CN101565498A - Polyaspartic diol ester containing amino side chain and its synthesis process and use - Google Patents
Polyaspartic diol ester containing amino side chain and its synthesis process and use Download PDFInfo
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- CN101565498A CN101565498A CNA2008101047495A CN200810104749A CN101565498A CN 101565498 A CN101565498 A CN 101565498A CN A2008101047495 A CNA2008101047495 A CN A2008101047495A CN 200810104749 A CN200810104749 A CN 200810104749A CN 101565498 A CN101565498 A CN 101565498A
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- Prior art keywords
- polyaspartic
- diol ester
- amino side
- chain
- blocking group
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- -1 diol ester Chemical class 0.000 title claims abstract description 78
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 47
- 229920000608 Polyaspartic Polymers 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims description 12
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 17
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 17
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 14
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 230000000903 blocking effect Effects 0.000 claims description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 claims description 6
- 238000006068 polycondensation reaction Methods 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- ADCOVFLJGNWWNZ-UHFFFAOYSA-N antimony trioxide Chemical compound O=[Sb]O[Sb]=O ADCOVFLJGNWWNZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- YHWCPXVTRSHPNY-UHFFFAOYSA-N butan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] YHWCPXVTRSHPNY-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 2
- YNVZDODIHZTHOZ-UHFFFAOYSA-K 2-hydroxypropanoate;iron(3+) Chemical compound [Fe+3].CC(O)C([O-])=O.CC(O)C([O-])=O.CC(O)C([O-])=O YNVZDODIHZTHOZ-UHFFFAOYSA-K 0.000 claims description 2
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 2
- BCIKWDOSPUNGKB-UHFFFAOYSA-N butoxygermanium Chemical compound CCCCO[Ge] BCIKWDOSPUNGKB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- YBMRDBCBODYGJE-UHFFFAOYSA-N germanium dioxide Chemical compound O=[Ge]=O YBMRDBCBODYGJE-UHFFFAOYSA-N 0.000 claims description 2
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- AFCAKJKUYFLYFK-UHFFFAOYSA-N tetrabutyltin Chemical compound CCCC[Sn](CCCC)(CCCC)CCCC AFCAKJKUYFLYFK-UHFFFAOYSA-N 0.000 claims description 2
- 229910001887 tin oxide Inorganic materials 0.000 claims description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 2
- 229920000805 Polyaspartic acid Polymers 0.000 abstract description 21
- 108010064470 polyaspartate Proteins 0.000 abstract description 21
- 239000000178 monomer Substances 0.000 abstract description 6
- 229920000728 polyester Polymers 0.000 abstract description 6
- 238000006116 polymerization reaction Methods 0.000 abstract description 6
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract 2
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229960001701 chloroform Drugs 0.000 description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229920000747 poly(lactic acid) Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000012869 ethanol precipitation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 238000009736 wetting Methods 0.000 description 4
- 238000011068 loading method Methods 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229920001610 polycaprolactone Polymers 0.000 description 3
- 239000004632 polycaprolactone Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 229920003232 aliphatic polyester Polymers 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229920002961 polybutylene succinate Polymers 0.000 description 2
- 239000004631 polybutylene succinate Substances 0.000 description 2
- 238000012643 polycondensation polymerization Methods 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000004622 biodegradable polyester Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000009614 chemical analysis method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000005474 octanoate group Chemical group 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Abstract
The invention belongs to the field of polyester, and particularly relates to polyaspartic diol ester containing an amino side chain, a synthesis method and application thereof. The synthesis method of the poly-aspartic acid diol ester containing the amino side chain is mainly characterized in that aspartic acid with a protective group and dihydric alcohol are used as initial monomers, and the poly-aspartic acid diol ester containing the amino side chain has the following structure through a high molecular polymerization reaction and the generation of a hydrogenated deprotection functional group of a side group of a high molecular. The polyaspartic diol ester containing the amino side chain synthesized by the invention can be used for drug carrier materials, biomedical stent materials and environment-friendly materials.
