CN100509921C - Polyacrylic acid/polyglutamic acid block copolymer and synthesis method thereof - Google Patents
Polyacrylic acid/polyglutamic acid block copolymer and synthesis method thereof Download PDFInfo
- Publication number
- CN100509921C CN100509921C CNB2006101163868A CN200610116386A CN100509921C CN 100509921 C CN100509921 C CN 100509921C CN B2006101163868 A CNB2006101163868 A CN B2006101163868A CN 200610116386 A CN200610116386 A CN 200610116386A CN 100509921 C CN100509921 C CN 100509921C
- Authority
- CN
- China
- Prior art keywords
- acid
- benzyl
- reaction
- benzyl ester
- polyglutamic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Polyamides (AREA)
Abstract
The invention discloses a biological decomposalbe polyacrylic acid/polyglutamic acid block copolymer and synthesizing method, which is characterized by the following: the copolymer contains acroleic acid carbobenzoxy, amido dead-end polyacroleic acid carbobenzoxy, gamma-benzyl-L-glutamic acid-N-carboxylic acid anhydrides, polyacroleic acid carbobenzoxy/poly-L-glutamic benzyl; the synthesizing course of gamma-benzyl-L-glutamic acid-N-carboxylic acid anhydrides adopts safe, little-toxic and strong operating gamma-benzyl-L-glutamic acid-N-carboxylic acid trianhydrides, which produces new biological decomposable material.
Description
Technical field:
The present invention relates to a kind of polyamino acid derivative and synthetic method thereof.Poly propenoic acid L-L-glutamic acid segmented copolymer and synthetic method thereof that particularly a kind of biodegradable molecular weight is controlled.
Background technology:
Biodegradable polymers has a wide range of applications in pharmacy and biomedical aspect.Poly-a-amino acid has the favorable biological degradability energy, and low genetic immunization and biocompatibility are widely used in pharmacy and biomedical aspect.Various functional groups can more easily be incorporated on many amino acid forms amino acid derivative.L-glutamic acid is a seed amino acid of wherein studying early, and it is the important carrier or the intermediate of preparation bonding type and occurring matrix type slow releasing pharmaceutical system.
High molecular weight polypropylene acid is a kind of biological viscosity polymkeric substance, and it can be attached on the mucous membrane that eye, nose, mouth, lung, enteron aisle, vagina, anus etc. locate.In order to prolong the action time of these local medicines, polyacrylic acid often is referred to drug delivery system.In addition, polyacrylic acid still is the pH value sensitive polymers, can prepare some intelligent polymkeric substance, has certain application prospect aspect organizational project.
Polyglutamic acid and polyacrylic acid copolymerized resulting segmented copolymer have been gathered polyglutamic acid and polyacrylic advantage, certainly will have good application potential in pharmacy and biomedical aspect.This block polymer yet there are no bibliographical information at present.
Summary of the invention:
One of purpose of the present invention is to provide a kind of polyacrylic acid/polyglutamic acid block copolymer.
Two of purpose of the present invention is to provide the synthetic method of this segmented copolymer, and this method can be sloughed the benzyl protection group smoothly under condition of normal pressure, and preparation gathers-L-L-glutamic acid/polyacrylic acid segmented copolymer.
For achieving the above object, the present invention adopts following technical scheme:
A kind of polyacrylic acid/polyglutamic acid block copolymer is characterized in that this block polymer is a linear polymer, and wherein the molecular weight of polyglutamic acid section is 50000-100000; The molecular weight of polyacrylic acid section is 1000-5000.
