CN105949343A - Synthetic method of aldehyde dextran, aldehyde dextran-based coating method, and preparation method of microsphere composition - Google Patents
Synthetic method of aldehyde dextran, aldehyde dextran-based coating method, and preparation method of microsphere composition Download PDFInfo
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- CN105949343A CN105949343A CN201610289196.XA CN201610289196A CN105949343A CN 105949343 A CN105949343 A CN 105949343A CN 201610289196 A CN201610289196 A CN 201610289196A CN 105949343 A CN105949343 A CN 105949343A
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- microsphere
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- aldehydedodextrans
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- 239000004005 microsphere Substances 0.000 title claims abstract description 224
- 239000000203 mixture Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000010189 synthetic method Methods 0.000 title claims abstract description 31
- 238000000576 coating method Methods 0.000 title claims abstract description 22
- 229920002307 Dextran Polymers 0.000 title abstract 7
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 title abstract 6
- 238000000034 method Methods 0.000 claims abstract description 41
- 239000011248 coating agent Substances 0.000 claims abstract description 17
- 229920001503 Glucan Polymers 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 239000004593 Epoxy Substances 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 138
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 105
- 239000001301 oxygen Substances 0.000 claims description 105
- 229910052760 oxygen Inorganic materials 0.000 claims description 105
- 239000000243 solution Substances 0.000 claims description 86
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000008363 phosphate buffer Substances 0.000 claims description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 37
- 239000007787 solid Substances 0.000 claims description 35
- 238000004176 ammonification Methods 0.000 claims description 34
- -1 hydrogen boron sodium cyanide Chemical class 0.000 claims description 34
- 238000001556 precipitation Methods 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 28
- 229910052693 Europium Inorganic materials 0.000 claims description 22
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 claims description 22
- 239000012074 organic phase Substances 0.000 claims description 21
- 238000001953 recrystallisation Methods 0.000 claims description 20
- 238000004140 cleaning Methods 0.000 claims description 19
- 238000010992 reflux Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 229910052796 boron Inorganic materials 0.000 claims description 18
- 239000003504 photosensitizing agent Substances 0.000 claims description 18
- 238000007037 hydroformylation reaction Methods 0.000 claims description 17
- DHDHJYNTEFLIHY-UHFFFAOYSA-N 4,7-diphenyl-1,10-phenanthroline Chemical compound C1=CC=CC=C1C1=CC=NC2=C1C=CC1=C(C=3C=CC=CC=3)C=CN=C21 DHDHJYNTEFLIHY-UHFFFAOYSA-N 0.000 claims description 15
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000002243 precursor Substances 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 13
- 238000000502 dialysis Methods 0.000 claims description 13
- 239000012510 hollow fiber Substances 0.000 claims description 13
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims description 12
- 238000013329 compounding Methods 0.000 claims description 12
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 12
- 229910052761 rare earth metal Inorganic materials 0.000 claims description 12
- 150000002910 rare earth metals Chemical class 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 10
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 9
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 9
- OIAQMFOKAXHPNH-UHFFFAOYSA-N 1,2-diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1C1=CC=CC=C1 OIAQMFOKAXHPNH-UHFFFAOYSA-N 0.000 claims description 8
- KOFZTCSTGIWCQG-UHFFFAOYSA-N 1-bromotetradecane Chemical compound CCCCCCCCCCCCCCBr KOFZTCSTGIWCQG-UHFFFAOYSA-N 0.000 claims description 8
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- ILCQYORZHHFLNL-UHFFFAOYSA-N n-bromoaniline Chemical compound BrNC1=CC=CC=C1 ILCQYORZHHFLNL-UHFFFAOYSA-N 0.000 claims description 6
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 229910052771 Terbium Inorganic materials 0.000 claims description 4
- 229930002868 chlorophyll a Natural products 0.000 claims description 4
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- JKXCZYCVHPKTPK-UHFFFAOYSA-N hydrate;trihydrochloride Chemical compound O.Cl.Cl.Cl JKXCZYCVHPKTPK-UHFFFAOYSA-N 0.000 claims description 4
- 229960004337 hydroquinone Drugs 0.000 claims description 4
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical group [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 claims description 4
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 4
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 3
- 125000003172 aldehyde group Chemical group 0.000 abstract 2
- 239000002245 particle Substances 0.000 abstract 2
- 229960004279 formaldehyde Drugs 0.000 abstract 1
- 235000019256 formaldehyde Nutrition 0.000 abstract 1
- 150000002337 glycosamines Chemical class 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 17
- 150000002431 hydrogen Chemical class 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000004531 microgranule Substances 0.000 description 7
- 239000008176 lyophilized powder Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229940049706 benzodiazepine Drugs 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 3
- PCJQOISZFZOTRH-UHFFFAOYSA-K trichloroeuropium;hydrate Chemical compound O.[Cl-].[Cl-].[Cl-].[Eu+3] PCJQOISZFZOTRH-UHFFFAOYSA-K 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 238000001994 activation Methods 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000005661 hydrophobic surface Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
- 229960004419 dimethyl fumarate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/12—Chemical modification
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
- C08J2325/02—Homopolymers or copolymers of hydrocarbons
- C08J2325/04—Homopolymers or copolymers of styrene
- C08J2325/06—Polystyrene
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthetic method of aldehyde dextran, an aldehyde dextran-based coating method, and a preparation method of a microsphere composition. The aldehyde dextran is prepared from haloacetal and glucan through substitution and hydrolysis reactions, generated aldehyde groups are difficult to cross-link, the density of the active groups aldehyde groups is controllable, and the reappearance is good, so monoclonal antibody and protein connection is facilitated. The coating method is characterized in that epoxy ethyl particles are adopted as an initial raw material to substitute traditional carboxyl particles. Organic micromolecules can be used to substitute aminosugar, so the whole coating process is simple, and the coating period is short, so the coating method is suitable for industrial production. The preparation method of the microsphere composition is characterized in that the surfaces of microspheres are coated with the aldehyde dextran to form aldehyde dextran microspheres used for covalent coupling of biological molecules. The preparation method has the advantages of simple process, simple operation and good repeatability.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the synthetic method of a kind of aldehydedodextrans, method for coating based on described aldehydedodextrans and the preparation method of microsphere composition.
