invention there is no particular requirement to described organic solvent, can dissolve described end group and get final product for amino Tetraaniline and Succinic anhydried, and the present invention is preferably methylene dichloride; Described end group is that the Tetraaniline of amino and the mol ratio of Succinic anhydried are preferably 1:5 ~ 15, more preferably 1:8 ~ 12; The time of described reaction is preferably 2h ~ 10h, more preferably 3h ~ 8h; The present invention there is no particular requirement to the temperature of described reaction, can be room temperature reaction; The present invention preferably reacts under nitrogen protection.After reaction finishes, preferred, the solid that obtains is used the methylene dichloride extracting in apparatus,Soxhlet's, then washing and drying (the compound of structure of V-a) that obtains having formula.
Formula (compound shown in the V-b) is in accordance with the following methods preparation preferably:
With the N-(4-anilino)-Isosorbide-5-Nitrae-Ursol D and N, N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D reacts under catalyst action, obtains end group and is amino aniline pentamer;
With the end group that obtains for amino aniline pentamer and Succinic anhydried react, (the compound of structure of V-b) that obtains having formula.
At first with the N-(4-anilino)-Isosorbide-5-Nitrae-Ursol D and N, N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D reacts under the oxygenant effect, and described oxygenant is preferably ammonium persulphate, can be for generally commercially available.Described N-(4-anilino)-and Isosorbide-5-Nitrae-Ursol D and N, N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D can be for generally commercially available.Concrete, described N-(4-anilino)-Isosorbide-5-Nitrae-Ursol D and N, N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D preferably is dissolved in first in the mixing solutions of concentrated hydrochloric acid, organic solvent and water, described organic solvent be can be miscible with water organic solvent, the present invention is preferably acetone or DMF; Described N-(4-anilino)-and quality and the N of Isosorbide-5-Nitrae-Ursol D, the volume ratio of the quality of N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D and concentrated hydrochloric acid, organic solvent and water is preferably 2g ~ 4g:2g ~ 4g:10mL ~ 30mL:80mL ~ 120mL:10mL ~ 120mL.Then add oxygenant, described oxygenant and described N-(4-anilino)-Isosorbide-5-Nitrae-Ursol D and N, the mass ratio of N-phenylbenzene-Isosorbide-5-Nitrae-Ursol D is preferably 1:0.5 ~ 2:0.5 ~ 2; Described catalyzer preferably is dissolved in first the aqueous hydrochloric acid that concentration is 0.8mol/L ~ 1.5mol/L, be added dropwise to again described N-(4-anilino)-1,4-Ursol D and N, N-phenylbenzene-1, carry out oxidizing reaction in the mixing solutions of 4-Ursol D, described dropping is preferably carried out in ice-water bath, and the time of described reaction is preferably 1h ~ 5h, the present invention there is no particular requirement to the temperature of described reaction, is preferably in the ice bath and reacts.After reaction finished, filtration can obtain solid, and described solid is 0.1mol/L ~ 0.8mol/L hydrochloric acid and water washing with concentration successively preferably, after the filtration, carry out contra-doping with 0.1mol/L ~ 0.6mol/L ammoniacal liquor and process, be washed at last neutral and drying, obtain end group and be amino aniline pentamer.
After obtaining the aniline pentamer of end group for amino, it is mixed, reacts with Succinic anhydried, preferred, first described end group is dissolved in the organic solvent for amino aniline pentamer; Then, under the nitrogen protection Succinic anhydried is dissolved in the organic solvent; Then with the two mixing, stirring reaction.The present invention there is no particular requirement to described organic solvent, can dissolve described end group and get final product for amino aniline pentamer and Succinic anhydried, and the present invention is preferably methylene dichloride; Described end group is that the aniline pentamer of amino and the mol ratio of Succinic anhydried are preferably 1:5 ~ 15, more preferably 1:8 ~ 12; The time of described reaction is preferably 2h ~ 10h, more preferably 3h ~ 8h; The present invention there is no particular requirement to the temperature of described reaction, can be room temperature reaction; The present invention preferably reacts under nitrogen protection.After reaction finishes, preferred, the solid that obtains is used the methylene dichloride extracting in apparatus,Soxhlet's, then washing and drying (the compound of structure of V-b) that obtains having formula.
With segmented copolymer intermediate and coupling reagent and the compound with formula (V) structure, condensation reaction occurs, described segmented copolymer intermediate and described mass ratio with compound of formula (V) structure are preferably 1:0.01 ~ 1, more preferably 1:0.02 ~ 0.6; The mass ratio of described coupling reagent and described segmented copolymer intermediate is preferably 0.001 ~ 1:1, more preferably 0.003 ~ 0.8:1.The present invention preferably carries out condensation reaction in organic solvent, the present invention there is no particular restriction to described organic solvent, the compound that can dissolve described segmented copolymer intermediate, coupling reagent and have formula (V) structure gets final product, the present invention is preferably any one or a few in DMF, dimethyl sulfoxide (DMSO) and the N-Methyl pyrrolidone.The present invention preferably carries out under nitrogen protection.
