CN101284883B - Preparation method of polylactic acid-chitose graft copolymer - Google Patents
Preparation method of polylactic acid-chitose graft copolymer Download PDFInfo
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- CN101284883B CN101284883B CN2008100181853A CN200810018185A CN101284883B CN 101284883 B CN101284883 B CN 101284883B CN 2008100181853 A CN2008100181853 A CN 2008100181853A CN 200810018185 A CN200810018185 A CN 200810018185A CN 101284883 B CN101284883 B CN 101284883B
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- lactic acid
- chitosan
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- polylactic acid
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Abstract
The invention discloses a method for making polylactic acid-chitosan graft copolymer. The method comprises the following steps that: (1) the chitosan with a deacetylation between 50 and 90 percent and a molecular weight between 500 and 30000 is dissolved into a lactic acid solution; (2) a nonpolar solvent capable of forming a low-boiling point azeotrope is added into the mixture to dehydrate at the temperature of between 40 and 90 DEG C; (3) after the dehydration is finished, an organic base and a catalyst are added to react at the temperature of between 10 and 100 DEG C, the catalyst is an acid catalyst, a Lewis acid catalyst, a strong acid type positive ion-exchange resin or an N, N'- dicyclohexylamine carbimide; (4) the drying and concentrating processes are performed and the product is obtained. The synthetic method is simple, the reaction condition is moderate, and the energy consumption is low, therefore, the method is suitable for the industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of bio-medical material, in more detail the preparation method of chitosan-polylactic acid graft copolymer.
Technical background
Poly(lactic acid) is to be the new bio degradable polymer material of monomer through chemosynthesis with lactic acid, and its nontoxic, nonirritant has good biocompatibility, biodegradable, absorption, and the intensity height, plasticity-is good, easily machine-shaping.Poly(lactic acid) is decomposed through enzyme in vivo, finally forms carbonic acid gas and water, can not assemble at vitals, therefore becomes one of material the most attractive in the medical field.Yet poly-lactic acid material exists degradation cycle to be difficult to control in biomedical applications, the acid degradation product causes aseptic inflammation in vivo easily, defectives such as hydrophobicity is strong, in addition, the more important thing is the shortage activity functional groups, be difficult to the discernible signaling molecule of coupling cell in polylactic acid chain, to improve material and intercellular interaction.Therefore, poly-lactic acid material is carried out the bioactivation modification, introduce cell signal on material, it is necessary giving material biological activity etc.
Sugar is organic important composition composition and main energy derive, and most zooblast all has one deck sugar-albumen composition outward, so be that monose or polysaccharide all have affinity preferably to polypeptide, protein, pair cell also has affinity preferably.Chitosan is unique natural alkaline polysaccharide, also is a kind of biological medical polymer material of excellent performance.Itself has some physiologically actives, has free amino, is weakly alkaline, can effectively regulate pH value of human body, both can improve the activity and the phagocytic activity of scavenger cell, can suppress the growth of undesirable cell again.But its mechanical strength is low, the degree of crystallinity height.Exploitation poly(lactic acid)/poly-polysaccharide compound bio medical material should be an effective way improving poly(lactic acid) cellular affinity and chitosan processing characteristics.