Background technology
Polystyrene microsphere has been widely used in medical diagnostic field, and its cardinal principle is that protein can be covalently bonded to microsphere surface in several ways.Microsphere surface can react with the amino of the Fc end of antibody with the group of the functionalization such as trimming loop epoxide, chloromethyl, aldehyde radical, carboxyl, forms covalent bond.When selecting covalent cross-linking mode when, generally require effect phase, complex process degree and the last charge stable situation considering crosslinking.First three group can directly amino with albumen react, and forms covalent bond, uses more convenient, but storage stability is slightly worse than carboxyl microsphere.Carboxyl microsphere then needs after EDC/NHS activates, and just the amino with albumen reacts, and forms covalent bond, and the method is the most stable, and is the labeling method of main flow in the market.
But the method there is also defect:
1, with carboxyl microgranule as raw material, form amino microgranule by adding EDC/NHS activation, then react with the amino in albumen.This reaction, because adding requisite activation process, is compared the reaction of aldehyde radical one-step method and is more easy to occur the union phenomenon of microgranule, and condition is wayward.
2, owing to microsphere surface is in addition to carboxyl, remaining is all the hydrophobic surface of naked leakage, and these hydrophobic surfaces are susceptible to nonspecific absorption in the albumen cohesive process with microsphere, and more susceptible to solvent, the pH even impact of salinity, thus interference detection results.
Summary of the invention
In order to solve the problems referred to above that prior art exists, the invention provides the synthetic method of a kind of aldehydedodextrans, method for coating based on described aldehydedodextrans and the preparation method of microsphere composition.The present invention proposes the synthetic method of a kind of brand-new aldehydedodextrans, and is coated on microsphere surface and forms aldehydedodextrans microsphere and be used for the covalent coupling of biomolecule, and the method technique is simple, easy and simple to handle, reproducible.
The technical solution adopted in the present invention is:
A kind of synthetic method of aldehydedodextrans,
The novel synthesis circuit of aldehydedodextrans can be expressed as follows:
Comprise the following steps:
A, glucosan is dissolved in water after, under inert gas shielding, add EDTA, 1, 4-benzenediol, sodium borohydride, NaOH and toluene, be stirred at reflux 1-3 hour；
B, in system drip 2-bromo-1,1-diethoxyethane solution, time for adding be no less than 1 hour；After being added dropwise to complete, it is stirred at reflux 12-18 hour；
C, by the organic phase washed with water in system, obtain aqueous solution, described aqueous solution adds in methanol, obtains hydroformylation sugar precursor precipitation；
D, by described hydroformylation sugar precursor precipitation soluble in water, add toluenesulfonic acid adjust pH to 1-2, after adding pyrohydrolysis, use NaOH solution be adjusted to neutrality, with precipitation form obtain aldehydedodextrans.
Pass through above-mentioned steps, it is possible to synthesize purity good, the aldehydedodextrans that yield is high.
Preferably, the synthetic method of a kind of aldehydedodextrans, comprise the following steps:
A, the glucosan of 20000-40000 weight portion is dissolved in the water of 50-130 parts by volume after; under nitrogen protection; the 1 of EDTA, 5-15 weight portion of addition 5-15 weight portion; 4-Benzodiazepines, the sodium borohydride of 5-15 weight portion, the toluene of NaOH and 40-80 parts by volume of 4000-8000 weight portion, be stirred at reflux 1-3 hour；
B, dripping 2-bromo-1 in system, the toluene solution of 1-diethoxyethane, time for adding is no less than 1 hour, 2-bromo-1, and the volume ratio of 1-diethoxyethane and toluene is 1:4-5；After being added dropwise to complete, it is stirred at reflux 12-18 hour；
C, be cooled to room temperature after, by the organic phase washed with water in system three times, the volume of water the most used is 120-180 parts by volume, merge aqueous phase and obtain aqueous solution, described aqueous solution adds in the methanol of 1500-2500 parts by volume, uses washing with alcohol three times after sucking filtration, and the volume of ethanol the most used is 200-280 parts by volume, and by washed precipitation vacuum drying, obtain hydroformylation sugar precursor precipitation；
D, the described hydroformylation sugar precursor of 5000-15000 weight portion is precipitated in the water being dissolved in 30-70 parts by volume, add toluenesulfonic acid and adjust pH to 1-2, it is heated to 70-90 DEG C to be hydrolyzed, after hydrolyzing 1-3 hour, the NaOH solution using mass fraction to be 30-50% is adjusted to neutrality, after filtration, remove impurity, obtain aldehydedodextrans with the form of precipitation.
Present invention also offers a kind of method for coating based on described aldehydedodextrans synthetic method,
The circuit that is coated of aldehydedodextrans is illustrated to be expressed as follows, and wherein microsphere ball represents:
Comprise the following steps:
A, by microsphere add 1, in 6-hexamethylene diamine solution, react 8-16 hour, obtain ammonification microsphere；
B, described aldehydedodextrans is dissolved in phosphate buffer, adds described ammonification microsphere, drip three hydrogen boron sodium cyanide solutions after mix homogeneously, react 8-16 hour；
C, eccentric cleaning, obtain being coated with the microsphere of aldehydedodextrans.
Preferably, a kind of method for coating based on described aldehydedodextrans synthetic method, comprise the following steps:
A, at 70 DEG C, the epoxy ethyl microsphere of 500-1500 weight portion is added mass fraction is 10% the 1 of 10-30 parts by volume, in 6-hexamethylene diamine solution, after stirring is reacted 8-16 hour at 90 DEG C, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；
B, the described aldehydedodextrans of 2000-3000 weight portion is dissolved in the phosphate buffer of 40-60 parts by volume, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that three hydrogen boron Cyanogran .s of 400 weight portions are dissolved in the 0.1mol/L phosphate buffer of 2.5 parts by volume and obtaining, and react 8-16 hour at 37 DEG C；
C, eccentric cleaning remove unreacted little molecule, obtain being coated with the microsphere of aldehydedodextrans.
Synthetic method and the method for coating of described aldehydedodextrans have the advantage that
1, described hydroformylation glucosan is with halo acetal and glucosan as raw material, is substituted, hydrolysis forms, and the aldehyde radical of generation is not susceptible to cross-linking reaction, and active group aldehyde radical density is controlled, favorable reproducibility, is more beneficial for the connection of monoclonal antibody, albumen.
