CN100491406C - Phosphoryl choline chitosan derivative synthesis method - Google Patents
Phosphoryl choline chitosan derivative synthesis method Download PDFInfo
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- CN100491406C CN100491406C CNB2006101237471A CN200610123747A CN100491406C CN 100491406 C CN100491406 C CN 100491406C CN B2006101237471 A CNB2006101237471 A CN B2006101237471A CN 200610123747 A CN200610123747 A CN 200610123747A CN 100491406 C CN100491406 C CN 100491406C
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- choline
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- phosphonates
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Abstract
The invention discloses a synthesizing method of phosphocholine chitosan derivant, which comprises the following steps: reacting chitose powder and disubstituted Choline phosphonate with different proportions in the composite system of alkaline, carbon tetrachloride and secondary alcohol at 0-40 Deg C for 12-24h; hydrolyzing through alkaline liquid to obtain the product with different coupling rate. The invention modifies biological function and compatibility, which can be applied in the drug and gene carrier, tissue engineering rack, biological medical film, aquagel and biological intelligent instrument domain.
Description
Technical field
The present invention relates to a kind of synthetic method of phosphoryl choline chitosan derivative.The bionics techniques modification field that belongs to the biodegradation type medical material.
Background technology
Chitosan is that a kind of toxicity is extremely low, and natural alkaline polymer with excellent biological compatibility and biodegradability, contain free amine group and hydroxyl in its molecular structure, can further carry out chemically modified, introduce the molecule that has property in multiple functional group or the coupling.Therefore, chitosan and derivative thereof are widely used in fields such as agricultural, foodstuffs industry, environment protection and medical and health, especially at pharmaceutical sanitary field, can be used for aspects such as wound healing, medicine sustained release, organizational project.
Because chitosan itself has character such as easy generation nonspecific proteins matter absorption, and its practical application effect is affected.For example, chitosan-based Nano medication/gene vector system easily activates the foreign matter recognition system rapidly in blood, make it to be captured and to eat, thereby reduced the residence time in blood, also influences its target, and then influences drug effect; Aspect organizational project, the absorption of nonspecific proteins matter will influence the specificity interaction of support to biologically active substance, be unfavorable for realizing the specific recognition of cell and the tissue growth of hope.
Biomimetic material derives from intersecting of Materials science and biotechnology, the material that is meant the various characteristics of mimic biology body or characteristic and develops, can be the material of bionic structure or function bionics, also can be the bionical assembly behavior of employing process, the material of preparation structure and function bionics.The biomedical polymer that is used for human body at first requires it to have biological functionality (reaction that can bring into play desired function in vivo or bring out expection) and biocompatibility; And introduce the biomimetic chemistry structure, can improve the biological functionality of medical polymer, and further improve its biocompatibility.The macromolecular material that existing bibliographical information has the phosphorylcholine group of bionical thing membrane structure adsorbs and improves its biocompatibility by suppressing nonspecific proteins matter, can be applied in comprising many medical apparatus such as graft materials, conduit and drug delivery system.[1.L.Ruiz，J.G.Hilborn，D.Léonard，etc，Synthesis，Structure?and?Surface?Dynamics?of?Phosphorylchol?ine?FunctionalBiomimicking?Polymers，Biomaterials，19，987～998(1998).2.T.Konno，K.Kurita，Y.Iwasaki，etc，Preparation?of?Nanoparticles?Composed?withBioinspired?2-methacryloyloxyethyl?Phosphorylchol?ine?Polymer，Biomaterials，22，1883～1889(2001).3.A.L.Lewis，J.Berwick，M.C.Davies，etc，Synthesis?and?Characterisation?of?Cationically?Modified?PhospholipidPolymers，Biomaterials，25，3099～3108(2004).]
If by chitosan is directly carried out the phosphorus chemistry modification, on its molecular skeleton, introduce the phosphorylcholine group of bionical thing membrane structure, then can be on the biological degradability that keeps chitosan and other good biomedical active bases, suppress the nonspecific action of itself and organism, thereby further improve its biological functionality and biocompatibility.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of phosphoryl choline chitosan derivative, by chitosan is carried out the phosphorus chemistry modification, introduce the both sexes phosphorylcholine group of bionical thing membrane structure, with further biological functionality and the biocompatibility that improves chitosan, the phosphoryl choline chitosan derivative that obtains can be used as bio-medical material widespread use in fields such as medicine and genophore, tissue engineering bracket, biological medicinal membrane, hydrogel, biological intelligence device.
