CN1597700A - Method of synthesising polysaccharide or its derivative modified by phospho lipid group - Google Patents
Method of synthesising polysaccharide or its derivative modified by phospho lipid group Download PDFInfo
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- CN1597700A CN1597700A CN 200410054022 CN200410054022A CN1597700A CN 1597700 A CN1597700 A CN 1597700A CN 200410054022 CN200410054022 CN 200410054022 CN 200410054022 A CN200410054022 A CN 200410054022A CN 1597700 A CN1597700 A CN 1597700A
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Abstract
A process for preparing the phosphatide gruop modified polyose or its derivative, which has high hydrophilicity and biocompatibility, features that the phoshpatidylchloine group with biojnic function is covalently bonded to natural biodegradable polyose molecular chain by condensation reaction.
Description
Technical field
The invention belongs to technical field of biological materials, be specifically related to a kind of synthetic method of natural polysaccharide or derivatives thereof material of phosphatide base group modification.
Background technology
In the past few decades, people are attempting to develop always and a kind ofly can thoroughly solve the type material of material in the biomedical aspect problem, comprising multiple synthetic or natural biomaterial, but also have many problems to need to be resolved hurrily up to now.
As everyone knows, the biocompatibility of natural biological film should be optimal, and therefore, for many years, the similar macromolecular material of structure of phospholipid is an important directions of exploitation biomaterial in synthetic and the microbial film.
Umeda and Nakaya etc. have then at first synthesized a kind of methacrylic monomer that has Phosphorylcholine: 2-methylacryoyloxyethyl-2 '-Trimethylamine 99 ethyl phosphonic acid ester inner salt (MPC), Nakabayashi and co-workers thereof have then carried out comparatively deep research to this monomer and multipolymer thereof, even the multipolymer that they find MPC and esters of acrylic acid is with during the whole blood that does not have anti-freezing contacts, also proteic absorption and sex change can be well reduced, more being activated of cell can be prevented.
In addition, phospholipid polyalcohol is zwitterionic phosphatidylcholine type polymkeric substance mostly, contains N in their molecule
+, O
-, when environment PH changed, molecular conformation changed with the molecule change in charge, and ambient moisture is had high susceptibility.
Nakabayashi and his co-workers also carried out preliminary research to the degradable polymer that contains Phosphorylcholine in 2003, they come catalysis to cause the rac-Lactide open loop by a kind of 1-α-glycerophosphoryl choline (LGPC) and stannous octoate that has the Phosphorylcholine group, have obtained having the polylactic acid molecule that Phosphorylcholine causes end.
In up-to-date report, Hilborn etc. have received the Phosphorylcholine group on the one side base of homemade polycaprolactone, and to the self-organization of Phosphorylcholine group in this material and the surface properties that some are special, have carried out preliminary research.
But,, rarely have report so far aspect the phosphatide modification of natural biologic material.
Chitosan (Chitosan; (1; 4)-and 2-amido-2-deoxidation-callose) be a kind of biopolymer that obtains through deacetylated reaction by chitin (Chitin), be alkaline polysaccharide unique in the natural polysaccharide, also be minority has one of natural product of charge.Because advantages such as chitosan biologically actives, biocompatibility, it is biodegradable, nontoxicity, excellent biological compatibility etc., has the due characteristic of bio-medical material.Chitosan and derivative thereof have been applied to biomedical sector at present, in chitosan molecule, contain a large amount of active groups as amino and hydroxyl etc., have the potentiality of chemical modification.
Shen Jian etc. are by the Micheal addition reaction under the heterogeneous conditions, make MPC (2-methylacryoyloxyethyl-2 '-Trimethylamine 99 ethyl phosphonic acid ester inner salt) be bonded in the chitosan surface, have obtained a good Hemocompatible surfaces.
In addition, discoveries such as Nakabayashi and Ishihara, when the molar content of cellulose surface grafting MPC reaches 30%, even in the whole blood that does not add antithrombotics, hemocyte bonds to material surface hardly.
Summary of the invention
The objective of the invention is to propose the synthetic method of a kind of reaction conversion ratio height, product good biocompatibility, natural polysaccharide or derivatives thereof material by the phosphatide base group modification simple to operation.