2, described method for coating is with epoxy ethyl microgranule as initiation material, replaces traditional carboxyl microgranule.Can replace amination sugar with organic molecule, the whole process of being coated seems simply, the cycle is short, preferably for industrialized production.
Present invention also offers the preparation method of a kind of microsphere composition based on described method for coating, comprise the following steps:
A, prepared by oxygen microsphere: thioxene, β-two butanone and rare earth compounding are put in microsphere, formed by oxygen microsphere；
B, the preparation of oxygen supply microsphere: put into by photosensitizer in microsphere, form oxygen supply microsphere；
C, aldehydedodextrans are coated microsphere: will be added 1 by oxygen microsphere or oxygen supply microsphere, and in 6-hexamethylene diamine solution, react 8-16 hour, obtain ammonification microsphere；Described aldehydedodextrans is dissolved in phosphate buffer, adds described ammonification microsphere, drip three hydrogen boron sodium cyanide solutions after mix homogeneously, react 8-16 hour；Eccentric cleaning, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Preferably, the preparation method of a kind of microsphere composition, comprise the following steps:
A, prepared by oxygen microsphere: thioxene, β-two butanone and rare earth compounding are put in microsphere, formed by oxygen microsphere；
B, the preparation of oxygen supply microsphere: put into by photosensitizer in microsphere, form oxygen supply microsphere；
C, aldehydedodextrans are coated microsphere: at 70 DEG C, 500-1500 weight portion added mass fraction is 10% the 1 of 10-30 parts by volume by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, after at 90 DEG C, stirring is reacted 8-16 hour, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；The described aldehydedodextrans of 2000-3000 weight portion is dissolved in the phosphate buffer of 40-60 parts by volume, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that three hydrogen boron Cyanogran .s of 400 weight portions are dissolved in the 0.1mol/L phosphate buffer of 2.5 parts by volume and obtaining, and react 8-16 hour at 37 DEG C；Eccentric cleaning removes unreacted little molecule, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Preferably, described rare earth compounding is europium complex or terbium coordination compound；Described photosensitizer is light oxygen dye substance methylene blue, rose-red, the one in phthalocyanine compound and chlorophyll A or combination.Because the character of described europium complex and terbium coordination compound is close, the needs of the present invention all can be met.
Preferably, the synthetic method of described europium complex, comprise the following steps:
A, adjacent phenyl biphenyl are dissolved in dichloromethane, add aluminum chloride, are cooled to 0 DEG C；Dropping chloroacetic chloride, drips complete rear chamber temperature and reacts 1-2 hour, be dried to obtain solids I；
B, described solids I is dissolved in absolute ether, adds Feldalat NM and Trifluoroacetic Acid Ethyl Ester, room temperature reaction 2-3 hour, be dried to obtain solids II；
C, being mixed homogeneously with described solids II by six trichloride hydrate europiums, add anhydrous alcohol solution, stirring adds ammonia to pH to 7-9, and room temperature reaction, after 1-2 hour, adds water in system, filters, be dried to obtain solids III；
D, taking 4,7-diphenyl-1,10-phenanthroline heating for dissolving collects recrystallization crystal after ethanol, cooling；Taking described recrystallization crystal and 4,7-diphenyl-1,10-phenanthroline adds in toluene, stirs 1-2 hour, be cooled to room temperature, except toluene, obtain europium complex.
Further, the synthetic method of described europium complex, comprise the following steps
A, the adjacent phenyl biphenyl of 4500-5000 weight portion is dissolved in the anhydrous methylene chloride of 30-50 parts by volume, adds the aluminum chloride of 5500-6000 weight portion, be cooled to 0 DEG C；The chloroacetic chloride of dropping 3500-4500 weight portion, drips complete rear chamber temperature and reacts 1-2 hour, after the organic phase washed with water in system three times, be dried to obtain 5000-6000 parts by weight solids thing I with anhydrous sodium sulfate；
B, the described solids I taking 3000-3500 weight portion are dissolved in the absolute ether of 30-50 parts by volume, add Feldalat NM and the Trifluoroacetic Acid Ethyl Ester of 3000-5000 weight portion of 1500-2500 weight portion, room temperature reaction 2-3 hour, after the organic phase washed with water in system three times, it is dried to obtain the solids II of 1000-2000 weight portion with anhydrous sodium sulfate；
C, six trichloride hydrate europiums of 2800-3200 weight portion are mixed homogeneously with the described solids II of 6000-6800 weight portion, add the anhydrous alcohol solution of 30-50 parts by volume, stirring adds the ammonia of 1500-2500 parts by volume to pH to 7-9, after room temperature reaction 1 hour, the water of 600-1000 parts by volume is added in system, precipitation is collected by filtration, and precipitation is dried to obtain solids III；
D, taking the 4 of 3000-5000 weight portion, 7-diphenyl-1,10-phenanthroline heating for dissolving, in the ethanol of 100-150 parts by volume, collects recrystallization crystal after cooling；Taking the described recrystallization crystal of 2500-3500 weight portion and the 4 of 800-1200 weight portion, 7-diphenyl-1,10-phenanthroline adds in the toluene of 200-400 parts by volume, stirs 1-2 hour, be cooled to room temperature, except toluene, obtain europium complex at 62 DEG C.
Preferably, described thioxene and the synthetic method of β-two butanone, comprise the following steps:
A, being dissolved in DMF by bromoaniline, add bromotetradecane and diisopropylethylamine, after 100 DEG C of reactions 10-14 hour, add dichloromethane in reactant liquor, recrystallization obtains the dibasic para-bromoaniline of N, N-；
B, by described N, the dibasic para-bromoaniline of N-, magnesium rod and iodine are dissolved in wiring solution-forming in THF, under the conditions of maintaining the reflux for, solution is added drop-wise in THF, back flow reaction 1 hour after liquid feeding, is cooled to 0 DEG C, in system, add benzoyl hydroperoxide and THF, react 2-3 hour under room temperature；After adding the hydrochloric acid salt with hydrolysis generation in system, in system, add dichloromethane, be dried chromatography isolated intermediate；
C, being dissolved in toluene solution by described intermediate, add zinc chloride and 2 mercapto ethanol, back flow reaction 3-5 hour, except toluene chromatography obtains thioxene and β-two butanone.