Description
Technical field
The invention belongs to polyester art, is monomer synthesizes fully biodegradable through the condensation polymerization method the polyaspartic diol ester that contains amino side-chain with aspartic acid and dibasic alcohol particularly.But this polyester has reactive activity group and wetting ability preferably, can be used for drug carrier material, bio-medical timbering material and environment-friendly material.
Background technology
Bio-medical material is the diagnosis that is used for the biosystem disease, treatment, reparation or replaces bio-tissue or organ, promotes or recovers its materials with function.Biodegradable polymer is a current class biomaterial of attracting attention most, and its modern medicine that appears as has brought development of revolutionary significance.Aliphatic polyester is as the important chemosynthesis Biodegradable high-molecular of a class, research at present is most widely used, and comprises poly(lactic acid) (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), poly butylene succinate kind polyester (PBS) and their multipolymer etc.
Because the existing biodegradable aliphatic polyester of great majority is formed by the straight chain type carbon-chain structure of high hydrophobicity, the macromolecular chain wetting ability is poor, lacks active reactive group, thereby restricts its application in biomedical materials field; By introducing hydrophilic amino acid unit, form wetting ability and have the polyester of active reactive group, can self-assembly in macromolecular solution, at pharmaceutical carrier, tissue engineering bracket material, fields such as biodegradation high molecular tensio-active agent have a wide range of applications.Biomacromolecules, 2005,6,720～725 have reported the multipolymer of a kind of poly aspartic acid and poly(lactic acid), have improved the hydrophilicity and hydrophobicity of poly(lactic acid), can be applied to the slow releasing carrier of medication field.Journal ofPolymer Science:Part A:Polymer Chemistry; Vol.36; 2949～2959 (1998) have reported a kind of aspartic acid and ethylene glycol copolymer that contains amino side-chain; aspartic acid by the carbobenzoxy-(Cbz) protection forms acid anhydrides earlier, obtains multipolymer by acid anhydrides and polyoxyethylene glycol ring-opening polymerization again.This synthetic route is longer, and productive rate is lower, should not apply.
Summary of the invention
The object of the present invention is to provide a class is the polyaspartic diol ester that contains amino side-chain that repeats unitary fully biodegradable with aspartic acid and dibasic alcohol.
It is monomer that a further object of the present invention is to provide a kind of aspartic acid and dibasic alcohol with the band blocking group, prepares the method for the polyaspartic diol ester that contains amino side-chain through condensation polymerization.
Another object of the present invention is to provide a kind of purposes that contains the polyaspartic diol ester of amino side-chain.
The polyaspartic diol ester that contains amino side-chain of the present invention has following structure:
Wherein x is 2～6, n=2～2000;
The molecular weight that contains the polyaspartic diol ester of amino side-chain of the present invention is: 500～200000.
The synthetic method that contains the polyaspartic diol ester of amino side-chain of the present invention is an initial monomers with aspartic acid and the dibasic alcohol that has blocking group mainly, and going to protect functional group through high molecular polyreaction and the hydrogenation that generates high molecular side group is feature.
R is tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl or carbobenzoxy-(Cbz), n=2～2000, m=3～2100 and m 〉=n
The synthetic method that contains the polyaspartic diol ester of amino side-chain of the present invention may further comprise the steps:
1) in reactor, for aspartic acid and the dibasic alcohol of band blocking group are 1: 1～3 mixed by mole ratio, be to carry out normal pressure esterification under 100～200 ℃ to react with raw material in protection of inert gas and temperature, esterification time is 2～4 hours; Be 120～280 ℃ in temperature then, and the polycondensation of reducing pressure in the presence of catalyzer obtain the polyaspartic diol ester with blocking group;
The polyaspartic diol ester of the band blocking group that 2) step 1) is obtained is mixed in the organic solvent; pour in the autoclave then; in nitrogen atmosphere and in the presence of Pd/carbon catalyst, reacting 1～200 hour, slough the polyaspartic diol ester that blocking group obtains containing amino side-chain.
Described raw material can be tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl or carbobenzoxy-(Cbz) for the blocking group of the aspartic acid of band blocking group.
Described diatomic alcohol compounds is an ethylene glycol, 1, ammediol, 1,4-butyleneglycol, 1,5-pentanediol or 1,6-hexylene glycol etc.
Described rare gas element is nitrogen or argon gas.