The synthetic method of above-mentioned polyacrylic acid/polyglutamic acid block copolymer is characterized in that, the concrete steps of this method are as follows:
I. γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA's is synthetic;
Ii. the preparation of benzyl acrylate monomers B zA: preparation method's preparation of ester routinely;
Iii. the polypropylene acid benzyl ester that synthesizes the band edge amido: in the exsiccant reaction flask, add step b gained benzyl acrylate, Diisopropyl azodicarboxylate is that initiator, mercaptoethylamine are that chain-transfer agent, toluene are made solvent, under the vacuum state, in 70 ± 1 ℃ of water-baths, stirring reaction 2～3 days, reaction precipitates with dehydrated alcohol after finishing, get faint yellow thick material, vacuum-drying; The mol ratio of benzyl acrylate, Diisopropyl azodicarboxylate, mercaptoethylamine is: 40～50:1～3:4～8;
Iv. synthetic polypropylene acid benzyl ester/polyglutamic acid-γ-benzyl ester block copolymer: in the inert atmosphere, polypropylene acid benzyl ester and the step a gained γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA with step c gained band edge amido is dissolved in the chloroform respectively; Then in inert atmosphere with above-mentioned two kinds of solution thorough mixing, stirring at room reaction three days after reaction finishes, with the dehydrated alcohol precipitation, obtains white flocculent substance, filters the final vacuum drying; The mol ratio of the polypropylene acid benzyl ester of band edge amido and γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA is 1:80-140;
V. the preparation of polyglutamic acid/polyacrylic acid segmented copolymer: in 35～50 ℃ of waters bath with thermostatic control, steps d gained polypropylene acid benzyl ester/polyglutamic acid-γ-benzyl ester block copolymer is dissolved in dichloro acetic acid or the trifluoroacetic acid, under whipped state, add weight percent concentration again and be 25-33% HBr acetic acid, and the weight percent of control segmented copolymer: HBr is 1:0.5 ~ 1.5, isothermal reaction 1.5-2.5 hours, room temperature left standstill 10 hours, the excessive ether sedimentation of reaction solution, after filtration, drying, get final product product polyglutamic acid/polyacrylic acid segmented copolymer.The synthetic method of γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA sees also Chinese patent 200510024596.X.
And the preparation of benzyl acrylate monomer (BzA), the present invention does not adopt traditional alcohol and the esterification between the acid, but higher acyl chlorides and the needed ester of alcohol preparation of selective reaction activity, concrete reaction formula is as follows:
The preparating mechanism of macromole evocating agent is as follows:
The reaction formula of synthetic polypropylene acid benzyl ester/poly benzyl glutamate segmented copolymer is as follows:
In reaction process, at first by the carbonylic carbon atom of the end amido on the macromole evocating agent as last No. 5 positions of nucleophilic reagent attack NCA, then open loop, prototropy, slough carbonyldioxy and form the amino acid oligomer, this amino acid oligomer causes other NCA monomer ring-opening polymerization by above process again, the higher polymkeric substance of final generation molecular weight, and the end of polymer chain all contains initiator fragments.Slough benzyl protecting group at last, obtain polyacrylic acid/polyglutamic acid block copolymer.
Compare with prior art, the present invention has following conspicuous outstanding preferential and distinguishing feature: in the building-up process of the γ-benzyl of the inventive method-L-L-glutamic acid-N-carboxylic acid anhydride, use triphosgene to replace conventional phosgene to have safety, little, the workable characteristics of toxicity; Polyglutamic acid/polyacrylic acid segmented copolymer is a kind of novel Biodegradable material, has not yet to see bibliographical information; The inventive method is sloughed benzyl with HBr solution and has been obtained effect preferably under normal pressure.
Resulting polymers characterizes with means such as GPC, IR, H-NMR, and the dependency structure of product and molecular weight have all obtained confirmation.
Description of drawings
Fig. 1 is the infrared spectrogram of PBzA-b-PBLG and PAA-b-PLGA, and wherein a is the infrared spectrogram of PAA-b-PLGA, and b is the infrared spectrogram of PBzA-b-PBLG.
Fig. 2 is PbzA and PBzA-b-PBLG's
1The H-nuclear magnetic resonance spectrum, wherein a is PbzA's
1H-nuclear magnetic resonance spectrum, b are PBzA-b-PBLG's
1The H-nuclear magnetic resonance spectrum.
Fig. 3 is PBzA-b-PBLG and PAA-b-PLGA's
1The H-nuclear magnetic resonance spectrum, wherein a is PBzA-b-PBLG's
1H-nuclear magnetic resonance spectrum, b are PAA-b-PLGA's
1The H-nuclear magnetic resonance spectrum.
Fig. 4 is PBzA-NH
2(5000) GPC figure.
Fig. 5 is PBzA-NH
2(10000) GPC figure.
Fig. 6 is the GPC figure of PBzA-b-PBLG
Embodiment:
Embodiment one: these embodiment concrete steps are as follows:
1. γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride is synthetic:
Synthesizing of a.L-L-glutamic acid-γ-benzyl ester (BLG): in there-necked flask, add 120 gram L-L-glutamic acid and 100ml phenylcarbinols, there-necked flask is inserted violent stirring in 70 ± 1 ℃ of water-baths, when homo(io)thermism, slowly drip 60% vitriol oil, after the clarification of question response liquid, stop to stir and heating, naturally cool to room temperature, slowly pour reaction solution into the excessive NaHCO of being dissolved with
3Supersaturation frozen water solution in, put into the refrigerator freeze overnight after stirring.Filter the dissolved in distilled water of back filter cake, slowly cool to room temperature then with 80 ℃ of 2000ml, freezing again about 3 hours, filter, filter cake cleans respectively three times with ethanol, ether, and room temperature vacuum-drying 24 hours obtains white flakey material and is BLG.