The synthetic method of the phosphatide base group modification natural polysaccharide or derivatives thereof material that the present invention proposes, be by condensation reaction, the phosphatide group (as Phosphorylcholine etc.) that will have bionic function, be covalently bound to natural, biodegradable biological polyoses and derivative surface thereof, be prepared into and contain the novel polysaccharide material of modifying with Phosphorylcholine, thereby this traditional, natural, Biodegradable material and Phosphorylcholine are combined.This kind material is with good hydrophilicity and biocompatibility.
Natural polysaccharide of the present invention comprises chitosan, chitin, hyaluronic acid, starch, Lalgine, Mierocrystalline cellulose etc.Its derivative comprises its sulfonation, etherificate, carboxymethylation, hydroxyethylation, alkylation, nitrated, halogenation or crosslinked derived products.On the molecular backbone chain or side chain of special requirement material, contain the hydroxyl with reactive behavior or the amido functional group of some amount.
Among the present invention, the form of above-mentioned polysaccharide or derivatives thereof can be powder, porous small ball or particle, or the film of different shape.
The present invention is with reference to method synthetic phosphorated ring reaction intermediate CUP (2-chloro-1, the 3-dioxaphospholane of Lucas etc.; ); On this basis, carry out phosphoryl chloride COP (2-Chloro-2-oxo-1,3,2-dioxaphospholane) (2-chloro-2-oxygen-1,3,2-diethoxy acyl chlorides) is synthetic.All above-mentioned being reflected under the anhydrous and oxygen-free condition are carried out, and reaction product is a colourless transparent liquid, and the easy crystallization of low temperature is stored in the dry low temperature environment that seals and is used.
Among the present invention, the synthetic route of COP is as follows:
Synthesis step of the present invention comprises condensation reaction and two parts of ring-opening reaction:
The first step, condensation reaction.Above-mentioned polysaccharide or derivatives thereof, triethylamine (TEA) and exsiccant solvent are pressed given mixed in molar ratio, stirring, make and suspend evenly, reaction system is cooled to low temperature environment, be generally-30 ℃ to room temperature range, splash into phosphoryl chloride COP (the 2-chloro-2-oxygen-1,3 that is dissolved in dry solvent gradually, 2-diethoxy acyl chlorides (2-chloro-2-oxo-1,3,2-dioxaphospolane)), continued stirring reaction 1-5 hour.Whole process control temp is constant relatively good.Wherein, the control of the molar ratio of polysaccharide or derivatives thereof, triethylamine, COP is as follows: polysaccharide or derivatives thereof: COP is 1: 1-1: 5, and COP is suitably excessive, and complete thorough to guarantee that reaction is carried out, triethylamine: COP is 1: 1-3: 1.
In this step, solvent for use is inert solvent system or suspension agent, for example: one of tetrahydrofuran (THF) (THF), benzene, toluene, cyclohexane, acetonitrile, chloroform, methylene dichloride, dioxane we or several mixed solutions etc.Preferred tetrahydrofuran (THF).
Reaction system is warming up to 20-30 ℃ then, restir reaction 1-8 hour preferred 2-3 hour, guarantees to react completely.Extrct desolvates, and vacuum-drying obtains intermediate product.
Second step, ring-opening reaction.Intermediate product and solvent (as acetonitrile or toluene or benzene) that back makes are put into the single port container with piston, stir, make suspending stabilized; Add the saturated solution of the above-mentioned solvent of open loop reagent (as Trimethylamine 99 or triethylamine) again, wherein, the consumption of open loop reagent must guarantee excessive greatly, general open loop reagent be solvent 5-10 doubly, perhaps open loop reagent be intermediate product 3-30 doubly.Closure piston is put into 60-70 ℃ water-bath, reacts 30-60 hour.Open piston, be heated to 70-90 ℃, remove remaining open loop reagent.Under nitrogen protection, filter, washing, solvent is thoroughly removed in vacuum-drying, promptly gets final product one by phosphide base group modification natural polysaccharide or derivatives thereof.