Concrete, first segmented copolymer intermediate, coupling reagent and compound with formula (V) structure are processed with organic reagent respectively, then with its mixing, reaction.Described organic reagent is preferably any one or a few in DMF, dimethyl sulfoxide (DMSO) and the N-Methyl pyrrolidone, and the present invention preferably processes raw material under nitrogen protection and mixes and react.The temperature of described reaction is preferably 0 ℃ ~ 60 ℃, more preferably 20 ℃ ~ 50 ℃; The time of described condensation reaction is preferably 24h ~ 72h, more preferably 24h ~ 48h.
After reaction finishes, preferably, with ether reaction solution is carried out sedimentation, suction filtration gets crude product, then with chloroform crude product is dissolved, and removes by filter insolubles, with ethanol chloroformic solution is carried out sedimentation again, suction filtration obtains solid, and the step of repeatedly chloroform dissolving, ethanol sedimentation is further purified product, and drying obtains described segmented copolymer.
Described segmented copolymer is carried out nuclear magnetic resonance spectroscopy, and the result shows the segmented copolymer that obtains, and comprises the have formula A block of (I) or formula (II) structure and the B block with formula (III) formula IV structure:
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
The segmented copolymer for preparing is carried out uv-absorbing detect, the result shows, segmented copolymer provided by the invention has good electroactive.
Among the present invention, the poly glycol monomethyl ether of different molecular weight or polyoxyethylene glycol are as (L/D) rac-Lactide ring-opening reaction of initiator from different charging capacitys, can obtain the poly glycol monomethyl ether of different zip lengths-poly-(L/D) rac-Lactide or poly-(L/D) rac-Lactide-polyethylene glycol-(L/D) lactide copolymer, and then react with oligomer of phenylamine, control the ratio of (L/D) rac-Lactide and the type of oligomer of phenylamine, can prepare the polymer materials of different concns and recombination rate, electroactive response property, polarimetry nature.
The invention also discloses a kind of hydrogel, comprise aqueous medium and three-dimensional compound segmented copolymer, described aqueous medium is selected from any one or a few in water, physiological saline, buffered soln, tissue culture medium or the body fluid; The compound segmented copolymer of described solid is formed with the second segmented copolymer that formula IV forms by the first segmented copolymer and the formula (I) that formula (I) and formula (III) form; The first segmented copolymer and the formula (II) that are perhaps formed by formula (II) and formula (III) form with the second segmented copolymer that formula IV forms;
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
Preferably, x is 3 or 4.
Segmented copolymer provided by the present invention is formed by poly glycol monomethyl ether or polyoxyethylene glycol and rac-Lactide condensation, because rac-Lactide has the steric configuration of left-handed or dextrorotation, therefore, the segmented copolymer for preparing also has the steric configuration of left-handed or dextrorotation.The segmented copolymer of structure is close, that number-average molecular weight is close laevo-oonfiguration mixes with the segmented copolymer of dextrorotation configuration, mix with poly glycol monomethyl ether-poly-(D) rac-Lactide coupling Tetraaniline such as poly glycol monomethyl ether-poly-(L) rac-Lactide coupling Tetraaniline, or gather (L) rac-Lactide-polyethylene glycol-(L) rac-Lactide coupling aniline pentamer and mix with poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide coupling aniline pentamer, can obtain three-dimensional compound segmented copolymer.This three-dimensional compound segmented copolymer is mixed with aqueous medium, can be changed by solution gradually, formation has electroactive three-dimensional composite water gel.
The first segmented copolymer that described formula (I) and formula (III) form and described formula (I) are preferably 0.5 ~ 1.5:1, more preferably 0.8 ~ 1.2:1 with the ratio of the number-average molecular weight of the second segmented copolymer of formula IV formation; The first segmented copolymer that described formula (II) and formula (III) form and described formula (II) are preferably 0.5 ~ 1.5:1, more preferably 0.8 ~ 1.2:1 with the ratio of the number-average molecular weight of the second segmented copolymer of formula IV formation.
Most preferred, in the second segmented copolymer that the first segmented copolymer that described formula (I) and formula (III) form and described formula (I) and formula IV form, x has identical value; In the second segmented copolymer that the first segmented copolymer that described formula (II) and formula (III) form and described formula (II) and formula IV form, x has identical value.