B. add freshly prepd BLG and the new tetrahydrofuran (THF) (THF) that steams in the exsiccant there-necked flask, stir and form suspension, reaction flask inserted in 50 ± 2 ℃ the water bath with thermostatic control, in reaction solution, lead to nitrogen simultaneously, when homo(io)thermism, add a certain amount of triphosgene (using chloroform recrystallization three times), become to reaction solution and clarify, stop to stir and removing water-bath, continue logical nitrogen half an hour; Under violent stirring, reaction solution poured in a large amount of sherwood oils precipitates, filter, white crystal be the BLG-NCA head product; This head product is dissolved in the ethyl acetate, transfers to then in the separating funnel, clean with the 50ml frozen water again after cleaning with 50ml saturated sodium bicarbonate frozen water solution; Collect the supernatant liquid body, add to insert in the refrigerator behind an amount of anhydrous magnesium sulfate and spend the night; Take out and filter, transfer in the exsiccant confined reaction bottle, vacuum nitrogen filling gas (triplicate) is concentrated into filtrate about 40ml, injects the new sherwood oil (boiling range is 60-90 ℃) that steams about 40ml, carries out recrystallization; Filter, filter cake with the 20ml acetic acid ethyl dissolution after adding 20ml left and right sides sherwood oil (boiling range is 60-90 ℃) carry out recrystallization; Behind the recrystallization three times, after filtration,, obtain white needle-like crystals and be γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride monomer that purity reaches polymerization-grade, productive rate about 65% so repeatedly filter cake vacuum-drying at room temperature 12 hours.
2. the preparation of benzyl acrylate monomer (BzA)
Acrylate chloride is dissolved in tetrahydrofuran (THF) (THF) forms solution 1., get the equivalent phenylcarbinol and be dissolved in THF/ triethylamine (TEA) mixing solutions (volume ratio 4:1) formation solution 2., in nitrogen atmosphere, under the condition of ice bath, 1. solution slowly be added drop-wise to solution and go in 2., do not stop to stir.Have a large amount of smog to generate in the reaction process, and the adularescent solid matter is separated out.Finish reaction after two hours, elimination precipitation of salts thing fully to remove THF, is used saturated NaHCO with 60 ℃ of rotary evaporations of filtrate then
3Solution washing three times is used the anhydrous magnesium sulfate thorough drying again.Elimination sal epsom can obtain the very high benzyl acrylate of purity.
3. macromole evocating agent is that end is the preparation of the polypropylene acid benzyl ester of amido
In the exsiccant reaction flask, put into 25mmol benzyl acrylate, 0.5mmol Diisopropyl azodicarboxylate (AIBN), add toluene and make it dissolving, other takes by weighing mercaptoethylamine 4mmol and is dissolved in dimethyl formamide (DMF), mercaptoethylamine after the dissolving is added in the reaction flask, stir, be reflected under 70 ± 1 ℃ of vacuum states and reacted 3 days.Reaction solution precipitates with a large amount of dehydrated alcohols, and purifying three times, 40 ℃ of vacuum-drying 24 hours.The end that obtains is that the polypropylene acid benzyl ester number-average molecular weight of amido is about 5000.
4. polypropylene acid benzyl ester/poly--L-benzyl glutamate segmented copolymer (PBzA-b-PLGA) is synthetic: A/I is that 95 (A represents NCA in molar ratio, I represents macromole evocating agent) end that takes by weighing in NCA and the step 3 preparation is the polypropylene acid benzyl ester of amido, put into the exsiccant reaction flask, vacuum nitrogen filling gas injects the new chloroform that steams and makes it dissolving.Stirring at room was reacted 2～3 days.After the end reaction solution slowly poured in the 500ml dehydrated alcohol that is stirring and precipitate, have a large amount of white flosss to separate out.Filter purifying three times, 40 ℃ of vacuum-drying 24 hours.