In this step, solvent for use can be acetonitrile or benzene or toluene, and used open loop reagent is Trimethylamine 99 (TMA) or triethylamine (TEA), and the solvent of cleaning product can be water, methyl alcohol or ethanol.Vacuum drying temperature is the 0-50 degree, and the time was generally 1-50 hour.
In the above-mentioned synthesis step, employed various chemical reagent, all the experimental technique according to standard carries out drying treatment, and the entire operation process is a waterless operation.
Embodiment
Advance to describe down the present invention below by embodiment.
Embodiment 1
In a there-necked flask of being furnished with constant pressure funnel and magnetic stirring apparatus, add a 100 purpose chitosan powder (by the mole mark, down with), 3 parts of TEA and 10 parts of exsiccant tetrahydrofuran (THF)s.Stir, use cryosel to bathe and reaction system is cooled to-17 ℃, slowly splash into three parts of COP that are dissolved in a certain amount of dry tetrahydrofuran, last 3 hours, continue then to stir 2 hours.Controlled temperature is at-17 ℃.Naturally be warming up to room temperature, restir reaction 2.5 hours.Suction filtration removes the THF that desolvates, and obtains faint yellow product C OP-Chitosan.
Add exsiccant acetonitrile and COP-Chitosan in the heavy wall single port flask of a tool piston, stirring makes system suspending stabilized, adds the acetonitrile saturated solution that contains 20 parts of dry Trimethylamine 99s again.Closure piston is put into 70 ℃ water-bath, keeps 48 hours.Open piston, be heated to 75 ℃, remaining Trimethylamine 99 is caught up with in the vitriol oil.Filter product vacuum-drying.After the desciccate washing, vacuum-drying gets required product to constant weight.
Embodiment 2
In a there-necked flask of being furnished with constant pressure funnel and magnetic stirring apparatus, add 1 part of thickness and be the toluene of 20 microns chitin film, 1 part of triethylamine and 20 parts.Stir, use cryosel to bathe reaction system is cooled to 0 ℃, slowly splash into the COP that is dissolved in a certain amount of dry toluene, last 2-5 hour, continue then to stir 3 hours.Controlled temperature is at 0 ℃.Naturally be warming up to room temperature, restir reaction 2 hours.Suction filtration is removed solvent toluene, and filter residue vacuum-drying obtains yellow product COP-Chitin.
In the heavy wall single port flask of a tool piston, add exsiccant acetonitrile and previous step product, be stirred to suspending stabilizedly, add the acetonitrile saturated solution that contains 10 parts of Trimethylamine 99s again.Closure piston is put into 50 ℃ water-bath, keeps 60 hours.Open piston, be heated to 70 ℃, remaining Trimethylamine 99 is caught up with in the vitriol oil.Filter, product is with water washing, and vacuum-drying afterwards promptly obtains required target product to constant weight.
Embodiment 3
In a there-necked flask of being furnished with constant pressure funnel and magnetic stirring apparatus, add 1 part, 2 parts triethylamines of Natvosol dried powder and exsiccant dioxane.Stirring makes system keep suspended state, uses cryosel to bathe and reaction system is cooled to-10 ℃, slowly splashes into excessive 100% the COP that is dissolved in dry dioxane, lasts 2 hours, continues then to stir 2 hours.Controlled temperature is at-10 ℃.Naturally be warming up to room temperature, restir reaction 2 hours.Filter, vacuum is taken out the muriate of triethylamine, obtains yellow product.
Add exsiccant acetonitrile and intermediate product in the heavy wall single port flask of a tool piston, stirring makes suspending stabilized, to wherein feeding excessive dry Trimethylamine 99.Closure piston is put into 100 ℃ water-bath, keeps 5 hours.Open piston, be heated to remaining Trimethylamine 99 is caught up with in the vitriol oil.Suction filtration removes and to desolvate, product with washing with alcohol for several times after, vacuum-drying promptly obtains required target product to constant weight.