The massfraction of the compound segmented copolymer of described solid in described aqueous medium is preferably 5% ~ 30%, and more preferably 10% ~ 25%.
The segmented copolymer of laevo-oonfiguration is mixed in solvent with the segmented copolymer of dextrorotation configuration, can prepare and have electroactive three-dimensional compound water congealing glue material, and gelation time, intensity and the solvability of the three-dimensional composite aquogel of concentration adjustment of chain length that can be by regulating segmented copolymer and polymers soln, owing to introduce oligomer of phenylamine, the hydrogel for preparing has good electroactive.Because prepared segmented copolymer all has good water-soluble, the hydrogel that therefore prepares also has good water-soluble.Its degradation cycle is tested, and the result shows that the degradation cycle of described hydrogel was 4 ~ 8 weeks.Therefore, hydrogel provided by the invention has injectable, degradable, good, the electroactive good characteristics of biocompatibility, can be used for biomedical materials field, especially has wide range of application at aspects such as medicine controlled releasing and organizational projects.
Segmented copolymer provided by the invention comprises the have formula A block of (I) or formula (II) structure and the B block with formula (III) or formula IV structure.Contain the aniline oligomer fragment owing to have the B block of formula (III) or formula IV structure, itself have Intermolecularπ πinteraction power, the π-electron of conjugation has electroconductibility, and therefore, the segmented copolymer for preparing has good electrochemical response characteristic; Simultaneously, because A block and the formed micella of B block of certain chain number ratio are water-soluble, therefore, segmented copolymer provided by the invention also has good water-soluble.The segmented copolymer of the laevo-oonfiguration of the present invention preparation is mixed in aqueous medium with the segmented copolymer of dextrorotation configuration, after for some time, can form three-dimensional compound water congealing glue material, the character such as that the hydrogel that obtains has is electroactive, water-soluble, degradable, injectable can be used as pharmaceutical carrier or timbering material etc. and are applied to biomedical materials field.
In order to further specify the present invention, below in conjunction with embodiment segmented copolymer provided by the invention, its preparation method and hydrogel are described in detail.
Embodiment 1
With N-phenyl-Isosorbide-5-Nitrae-Ursol D 3.68g(0.02mol) be dissolved in the mixed solution of 100mL acetone, 100mL water and 25mL concentrated hydrochloric acid and obtain N-phenyl-Isosorbide-5-Nitrae-Ursol D mixed solution, and be refrigerated to 0 ℃; Take by weighing again ammonium persulphate (APS) 4.56g(0.02mol) be dissolved in the 50mL1mol/L HCl aqueous solution and obtain APS solution, under the ice bath APS solution is slowly splashed into N-phenyl-1, (drip off half an hour approximately) in the 4-Ursol D mixed solution, dripped off afterreaction 3 hours, then filter and obtain solid, use successively again the 0.6mol/L HCl aqueous solution, washing with acetone solid, with 0.5mol/L ammoniacal liquor solid is carried out contra-doping after filtering, use at last water washing solid three times to neutral, the freeze-drying final vacuum is dry, gets the product end group and is amino Tetraaniline.Productive rate is 80%.
Embodiment 2
With the N-(4-anilino)-1,4-Ursol D 3.5g and N, N-phenylbenzene-1,4-Ursol D 2.6g is dissolved in 100mL N, obtain the N-(4-anilino in the mixed solution of dinethylformamide, 15mL water and 15mL concentrated hydrochloric acid)-Isosorbide-5-Nitrae-Ursol D and N, N-phenylbenzene-1,4-Ursol D mixed solution, and be refrigerated to 0 ℃; Take by weighing again ammonium persulphate APS2.28g(0.01mol) be dissolved in the 50mL1mol/L HCl aqueous solution and obtain APS solution, under the ice bath APS solution is slowly splashed into the N-(4-anilino)-1,4-Ursol D and N, N-phenylbenzene-1, (drip off half an hour approximately) in the 4-Ursol D mixed solution, dripped off afterreaction 1 hour, then product is poured in the 700mL water and precipitated, filtration obtains solid, use successively the 0.1mol/L HCl aqueous solution, water washing solid three times, then the ammoniacal liquor with 0.1mol/L carries out contra-doping to solid, uses at last water washing solid three times to neutral, the freeze-drying final vacuum is dry, gets the product end group and is amino aniline pentamer.Productive rate 80%.
Embodiment 3
The end group that obtains among the embodiment 1 for being dissolved in, amino Tetraaniline 3g is obtained Tetraaniline solution in the methylene dichloride; Then get Succinic anhydried 4.1g, under the nitrogen protection, be dissolved in and obtain Succinic anhydried solution in the 400mL methylene dichloride; Tetraaniline solution is mixed with Succinic anhydried solution; the rapid stirring reaction has black precipitate progressively to separate out, and reacts after 5 hours; reaction product is filtered; get black precipitate, in apparatus,Soxhlet's, use the methylene dichloride extracting, at last with once washing three times; the freeze-drying final vacuum is dry, gets the Tetraaniline that the product end group is carboxyl.Productive rate is 80%.