5. the preparation of polyglutamic acid/polyacrylic acid segmented copolymer: in 35～50 ℃ of waters bath with thermostatic control, take by weighing step 4 gained polypropylene acid benzyl ester/polyglutamic acid-γ-benzyl ester block copolymer 0.3 gram, be dissolved in the 3ml dichloro acetic acid, under whipped state, add concentration again and be 1.5 milliliters of 33% HBr acetums, isothermal reaction 1.5-2.5 hours, room temperature were left standstill 10 hours, the excessive ether sedimentation of reaction solution, after filtration, drying, get final product product polyglutamic acid/polyacrylic acid segmented copolymer.
Embodiment two: present embodiment and embodiment one are basic identical, and the consumption of different is mercaptoethylamine is 2mmol, and the end that obtains is that the number-average molecular weight of the polypropylene acid benzyl ester of amido is about 10000.
Embodiment three: present embodiment and embodiment one are basic identical, and different is that A/I ratio is 110.
Embodiment four: present embodiment and embodiment one are basic identical, and different is that A/I ratio is 140.
Embodiment five: present embodiment and embodiment two are basic identical, and different is that A/I ratio is 80.
Embodiment six: present embodiment and embodiment two are basic identical, and different is that A/I ratio is 90.
Embodiment seven: present embodiment and embodiment two are basic identical, and different is that A/I ratio is 100.
Embodiment eight: present embodiment and embodiment two are basic identical, and different is that A/I ratio is 120.
The molecule measuring metering method is gel chromatography (GPC) method in above each example, and the gained molecular weight sees the following form 1:
Table 1
This segmented copolymer is water miscible, and wherein the L-glutamic acid segment is biodegradable, though and the vinylformic acid segment is not degraded its molecular weight control below 5000, so can be excreted to external by metabolism.Thereby it is a kind of brand-new Biodegradable material on the whole, and up to the present yet there are no has bibliographical information both at home and abroad.
The water-soluble test by contact angle is confirmed, and data see Table 2
Table 2 contact angle
Claims (1)
1. a polyacrylic acid/polyglutamic acid block copolymer is characterized in that this block polymer is a linear polymer, and wherein the molecular weight of polyglutamic acid section is 50000-100000; The molecular weight of polyacrylic acid section is 1000-5000; The concrete preparation method of this polymkeric substance is as follows:
A. γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA's is synthetic;
B. the preparation of benzyl acrylate monomers B zA;
C. the polypropylene acid benzyl ester that synthesizes the band edge amido: in the exsiccant reaction flask, add step b gained benzyl acrylate, Diisopropyl azodicarboxylate is that initiator, mercaptoethylamine are that chain-transfer agent, toluene are made solvent, under the vacuum state, in 70 ± 1 ℃ of water-baths, stirring reaction 2～3 days, reaction precipitates with dehydrated alcohol after finishing, get faint yellow thick material, vacuum-drying; The mol ratio of benzyl acrylate, Diisopropyl azodicarboxylate, mercaptoethylamine is: 40～50: 1～3: 4～8;
D. synthetic polypropylene acid benzyl ester/polyglutamic acid-γ-benzyl ester block copolymer: in the inert atmosphere, polypropylene acid benzyl ester and the step a gained γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA with step c gained band edge amido is dissolved in the chloroform respectively; Then in inert atmosphere with above-mentioned two kinds of solution thorough mixing, stirring at room reaction three days after reaction finishes, with the dehydrated alcohol precipitation, obtains white flocculent substance, filters the final vacuum drying; The mol ratio of the polypropylene acid benzyl ester of band edge amido and γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride NCA is 1: 80-140;
E. the preparation of polyglutamic acid/polyacrylic acid segmented copolymer: in 35～50 ℃ of waters bath with thermostatic control, steps d gained polypropylene acid benzyl ester/polyglutamic acid-γ-benzyl ester block copolymer is dissolved in dichloro acetic acid or the trifluoroacetic acid, under whipped state, add concentration again and be 25-33% HBr acetum, and to make segmented copolymer and HBr weight percent be 1: 0.5～1.5, isothermal reaction 1.5-2.5 hours, room temperature left standstill 10 hours, the excessive ether sedimentation of reaction solution, after filtration, drying, get final product product polyglutamic acid/polyacrylic acid segmented copolymer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101163868A CN100509921C (en) | 2006-09-21 | 2006-09-21 | Polyacrylic acid/polyglutamic acid block copolymer and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101163868A CN100509921C (en) | 2006-09-21 | 2006-09-21 | Polyacrylic acid/polyglutamic acid block copolymer and synthesis method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1951980A CN1951980A (en) | 2007-04-25 |