Pressure during described decompression polycondensation is to less than 200Pa greater than 0.
The time of decompression polycondensation is 0.5～6 hour in the described polyreaction.
The described catalyzer of step 1) is selected from Phenylsulfonic acid, stannic oxide, tetrabutyl tin oxide compound, tetrabutyl titanate, metatitanic acid orthocarbonate, germanic acid four butyl esters, antimonous oxide, stannous octoate, more than one in four n-butoxy germanium and the iron lactate etc.
The described catalyst consumption of step 1) for the band blocking group the aspartic acid mole number 0.01%～5%.
Step 2) consumption of described Pd/carbon catalyst for the band blocking group the polyaspartic diol ester mole number 0～10%.
Described organic solvent is selected from methyl alcohol, ethanol, more than one in methylene dichloride and the trichloromethane etc.
Step 2) to be mixed in the concentration range in the organic solvent be 0.1～10g/ml to the polyaspartic diol ester of described band blocking group.
Step 2) described hydrogen pressure scope in nitrogen atmosphere is 1～15MPa.
Step 2) described temperature of reaction is a room temperature.
According to synthetic method provided by the present invention, the outward appearance of the polyaspartic diol ester that contains amino side-chain that obtains is the white powder compound.The polyaspartic diol ester that contains amino side-chain that obtains can further be purified, possible method of purification is: the mixed solution of the polyaspartic diol ester that contains amino side-chain that obtains after earlier hydrogenation being finished, by removing by filter catalyzer, then the mixed solution of removing catalyzer is concentrated, concentrated solution after concentrating is poured into respect to precipitating in the ethanol of concentrated solution volume more than 3 times, the polyaspartic diol ester throw out that contains amino side-chain is carried out vacuum-drying to constant weight.
The polyaspartic diol ester that contains amino side-chain of the present invention can be used for drug carrier material and bio-medical timbering material etc.
The synthetic method that contains the polyaspartic diol ester of amino side-chain of the present invention has following advantage:
(1) synthetic method that contains the polyaspartic diol ester of amino side-chain of the present invention, required starting monomer is the commercial goods, does not need complicated monomer preparation process.
(2) synthetic method that contains the polyaspartic diol ester of amino side-chain of the present invention, entire synthesis process is simple, extensive easily enforcement.
(3) class provided by the present invention contains the polyaspartic diol ester possess hydrophilic property characteristics of amino side-chain, is different from the Biodegradable polyester of existing high hydrophobicity, as poly(lactic acid), and polycaprolactone and poly butylene succinate etc.
(4) the class provided by the present invention polyaspartic diol ester that contains amino side-chain has the characteristics of active reaction side group, is convenient to the further chemical reaction modification of prepared polyester.
Chemical analysis method of the present invention and analytical instrument specify as follows:
1. chemical constitution and structure
Examination of infrared spectrum (FT-IR): the U.S. Nicolet-8700 of Thwrmoelectron company type Fourier transformation infrared spectrometer, KBr compressing tablet.Proton nmr spectra (
1H-NMR): the mercury-plus of U.S. Varian company 400 types 400,000,000 nuclear magnetic resonance spectrometers are measured, and solvent is CDCl
3
2. molecular weight and molecular weight distribution
Gel chromatograph (GPC): Waters 1515 HPLC type gel chromatographs are measured the molecular weight and the molecular weight distribution of polymkeric substance, and polystyrene is as proofreading and correct standard specimen, and trichloromethane is as moving phase, and temperature is 35 ℃.
3. wetting ability
Adopt the water contact angle method to measure: on quiet contact angle of JC2000 solid/interfacial tension survey meter, measure, 6 points of every sheet material, each point is surveyed left and right sides contact angle respectively, averages, and the base of calculation deviation.
4. scanning electron microscopic observation
HITACHI S-4300 type sem observation poly aspartic acid butanediol ester drug-loading microcapsule.Acceleration voltage is 15kV, and metal spraying is handled 50s before the test.
Description of drawings
Fig. 1. the embodiment of the invention 1,2 and 3 the poly aspartic acid butanediol ester that contains amino side-chain
1The H-NMR spectrogram.