Embodiment 4
The end group that obtains among the embodiment 2 for being dissolved in, amino aniline pentamer 3g is obtained aniline pentamer solution in the methylene dichloride; Then get Succinic anhydried 5.6g, under the nitrogen protection, be dissolved in and obtain Succinic anhydried solution in the 400mL methylene dichloride; aniline pentamer solution is mixed with Succinic anhydried solution; the rapid stirring reaction has black precipitate progressively to separate out, and reacts after 5 hours; reaction product is filtered; get black precipitate, in apparatus,Soxhlet's, use the methylene dichloride extracting, at last with once washing three times; the freeze-drying final vacuum is dry, and getting the product end group is the aniline pentamer of carboxyl.Productive rate is 70%.
Embodiment 5 ~ 16
Poly glycol monomethyl ether is placed the dry reaction bottle, and with toluene azeotropic water removing in 140 ℃ of oil baths, vacuum is drained, the poly glycol monomethyl ether after obtaining dewatering.Left-handed (L)-rac-Lactide is placed the dry reaction bottle, and with re-crystallizing in ethyl acetate three times, vacuum is drained, and obtains the L-rac-Lactide behind the recrystallization.Proportioning according to table 1, poly glycol monomethyl ether 5g after will dewatering respectively and the L-rac-Lactide behind the recrystallization together add in the dry reaction flask, under the anhydrous and oxygen-free condition, adding concentration is the stannous octoate catalyst toluene solution of 0.05mmol/mL, add again toluene, place 120 ℃ of oil baths, stirring reaction 24 hours.After reaction finished, with reaction solution 500mL ethanol/ether mixed solution sedimentation, suction filtration obtained solid, solid with the dissolving of 50mL chloroform, is then used 500mL ethanol/ether mixed solution sedimentation, three times so repeatedly, with the solid vacuum-drying that obtains 48 hours, get product at last.Productive rate is more than 80%.
The segmented copolymer that obtains is carried out respectively nuclear magnetic resonance spectroscopy, the result is referring to Fig. 1, Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer that obtains in the embodiment of the invention 8, by Fig. 1 chemical shift as can be known, 3.5ppm be the poly glycol monomethyl ether characteristic peak, rac-Lactide is 5.1ppm, illustrates that reaction has occured for poly glycol monomethyl ether and L-rac-Lactide, has generated segmented copolymer.Use gel permeation chromatography (GPC) that the number-average molecular weight of the segmented copolymer that obtains is tested, the results are shown in Table 1, table 1 is in the embodiment of the invention 5 ~ 16, and each raw material consumption and product number-average molecular weight gather.
In table 1 embodiment of the invention 5 ~ 16, each raw material consumption and product number-average molecular weight gather
Embodiment 17 ~ 28
Poly glycol monomethyl ether is placed the dry reaction bottle, and with toluene azeotropic water removing in 140 ℃ of oil baths, vacuum is drained, the poly glycol monomethyl ether after obtaining dewatering.Dextrorotation (D)-rac-Lactide is placed the dry reaction bottle, and with re-crystallizing in ethyl acetate three times, vacuum is drained, and obtains the D-rac-Lactide behind the recrystallization.Proportioning according to table 2, poly glycol monomethyl ether 5g after will dewatering respectively and the D-rac-Lactide behind the recrystallization together add in the dry reaction flask, under the anhydrous and oxygen-free condition, adding concentration is the stannous octoate catalyst toluene solution of 0.05mmol/mL, add again toluene, place 120 ℃ of oil baths, stirring reaction 24 hours.After reaction finished, with reaction solution 500mL ethanol/ether mixed solution sedimentation, suction filtration obtained solid, solid with the dissolving of 50mL chloroform, is then used 500mL ethanol/ether mixed solution sedimentation, three times so repeatedly, with the solid vacuum-drying that obtains 48 hours, get product at last.Productive rate is more than 80%.
The segmented copolymer that obtains is carried out respectively nuclear magnetic resonance spectroscopy, and the result shows that reaction has occured for poly glycol monomethyl ether and D-rac-Lactide, has generated segmented copolymer.Use GPC that the number-average molecular weight of the segmented copolymer that obtains is tested, the results are shown in Table 2, table 2 is in the embodiment of the invention 17 ~ 28, and each raw material consumption and product number-average molecular weight gather.