| CN100509921C true CN100509921C (en) | 2009-07-08 |
Family
ID=38058547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101163868A Expired - Fee Related CN100509921C (en) | 2006-09-21 | 2006-09-21 | Polyacrylic acid/polyglutamic acid block copolymer and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100509921C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219908B (en) * | 2011-04-26 | 2012-08-22 | 东北师范大学 | Completely-biodegraded nanometer starch grafted poly glutamic acid benzyl ester |
| CN104826161A (en) * | 2015-04-28 | 2015-08-12 | 上海大学 | Poly(amino acid) based porous microgel material for tissue engineering and preparation method thereof |
| CN107586209A (en) * | 2017-10-30 | 2018-01-16 | 成都云图控股股份有限公司 | A kind of instant chelating solid Water soluble fertilizer and preparation method thereof |
| CN107793219A (en) * | 2017-10-30 | 2018-03-13 | 成都云图控股股份有限公司 | A kind of organic trace element Water soluble fertilizer and preparation method thereof |
| CN117488302B (en) * | 2023-10-18 | 2024-06-07 | 珠海市板明科技有限公司 | Circuit etching solution |
-
2006
- 2006-09-21 CN CNB2006101163868A patent/CN100509921C/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| Synthesis of AB diblock......N-carboxyanhydrides. Krystyna R. Brzezinska, Timothy J. Deming.Macromolecular bioscience,No.4. 2004 |
| Synthesis of AB diblock......N-carboxyanhydrides. Krystyna R. Brzezinska, Timothy J. Deming.Macromolecular bioscience,No.4. 2004 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1951980A (en) | 2007-04-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100509921C (en) | Polyacrylic acid/polyglutamic acid block copolymer and synthesis method thereof | |
| KR0148704B1 (en) | Biodegradable polymer as drug delivery | |
| ES2211028T3 (en) | NEW TENSIOACTIVE COPOLYMERS BASED ON METHYLIDENE MALONATE. | |
| CN102408561A (en) | Segmented copolymer and its preparation method, and temperature sensitive type hydrogel | |
| CN102964593B (en) | Block polymer, preparation method thereof and electrically active hydrogel | |
| CN105694030B (en) | A kind of oligomeric amino acid and the compound hydridization anti-bacterial hydrogel of sodium alginate | |
| CN107619475A (en) | A kind of antibacterial peptide of the adhesive groups containing dopamine and its preparation method and application | |
| CN105968367A (en) | Amphiphilic polypeptide copolymer and self-assembled body as well as preparation method and application thereof | |
| CN109608633A (en) | A kind of novel specific multi-arm polyethylene glycol derivative and preparation method thereof | |
| CN108484905A (en) | A kind of side chain has the cluster peptide and preparation method thereof of UCST behaviors containing carboxyl | |
| CN102924653B (en) | Poly (N- isopropyl acrylamide)- poly (crylic acid or acrylic acid derivative) copolymer and preparation method thereof | |
| CN102964582B (en) | Segmented copolymer, preparation method thereof and hydrogel | |
| CN1264892C (en) | Process for synthesizing L-glutamic acid with high molecular weight | |
| US4190716A (en) | Polymeric agent for releasing 5-aminosalicylic acid or its salts into the gastrointestinal tract | |
| CN101845120B (en) | Method for synthesizing temperature-sensitive and biodegradable in situ gel | |
| CN101450996B (en) | Glucose responding type polyphosphazene hydrogel | |
| CN102775530A (en) | RAFT (reversible addition fragmentation chain transfer) preparation method of polylysine derivative | |
| CN102786536B (en) | Sulbactam amoxicillin amide complex for treatment of acute bacterial infection of pig and synthesis method | |
| CN110845713B (en) | Main chain type biodegradable liquid crystal polymer and preparation method thereof | |
| Paredes et al. | Synthesis and structural study of a new biodegradable copolymer of nylon-11 and L-alanine | |
| CN101265331B (en) | PEG modifying PHPMA material and preparation method thereof | |
| CN108003342A (en) | Polyaminoacid, its preparation method and load medicinal gel | |
| CN106674516A (en) | Amino acid block copolymer and preparation method thereof and temperature-sensitive water gel | |
| CN109880110A (en) | Containing poly- (2- vinylpyridine) poly- polypeptide block copolymer and its preparation method and application | |
| CN101747503A (en) | Chloroethyl alcohol functional poly (L-glutamic acid) homopolymer and random copolymer and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090708 Termination date: 20180921 |