The synthetic method of phosphoryl choline chitosan derivative of the present invention comprises the steps:
(1) chitosan and two choline phosphonic acid esters that replace are put in the reaction medium according to the amino in the chitosan and two ratios that replace mol ratio 1:0.5～20 of the phosphonic acid ester in the choline phosphonic acid ester, in 0～40 ℃ of reaction 12～24 hours, be spin-dried for solvent, add alkaline aqueous solution, hydrolysis obtained reaction solution in 0.5～12 hour;
(2) reaction solution that obtains of step (1) obtains phosphoryl choline chitosan derivative through ethanol sedimentation, filtration, washing, drying;
Preferred version of the present invention is as follows:
The preferred deacetylation of the described chitosan of step (1) is 50%～100%, molecular weight is 5000～5,000,000 chitosan.
Step (1) described two replace the choline phosphonic acid esters by choline chloride 60 and to the phenoxy group phosphonic acid ester in molar ratio 2:1 in methyl-sulphoxide/pyridine mixed solvent, react and made in 2 hours.
The described reaction medium preferred bases of step (1), tetracol phenixin or secondary alcohol.
Preferred Virahol of described secondary alcohol or 2-butanols.
The preferred ammoniacal liquor of alkaline aqueous solution, potassium hydroxide or aqueous sodium hydroxide solution described in the step (1).
It is as follows to adopt the inventive method to prepare the reaction formula of phosphoryl choline chitosan derivative:
The present invention compared with prior art has following advantage: the phosphoryl choline chitosan derivative of the inventive method preparation, owing to introduced the both sexes phosphorylcholine group of bionical thing membrane structure, its water-soluble improving of one side, for example, substitution value reaches 20% phosphoryl choline chitosan derivative and not only is dissolvable in water acidic aqueous solution, also is dissolvable in water in neutral and the alkaline aqueous solution; On the other hand, can suppress it in vivo to proteinic non-specific adsorption, the biological functionality and the biocompatibility of this derivative are effectively improved, for example, the medicament carrier microspheres of phosphoryl choline chitosan derivative preparation significantly reduces absorption of proteins in the blood than chitosan microball, help the residence time of prolong drug carrier in blood, improve drug effect.
Embodiment
Embodiment 1
(1) the two choline phosphonic acid esters that replace of preparation
The choline chloride 60 of 0.01mol is dissolved in 30～50ml methyl-sulphoxide, the heating, vacuum drying, remove moisture fully, add the anhydrous pyridine to phenoxy group phosphonic acid ester and 3～5ml of 0.005mol again, stirring reaction made two choline phosphonic acid ester solution that replace in 2 hours at normal temperatures.
(2) preparation phosphoryl choline chitosan derivative
Two choline phosphonic acid ester solution that replace of step (1) preparation are spin-dried for solvent, are dissolved in and obtain reaction solution A in the anhydrous isopropyl alcohol.
With the chitosan powder of the deacetylation 50% of 0.0005mol, molecular weight 228,000 50 ℃ of dryings 24 hours in vacuum drying oven, slough the planar water on surface, the isopropyl alcohol mixed solvent of the triethylamine of the 3ml of adding drying treatment, the tetracol phenixin of 2ml, 5ml obtains reaction solution B as dispersion agent.At room temperature reaction solution A is splashed into reaction solution B gradually, stirring reaction 24 hours obtains two choline phosphorylated chitosan derivatives.Be spin-dried for solvent, add under the 20ml ammoniacal liquor normal temperature again and stirred 5 hours, with ethanol sedimentation and washing, vacuum-drying obtains the phosphoryl choline chitosan derivative product, yield 81%.
Embodiment 2
(1) the two choline phosphonic acid esters that replace of preparation
The choline chloride 60 of 0.02mol is dissolved in 60～120ml methyl-sulphoxide, and the heating, vacuum drying is removed moisture fully, adds the anhydrous pyridine to phenoxy group phosphonic acid ester and 6～10ml of 0.01mol again, and stirring reaction made two choline phosphonic acid esters that replace in 2 hours at normal temperatures.