In table 2 embodiment of the invention 17 ~ 28, each raw material consumption and product number-average molecular weight gather
Embodiment 29 ~ 40
Polyoxyethylene glycol is placed the dry reaction bottle, and with toluene azeotropic water removing in 140 ℃ of oil baths, vacuum is drained, the polyoxyethylene glycol after obtaining dewatering.The L-rac-Lactide is placed the dry reaction bottle, and with re-crystallizing in ethyl acetate three times, vacuum is drained, and obtains the L-rac-Lactide behind the recrystallization.Proportioning according to table 3, polyoxyethylene glycol 5g after will dewatering respectively and the L-rac-Lactide behind the recrystallization together add in the dry reaction flask, under the anhydrous and oxygen-free condition, adding concentration is the stannous octoate catalyst toluene solution of 0.05mmol/mL, add again toluene, place 120 ℃ of oil baths, stirring reaction 24 hours.After reaction finished, with reaction solution 500mL ethanol/ether mixed solution sedimentation, suction filtration obtained solid, solid with the dissolving of 50mL chloroform, is then used 500mL ethanol/ether mixed solution sedimentation, three times so repeatedly, with the solid vacuum-drying that obtains 48 hours, get product at last.Productive rate is more than 80%.
The segmented copolymer that obtains is carried out respectively nuclear magnetic resonance spectroscopy, and the result shows that polyoxyethylene glycol and L-rac-Lactide react, and have generated segmented copolymer.Use GPC that the number-average molecular weight of the segmented copolymer that obtains is tested, the results are shown in Table 3, table 3 is in the embodiment of the invention 29 ~ 40, and each raw material consumption and product number-average molecular weight gather.
In table 3 embodiment of the invention 29 ~ 40, each raw material consumption and product number-average molecular weight gather
Embodiment 41 ~ 52
Polyoxyethylene glycol is placed the dry reaction bottle, and with toluene azeotropic water removing in 140 ℃ of oil baths, vacuum is drained, the polyoxyethylene glycol after obtaining dewatering.The D-rac-Lactide is placed the dry reaction bottle, and with re-crystallizing in ethyl acetate three times, vacuum is drained, and obtains the D-rac-Lactide behind the recrystallization.Proportioning according to table 4, polyoxyethylene glycol 5g after will dewatering respectively and the D-rac-Lactide behind the recrystallization together add in the dry reaction flask, under the anhydrous and oxygen-free condition, adding concentration is the stannous octoate catalyst toluene solution of 0.05mmol/mL, add again toluene, place 120 ℃ of oil baths, stirring reaction 24 hours.After reaction finished, with reaction solution 500mL ethanol/ether mixed solution sedimentation, suction filtration obtained solid, solid with the dissolving of 50mL chloroform, is then used 500mL ethanol/ether mixed solution sedimentation, three times so repeatedly, with the solid vacuum-drying that obtains 48 hours, get product at last.Productive rate is more than 80%.
The segmented copolymer that obtains is carried out respectively nuclear magnetic resonance spectroscopy, and the result shows that polyoxyethylene glycol and D-rac-Lactide react, and have generated segmented copolymer.Use GPC that the number-average molecular weight of the segmented copolymer that obtains is tested, the results are shown in Table 4, table 4 is in the embodiment of the invention 41 ~ 52, and each raw material consumption and product number-average molecular weight gather.
In table 4 embodiment of the invention 41 ~ 52, each raw material consumption and product number-average molecular weight gather
Embodiment 53 ~ 64
Proportioning according to table 5, respectively the poly glycol monomethyl ether of preparation among the embodiment 5-poly-(L) rac-Lactide segmented copolymer intermediate 1g and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl Tetraaniline of the embodiment 3 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain Tetraaniline solution; Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and Tetraaniline solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is obtained poly glycol monomethyl ether-poly-(L) rac-Lactide coupling Tetraaniline segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows that the characteristic peak of Tetraaniline has appearred in the 6.5-7.5ppm place, illustrates that Tetraaniline and poly glycol monomethyl ether-poly-(L) rac-Lactide reaction has occured, generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 5, table 5 is in the embodiment of the invention 53 ~ 64, and each raw material consumption and product number-average molecular weight gather.
In table 5 embodiment of the invention 53 ~ 64, each raw material consumption and product number-average molecular weight gather
Embodiment 65 ~ 76
Proportioning according to table 6, respectively poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide segmented copolymer intermediate 1g of preparation among the embodiment 29 and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl Tetraaniline of the embodiment 3 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain Tetraaniline solution; Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and Tetraaniline solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is gathered (L) rac-Lactide-polyethylene glycol-(L) rac-Lactide coupling Tetraaniline segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, the results are shown in Figure 2, Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the segmented copolymer of the embodiment of the invention 70 preparations, as shown in Figure 2,6.5-7.5ppm located to occur the characteristic peak of Tetraaniline, illustrate that reaction has occured for Tetraaniline and poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide, has generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 6, table 6 is in the embodiment of the invention 65 ~ 76, and each raw material consumption and product number-average molecular weight gather.