Embodiment 4
In a there-necked flask of being furnished with constant pressure funnel and magnetic stirring apparatus, add a hyaluronic acid membrane, 4 parts of TEA and 12 parts of exsiccant tetrahydrofuran (THF)s with glutaraldehyde cross-linking.Stir, use cryosel to bathe and reaction system is cooled to-15 ℃, slowly splash into three parts of COP that are dissolved in a certain amount of dry tetrahydrofuran, last 3 hours, continue then to stir 4 hours.Controlled temperature is at-15 ℃.Naturally be warming up to room temperature, restir reaction 4 hours.Suction filtration removes the THF that desolvates, and obtains white product.
Add exsiccant acetonitrile and intermediate product in the heavy wall single port flask of a tool piston, the careful stirring makes system suspending stabilized, adds the acetonitrile saturated solution that contains 20 parts of dry Trimethylamine 99s again.Closure piston is put into 70 ℃ water-bath, keeps 50 hours.Open piston, be heated to 75 ℃, remaining Trimethylamine 99 is caught up with in the vitriol oil.Filter product vacuum-drying.After the desciccate washing, vacuum-drying promptly obtains required target product to constant weight.
Embodiment 5
In a there-necked flask of being furnished with constant pressure funnel and magnetic stirring apparatus, add a sodium alginate powder, 3 parts of TEA and 15 parts of exsiccant tetrahydrofuran (THF)s.Stirring makes suspending stabilized, uses cryosel to bathe and reaction system is cooled to-10 ℃, slowly splashes into three parts of COP that are dissolved in a certain amount of dry tetrahydrofuran, lasts 1 hour, continues then to stir 1 hour.Controlled temperature is at-10 ℃.Naturally be warming up to room temperature, restir reaction 1 hour.Suction filtration removes the THF that desolvates, and obtains white product.
Add exsiccant acetonitrile and intermediate product in the heavy wall single port flask of a tool piston, the careful stirring makes system suspending stabilized, adds the acetonitrile saturated solution that contains 20 parts of dry Trimethylamine 99s again.Closure piston is put into 80 ℃ oil bath pan, keeps 30 hours.Open piston, heating is caught up with remaining Trimethylamine 99 in the vitriol oil.Filter product vacuum-drying.After the desciccate washing, vacuum-drying promptly obtains required target product to constant weight.
The above embodiment that narrates should be considered to all belong to exemplary in nature in all fields and not belong to restrictive, should not be construed as to limit the scope of the invention.
Claims (7)
1, a kind of synthetic method of polysaccharide or derivatives thereof material of phosphatide base group modification, it is characterized in that by condensation reaction, the phosphatide group that will have bionic function, be covalently bound to natural, biodegradable biological polyoses and derivative surface thereof, be prepared into and contain the novel polysaccharide material of modifying with Phosphorylcholine.
2, synthetic method according to claim 1, it is characterized in that said polysaccharide comprises chitosan, chitin, hyaluronic acid, starch, Lalgine, Mierocrystalline cellulose, described polysaccharide derivates comprises: the sulfonation of polysaccharide, etherificate, carboxymethylation, hydroxyethylation, alkylation, nitrated, halogenation or crosslinked derived products.
3,, it is characterized in that said polysaccharide or derivatives thereof has hydroxyl or the amino with reactive behavior according to the preparation method described in the claim 2.
4, synthetic method according to claim 3, the form that it is characterized in that said polysaccharide or derivatives thereof is powder, porous small ball or particle, perhaps film.
5, synthetic method according to claim 1 is characterized in that comprising two parts of condensation reaction and ring-opening reaction, and concrete steps are as follows:
The first step, condensation reaction, above-mentioned polysaccharide or derivatives thereof, triethylamine and exsiccant solvent are pressed given mixed in molar ratio, stirring, make to suspend evenly, reaction system is cooled to-30 ℃ of low temperature environments, splash into phosphoryl chloride COP (the 2-chloro-2-oxygen-1 that is dissolved in dry solvent gradually to room temperature, 3,2-diethoxy acyl chlorides), continued stirring reaction 1-5 hour, whole process control temp is constant; Wherein, your the ratio control that feeds intake of polysaccharide or derivatives thereof, triethylamine, COP is as follows: polysaccharide or derivatives thereof: COP is 1: 1-1: 5, and COP is excessive, triethylamine: COP is 1: 1-3: 1;
Reaction system is warming up to 20-30 ℃ then, restir reaction 1-8 hour, extrct desolvates, and vacuum-drying obtains intermediate product;
In second step, ring-opening reaction is put into the single port container with piston with intermediate product and solvent that back makes, stirs, and makes suspending stabilized; The saturated solution that adds the above-mentioned solvent of open loop reagent again, wherein, the weight consumption of open loop reagent is 5-10 a times of solvent; Closure piston is put into 60-70 ℃ water-bath, reacts 30-60 hour; Open piston, be heated to 70-90 ℃, remove remaining open loop reagent; Under nitrogen protection, filter, washing, solvent is thoroughly removed in vacuum-drying, promptly gets the natural polysaccharide or derivatives thereof by the phosphide base group modification.