(2) preparation phosphoryl choline chitosan derivative
Two choline phosphonic acid ester solution that replace of step (1) preparation are spin-dried for solvent, are dissolved in the anhydrous 2-butanols and obtain reaction solution A.
With the chitosan powder of the deacetylation 80% of 0.005mol, molecular weight 46,000 50 ℃ of dryings 24 hours in vacuum drying oven, slough the planar water on surface, the 2-butanols mixed solvent of the triethylamine of the 6ml of adding drying treatment, the tetracol phenixin of 3ml, 10ml obtains reaction solution B as dispersion agent.In 40 ℃, reaction solution A is splashed into reaction solution B gradually, stirring reaction is 12 hours under the normal temperature, obtains two choline phosphorylated chitosan derivatives.Be spin-dried for solvent, the 0.1M sodium hydroxide solution normal temperature that adds 20ml again stirred 2 hours down, and with ethanol sedimentation and washing, vacuum-drying obtains the phosphoryl choline chitosan derivative product, yield 78%.
Embodiment 3
(1) the two choline phosphonic acid esters that replace of preparation
The choline chloride 60 of 0.01mol is dissolved in 30～50ml methyl-sulphoxide, the heating, vacuum drying, remove moisture fully, add the anhydrous pyridine to phenoxy group phosphonic acid ester and 3～5ml of 0.005mol again, stirring reaction made two choline phosphonic acid ester solution that replace in 2 hours at normal temperatures.
(2) preparation phosphoryl choline chitosan derivative
Two choline phosphonic acid ester solution that replace of step (1) preparation are spin-dried for solvent, are dissolved in and obtain reaction solution A in the anhydrous isopropyl alcohol.
With the chitosan powder of the deacetylation 100% of 0.005mol, molecular weight 5,000 50 ℃ of dryings 24 hours in vacuum drying oven, slough the planar water on surface, the isopropyl alcohol mixed solvent of the triethylamine of the 3ml of adding drying treatment, the tetracol phenixin of 1.5ml, 10ml obtains reaction solution B as dispersion agent.In ice-water bath, reaction solution A is splashed into reaction solution B gradually, stirring reaction is 12 hours under the normal temperature, obtains two choline phosphorylated chitosan derivatives.Be spin-dried for solvent, add under the 20ml ammoniacal liquor normal temperature again and stirred 5 hours, with ethanol sedimentation and washing, vacuum-drying obtains the phosphoryl choline chitosan derivative product, yield 85%.
The nucleus magnetic resonance test is as follows to the structural characterization of the phosphoryl choline chitosan derivative that embodiment obtains:
31P NMRat 293K (D
2O): δ 6.81 (NH-PC);
1H NMR at 293 K (D
2O): δ 2.89 (br, H
2OfGlcN and GlcN-PC), 3.22 (s ,-N
+(CH
3)
3), 3.63～4.06 (m, N
+CH
2-, H
3, H
4, H
5, H
6Of GlcN and GlcN-PC), 4.28 (br, OPOCH
2-), 4.52 (br, H
1Of GlcN-PC), 4.59 (br, H
1Of GlcN);
13CNMR at 293 K (D
2O): δ 54.0 ((CH
3)
3N
+), 56.4 (N
+CH
2-), 58.5 (C
2Of GlcN), 60.2 (C
6Of GlcN), 66.3 (OPOCH
2-), 72.9 (C
3Of GlcN), 74.9 (C
5OfGlcN), 77.5 (C
4Of GlcN), 100.7 (C
1Of GlcN), 102.7 (C
1Of GlcN-PC).This sign confirms that tester is a phosphoryl choline chitosan derivative.
Claims (2)
1, a kind of synthetic method of phosphoryl choline chitosan derivative is characterized in that comprising the steps:
(1) chitosan and two choline phosphonates that replace are put in the reaction medium according to the amino in the chitosan and two ratios that replace mol ratio 1:0.5～20 of the phosphonates in the choline phosphonates, in 0～40 ℃ of reaction 12～24 hours, be spin-dried for solvent, add alkaline aqueous solution, hydrolysis obtained reaction solution in 0.5～12 hour;
(2) reaction solution that obtains of step (1) obtains phosphoryl choline chitosan derivative through ethanol sedimentation, filtration, washing, drying;
The described chitosan of step (1) selects that deacetylation is 50%～100% for use, molecular weight is 5000～5,000,000 chitosan;
Step (1) described two replace the choline phosphonates by choline chloride 60 and to the phenoxy group phosphonates in molar ratio 2:1 in methyl-sulphoxide/pyridine mixed solvent, react and made in 2 hours;
The described reaction medium of step (1) is the mixture of triethylamine, tetracol phenixin and secondary alcohol;
Described secondary alcohol is Virahol or 2-butanols.