In table 6 embodiment of the invention 65 ~ 76, each raw material consumption and product number-average molecular weight gather
Embodiment 77 ~ 88
Proportioning according to table 7, respectively the poly glycol monomethyl ether of preparation among the embodiment 17-poly-(D) rac-Lactide segmented copolymer intermediate 1g and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl Tetraaniline of the embodiment 3 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain Tetraaniline solution.Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and Tetraaniline solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is obtained poly glycol monomethyl ether-poly-(D) rac-Lactide coupling Tetraaniline segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows that the characteristic peak of Tetraaniline has appearred in the 6.5-7.5ppm place, illustrates that Tetraaniline and poly glycol monomethyl ether-poly-(D) rac-Lactide reaction has occured, generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 7, table 7 is in the embodiment of the invention 77 ~ 88, and each raw material consumption and product number-average molecular weight gather.
In table 7 embodiment of the invention 77 ~ 88, each raw material consumption and product number-average molecular weight gather
Embodiment 89 ~ 100
Proportioning according to table 8, respectively poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide segmented copolymer intermediate 1g of preparation among the embodiment 41 and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl Tetraaniline of the embodiment 3 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain Tetraaniline solution.Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and Tetraaniline solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is gathered (D) rac-Lactide-polyethylene glycol-(D) rac-Lactide coupling Tetraaniline segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, the result shows, 6.5-7.5ppm located to occur the characteristic peak of Tetraaniline, illustrated that reaction has occured for Tetraaniline and poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide, has generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 8, table 8 is in the embodiment of the invention 89 ~ 100, and each raw material consumption and product number-average molecular weight gather.
In table 8 embodiment of the invention 89 ~ 100, each raw material consumption and product number-average molecular weight gather
Embodiment 101 ~ 112
Proportioning according to table 9, respectively the poly glycol monomethyl ether of preparation among the embodiment 5-poly-(L) rac-Lactide segmented copolymer intermediate 1g and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains block copolymer solution, EDC solution, DMAP solution.With the end carboxyl aniline pentamer of the embodiment 4 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain aniline pentamer solution.Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and aniline pentamer solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is obtained poly glycol monomethyl ether-poly-(L) rac-Lactide coupling aniline pentamer segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows that aniline pentamer and poly glycol monomethyl ether-poly-(L) rac-Lactide reaction has occured, generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 9, table 9 is in the embodiment of the invention 101 ~ 112, and each raw material consumption and product number-average molecular weight gather.
In table 9 embodiment of the invention 101 ~ 112, each raw material consumption and product number-average molecular weight gather
Embodiment 113 ~ 124
Proportioning according to table 10, respectively poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide segmented copolymer intermediate 1g of preparation among the embodiment 29 and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl aniline pentamer of the embodiment 4 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain aniline pentamer solution.Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and aniline pentamer solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is gathered (L) rac-Lactide-polyethylene glycol-(L) rac-Lactide coupling aniline pentamer segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows that the aniline pentamer with poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide reaction has occured, and has generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 10, table 10 is in the embodiment of the invention 113 ~ 124, and each raw material consumption and product number-average molecular weight gather.
In table 10 embodiment of the invention 113 ~ 124, each raw material consumption and product number-average molecular weight gather
Embodiment 125 ~ 136
Proportioning according to table 11, respectively the poly glycol monomethyl ether of preparation among the embodiment 17-poly-(D) rac-Lactide segmented copolymer intermediate 1g and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl aniline pentamer of the embodiment 4 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain aniline pentamer solution.Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and aniline pentamer solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is obtained poly glycol monomethyl ether-poly-(D) rac-Lactide coupling aniline pentamer segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows that aniline pentamer and poly glycol monomethyl ether-poly-(D) rac-Lactide reaction has occured, generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 11, table 11 is in the embodiment of the invention 125 ~ 136, and each raw material consumption and product number-average molecular weight gather.