Fig. 2. the FT-IR spectrogram of the embodiment of the invention 1,2 and 3 the poly aspartic acid butanediol ester that contains amino side-chain.
Fig. 3. the embodiment of the invention 1,2 and 3 the poly aspartic acid butanediol ester that contains amino side-chain and the contact angle of water.
Fig. 4. the poly aspartic acid glycol ester that contains amino side-chain of the embodiment of the invention 4
1The H-NMR spectrogram.
Fig. 5. the FT-IR spectrogram of the poly aspartic acid glycol ester that contains amino side-chain of the embodiment of the invention 4.
Fig. 6. the poly aspartic acid glycol ester that contains amino side-chain of the embodiment of the invention 4 and the contact angle of water.
Fig. 7. the sem photograph of the poly aspartic acid butanediol ester drug-loading microcapsule that contains amino side-chain of the embodiment of the invention 5.
Embodiment
Embodiment 1.
In reactor; aspartic acid, 1 with the carbobenzoxy-(Cbz) protection; the 4-butyleneglycol according to mol ratio be 1: 2 totally 218 the gram join in the four-hole bottle that has stirring, heating and nitrogen protection device; reaction treated that aquifer yield reaches theoretical value after 2 hours under temperature is 140 ℃, added the 0.2g tetrabutyl titanate; at 180 ℃; polymerization is 2 hours under the 50Pa, obtains thick melt, is cooled to faint yellow solid.After product is used chloroform and ethyl alcohol recrystallization,, standby 60～80 ℃ of following vacuum-dryings.The poly aspartic acid butanediol ester that 5 grams is contained the carbobenzoxy-(Cbz) protection is dissolved in the mixed solvent of 100ml methylene dichloride and methyl alcohol; pour in the autoclave then; 25 ℃; hydrogen atmosphere and pressure are 12MPa; hydrogenation removes blocking group 0.5 gram mass concentration is for the 10%Pd/C catalyzer exists down; take out solution after 48 hours and filter, the cold ethanol precipitation crystallization obtains containing the poly aspartic acid butanediol ester of amino side-chain.Recording weight-average molecular weight is 2.5 * 104,
1The H-NMR spectrogram as shown in Figure 1, the FT-IR spectrogram as shown in Figure 2, with the contact angle of water as shown in Figure 3.
In reactor; aspartic acid, 1 with the tertbutyloxycarbonyl protection; the 4-butyleneglycol according to mol ratio be 1: 2 totally 196 the gram join in the four-hole bottle that has stirring, heating and nitrogen protection device; reaction treated that aquifer yield reaches theoretical value after 2 hours under temperature is 120 ℃, added 0.2g stannic oxide; at 140 ℃; polymerization is 2 hours under the 50Pa, obtains thick melt, is cooled to solid.After product is used chloroform and ethyl alcohol recrystallization,, standby 60～80 ℃ of following vacuum-dryings.The poly aspartic acid butanediol ester that 5 grams is contained the tertbutyloxycarbonyl protection is dissolved in 100ml trichloromethane and the ethanol mixed solvent; pour in the autoclave then; 25 ℃; hydrogen atmosphere and pressure are 8MPa; 0.5 gram mass concentration is for sloughing blocking group under the existence of 10%Pd/C catalyzer; take out solution after 48 hours and filter, the cold ethanol precipitation crystallization obtains containing the poly aspartic acid butanediol ester of amino side-chain.Weight-average molecular weight is 2.6 * 10
4, with the contact angle of water be 54.1 °.
1The H-NMR spectrogram as shown in Figure 1, the FT-IR spectrogram as shown in Figure 2, with the contact angle of water as shown in Figure 3.
Embodiment 3.