Further, described thioxene and the synthetic method of β-two butanone, comprise the following steps:
A, the bromoaniline of 30000-40000 weight portion is dissolved in the DMF of 100-150 parts by volume, add bromotetradecane and the diisopropylethylamine of 50000-100000 weight portion of 120000-200000 weight portion, after 100 DEG C are reacted 12 hours, the dichloromethane of 200-400 parts by volume is added in reactant liquor, after system is washed with water three times, add ethyl alcohol recrystallization, obtain the dibasic para-bromoaniline of N, N-；
B, by described N, the dibasic para-bromoaniline of N-, the magnesium rod of 2500-3500 weight portion and iodine are dissolved in wiring solution-forming in the THF of 40-60 parts by volume, and be added drop-wise to solution in the THF of 80-120 parts by volume maintain the reflux for, after liquid feeding, back flow reaction is reacted 1 hour, it is cooled to 0 DEG C, in system, add benzoyl hydroperoxide and the THF of 40-60 parts by volume of 10000-15000 weight portion, react 2-3 hour under room temperature；After addition molar concentration is the 0.1mol/L hydrochloric acid salt with hydrolysis generation in system, adding the dichloromethane of 150-250 parts by volume, after the organic phase washed with water in system three times, be dried with anhydrous sodium sulfate in system, column chromatography for separation obtains intermediate；
C, being dissolved in the toluene solution of 80-120 parts by volume by described intermediate, add zinc chloride and the 2 mercapto ethanol of 7000-10000 weight portion, back flow reaction 3-5 hour, except toluene, column chromatography obtains thioxene and β-two butanone.
About the english abbreviation occurred in the present invention and the Name Resolution of other materials:
DMF: dimethyl fumarate, No. CAS: 68-12-2；
THF；Oxolane, No. CAS: 109-99-9；
DPP:4,7-diphenyl-1,10-phenanthroline, No. CAS: 1662-01-7；
EDTA: ethylenediaminetetraacetic acid, No. CAS: 60-00-4；
1, 4-benzenediol, No. CAS: 123-31-9；
Sodium borohydride, No. CAS: 16940-66-2；
2-bromo-1,1-diethoxyethane, chemical formula: C6H13BrO2, No. CAS: 2032-35-1；
Toluenesulfonic acid, No. CAS: 98-11-3；
1,6-hexamethylene diamine, No. CAS: 124-09-4；
Three hydrogen boron Cyanogran .s, have another name called sodium cyanoborohydride, and No. CAS: 25895-60-7；
2,5 thioxenes, No. CAS: 638-02-8；
Adjacent phenyl biphenyl, C12H10, No. CAS: 92-52-4；
Chloroacetic chloride, No. CAS: 75-36-5；
Trifluoroacetic Acid Ethyl Ester；No. CAS: 383-63-1；
To amino bromination benzene, No. CAS: 106-40-1；
Bromotetradecane, No. CAS: 112-71-0；
Diisopropylethylamine, No. CAS: 7087-68-5；
In the present invention, water used is deionized water.
It should be noted that the weight portion in the present invention and parts by volume, it is intended merely to show the proportionate relationship of each material, the most specifically represent certain quantitative value, in the present invention, described weight portion and parts by volume have following corresponding relation: when 1 weight portion is 1g, and 1 parts by volume is 1L.
The invention have the benefit that
1, described hydroformylation glucosan is with halo acetal and glucosan as raw material, is substituted, hydrolysis forms, and the aldehyde radical of generation is not susceptible to cross-linking reaction, and active group aldehyde radical density is controlled, favorable reproducibility, is more beneficial for the connection of monoclonal antibody, albumen.
2, described method for coating is with epoxy ethyl microgranule as initiation material, replaces traditional carboxyl microgranule.Can replace amination sugar with organic molecule, the whole process of being coated seems simply, the cycle is short, preferably for industrialized production.
3, the preparation method of described microsphere composition, is coated on described hydroformylation glucosan microsphere surface formation aldehydedodextrans microsphere and is used for the covalent coupling of biomolecule, and the method technique is simple, easy and simple to handle, reproducible.
Detailed description of the invention
In the present invention, if not refering in particular to, all of part, percentage ratio are unit of weight, and all of equipment and raw material etc. are all commercially available or the industry is conventional.Method in following embodiment, if no special instructions, is the conventional method of this area.
The invention provides the synthetic method of a kind of aldehydedodextrans, method for coating based on described aldehydedodextrans and the preparation method of microsphere composition.
Below in conjunction with embodiment, further illustrate present disclosure.Should be appreciated that the enforcement of the present invention is not limited to the following examples, any pro forma accommodation and/or the change of being made the present invention fall within scope.
Embodiment 1
The synthetic method of a kind of aldehydedodextrans, comprises the following steps:
A, 30g glucosan is dissolved in the water of 90ml after, under nitrogen protection, add 10mg EDTA, 10mg1,4-Benzodiazepines, 10mg sodium borohydride, 6g NaOH and 60ml toluene, be stirred at reflux 2 hours；
B, being slowly added dropwise 2-bromo-1 in system, the toluene solution of 1-diethoxyethane, time for adding is no less than 1 hour, and 2-bromo-1, the toluene solution of 1-diethoxyethane is 50ml2-bromo-1, and 1-diethoxyethane is dissolved in 200ml toluene solution and makes；After being added dropwise to complete, it is stirred at reflux 15 hours；
C, be cooled to room temperature after, by the organic phase washed with water in system three times, the volume of water the most used is 150ml, merge aqueous phase and obtain aqueous solution, described aqueous solution adds in the methanol of 2000ml, uses washing with alcohol three times after sucking filtration, and the volume of ethanol the most used is 240ml, and by washed precipitation vacuum drying, obtain 33g hydroformylation sugar precursor precipitation；
D, by described in 10g hydroformylation sugar precursor precipitation be dissolved in 50ml water, add toluenesulfonic acid and adjust pH to 1-2, it is heated to 80 DEG C to be hydrolyzed, after hydrolyzing 2 hours, the NaOH solution using mass fraction to be 40% is adjusted to neutrality, filtering, dialyse or eccentric cleaning removing small molecular weight impurity, lyophilizing obtains aldehydedodextrans lyophilized powder 9g.
