CN105694030A - Oligo-polyamino acid and sodium alginate combined hybrid antibacterial hydrogel - Google Patents
Oligo-polyamino acid and sodium alginate combined hybrid antibacterial hydrogel Download PDFInfo
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Abstract
The invention discloses oligo-polyamino acid and sodium alginate combined hybrid antibacterial hydrogel. The invention provides an amphiphilic molecule based on oligo-polyamino acid as shown by formula I or II and a preparation method of the amphiphilic molecule based on oligo-polyamino acid. In the invention, the hybrid hydrogel prepared by combining the amphiphilic molecule based on polyamino acid with sodium alginate has the characteristics of biocompatibility, biodegradability and the like. A cationic lysine residue is introduced into the polyamino acid segment and experiences static combination with carboxyl on the sodium alginate to generate crosslinking, and the mechanical strength of the hydrogel is improved; and moreover, the cationic lysine has antibacterial activity, and thus the hybrid hydrogel has excellent antibacterial property. Moreover, compared with other types of antibacterial hydrogel materials, the hybrid antibacterial hydrogel has the advantages of low preparation cost, simplicity in preparation method, short preparation cycle, easiness in large-scale production, intrinsic antibacterial activity and the like and has a remarkably broad application prospect in the field of biomedical materials.
Description
Technical field
The present invention relates to the hydridization anti-bacterial hydrogel of a kind of oligomeric amino acid and sodium alginate compound, belong to Biodegradable material and biomedical materials field。
Background technology
Hydrogel is a kind of gel rubber system being disperse medium with water, and its water content can more than 80%。Due to advantageous property and the feature of hydrogel, it is widely used in food engineering, environmental project and biomedicine field。According to its Forming Mechanism, hydrogel can be divided into chemical gel and physical gel。Chemical gel is to be formed by intermolecular chemical crosslinking, its excellent in mechanical performance, stable performance。Physical gel is then formed by non-covalent bond (hydrogen bond, hydrophobe interact and electrostatic interaction) active force generation physical crosslinking, generally can there is reversible sol-gel transition in this gellike, it is not related to chemical reaction, preparation condition is gentle, is particluarly suitable for biomedical sector and applies。
Natural polymer is widely used in preparing hydrogel, such as carboxymethyl cellulose, chitosan, gelatin and sodium alginate etc., although above-mentioned hydrogel excellent in mechanical performance, but its function singleness, limits they application at medical field。In recent years, the research with polyfunctional polyamino acid class hydrogel receives much concern, and polyamino acid hydrogel has inherent good biocompatibility, biodegradability and Bioabsorbable。Different amino acid residue side is with different functional groups, and they can give material abundant functional, for instance electropositive lysine can give the anti-microbial property that material is good。The hydrogel with good anti-microbial property can greatly reduce the probability that injection site antibacterial infection occurs。At present, give its anti-microbial property (physics cladded type anti-bacterial hydrogel) usually through adding antibacterial in hydrogel, but this type of anti-bacterial hydrogel exists the shortcomings such as bactericidal action time short, adverse effect, limits its application clinically。Therefore, develop a kind of hydrogel self possessing anti-microbial property to be then particularly important。
Summary of the invention
It is an object of the invention to provide a kind of oligomeric amino acid amphiphile, amphiphilic molecule containing lysine and be compounded to form the stable hybridized hydrogel self with anti-microbial property with sodium alginate, described hybridized hydrogel can realize the anti-microbial property of self without additionally adding antibacterial, and the mechanical property of its hydrogel can be regulated and controled by changing molecular structural parameter and component ratio, the invention solves the current physics cladded type anti-bacterial hydrogel problem that anti-microbial property declines along with antibacterial release。
Present invention firstly provides a kind of amphiphile, amphiphilic molecule based on oligomeric amino acid, shown in its structural formula such as formula I or formula II,