In reactor; aspartic acid, 1 with the fluorenylmethyloxycarbonyl protection; the 4-butyleneglycol according to mol ratio be 1: 2 totally 226 the gram join in the four-hole bottle that has stirring, heating and nitrogen protection device; reaction treated that aquifer yield reaches theoretical value after 2 hours under temperature is 140 ℃, added the inferior tin of 0.2g octoate catalyst; at 160 ℃; polymerization is 2 hours under the 50Pa, obtains thick melt, is cooled to faint yellow solid.After product is used chloroform and ethyl alcohol recrystallization,, standby 60～80 ℃ of following vacuum-dryings.The poly aspartic acid butanediol ester that 5 grams is contained the carbobenzoxy-(Cbz) protection is dissolved in the mixed solvent of 100ml methylene dichloride and methyl alcohol; pour in the autoclave then; 25 ℃; hydrogen atmosphere and pressure are 5MPa; hydrogenation removes blocking group 0.5 gram mass concentration is for the 10%Pd/C catalyzer exists down; take out solution after 48 hours and filter, the cold ethanol precipitation crystallization obtains containing the poly aspartic acid butanediol ester of amino side-chain.Recording weight-average molecular weight is 1.8 * 10
4,
1The H-NMR spectrogram as shown in Figure 1, the FT-IR spectrogram as shown in Figure 2, with the contact angle of water as shown in Figure 3.
In reactor; with the aspartic acid of carbobenzoxy-(Cbz) protection, ethylene glycol according to mol ratio be 1: 2 totally 162 grams join in the four-hole bottle that has stirring, heating and nitrogen protection device; reaction is after 2 hours under temperature is 140 ℃; treat that aquifer yield reaches theoretical value; add the 0.15g tosic acid, at 160 ℃, polymerization is 2 hours under the 50Pa; obtain thick melt, be cooled to gray solid.After product is used chloroform and recrystallizing methanol,, standby 60～80 ℃ of following vacuum-dryings.The poly aspartic acid glycol ester that 5 grams is contained the carbobenzoxy-(Cbz) protection is dissolved in the 100ml dichloromethane solvent; pour in the autoclave then; 25 ℃; hydrogen atmosphere and pressure are 12MPa; hydrogenation removes blocking group 0.5 gram mass concentration is for the 10%Pd/C catalyzer exists down; take out solution after 48 hours and filter, the cold ethanol precipitation crystallization obtains containing the poly aspartic acid glycol ester of amino side-chain.Recording weight-average molecular weight is 1.2 * 10
4,
1The H-NMR spectrogram as shown in Figure 4, the FT-IR spectrogram as shown in Figure 5, with the contact angle of water as shown in Figure 6.
Embodiment 5 application experiments
Under the normal temperature, in the 20ml methylene dichloride, the poly aspartic acid butanediol ester that contains amino side-chain of dissolving 0.6 gram embodiment 1, embodiment 2 or embodiment 3 dissolves the 0.6g indomethacin again.0.1g dodecane agent base sodium sulfate and 0.4 gram polyvinyl alcohol are dissolved in the 150ml water.Wherein the polyvinyl alcohol polymerization degree is 1750, and alcoholysis degree is 88%.The above-mentioned aqueous solution and the dichloromethane solution that is dissolved with indomethacin and contains the poly aspartic acid butanediol ester of amino side-chain are mixed, use the dispersion machine emulsify at a high speed, emulsification is 5～10 minutes under the 12000rpm stirring velocity.The emulsion that emulsification is finished slowly is heated to 40 ℃ with water-bath from room temperature, removes methylene dichloride at 800rpm.In heat-processed, final, make to such an extent that mean diameter is the drug-loading microcapsule of 0.3～40 μ m, as shown in Figure 7.
Claims (10)
1. polyaspartic diol ester that contains amino side-chain, it is characterized in that: the described polyaspartic diol ester that contains amino side-chain has following structure:
Wherein x is 2～6, n=2～2000.
2. the polyaspartic diol ester that contains amino side-chain according to claim 1 is characterized in that: the described molecular weight that contains the polyaspartic diol ester of amino side-chain is: 500～200000.
3. synthetic method that contains the polyaspartic diol ester of amino side-chain according to claim 1 and 2, it is characterized in that: described synthetic method may further comprise the steps:
1) in reactor, for aspartic acid and the dibasic alcohol of band blocking group are 1: 1～3 mixed by mole ratio, be to carry out normal pressure esterification under 100～200 ℃ to react with raw material in protection of inert gas and in temperature, esterification time is 2～4 hours; Be 120～280 ℃ in temperature then, and the polycondensation of reducing pressure in the presence of catalyzer obtain the polyaspartic diol ester with blocking group;
The polyaspartic diol ester of the band blocking group that 2) step 1) is obtained is mixed in the organic solvent; pour in the autoclave then; in nitrogen atmosphere and in the presence of Pd/carbon catalyst, reacting 1～200 hour, slough the polyaspartic diol ester that blocking group obtains containing amino side-chain.