At present, the method of synthetic chitosan-polylactic acid graft copolymer mainly contains: (1) is catalyzer with the triethyl aluminum, toluene solution is as reaction medium, utilize the amino of chitosan or one-level methylol as reaction site, cause D, the L-rac-Lactide carries out polymerization on the chitosan molecule chain, form comb-grafted copolymer (Y Liu, F Tian, K.A.Hu.Synthesis and characterization of a brush-likecopolymer of polylactide grafted onto chitosan.Carbohydrate Research, 2004,339:845-851.).Because chitosan is suspended in the reaction medium, can not form the reaction system of homogeneous with rac-Lactide, the percentage of grafting of chitosan-polylactic acid graft copolymer is lower.(2) poly(lactic acid) and dibasic alcohol carry out esterification in 150 ℃ and obtain the primary hydroxyl poly(lactic acid) under catalyst action, with sulfoxide compound the primary hydroxyl of poly(lactic acid) is oxidized to aldehyde radical, amino with chitosan reacts then, realizes graft copolymerization (preparation method of Chinese patent ZL 02155475.7 chitosan-copolymer of poly lactic acid).This method operational path is comparatively complicated.(3) chitosan is dissolved in lactic acid aqueous solution, amino on the chitosan and the carboxyl on the lactic acid form ammonium salt, lactic acid polycondensation simultaneously becomes low-molecular-weight oligopolymer, obtaining main chain is chitosan, side chain is the chitosan-poly(lactic acid) gel (Yao Fanglian etc. of low molecular weight, synthetic and the cell compatibility analysis of chitosan-poly(lactic acid) gel, the academic free paper session paper of national polymer in 2005).
Summary of the invention
The purpose of this invention is to provide a kind of in homogeneous system, the reaction conditions gentleness, synthetic route is easy, and poly(lactic acid) graft copolymerization on the chitosan molecule chain, is formed the preparation method of polylactic acid-chitose graft copolymer.
The preparation method of chitosan-polylactic acid graft copolymer of the present invention carries out as follows:
(1) be 50-90% with deacetylation, molecular weight is that the chitosan of 0.5-3 ten thousand is dissolved in the lactic acid solution;
(2) add and to form the non-polar solvent of lower boiling azeotrope in 40-90 ℃ of azeotropic dehydration with water;
(3) dehydration finishes, and adds organic bases and catalyzer in 10-100 ℃ of reaction, and described catalyzer is an acidic catalyst, lewis acid catalyst, strongly acidic cation-exchange or N, N '-dicyclohexyl carbimide (DCC);
(4) dry, concentrated organic phase gets product.
After reaction finishes, use distilled water wash reaction solution 1-2 time, behind the branch water, the organic phase anhydrous Na
2SO
4Drying is spent the night, and removes by filter Na
2SO
4After reaction solution process rotary evaporation concentrates, pour in the dehydrated alcohol and purify, obtain white precipitate, filter and drying, get white yellow solid powder, be product.
Lactic acid of the present invention is DL-lactic acid, D-lactic acid and/or L-lactic acid, and its mass percent concentration is 15-85%; Described non-polar solvent is selected from benzene, toluene, methylene dichloride or trichloromethane; Described organic bases is selected from triethylamine, pyridine or dimethylamino pyridine (DMAP); Described catalyzer is AlCl
3, H
2SO
4, D001 large porous strong acid cation exchange resin or N, N '-dicyclohexyl carbimide.
Advantage of the present invention and positively effect: the present invention is dissolved in chitosan in the lactic acid, adopts azeotropic dehydration, and condensation under catalyst action, has guaranteed the reaction system of homogeneous, can make in the chitosan structure functional group-OH or-NH
2Fully react with lactic acid units, it is higher to obtain percentage of grafting, and the multipolymer that molecular weight is bigger is the operational path of a new synthetic chitosan grafted polylactic acid multipolymer.Synthetic method is simple, the reaction conditions gentleness, and energy consumption is lower, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1:
Taking by weighing 0.25g chitosan (90%) joins in the 6g L-lactic acid (80%), stirring under the room temperature fully dissolves it, pour into solution in the 250ml there-necked flask and add an amount of (about 200ml) methylene dichloride, 40 ℃ of azeotropic dehydration 2-4h in the rectification device.After dehydration finishes, in solution, add 0.184g DMAP, fully after the dissolving, when putting into ice-water bath and being cooled to 0 ℃, add the DCC of 5.846g then within a short period of time.Take condensation reflux unit, assurance reaction soln volume maintenance is reacted 24h at 60ml under the room temperature.