In formula I and formula II, m is the natural number between 10～16, and n is the natural number between 2～20, and k is the natural number between 1～5, and x is 1 or 2；
In formula I, y is the natural number between 2～6；
In formula II, z is the natural number between 1～3。
In formula I, m concretely 14, n concretely 3 or 4, x concretely 2, y concretely 3。
The preparation method that invention further provides the shown amphiphile, amphiphilic molecule based on oligomeric amino acid of formula I, comprises the steps:
(1) γ-benzyl-Pidolidone ester reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining γ-benzyl-Pidolidone；
(2) ε-benzyloxycarbonyl group-1B reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining ε-benzyloxycarbonyl group-1B；
(3) under the initiation of alkyl chain primary amine, the N-carboxyl of described γ-benzyl-Pidolidone-ring inner-acid anhydride compound is obtained by reacting alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B) with the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B through ring-opening copolymerization；
(4) described alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B) carries out aminolysis reaction with alcamine compound, obtains alkyl chain-polyglutamic acid alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B)；
(5) under the catalysis of HBr, described alkyl chain-polyglutamic acid alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), through deprotection reaction, namely obtains the amphiphile, amphiphilic molecule based on oligomeric amino acid shown in formula I。
The preparation method that the present invention still further provides the amphiphile, amphiphilic molecule shown in formula II based on oligomeric amino acid, comprises the steps:
(1) β-benzyl-L-aspartate ester reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining β-benzyl-L-aspartate；
(2) ε-benzyloxycarbonyl group-lysine reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining ε-benzyloxycarbonyl group-1B；
(3) under the initiation of alkyl chain primary amine, the N-carboxyl of described β-benzyl-L-aspartate-ring inner-acid anhydride compound is obtained by reacting alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B) with the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B through ring-opening copolymerization；
(4) described alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B) carries out aminolysis reaction with alcamine compound, obtains alkyl chain-poly-aspartate alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B)；
(5) under the catalysis of HBr, described alkyl chain-poly-aspartate alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), through deprotection reaction, namely obtains the amphiphile, amphiphilic molecule based on oligomeric amino acid shown in formula II。
In above-mentioned preparation method, in step (1) and (2), the solvent of described reaction can be oxolane, ethyl acetate or dichloromethane；
The temperature of described reaction can be 40 DEG C～60 DEG C, concretely 50 DEG C；
The time of described reaction can be 3～5 hours, concretely 4 hours；
Described reaction carries out under atmosphere of inert gases, such as argon or nitrogen。
In above-mentioned preparation method, in step (3), described alkyl chain primary amine can be lauryl amine, tetradecy lamine, cetylamine or 18-amine.；
The solvent of described ring-opening polymerization can be at least one in dimethylformamide, dimethyl acetylamide, dimethyl sulfoxide, oxolane and dioxane；
The mol ratio of the integral molar quantity of the N-carboxyl-ring inner-acid anhydride compound of described alkyl chain primary amine and described γ-benzyl-Pidolidone and the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B can be 1:2～20, concretely 1:5；
The mol ratio of the integral molar quantity of the N-carboxyl-ring inner-acid anhydride compound of described alkyl chain primary amine and described β-benzyl-L-aspartate and the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B can be 1:2～20, concretely 1:5；
The mol ratio of the N-carboxyl-ring inner-acid anhydride compound of described alkyl chain primary amine and described ε-benzyloxycarbonyl group-1B can be 1:1～5, concretely 1:1 or 1:2；
The temperature of described ring-opening copolymerization reaction can be 20 DEG C～50 DEG C, concretely 40 DEG C；
The time of described ring-opening copolymerization reaction can be 8 hours～36 hours, concretely 12 hours；
The reaction of described ring-opening copolymerization can carry out under an inert gas, such as argon or nitrogen。
In above-mentioned preparation method, in step (4), described aminolysis reaction carries out under catalyst existent condition, and described catalyst can be 2 hydroxy pyrimidine；
Described alcamine compound can be at least one in linear paraffin hydramine, branching type hydramine and the alcohol amine compound containing oligomeric ethylene glycol class；