Embodiment 2
The synthetic method of a kind of aldehydedodextrans, comprises the following steps:
A, 20g glucosan is dissolved in the water of 130ml after, under nitrogen protection, add 5mg EDTA, 15mg1,4-Benzodiazepines, 5mg sodium borohydride, 8g NaOH and 40ml toluene, be stirred at reflux 3 hours；
B, being slowly added dropwise 2-bromo-1 in system, the toluene solution of 1-diethoxyethane, time for adding is no less than 1 hour, and 2-bromo-1, the toluene solution of 1-diethoxyethane is 40ml2-bromo-1, and 1-diethoxyethane is dissolved in 200ml toluene solution and makes；After being added dropwise to complete, it is stirred at reflux 12 hours；
C, be cooled to room temperature after, by the organic phase washed with water in system three times, the volume of water the most used is 180ml, merge aqueous phase and obtain aqueous solution, described aqueous solution adds in the methanol of 1500ml, uses washing with alcohol three times after sucking filtration, and the volume of ethanol the most used is 280ml, and by washed precipitation vacuum drying, obtain 22g hydroformylation sugar precursor precipitation；
D, by described in 5g hydroformylation sugar precursor precipitation be dissolved in 70ml water, add toluenesulfonic acid and adjust pH to 1-2, it is heated to 70 DEG C to be hydrolyzed, after hydrolyzing 3 hours, the NaOH solution using mass fraction to be 30% is adjusted to neutrality, filtering, dialyse or eccentric cleaning removing small molecular weight impurity, lyophilizing obtains aldehydedodextrans lyophilized powder 4.5g.
Embodiment 3
The synthetic method of a kind of aldehydedodextrans, comprises the following steps:
A, 40g glucosan is dissolved in the water of 50ml after, under nitrogen protection, add 15mg EDTA, 5mg1,4-Benzodiazepines, 15mg sodium borohydride, 4g NaOH and 80ml toluene, be stirred at reflux 1 hour；
B, being slowly added dropwise 2-bromo-1 in system, the toluene solution of 1-diethoxyethane, time for adding is no less than 1 hour, and 2-bromo-1, the toluene solution of 1-diethoxyethane is 45ml2-bromo-1, and 1-diethoxyethane is dissolved in 200ml toluene solution and makes；After being added dropwise to complete, it is stirred at reflux 18 hours；
C, be cooled to room temperature after, by the organic phase washed with water in system three times, the volume of water the most used is 120ml, merge aqueous phase and obtain aqueous solution, described aqueous solution adds in the methanol of 2500ml, uses washing with alcohol three times after sucking filtration, and the volume of ethanol the most used is 200ml, and by washed precipitation vacuum drying, obtain 44g hydroformylation sugar precursor precipitation；
D, by described in 15g hydroformylation sugar precursor precipitation be dissolved in 30ml water, add toluenesulfonic acid and adjust pH to 1-2, it is heated to 90 DEG C to be hydrolyzed, after hydrolyzing 1 hour, the NaOH solution using mass fraction to be 50% is adjusted to neutrality, filtering, dialyse or eccentric cleaning removing small molecular weight impurity, lyophilizing obtains aldehydedodextrans lyophilized powder 13.5g.
Embodiment 4
A kind of based on the method for coating of aldehydedodextrans described in embodiment 1, comprise the following steps:
A, at 70 DEG C, by 1g epoxy ethyl microsphere (purchased from U.S. Bangs Laboratories, INC) adding 20ml mass fraction is the 1 of 10%, in 6-hexamethylene diamine solution, after at 90 DEG C, stirring is reacted 12 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；
B, the described aldehydedodextrans lyophilized powder taken in 2.5g embodiment 1 are dissolved in 50ml phosphate buffer, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions it are slowly added dropwise after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that 0.4g tri-hydrogen boron Cyanogran. is dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 12 hours at 37 DEG C；
C, eccentric cleaning remove unreacted little molecule and constant volume becomes 50ml, obtain 0.9g and are coated with the microsphere of aldehydedodextrans.
Embodiment 5
A kind of based on the method for coating of aldehydedodextrans described in embodiment 2, comprise the following steps:
A, at 70 DEG C, by 15g epoxy ethyl microsphere (purchased from U.S. Bangs Laboratories, INC) adding 10ml mass fraction is the 1 of 10%, in 6-hexamethylene diamine solution, after at 90 DEG C, stirring is reacted 16 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；
B, the described aldehydedodextrans lyophilized powder taken in 2g embodiment 2 are dissolved in 60ml phosphate buffer, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions it are slowly added dropwise after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that 0.4g tri-hydrogen boron Cyanogran. is dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 8 hours at 37 DEG C；
C, eccentric cleaning remove unreacted little molecule and constant volume becomes 50ml, obtain 1.35g and are coated with the microsphere of aldehydedodextrans.
Embodiment 6
A kind of based on the method for coating of aldehydedodextrans described in embodiment 3, comprise the following steps:
A, at 70 DEG C, by 0.5g epoxy ethyl microsphere (purchased from U.S. Bangs Laboratories, INC) adding 30ml mass fraction is the 1 of 10%, in 6-hexamethylene diamine solution, after at 90 DEG C, stirring is reacted 8 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；
B, the described aldehydedodextrans lyophilized powder taken in 3g embodiment 3 are dissolved in 40ml phosphate buffer, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions it are slowly added dropwise after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that 0.4g tri-hydrogen boron Cyanogran. is dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 16 hours at 37 DEG C；
C, eccentric cleaning remove unreacted little molecule and constant volume becomes 50ml, obtain 0.45g and are coated with the microsphere of aldehydedodextrans.