In table 11 embodiment of the invention 125 ~ 136, each raw material consumption and product number-average molecular weight gather
Embodiment 137 ~ 148
Proportioning according to table 12, respectively poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide segmented copolymer intermediate 1g of preparation among the embodiment 41 and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) and 4-dimethylamino pyridine (DMAP) are packed in three reaction flasks with stirrer, after each reaction flask changes nitrogen three times, each injects 20mL N, dinethylformamide is made solvent, room temperature reaction 2 days obtains respectively block copolymer solution, EDC solution, DMAP solution.With the end carboxyl aniline pentamer of the embodiment 4 preparation reaction flask of packing into, change nitrogen three times after, inject the 10mL DMF and make it to dissolve fully, obtain aniline pentamer solution.Under the nitrogen protection block copolymer solution, EDC solution, DMAP solution and aniline pentamer solution are mixed, be warming up to 50 ℃ of reactions 24 hours.Reaction is carried out sedimentation with ether to reaction soln after finishing, and suction filtration obtains crude product.Crude product is carried out purifying, at first with chloroform with dissolution of solid, after removing by filter insolubles, with ethanol chloroformic solution is carried out sedimentation, suction filtration obtains solid, continues to dissolve with chloroform, three times so repeatedly, at room temperature vacuum-drying of solid after 24 hours, is gathered (D) rac-Lactide-polyethylene glycol-(D) rac-Lactide coupling aniline pentamer segmented copolymer, and productive rate all is higher than 80%.
The segmented copolymer that obtains is carried out nuclear magnetic resonance spectroscopy, and the result shows that the aniline pentamer with poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide reaction has occured, and has generated segmented copolymer.Use GPC that the molecular weight of the segmented copolymer that obtains is detected, the results are shown in Table 12, table 12 is in the embodiment of the invention 137 ~ 148, and each raw material consumption and product number-average molecular weight gather.
In table 12 embodiment of the invention 137 ~ 148, each raw material consumption and product number-average molecular weight gather
Embodiment 149
Respectively the segmented copolymer of embodiment 53 ~ 148 preparation is mixed with mass concentration and is 20% the aqueous solution, according to poly glycol monomethyl ether-poly-(L) rac-Lactide coupling Tetraaniline and poly glycol monomethyl ether-poly-(D) rac-Lactide coupling Tetraaniline pairing, poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide coupling Tetraaniline and poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide coupling Tetraaniline pairing, poly glycol monomethyl ether-poly-(L) rac-Lactide coupling aniline pentamer and poly glycol monomethyl ether-poly-(D) rac-Lactide coupling aniline pentamer pairing, the matching method of poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide coupling aniline pentamer and poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide coupling aniline pentamer pairing, molecular weight is corresponding approaching, the segmented copolymer that chirality is different, as with embodiment 58 and embodiment 82, perhaps embodiment 67 and embodiment 91 are mixed with respectively the solution of 10wt% concentration, respectively getting 0.5mL mixes, leave standstill for some time, adopt the tubule inverted type to observe its viscosity and change, tubule is inverted the mobile gelation point that is not being occured in the 30s.
Experimental result shows, the segmented copolymer of laevo-oonfiguration provided by the invention is mixed in aqueous medium with the segmented copolymer of dextrorotation configuration, can be changed by solution gradually, form three-dimensional compound water congealing glue material.
Embodiment 150
The segmented copolymer of the embodiment of the invention 53 ~ 148 preparations is made three-dimensional composite aquogel according to the method for embodiment 149, then the 3mL phosphate buffer soln is joined in the above-mentioned hydrogel, every other day, solution is taken out, adopt weighting method that sample is analyzed, then add the new buffered soln of 3mL.The result shows that the degradation cycle of the segmented copolymer of the present invention's preparation was 4 ~ 8 weeks.
Embodiment 151
The segmented copolymer of the embodiment of the invention 53 ~ 148 preparations is made three-dimensional composite aquogel according to the method for embodiment 149, utilize rheometer to measure over time situation of the three-dimensional composite modulus of aqueous solutions of polymers.Experimental result is seen Fig. 3, and Fig. 3 is the dynamic mechanical test figure of the hydrogel that forms of the segmented copolymers of embodiment 58 and 82 preparations, as shown in Figure 3, the three-dimensional composite aquogel of the present invention's preparation, its Young's modulus is higher than its out-of-phase modulus.
Embodiment 152
With the segmented copolymer of the embodiment of the invention 53 ~ 148 preparations, be mixed with the aqueous solution of 0.05mg/mL, progressively to wherein adding the 0.1mol/L aqueous hydrochloric acid, the uv-absorbing change procedure that oligomer of phenylamine mixes gradually in the observation material.Experimental result is seen Fig. 4, Fig. 4 is the uv-absorbing figure of poly-(L) rac-Lactide-polyethylene glycol-(L) rac-Lactide coupling aniline pentamer segmented copolymer of the embodiment of the invention 114 preparations, as shown in Figure 4, segmented copolymer provided by the invention has good electroactive.