2, method according to claim 1 is characterized in that, the alkaline aqueous solution described in the step (1) is ammoniacal liquor, potassium hydroxide or aqueous sodium hydroxide solution.
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| CNB2006101237471A CN100491406C (en) | 2006-11-24 | 2006-11-24 | Phosphoryl choline chitosan derivative synthesis method |
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| CNB2006101237471A CN100491406C (en) | 2006-11-24 | 2006-11-24 | Phosphoryl choline chitosan derivative synthesis method |
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| CN100491406C true CN100491406C (en) | 2009-05-27 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265304B (en) * | 2008-04-18 | 2011-08-10 | 中国药科大学 | Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same |
| CN105384835A (en) * | 2015-11-11 | 2016-03-09 | 暨南大学 | Choline diphosphate chitosan salt and application thereof |
| CN105254780B (en) * | 2015-11-11 | 2017-07-04 | 暨南大学 | A kind of bionical derivative of cation type chitosan and its application |
| CN105504190B (en) * | 2016-01-05 | 2018-10-09 | 暨南大学 | A kind of photo-crosslinking biomim betatic and its preparation and application |
| CN110804104B (en) * | 2019-10-30 | 2021-12-07 | 暨南大学 | Cell membrane bionic surface modified bacterial cellulose and preparation method and application thereof |
| CN110791798B (en) * | 2019-11-28 | 2020-07-31 | 中国人民解放军西部战区总医院 | Method for constructing chitosan-poly (choline phosphate)/gelatin coating on surface of bionic porous titanium alloy |
| CN112625268B (en) * | 2020-12-22 | 2022-09-27 | 暨南大学 | Cell membrane bionic polyamide-amine dendritic macromolecular hydrogel and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1187948A (en) * | 1997-01-13 | 1998-07-22 | 陈乐玫 | Health-care chitosan-chitin food |
| CN1283634A (en) * | 2000-08-28 | 2001-02-14 | 李高霖 | Process for preparing water-soluble shitosan |
| WO2004070009A2 (en) * | 2003-01-31 | 2004-08-19 | Targesome Inc. | Targeted multivalent macromolecules |
-
2006
- 2006-11-24 CN CNB2006101237471A patent/CN100491406C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1187948A (en) * | 1997-01-13 | 1998-07-22 | 陈乐玫 | Health-care chitosan-chitin food |
| CN1283634A (en) * | 2000-08-28 | 2001-02-14 | 李高霖 | Process for preparing water-soluble shitosan |
| WO2004070009A2 (en) * | 2003-01-31 | 2004-08-19 | Targesome Inc. | Targeted multivalent macromolecules |
Non-Patent Citations (6)
| Title |
|---|
| Preparation of nanoparticles composed withbioinspired2-methacryloyloxyethyl phosphorylcholine polymer. Tomohiro Konno et al.Biomaterials,Vol.22 . 2001 |
| Preparation of nanoparticles composed withbioinspired2-methacryloyloxyethyl phosphorylcholine polymer. Tomohiro Konno et al.Biomaterials,Vol.22 . 2001 * |
| Synthesis and characterisation of cationically modifiedphospholipid polymers. AndrewL. Lewis et al.Biomaterials,Vol.25 . 2004 |
| Synthesis and characterisation of cationically modifiedphospholipid polymers. AndrewL. Lewis et al.Biomaterials,Vol.25 . 2004 * |
| Synthesis, structure and surface dynamics ofphosphorylcholine functional biomimicking polymers. L. Ruiz et al.Biomaterials,Vol.19 . 1998 |
| Synthesis, structure and surface dynamics ofphosphorylcholine functional biomimicking polymers. L. Ruiz et al.Biomaterials,Vol.19 . 1998 * |
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