After reacting end, the white precipitate dicyclohexylurea (DCU) (DCU) that suction filtration generates except that dereaction is washed the dilute hydrochloric acid of gained filtrate with 0.5M 3 times, uses distilled water wash 1-2 time, the organic phase anhydrous Na behind the branch water
2SO
4Dry.Under 0 ℃ of condition, spend the night, the DCU that is dissolved in the methylene dichloride is separated out under cold condition, remove by filter Na
2SO
4And DCU, after reaction solution process rotary evaporation concentrates, pour in the dehydrated alcohol and purify, obtain white precipitate, filter and drying, get white yellow solid powder, be product.
Embodiment 2:
Taking by weighing 0.25g chitosan (50%) joins in the 6g D-lactic acid (80%), stirring under the room temperature fully dissolves it, pour into solution in the 250ml there-necked flask and add an amount of (about 200ml) methylene dichloride, 40 ℃ of azeotropic dehydration 2-4h in the rectification device.After dehydration finishes, in solution, add 0.184g DMAP, fully after the dissolving, when putting into ice-water bath and being cooled to 0 ℃, add the DCC of 5.846g then within a short period of time.Take condensation reflux unit, assurance reaction soln volume maintenance is reacted 24h at 60ml under the room temperature.
After reacting end, the white precipitate dicyclohexylurea (DCU) (DCU) that suction filtration generates except that dereaction is washed the dilute hydrochloric acid of gained filtrate with 0.5M 3 times, uses distilled water wash 1-2 time, the organic phase anhydrous Na behind the branch water
2SO
4Dry.Under 0 ℃ of condition, spend the night, the DCU that is dissolved in the methylene dichloride is separated out under cold condition, remove by filter Na
2SO
4And DCU, after reaction solution process rotary evaporation concentrates, pour in the dehydrated alcohol and purify, obtain white precipitate, filter and drying, get white yellow solid powder, be product.
Embodiment 3:
Take by weighing 0.25g chitosan (90%) and join in the 6g L-lactic acid (80%), stir under the room temperature it is fully dissolved, pour into solution in the 250ml there-necked flask and add an amount of (about 200ml) toluene, 90 ℃ of azeotropic dehydration 2-4h in the rectification device.After dehydration finishes, in solution, add the AlCl of 0.56g
3Take condensation reflux unit, guarantee the reaction soln volume maintenance at 60ml, 100 ℃ are reacted 4h down.
After reaction finished, suction filtration was removed AlCl
3, gained filtrate is used distilled water wash 1-2 time, the organic phase anhydrous Na behind the branch water
2SO
4Dry.At room temperature spend the night, remove by filter Na
2SO
4, after reaction solution process rotary evaporation concentrates, pour in the dehydrated alcohol and purify, obtain white precipitate, filter and drying, get white yellow solid powder, be product.
Embodiment 4:
Take by weighing 0.25g chitosan (90%) and join in the 6g L-lactic acid (80%), stir under the room temperature it is fully dissolved, pour into solution in the 250ml there-necked flask and add an amount of (about 200ml) toluene, 90 ℃ of azeotropic dehydration 2-4h in the rectification device.After dehydration finishes, in solution, add the D001 macropore strong acid cation exchange resin of 0.8g.Take condensation reflux unit, and make the reaction soln volume maintenance at 60ml, 100 ℃ are reacted 8h down.
After reaction finished, suction filtration was removed D001, and gained filtrate is used distilled water wash 1-2 time, the organic phase anhydrous Na behind the branch water
2SO
4Dry.At room temperature spend the night, remove by filter Na
2SO
4, after reaction solution process rotary evaporation concentrates, pour in the dehydrated alcohol and purify, obtain white precipitate, filter and drying, get white yellow solid powder, be product.
Embodiment 5:
Take by weighing 0.25g chitosan (90%) and join in the 12g D-lactic acid (40%), stir under the room temperature it is fully dissolved, pour into solution in the 250ml there-necked flask and add an amount of (about 200ml) toluene, 90 ℃ of azeotropic dehydration 2-4h in the rectification device.After dehydration finishes, in solution, add the dense H of 0.25g
2SO
4Take condensation reflux unit, and make the reaction soln volume maintenance at 60ml, 100 ℃ are reacted 4h down.