Embodiment 153
With the segmented copolymer of the embodiment of the invention 53 ~ 148 preparation, be mixed with the aqueous solution of 0.05mg/mL, progressively to the ammonium persulfate solution that wherein adds 0.01mmol/L, the oligomer of phenylamine uv-absorbing change procedure of oxidation gradually in the observation material.Experimental result is seen Fig. 5, Fig. 5 is the uv-absorbing figure of poly-(D) rac-Lactide-polyethylene glycol-(D) rac-Lactide coupling aniline pentamer segmented copolymer of the embodiment of the invention 144 preparations, as shown in Figure 5, segmented copolymer provided by the invention has good electroactive.
Comparative example 1
With the segmented copolymer of the embodiment of the invention 5 ~ 52 preparations, be mixed with the aqueous solution of 0.05mg/mL, according to the method for embodiment 152, it is carried out the uv-absorbing test.Experimental result shows that the segmented copolymer of embodiment 5 ~ 52 preparations does not have electroactive.
By above-described embodiment and comparative example as can be known, segmented copolymer provided by the invention has good water-soluble and electroactive, the segmented copolymer of laevo-oonfiguration is mixed in aqueous medium with the segmented copolymer of dextrorotation configuration, after for some time, can form three-dimensional compound water congealing glue material, it has the character such as electroactive, water-soluble, degradable, injectable, can be used as pharmaceutical carrier or timbering material etc. and is applied to biomedical materials field.
The explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.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 carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (12)
1. segmented copolymer comprises have formula (I) or the A block of formula (II) structure and the B block with formula (III) or formula IV structure:
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
2. segmented copolymer according to claim 1 is characterized in that, in described formula (III) or the formula IV, x is selected from 3 or 4.
3. segmented copolymer according to claim 1 and 2 is characterized in that, the mass percent that described B block accounts for described segmented copolymer is 10% ~ 50%.
4. the preparation method of a segmented copolymer is characterized in that, comprising:
A) polyoxyethylene glycol or poly glycol monomethyl ether and rac-Lactide, catalyst mix are carried out ring-opening polymerization, obtain the segmented copolymer intermediate, and described rac-Lactide is left-handed-rac-Lactide or dextrorotation-rac-Lactide;
B) with steps A) segmented copolymer intermediate and the coupling reagent that obtains and the compound with formula (V) structure, condensation reaction occurs, obtain segmented copolymer;
Wherein,
X is the polymerization degree, 2≤x≤5.
5. method according to claim 4 is characterized in that, the mol ratio of described polyoxyethylene glycol or poly glycol monomethyl ether and rac-Lactide is 1:1 ~ 45.
6. method according to claim 4 is characterized in that, described steps A) the segmented copolymer intermediate and the described mass ratio with compound of formula (V) structure that obtain be 1:0.01 ~ 1.
7. method according to claim 4, it is characterized in that, described catalyzer is stannous octoate, and described coupling reagent is selected from N, any one or a few in N-carbodicyclo hexylimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and the 4-dimethylamino pyridine.
8. method according to claim 4 is characterized in that, described steps A) in, the temperature of described ring-opening polymerization is 100 ℃ ~ 150 ℃, the time of described ring-opening polymerization is 12h ~ 48h.
9. method according to claim 4 is characterized in that, described step B) in, the temperature of described condensation reaction is 0 ℃ ~ 60 ℃, the time of described condensation reaction is 24h ~ 72h.
10. a hydrogel comprises aqueous medium and three-dimensional compound segmented copolymer, and described aqueous medium is selected from any one or a few in water, physiological saline, buffered soln, tissue culture medium or the body fluid; The compound segmented copolymer of described solid is formed with the second segmented copolymer that formula IV forms by the first segmented copolymer and the formula (I) that formula (I) and formula (III) form; The first segmented copolymer and the formula (II) that are perhaps formed by formula (II) and formula (III) form with the second segmented copolymer that formula IV forms;
Wherein,
N is the polymerization degree, 23≤n≤500;
M is the polymerization degree, 3≤m≤90;
X is the polymerization degree, 2≤x≤5.
11. hydrogel according to claim 10 is characterized in that, the first segmented copolymer that described formula (I) and formula (III) form and described formula (I) are 0.5 ~ 1.5:1 with the ratio of the number-average molecular weight of the second segmented copolymer of formula IV formation; The first segmented copolymer that described formula (II) and formula (III) form and described formula (II) are 0.5 ~ 1.5:1 with the ratio of the number-average molecular weight of the second segmented copolymer of formula IV formation.
12. hydrogel according to claim 10 is characterized in that, described x is selected from 3 or 4.
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Address after: Changzhou City, Jiangsu province Hehai road 213000 No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 213000 Jiangsu City, Changzhou Province, East Sea Road, No. 9 Patentee before: Changzhou Institute of Energy Storage Materials & Devices |