Embodiment 7
The preparation method of a kind of microsphere composition, comprises the following steps:
A, prepared by oxygen microsphere: by the method in the embodiment of Patent No. US 5780646,200mg thioxene, β-two butanone and 100mg rare earth compounding are put into microsphere (purchased from U.S. Bangs Laboratories, INC), in, formed by oxygen microsphere；Described rare earth compounding is europium complex；
B, the preparation of oxygen supply microsphere: by the method in the embodiment of Patent No. US 5780646, put in microsphere by 200mg photosensitizer, form oxygen supply microsphere；Described photosensitizer is the chlorophyll A according to singlet oxygen releasable disclosed in United States Patent (USP) US 5709994；
C, aldehydedodextrans are coated microsphere: at 70 DEG C, 1g added mass fraction is 10% the 1 of 20ml by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, at 90 DEG C after stirring reaction 12 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；Aldehydedodextrans in 2.5g embodiment 1 is dissolved in the phosphate buffer of 50ml, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that the three hydrogen boron Cyanogran .s of 0.4g are dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 12 hours at 37 DEG C；Eccentric cleaning removes unreacted little molecule constant volume and becomes 50ml, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Embodiment 8
The preparation method of a kind of microsphere composition, comprises the following steps:
A, prepared by oxygen microsphere: by the method in the embodiment of Patent No. US 5780646,200mg thioxene, β-two butanone and 100mg rare earth compounding are put into microsphere (purchased from U.S. Bangs Laboratories, INC), in, formed by oxygen microsphere；Described rare earth compounding is europium complex；
B, the preparation of oxygen supply microsphere: by the method in the embodiment of Patent No. US 5780646, put in microsphere by 200mg photosensitizer, form oxygen supply microsphere；Described photosensitizer is for according to light oxygen dye substance methylene blue disclosed in United States Patent (USP) US 5709994；
C, aldehydedodextrans are coated microsphere: at 70 DEG C, 0.5g added mass fraction is 10% the 1 of 30ml by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, at 90 DEG C after stirring reaction 8 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；Aldehydedodextrans in 3g embodiment 2 is dissolved in the phosphate buffer of 40ml, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that the three hydrogen boron Cyanogran .s of 0.4g are dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 16 hours at 37 DEG C；Eccentric cleaning removes unreacted little molecule constant volume and becomes 50ml, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Embodiment 9
The preparation method of a kind of microsphere composition, comprises the following steps:
A, prepared by oxygen microsphere: by the method in the embodiment of Patent No. US 5780646,200mg thioxene, β-two butanone and 100mg rare earth compounding are put into microsphere (purchased from U.S. Bangs Laboratories, INC), in, formed by oxygen microsphere；Described rare earth compounding is terbium coordination compound；
B, the preparation of oxygen supply microsphere: by the method in the embodiment of Patent No. US 5780646, put in microsphere by 200mg photosensitizer, form oxygen supply microsphere；Described photosensitizer is for according to light oxygen dye substance rose-red disclosed in United States Patent (USP) US 5709994；
C, aldehydedodextrans are coated microsphere: at 70 DEG C, 1.5g added mass fraction is 10% the 1 of 10ml by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, at 90 DEG C after stirring reaction 16 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；Aldehydedodextrans in 2g embodiment 3 is dissolved in the phosphate buffer of 60ml, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that the three hydrogen boron Cyanogran .s of 0.4g are dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 8 hours at 37 DEG C；Eccentric cleaning removes unreacted little molecule constant volume and becomes 50ml, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Embodiment 10
The preparation method of a kind of microsphere composition, comprises the following steps:
A, the synthetic method of europium complex: be dissolved in the anhydrous methylene chloride of 40ml by the adjacent phenyl biphenyl of 4.8g, add the aluminum chloride of 5.88g, be cooled to 0 DEG C；The chloroacetic chloride of dropping 4g, drips complete rear chamber temperature and reacts 1.5 hours, after the organic phase washed with water in system three times, be dried to obtain 5.2g solids I with anhydrous sodium sulfate；Take solids I described in 3.2g to be dissolved in the absolute ether of 40ml, add 2g Feldalat NM and 4g Trifluoroacetic Acid Ethyl Ester, room temperature reaction 2.5 hours, after the organic phase washed with water in system three times, be dried to obtain 1.6g solids II with anhydrous sodium sulfate；2.932g six trichloride hydrate europium is mixed homogeneously with solids described in 6.39g II, adds 40ml anhydrous alcohol solution, stirring addition 2ml ammonia to pH to 8, after room temperature reaction 1 hour, in system, add 800ml water, precipitation is collected by filtration, and precipitation is dried to obtain 9g solids III；Taking 4.0g 4,7-diphenyl-1,10-phenanthroline (DPP) heating for dissolving, in 120ml ethanol, collects recrystallization crystal after cooling；Taking recrystallization crystal described in 3.014g and 0.997g 4,7-diphenyl-1,10-phenanthroline adds in 300ml toluene, stirs 1.5 hours, be cooled to room temperature, except toluene, obtain europium complex at 62 DEG C.
B, thioxene and the synthetic method of β-two butanone: 34.4g bromoaniline is dissolved in 125ml DMF, add 0.6mol bromotetradecane and 0.6mol diisopropylethylamine, after 100 DEG C are reacted 12 hours, the dichloromethane of 300ml is added in reactant liquor, after system is washed with water three times, add ethyl alcohol recrystallization, obtain the dibasic para-bromoaniline of N, N-；By described N, the dibasic para-bromoaniline of N-, 3g magnesium rod and iodine are dissolved in wiring solution-forming in 50ml THF, under the conditions of maintaining the reflux for, solution is added drop-wise in 100ml THF, back flow reaction 1 hour after liquid feeding, it is cooled to 0 DEG C, in system, adds 0.1mol benzoyl hydroperoxide and 50ml THF, react 2.5 hours under room temperature；After being slowly added to the molar concentration salt that to be 0.1mol/L hydrochloric acid generate with hydrolysis in system, adding 200ml dichloromethane, after the organic phase washed with water in system three times, be dried with anhydrous sodium sulfate in system, column chromatography for separation obtains intermediate；Being dissolved in the toluene solution of 100ml by described intermediate, add zinc chloride and 0.11mol 2 mercapto ethanol, back flow reaction 4 hours, Rotary Evaporators removes toluene, and column chromatography obtains thioxene and β-two butanone.