After reaction finishes, the NaOH solution neutralization with 10%, and with distilled water wash 1-2 time, the organic phase anhydrous Na behind the branch water
2SO
4Dry.At room temperature spend the night, remove by filter Na
2SO
4, after reaction solution process rotary evaporation concentrates, pour in the dehydrated alcohol and purify, obtain white precipitate, filter and drying, get white yellow solid powder, be product.
Claims (3)
1. the preparation method of a polylactic acid-chitose graft copolymer is characterized in that carrying out as follows:
(1) be 50-90% with deacetylation, molecular weight is that the chitosan of 0.5-3 ten thousand is dissolved in the lactic acid solution;
(2) add can form the lower boiling azeotrope with water non-polar solvent in 40-90 ℃ of azeotropic dehydration, non-polar solvent is selected from benzene, toluene, methylene dichloride or trichloromethane;
(3) dehydration finishes, and adds organic bases dimethylamino pyridine and catalyst n, and N '-dicyclohexyl carbimide is in 10-100 ℃ of reaction;
(4) dry, concentrated organic phase gets product.
2. according to the preparation method of the described polylactic acid-chitose graft copolymer of claim 1, it is characterized in that: dry, concentrated organic phase products obtained therefrom is purified in dehydrated alcohol.
3. according to the preparation method of claim 1 or 2 described polylactic acid-chitose graft copolymers, it is characterized in that described lactic acid is DL-lactic acid, D-lactic acid and/or L-lactic acid, its mass percent concentration is 15-85%.
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| CN101628947B (en) * | 2009-08-14 | 2012-06-06 | 暨南大学 | Chitosan-polylactic acid graft copolymer and preparation method and application thereof |
| CN102757626B (en) * | 2011-04-29 | 2014-05-14 | 李文涛 | Preparation method of chitosan and polylactic acid composite material |
| CN110523440B (en) * | 2019-08-28 | 2022-04-22 | 华南理工大学 | Desalination purification method of water-soluble chitosan derivative |
| CN112889712A (en) * | 2021-01-28 | 2021-06-04 | 海南昌江元道养殖有限公司 | Standardized healthy breeding method for high-quality golden pomfret |
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| US4273920A (en) * | 1979-09-12 | 1981-06-16 | Eli Lilly And Company | Polymerization process and product |
| CN1371921A (en) * | 2002-03-21 | 2002-10-02 | 上海交通大学 | Method for synthesizing crust extract or chitosan grafted lactide polymer |
| CN1418904A (en) * | 2002-12-16 | 2003-05-21 | 天津大学 | Method for preparing chitosan-polylactic acid grafted copolymer |
| EP1538166A1 (en) * | 2003-12-04 | 2005-06-08 | Industrial Technology Research Institute | Biodegradable hyaluronic acid derivative and composition containing micelles made therefom |
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| CN101003632A (en) * | 2006-10-12 | 2007-07-25 | 上海交通大学 | Method for preparing chitosan - grafting polylactic acid |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4273920A (en) * | 1979-09-12 | 1981-06-16 | Eli Lilly And Company | Polymerization process and product |
| CN1371921A (en) * | 2002-03-21 | 2002-10-02 | 上海交通大学 | Method for synthesizing crust extract or chitosan grafted lactide polymer |
| CN1418904A (en) * | 2002-12-16 | 2003-05-21 | 天津大学 | Method for preparing chitosan-polylactic acid grafted copolymer |
| EP1538166A1 (en) * | 2003-12-04 | 2005-06-08 | Industrial Technology Research Institute | Biodegradable hyaluronic acid derivative and composition containing micelles made therefom |
| CN1693341A (en) * | 2005-04-30 | 2005-11-09 | 中国科学院长春应用化学研究所 | Process for preparing surface lactic acid graft modified starch and aliphatic polyester graft copolymer |
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