In this step, solvent for use is acetonitrile or benzene or toluene, and used open loop reagent is Trimethylamine 99 or triethylamine.
6, synthetic method according to claim 5 is characterized in that solvent used in the synthesis step one is one or more a mixture of tetrahydrofuran (THF), benzene, toluene, hexanaphthene, acetonitrile, chloroform, methylene dichloride, dioxane.
7, synthetic method according to claim 5 is characterized in that the solvent that cleaning product is used in the synthesis step two is water, methyl alcohol or ethanol; Vacuum drying temperature is the 0-50 degree, and the time is 1-50 hour.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100540222A CN1319994C (en) | 2004-08-26 | 2004-08-26 | Method of synthesising polysaccharide or its derivative modified by phospho lipid group |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100540222A CN1319994C (en) | 2004-08-26 | 2004-08-26 | Method of synthesising polysaccharide or its derivative modified by phospho lipid group |
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| Publication Number | Publication Date |
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| CN1597700A true CN1597700A (en) | 2005-03-23 |
| CN1319994C CN1319994C (en) | 2007-06-06 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977275A (en) * | 2011-09-07 | 2013-03-20 | 佛山市博新生物科技有限公司 | Use of phosphorylcholine groups for improving biocompatibility of adsorption resin |
| CN107722321A (en) * | 2017-10-09 | 2018-02-23 | 西安科技大学 | The method of two kinds of phosphoryl choline polymer bionic coating Chitosan films containing epoxy and amino |
| CN108714236A (en) * | 2018-06-19 | 2018-10-30 | 北京化工大学 | Starch-choline compound system and its preparation method and application |
| CN109054030A (en) * | 2018-06-28 | 2018-12-21 | 华南理工大学 | A kind of amphoteric ion polymer brush and the preparation method and application thereof based on hyaluronic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09183819A (en) * | 1995-12-28 | 1997-07-15 | Nippon Oil & Fats Co Ltd | Copolymer having phospholipid-like structure and medical material |
-
2004
- 2004-08-26 CN CNB2004100540222A patent/CN1319994C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977275A (en) * | 2011-09-07 | 2013-03-20 | 佛山市博新生物科技有限公司 | Use of phosphorylcholine groups for improving biocompatibility of adsorption resin |
| CN102977275B (en) * | 2011-09-07 | 2014-12-10 | 佛山市博新生物科技有限公司 | Use of phosphorylcholine groups for improving biocompatibility of adsorption resin |
| CN107722321A (en) * | 2017-10-09 | 2018-02-23 | 西安科技大学 | The method of two kinds of phosphoryl choline polymer bionic coating Chitosan films containing epoxy and amino |
| CN107722321B (en) * | 2017-10-09 | 2019-08-13 | 西安科技大学 | The method of two kinds of phosphoryl choline polymer bionic coating Chitosan films containing epoxy and amino |
| CN108714236A (en) * | 2018-06-19 | 2018-10-30 | 北京化工大学 | Starch-choline compound system and its preparation method and application |
| CN109054030A (en) * | 2018-06-28 | 2018-12-21 | 华南理工大学 | A kind of amphoteric ion polymer brush and the preparation method and application thereof based on hyaluronic acid |
| CN109054030B (en) * | 2018-06-28 | 2021-05-14 | 华南理工大学 | Hyaluronic acid-based zwitterionic polymer brush and preparation method and application thereof |
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|---|---|
| CN1319994C (en) | 2007-06-06 |
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