C, prepared by oxygen microsphere: by the method in the embodiment of Patent No. US 5780646, europium complex described in thioxene described in 200mg, β-two butanone and 100mg is put into microsphere (purchased from U.S. Bangs Laboratories, INC), in, formed by oxygen microsphere；
D, the preparation of oxygen supply microsphere: by the method in the embodiment of Patent No. US 5780646, put in microsphere by 200mg photosensitizer, form oxygen supply microsphere；Described photosensitizer is the chlorophyll A according to singlet oxygen releasable disclosed in United States Patent (USP) US 5709994；
E, aldehydedodextrans are coated microsphere: at 70 DEG C, 1g added mass fraction is 10% the 1 of 20ml by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, at 90 DEG C after stirring reaction 12 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；Aldehydedodextrans in 2.5g embodiment 1 is dissolved in the phosphate buffer of 50ml, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that the three hydrogen boron Cyanogran .s of 0.4g are dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 12 hours at 37 DEG C；Eccentric cleaning removes unreacted little molecule constant volume and becomes 50ml, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
F, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Embodiment 11
The preparation method of a kind of microsphere composition, comprises the following steps:
C, the synthetic method of europium complex: be dissolved in the anhydrous methylene chloride of 50ml by the adjacent phenyl biphenyl of 4.5g, add the aluminum chloride of 5.50g, be cooled to 0 DEG C；The chloroacetic chloride of dropping 4.5g, drips complete rear chamber temperature and reacts 1 hour, after the organic phase washed with water in system three times, be dried to obtain 5.0g solids I with anhydrous sodium sulfate；Take solids I described in 3.5g to be dissolved in the absolute ether of 30ml, add 2.5g Feldalat NM and 3g Trifluoroacetic Acid Ethyl Ester, room temperature reaction 3 hours, after the organic phase washed with water in system three times, be dried to obtain 2.0g solids II with anhydrous sodium sulfate；2.800g six trichloride hydrate europium is mixed homogeneously with solids described in 6.00g II, adds 50ml anhydrous alcohol solution, stirring addition 1.5ml ammonia to pH to 7, after room temperature reaction 1 hour, in system, add 1000ml water, precipitation is collected by filtration, and precipitation is dried to obtain 10g solids III；Taking 3.0g 4,7-diphenyl-1,10-phenanthroline (DPP) heating for dissolving, in 150ml ethanol, collects recrystallization crystal after cooling；Taking recrystallization crystal described in 2.500g and 1.200g 4,7-diphenyl-1,10-phenanthroline adds in 200ml toluene, stirs 2 hours, be cooled to room temperature, except toluene, obtain europium complex at 62 DEG C.
D, thioxene and the synthetic method of β-two butanone: 30.0g bromoaniline is dissolved in 150ml DMF, add 0.45mol bromotetradecane and 0.8mol diisopropylethylamine, after 100 DEG C are reacted 12 hours, the dichloromethane of 200ml is added in reactant liquor, after system is washed with water three times, add ethyl alcohol recrystallization, obtain the dibasic para-bromoaniline of N, N-；By described N, the dibasic para-bromoaniline of N-, 3.5g magnesium rod and iodine are dissolved in wiring solution-forming in 40ml THF, under the conditions of maintaining the reflux for, solution is added drop-wise in 120ml THF, back flow reaction 1 hour after liquid feeding, it is cooled to 0 DEG C, in system, adds 0.8mol benzoyl hydroperoxide and 60ml THF, react 2 hours under room temperature；After being slowly added to the molar concentration salt that to be 0.1mol/L hydrochloric acid generate with hydrolysis in system, adding 250ml dichloromethane, after the organic phase washed with water in system three times, be dried with anhydrous sodium sulfate in system, column chromatography for separation obtains intermediate；Being dissolved in the toluene solution of 80ml by described intermediate, add zinc chloride and 0.13mol 2 mercapto ethanol, back flow reaction 3 hours, Rotary Evaporators removes toluene, and column chromatography obtains thioxene and β-two butanone.
C, prepared by oxygen microsphere: by the method in the embodiment of Patent No. US 5780646, europium complex described in 200mg thioxene, β-two butanone and 100mg is put into microsphere (purchased from U.S. Bangs Laboratories, INC), in, formed by oxygen microsphere；
D, the preparation of oxygen supply microsphere: by the method in the embodiment of Patent No. US 5780646, put in microsphere by 200mg photosensitizer, form oxygen supply microsphere；Described photosensitizer is for according to light oxygen dye substance methylene blue disclosed in United States Patent (USP) US 5709994；
E, aldehydedodextrans are coated microsphere: at 70 DEG C, 0.5g added mass fraction is 10% the 1 of 30ml by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, at 90 DEG C after stirring reaction 8 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；Aldehydedodextrans in 3g embodiment 2 is dissolved in the phosphate buffer of 40ml, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that the three hydrogen boron Cyanogran .s of 0.4g are dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 16 hours at 37 DEG C；Eccentric cleaning removes unreacted little molecule constant volume and becomes 50ml, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
F, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
Embodiment 12
The preparation method of a kind of microsphere composition, comprises the following steps:
E, the synthetic method of europium complex: be dissolved in the anhydrous methylene chloride of 30ml by the adjacent phenyl biphenyl of 5.0g, add the aluminum chloride of 6.00g, be cooled to 0 DEG C；The chloroacetic chloride of dropping 3.5g, drips complete rear chamber temperature and reacts 2 hours, after the organic phase washed with water in system three times, be dried to obtain 6.0g solids I with anhydrous sodium sulfate；Take solids I described in 3.0g to be dissolved in the absolute ether of 50ml, add 1.5g Feldalat NM and 5g Trifluoroacetic Acid Ethyl Ester, room temperature reaction 2 hours, after the organic phase washed with water in system three times, be dried to obtain 1.0g solids II with anhydrous sodium sulfate；3.200g six trichloride hydrate europium is mixed homogeneously with solids described in 6.80g II, adds 30ml anhydrous alcohol solution, stirring addition 2.5ml ammonia to pH to 9, after room temperature reaction 1 hour, in system, add 600ml water, precipitation is collected by filtration, and precipitation is dried to obtain 11g solids III；Taking 5.0g 4,7-diphenyl-1,10-phenanthroline (DPP) heating for dissolving, in 100ml ethanol, collects recrystallization crystal after cooling；Taking recrystallization crystal described in 3.500g and 0.800g 4,7-diphenyl-1,10-phenanthroline adds in 400ml toluene, stirs 1 hour, be cooled to room temperature, except toluene, obtain europium complex at 62 DEG C.