Described linear paraffin hydramine can be at least one in ethanolamine, Propanolamine, butanolamine, amylalcohol amine and hexanol amine；
Described branching type hydramine can be at least one in isopropanolamine, isobutyl hydramine and isoamyl hydramine；
The described alcohol amine compound containing oligomeric ethylene glycol class can be diethyleneglycolamin and/or triethylene glycol amine；
In described alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive glutamic acid can be 1:5～30, concretely 1:10 with the mol ratio of described alcamine compound；
In described alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive aminoacid can be 1:1～10 with the mol ratio of described 2 hydroxy pyrimidine；
In described alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive aspartic acid can be 1:5～30, concretely 1:10 with the mol ratio of described alcamine compound；
In described alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B), in repetitive, the mol ratio of repetitive aminoacid and described 2 hydroxy pyrimidine can be 1:1～10；
The temperature of described aminolysis reaction can be 40 DEG C～60 DEG C, concretely 45 DEG C；
The time of described aminolysis reaction can be 24 hours～72 hours, concretely 72 hours；
Described aminolysis reaction can carry out under atmosphere of inert gases, such as argon or nitrogen。
In above-mentioned preparation method, in step (5), described deprotection reaction can carry out in trifluoroacetic acid；
In described alkyl chain-polyglutamic acid alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive lysine can be 1:1.5～3 with the mol ratio of described HBr；
In described alkyl chain-poly-aspartate alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive lysine can be 1:1.5～3 with the mol ratio of described HBr；
The temperature of described deprotection reaction can be 0 DEG C～25 DEG C, concretely 25 DEG C；
The time of described deprotection reaction can be 20 minutes～60 minutes, concretely 30 minutes。
Shown in formula I provided by the present invention or formula II, the amphiphile, amphiphilic molecule based on oligomeric amino acid can be used for preparing anti-bacterial hydrogel。
Invention also provides a kind of anti-bacterial hydrogel, it forms based on the amphiphile, amphiphilic molecule of oligomeric amino acid and sodium alginate and disperse medium shown in formula I and/or formula II；
Described disperse medium can be the aqueous solution of water or salt；
The aqueous solution of described salt can be the one in normal saline, various types of cells culture medium solution etc.。
In described anti-bacterial hydrogel, shown in formula I and/or formula II, the weight/mass percentage composition based on the amphiphile, amphiphilic molecule of oligomeric amino acid is 0.5%～10%, concretely 1%～2%, 1% or 2%；
The weight/mass percentage composition of described sodium alginate is 0.5%～10%, concretely 0.2%,
The molecular weight of described sodium alginate can be 5kDa～500kDa。
The preparation method of the amphiphile, amphiphilic molecule based on oligomeric amino acid provided by the invention, its raw material sources are extensive, are commercially produced product, and cheap, synthetic method is simple, and synthesis cycle is short；Amphiphile, amphiphilic molecule based on polyamino acid provided by the invention and sodium alginate compound and the hybridized hydrogel that obtains, its polyamino acid block is Poly-L-glutamic acid or poly-L-Aspartic acid and poly-L-Lysine, and wherein poly-L-Lysine is antibacterial unit, must contain
There is due to polyamino acid good biocompatibility and biodegradability, and the alkyl short chain after degrading also can pass through renal metabolism approach and directly be excluded external without causing bio-toxicity。And sodium alginate is a kind of natural polysaccharide, and it has good biocompatibility and biodegradability equally。Therefore, the hybridized hydrogel that prepared by the amphiphile, amphiphilic molecule based on polyamino acid provided by the invention and sodium alginate compound has the feature such as biocompatibility and biodegradability。Introduce cationic lysine residue in polyamino acid section, one be can with the carboxyl electrostatic compound on sodium alginate and cross-link, improve the mechanical strength of hydrogel；Two is that the lysine of cationic has bacteriostatic activity, gives the anti-microbial property of hybridized hydrogel self excellence。And compared to other type of antibacterial hydrogel material, it has that preparation cost is cheap, preparation method is simple, manufacturing cycle is short, is prone to large-scale production and the advantage such as the antibacterial activity of inherence, has high application prospect in biomedical materials field。