4. method according to claim 3 is characterized in that: described raw material is tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl or carbobenzoxy-(Cbz) for the blocking group of the aspartic acid of band blocking group.
5. method according to claim 3 is characterized in that: described diatomic alcohol compounds is an ethylene glycol, 1, ammediol, 1,4-butyleneglycol, 1,5-pentanediol or 1,6-hexylene glycol.
6. method according to claim 3 is characterized in that: the pressure during described decompression polycondensation for greater than 0 to less than 200Pa.
7. method according to claim 3 is characterized in that: the described catalyst consumption of step 1) for the band blocking group the aspartic acid mole number 0.01%～5%; Step 2) consumption of described Pd/carbon catalyst for the band blocking group the polyaspartic diol ester mole number 0～10%.
8. according to claim 3 or 7 described methods, it is characterized in that: the described catalyzer of step 1) is selected from Phenylsulfonic acid, stannic oxide, tetrabutyl tin oxide compound, tetrabutyl titanate, metatitanic acid orthocarbonate, germanic acid four butyl esters, antimonous oxide, stannous octoate, more than one in four n-butoxy germanium and the iron lactate.
9. method according to claim 3 is characterized in that: step 2) described hydrogen pressure scope in nitrogen atmosphere is 1～15MPa.
10. purposes that contains the polyaspartic diol ester of amino side-chain according to claim 1 and 2, it is characterized in that: the polyaspartic diol ester that contains amino side-chain can be used in drug carrier material or bio-medical timbering material.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020765A (en) * | 2010-11-05 | 2011-04-20 | 北京工业大学 | Preparation methods of poly (aspartic acid-co-lactic acid) graft polymer and nanoparticles of poly (aspartic acid-co-lactic acid) graft polymer |
| CN102526744A (en) * | 2010-12-16 | 2012-07-04 | 国家纳米科学中心 | Medicinal composition and preparation method and application thereof |
| CN102552922A (en) * | 2010-12-16 | 2012-07-11 | 国家纳米科学中心 | Drug combination and preparation method and application thereof |
| CN104387583A (en) * | 2014-11-04 | 2015-03-04 | 中国林业科学研究院林产化学工业研究所 | Aspartic acid amino resin as well as preparation method and application thereof |
| CN113549206A (en) * | 2021-08-13 | 2021-10-26 | 温州医科大学 | Novel temperature-sensitive polyester and preparation method thereof |
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2008
- 2008-04-23 CN CNA2008101047495A patent/CN101565498A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020765A (en) * | 2010-11-05 | 2011-04-20 | 北京工业大学 | Preparation methods of poly (aspartic acid-co-lactic acid) graft polymer and nanoparticles of poly (aspartic acid-co-lactic acid) graft polymer |
| CN102020765B (en) * | 2010-11-05 | 2012-06-06 | 北京工业大学 | Preparation methods of poly (aspartic acid-co-lactic acid) graft polymer and nanoparticles of poly (aspartic acid-co-lactic acid) graft polymer |
| CN102526744A (en) * | 2010-12-16 | 2012-07-04 | 国家纳米科学中心 | Medicinal composition and preparation method and application thereof |
| CN102552922A (en) * | 2010-12-16 | 2012-07-11 | 国家纳米科学中心 | Drug combination and preparation method and application thereof |
| CN102526744B (en) * | 2010-12-16 | 2013-05-15 | 国家纳米科学中心 | Medicinal composition and preparation method and application thereof |
| CN104387583A (en) * | 2014-11-04 | 2015-03-04 | 中国林业科学研究院林产化学工业研究所 | Aspartic acid amino resin as well as preparation method and application thereof |
| CN113549206A (en) * | 2021-08-13 | 2021-10-26 | 温州医科大学 | Novel temperature-sensitive polyester and preparation method thereof |
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