Accompanying drawing explanation
Fig. 1 is the amphiphile, amphiphilic molecule shown in formula III based on polyamino acid1H-NMR spectrum。
Fig. 2 is the amphiphile, amphiphilic molecule shown in formula IV based on polyamino acid1H-NMR spectrum。
Fig. 3 be shown in formula III and formula IV based on polyamino acid amphiphile, amphiphilic molecule with sodium alginate compound before and after the mechanical strength of hydrogel material that formed。
Fig. 4 is the antibacterial test experimental result of the hybridized hydrogel being compounded to form based on the amphiphile, amphiphilic molecule of polyamino acid and sodium alginate shown in formula III。
Detailed description of the invention
The experimental technique used in following embodiment if no special instructions, is conventional method。
Material used in following embodiment, reagent etc., if no special instructions, all commercially obtain。
Based on the preparation of the amphiphile, amphiphilic molecule of polyamino acid and hybridized hydrogel thereof shown in embodiment 1, formula III
(1) take 10g γ-benzyl-Pidolidone ester and 5g triphosgene adds in reaction bulb; when nitrogen protection, both are dissolved by the oxolane of 200ml; it is warming up to 50 DEG C to react 4 hours; system is become clarification by muddiness; drain solvent, obtain faint yellow solid, with oxolane and normal hexane to its recrystallization three times; obtain N-carboxyl-ring inner-acid anhydride compound (BLG-NCA) 8.93g of white needle-like crystals γ-benzyl-Pidolidone, productivity 80.47%。Same method prepares N-carboxyl-ring inner-acid anhydride compound (ZLL-NCA) of ε-benzyloxycarbonyl group-lysine。
(2) polyreaction of this step reaction bulb under nitrogen protection carries out: take 5.26g (20mmol) BLG-NCA and 1.53g (5mmol) ZLL-NCA in step (1), be dissolved in 60ml oxolane。Rapidly join the cetylamine of 1.205g (5mmol)。In this system, step (1) obtains the molar fraction of BLG-NCA, ZLL-NCA and lauryl amine respectively than for 4:1,1:1。Then this system is reacted 12 hours at 40 DEG C。Reactant liquor is transferred in single port bottle after terminating by reaction, removes major part solvent with Rotary Evaporators。Reactant liquor is joined in substantial amounts of normal hexane, obtain white solid by centrifugal。Product quality 4.98g, productivity 72.22%。
Calculating its average degree of polymerization according to NMR spectra and Amino Acid Unit number is 5, wherein the average degree of polymerization of lysine is 1。
(3) reaction of this step reaction bulb under nitrogen protection carries out: take the white product of 2.76g (2mmol) step (2), be dissolved in 20 milliliters of DMF solvents。Add 6g (80mmol) Propanolamine and 2.28g (24mmol) 2 hydroxy pyrimidine。In this system, the molfraction of glutamic acid units, ethanolamine and 2 hydroxy pyrimidine ratio is for 1:10:3 (namely the mol ratio of Amino Acid Unit and 2 hydroxy pyrimidine is 1:8)。This system reacts 72h at 45 DEG C, after completion of the reaction, concentration of reaction solution, use substantial amounts of ether sedimentation, obtain yellow oily liquid。By soluble in water for this yellow oily liquid, dialyse 24h, and lyophilizing obtains white solid product。Product quality 1.57g, productivity 63%。
(4) take the white solid product of 1.25g (1mmol) step (3), be dissolved in 10ml trifluoroacetic acid, add appropriate hydrobromic acid (hydrobromic acid: lysine=1.5:1, mol ratio) catalysis, room temperature 25 DEG C is reacted 30 minutes, and after reaction terminates, rotation is evaporated off solvent, it is dissolved in water, dialysis 48h, lyophilizing, obtain white solid product, i.e. formula III, product quality 0.8g, productivity 72%, its1H-NMR nucleus magnetic hydrogen spectrum spectrogram is as shown in Figure 1。
It is dissolved in water based on the amphiphile, amphiphilic molecule of polyamino acid with the mass fraction of 1% shown in the formula III prepared by the present embodiment, stable hydrogel can be obtained through the standings of 12 hours。
It is dissolved in water based on the amphiphile, amphiphilic molecule of polyamino acid with the mass fraction of 1% shown in the formula III prepared by the present embodiment, and dissolve sodium alginate (molecular weight is 5000Da) that mass fraction is 0.2% and wherein, stable hybridized hydrogel can be obtained through the standings of 12 hours。
The hydrogel (before sodium alginate compound) of above-mentioned preparation and the mechanical strength of hybridized hydrogel (after sodium alginate compound) are as shown in Figure 3, as seen from Figure 3, the mechanical strength of the hydrogel being subsequently formed with sodium alginate compound has had and has been obviously improved。
The method of testing of mechanical strength: adopt AR2000ex rotational rheometer, the cone-plate mould test that angle is 1 °, diameter is 40mm, spacing is 31 μm, angular frequency is 6rad/s, and strain γ is 0.4%
Based on the preparation of the amphiphile, amphiphilic molecule of polyamino acid and hybridized hydrogel shown in embodiment 2, formula IV
(1) take 10g γ-benzyl-Pidolidone ester and 5g triphosgene adds in reaction bulb; when nitrogen protection, both are dissolved by the oxolane of 200ml; it is warming up to 50 DEG C to react 4 hours; system is become clarification by muddiness; drain solvent, obtain faint yellow solid, with oxolane and normal hexane to its recrystallization three times; obtain N-carboxyl-ring inner-acid anhydride compound (BLG-NCA) 8.93g of white needle-like crystals γ-benzyl-Pidolidone, productivity 80.47%。Same method prepares N-carboxyl-ring inner-acid anhydride compound (ZLL-NCA) of ε-benzyloxycarbonyl group-lysine。
(2) polyreaction of this step reaction bulb under nitrogen protection carries out: take 3.95g (15mmol) BLG-NCA and 3.06g (10mmol) ZLL-NCA in step (1), be dissolved in 60ml oxolane。Rapidly join the cetylamine of 1.205g (5mmol)。In this system, step (1) obtains the molar fraction of BLG-NCA, ZLL-NCA and lauryl amine respectively than for 3:1,2:1。Then this system is reacted 12 hours at 40 DEG C。Reactant liquor is transferred in single port bottle after terminating by reaction, removes major part solvent with Rotary Evaporators。Reactant liquor is joined in substantial amounts of normal hexane, obtain white solid by centrifugal。Product quality 4.9g, productivity 69%。
Calculating its average degree of polymerization according to NMR spectra and Amino Acid Unit number is 5, wherein the average degree of polymerization of lysine is 2。
(3) reaction of this step reaction bulb under nitrogen protection carries out: take the white product of 2.84g (2mmol) step (2), be dissolved in 20 milliliters of DMF solvents。Add 4.5g (60mmol) Propanolamine and 1.71g (18mmol) 2 hydroxy pyrimidine。In this system, the molfraction of glutamic acid units, ethanolamine and 2 hydroxy pyrimidine ratio is for 1:10:3 (namely the mol ratio of Amino Acid Unit number and 2 hydroxy pyrimidine is 1:7.5)。This system reacts 72h at 45 DEG C, after completion of the reaction, concentration of reaction solution, use substantial amounts of ether sedimentation, obtain yellow oily liquid。By soluble in water for this yellow oily liquid, dialyse 24h, and lyophilizing obtains white solid product。Product quality 1.96g, productivity 74.3%。
(4) take the white solid product of 1.32g (1mmol) step (3), be dissolved in 10ml trifluoroacetic acid, add appropriate hydrobromic acid (hydrobromic acid: lysine=2:1, mol ratio) catalysis, room temperature 25 DEG C is reacted 30 minutes, and after reaction terminates, rotation is evaporated off solvent, it is dissolved in water, dialysis 48h, lyophilizing, obtain white solid product, i.e. formula IV, product quality 0.84g, productivity 79.6%, its1H-NMR nucleus magnetic hydrogen spectrum spectrogram is as shown in Figure 2。
It is dissolved in water based on the amphiphile, amphiphilic molecule of polyamino acid with the mass fraction of 2% shown in the formula IV prepared by the present embodiment, stable hydrogel can be obtained through the standings of 12 hours。
It is dissolved in water based on the amphiphile, amphiphilic molecule of polyamino acid with the mass fraction of 2% shown in the formula IV prepared by the present embodiment, and dissolve sodium alginate (molecular weight is 5000Da) that mass fraction is 0.2% and wherein, stable hybridized hydrogel can be obtained through the standings of 12 hours。
The hydrogel (before sodium alginate compound) of above-mentioned preparation and the mechanical strength of hybridized hydrogel (after sodium alginate compound) are as shown in Figure 3, as seen from Figure 3, the mechanical strength of the hydrogel being subsequently formed with sodium alginate compound has had and has been obviously improved。
The method of testing of mechanical strength: adopt AR2000ex rotational rheometer, the cone-plate mould test that angle is 1 °, diameter is 40mm, spacing is 31 μm, angular frequency is 6rad/s, and strain γ is 0.4%。
Test with the anti-microbial property of sodium alginate hybridized hydrogel based on the amphiphile, amphiphilic molecule of polyamino acid shown in embodiment 3, formula III
(1) will be dissolved among pure water based on the amphiphile, amphiphilic molecule of polyamino acid with the mass fraction of 1% shown in formula III, and add the sodium alginate (molecular weight is 5000Da) that mass fraction is 0.2%, make both be sufficiently mixed dissolving, obtain both mixture aqueous solutions；
(2) obtained mixture aqueous solution adds room temperature in culture dish and stands 12 hours, can spontaneously form one layer of thin layer of hydrogel；
(3) being separately added into concentration in hydrogel surface obtained above is 104CFU/ml、105CFU/ml、106CFU/ml and 107The E. coli broth of CFU/ml, cultivates 24 hours (condition of culture: 37 DEG C, 180rpm), draws upper strata inoculum, is tested the OD of respective sample by ultraviolet spectrophotometer600nmValue characterizes this hydrogel sample escherichia coli suppression ratio to 4 kinds of density, and as shown in Figure 4, as seen from Figure 4, the present invention has good anti-microbial property based on the amphiphile, amphiphilic molecule of polyamino acid with sodium alginate hybridized hydrogel。
Claims (10)
1. based on the amphiphile, amphiphilic molecule of oligomeric amino acid, shown in its structural formula such as formula I or formula II,
In formula I and formula II, m is the natural number between 10～16, and n is the natural number between 2～20, and k is the natural number between 1～5, and x is 1 or 2；
In formula I, y is the natural number between 2～6；
In formula II, z is the natural number between 1～3。
2., based on the preparation method of the amphiphile, amphiphilic molecule of oligomeric amino acid shown in formula I, comprise the steps:
(1) γ-benzyl-Pidolidone ester reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining γ-benzyl-Pidolidone；
(2) ε-benzyloxycarbonyl group-1B reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining ε-benzyloxycarbonyl group-1B；
(3) under the initiation of alkyl chain primary amine, the N-carboxyl of described γ-benzyl-Pidolidone-ring inner-acid anhydride compound is obtained by reacting alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B) with the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B through ring-opening copolymerization；
(4) described alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B) carries out aminolysis reaction with alcamine compound, obtains alkyl chain-polyglutamic acid alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-lysine)；
(5) under the catalysis of HBr, described alkyl chain-polyglutamic acid alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), through deprotection reaction, namely obtains the amphiphile, amphiphilic molecule based on oligomeric amino acid shown in formula I；
In formula I, m is the natural number between 10～16, and n is the natural number between 2～20, and k is the natural number between 1～5, and x is 1 or 2, y is the natural number between 2～6。
3., based on the preparation method of the amphiphile, amphiphilic molecule of oligomeric amino acid shown in formula II, comprise the steps:
(1) β-benzyl-L-aspartate ester reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining β-benzyl-L-aspartate；
(2) ε-benzyloxycarbonyl group-1B reacts, with phosgene or triphosgene, the N-carboxyl-ring inner-acid anhydride compound obtaining ε-benzyloxycarbonyl group-1B；
(3) under the initiation of alkyl chain primary amine, the N-carboxyl of described β-benzyl-L-aspartate-ring inner-acid anhydride compound is obtained by reacting alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B) with the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B through ring-opening copolymerization；
(4) described alkyl chain-poly-(β-benzyl-=L-Aspartic acid ester)-co-poly-(ε-benzyloxycarbonyl group-=1B) carries out aminolysis reaction with alcamine compound, obtains alkyl chain-poly-aspartate alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B)；
(5) under the catalysis of HBr, described alkyl chain-poly-aspartate alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), through deprotection reaction, namely obtains the amphiphile, amphiphilic molecule based on oligomeric amino acid shown in formula II；
In formula II, m is the natural number between 10～16, and n is the natural number between 2～20, and k is the natural number between 1～5, and x is 1 or 2, z is the natural number between 1～3。
4. the preparation method according to Claims 2 or 3, it is characterised in that: in step (1) and (2), the solvent of described reaction is oxolane, ethyl acetate or dichloromethane；
The temperature of described reaction is 40 DEG C～60 DEG C；
The time of described reaction is 3～5 hours；
Described reaction carries out under atmosphere of inert gases。
5. the preparation method according to any one of claim 2-4, it is characterised in that: in step (3), described alkyl chain primary amine is lauryl amine, tetradecy lamine, cetylamine or 18-amine.；
The solvent of described ring-opening polymerization is at least one in dimethylformamide, dimethyl acetylamide, dimethyl sulfoxide, oxolane and dioxane；
The mol ratio of the integral molar quantity of the N-carboxyl-ring inner-acid anhydride compound of described alkyl chain primary amine and described γ-benzyl-Pidolidone and the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B is: 1:2～20；
The mol ratio of the integral molar quantity of the N-carboxyl-ring inner-acid anhydride compound of described alkyl chain primary amine and described β-benzyl-L-aspartate and the N-carboxyl-ring inner-acid anhydride compound of described ε-benzyloxycarbonyl group-1B is: 1:2～20；
The mol ratio of the N-carboxyl-ring inner-acid anhydride compound of described alkyl chain primary amine and described ε-benzyloxycarbonyl group-1B is 1:1～5；
The temperature of described ring-opening copolymerization reaction is 20 DEG C～50 DEG C；
The time of described ring-opening copolymerization reaction is 8 hours～36 hours；
The reaction of described ring-opening copolymerization carries out under an inert gas。
6. the preparation method according to any one of claim 2-5, it is characterised in that: in step (4), described alcamine compound is at least one in linear paraffin hydramine, branching type hydramine and the alcohol amine compound containing oligomeric ethylene glycol class；
Described linear paraffin hydramine is at least one in ethanolamine, Propanolamine, butanolamine, amylalcohol amine and hexanol amine；
Described branching type hydramine is at least one in isopropanolamine, isobutyl hydramine and isoamyl hydramine；
The described alcohol amine compound containing oligomeric ethylene glycol class is diethyleneglycolamin and/or triethylene glycol amine；
In described alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive glutamic acid is 1:5～30 with the mol ratio of described alcamine compound；
In described alkyl chain-poly-(γ-benzyl-Pidolidone ester)-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive aminoacid is 1:1～10 with the mol ratio of described 2 hydroxy pyrimidine；
In described alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive aspartic acid is 1:5～30 with the mol ratio of described alcamine compound；
In described alkyl chain-poly-(β-benzyl-L-aspartate ester)-co-poly-(ε-benzyloxycarbonyl group-1B), in repetitive, the mol ratio of repetitive aminoacid and described 2 hydroxy pyrimidine is 1:1～10；
The temperature of described aminolysis reaction is 40 DEG C～60 DEG C；
The time of described aminolysis reaction is 24 hours～72 hours；
Described aminolysis reaction carries out under atmosphere of inert gases。
7. the preparation method according to any one of claim 2-6, it is characterised in that: in step (5), described deprotection reaction carries out in trifluoroacetic acid；
In described alkyl chain-polyglutamic acid alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive lysine is 1:1.5～3 with the mol ratio of described HBr；
In described alkyl chain-poly-aspartate alcohol amine amide-co-poly-(ε-benzyloxycarbonyl group-1B), repetitive lysine is 1:1.5～3 with the mol ratio of described HBr；
The temperature of described deprotection reaction is 0 DEG C～25 DEG C；
The time of described deprotection reaction is 20 minutes～60 minutes。
8. formula I or the application in preparing anti-bacterial hydrogel of the formula II shown amphiphile, amphiphilic molecule based on oligomeric amino acid；
In formula I and formula II, m is the natural number between 10～16, and n is the natural number between 2～20, and k is the natural number between 1～5, and x is 1 or 2；
In formula I, y is the natural number between 2～6；
In formula II, z is the natural number between 1～3。
9. an anti-bacterial hydrogel, it forms based on the amphiphile, amphiphilic molecule of oligomeric amino acid and sodium alginate and disperse medium shown in formula I and/or formula II；
Described disperse medium is the aqueous solution of water or salt；
In formula I and formula II, m is the natural number between 10～16, and n is the natural number between 2～20, and k is the natural number between 1～5, and x is 1 or 2；
In formula I, y is the natural number between 2～6；
In formula II, z is the natural number between 1～3。
10. anti-bacterial hydrogel according to claim 9, it is characterised in that: in described anti-bacterial hydrogel, shown in formula I and/or formula II, the weight/mass percentage composition based on the amphiphile, amphiphilic molecule of oligomeric amino acid is 0.5%～10%；
The weight/mass percentage composition of described sodium alginate is 0.5%～10%。
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| CN114437246A (en) * | 2022-02-18 | 2022-05-06 | 山东海基生物科技有限公司 | Method for improving viscosity of sodium alginate |
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