F, thioxene and the synthetic method of β-two butanone: 40.0g bromoaniline is dissolved in 100ml DMF, add 0.8mol bromotetradecane and 0.45mol diisopropylethylamine, after 100 DEG C are reacted 12 hours, the dichloromethane of 400ml is added in reactant liquor, after system is washed with water three times, add ethyl alcohol recrystallization, obtain the dibasic para-bromoaniline of N, N-；By described N, the dibasic para-bromoaniline of N-, 2.5g magnesium rod and iodine are dissolved in wiring solution-forming in 60ml THF, under the conditions of maintaining the reflux for, solution is added drop-wise in 80ml THF, back flow reaction 1 hour after liquid feeding, it is cooled to 0 DEG C, in system, adds 0.12mol benzoyl hydroperoxide and 40ml THF, react 3 hours under room temperature；After being slowly added to the molar concentration salt that to be 0.1mol/L hydrochloric acid generate with hydrolysis in system, adding 150ml dichloromethane, after the organic phase washed with water in system three times, be dried with anhydrous sodium sulfate in system, column chromatography for separation obtains intermediate；Being dissolved in the toluene solution of 120ml by described intermediate, add zinc chloride and 0.09mol 2 mercapto ethanol, back flow reaction 5 hours, Rotary Evaporators removes toluene, and column chromatography obtains thioxene and β-two butanone.
C, prepared by oxygen microsphere: by the method in the embodiment of Patent No. US 5780646, europium complex described in 200mg thioxene, β-two butanone and 100mg is put into microsphere (purchased from U.S. Bangs Laboratories, INC), in, formed by oxygen microsphere；
D, the preparation of oxygen supply microsphere: by the method in the embodiment of Patent No. US 5780646, put in microsphere by 200mg photosensitizer, form oxygen supply microsphere；Described photosensitizer is for according to light oxygen dye substance phthalocyanine compound disclosed in United States Patent (USP) US 5709994；
E, aldehydedodextrans are coated microsphere: at 70 DEG C, 1.5g added mass fraction is 10% the 1 of 10ml by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution, at 90 DEG C after stirring reaction 16 hours, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；Aldehydedodextrans in 2g embodiment 3 is dissolved in the phosphate buffer of 60ml, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, add described ammonification microsphere, three hydrogen boron sodium cyanide solutions are dripped after mix homogeneously, described three hydrogen boron sodium cyanide solutions are that the three hydrogen boron Cyanogran .s of 0.4g are dissolved in the 0.1mol/L phosphate buffer of 2.5ml and obtaining, and react 8 hours at 37 DEG C；Eccentric cleaning removes unreacted little molecule constant volume and becomes 50ml, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
F, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
It should be noted last that; above example is only in order to illustrate technical scheme and unrestricted; although the present invention being described in detail with reference to preferred embodiment; it is it should be understood that; the foregoing is only the detailed description of the invention of the present invention, the protection domain being not intended to limit the present invention, all within the spirit and principles in the present invention; the any modification, equivalent substitution and improvement etc. done, should be included within the scope of the present invention.
Claims (10)
1. the synthetic method of an aldehydedodextrans, it is characterised in that comprise the following steps:
A, glucosan is dissolved in water after, under inert gas shielding, add EDTA, 1, 4-benzenediol,
Sodium borohydride, NaOH and toluene, be stirred at reflux 1-3 hour；
B, in system drip 2-bromo-1,1-diethoxyethane solution, time for adding be no less than 1 hour；
After being added dropwise to complete, it is stirred at reflux 12-18 hour；
C, by the organic phase washed with water in system, obtain aqueous solution, described aqueous solution adds in methanol,
Precipitate to hydroformylation sugar precursor；
D, by described hydroformylation sugar precursor precipitation soluble in water, add toluenesulfonic acid adjust pH to 1-2, add hot water
Xie Hou, uses NaOH solution to be adjusted to neutrality, obtains aldehydedodextrans with the form of precipitation.
The synthetic method of aldehydedodextrans the most according to claim 1, it is characterised in that include with
Lower step:
A, the glucosan of 20000-40000 weight portion is dissolved in the water of 50-130 parts by volume after, nitrogen is protected
Protect down, add the 1, 4-benzenediol of EDTA, 5-15 weight portion of 5-15 weight portion, 5-15 weight portion
Sodium borohydride, the toluene of NaOH and 40-80 parts by volume of 4000-8000 weight portion, be stirred at reflux 1-3 little
Time；
B, in system drip 2-bromo-1, the toluene solution of 1-diethoxyethane, time for adding be no less than 1
Hour, 2-bromo-1,1-diethoxyethane is 1:4-5 with the volume ratio of toluene；After being added dropwise to complete, stir back
Flow 12-18 hour；
C, be cooled to room temperature after, by the organic phase washed with water in system three times, the volume of water the most used is
120-180 parts by volume, merges aqueous phase and obtains aqueous solution, and described aqueous solution adds the first of 1500-2500 parts by volume
In alcohol, using washing with alcohol three times after sucking filtration, the volume of ethanol the most used is 200-280 parts by volume, and will
Washed precipitation vacuum drying, obtains hydroformylation sugar precursor precipitation；
D, the described hydroformylation sugar precursor of 5000-15000 weight portion is precipitated in the water being dissolved in 30-70 parts by volume,
Add toluenesulfonic acid and adjust pH to 1-2, be heated to 70-90 DEG C and be hydrolyzed, after hydrolyzing 1-3 hour, use
Mass fraction is that the NaOH solution of 30-50% is adjusted to neutrality, after filtration, remove impurity, obtains with the form of precipitation
Aldehydedodextrans.
3. a method for coating for the described aldehydedodextrans synthetic method obtained based on claim 1 or 2,
It is characterized in that, comprise the following steps:
A, by microsphere add 1, in 6-hexamethylene diamine solution, react 8-16 hour, obtain ammonification microsphere；
B, being dissolved in phosphate buffer by described aldehydedodextrans, add described ammonification microsphere, mixing is all
After even, dropping three hydrogen boron sodium cyanide solutions, react 8-16 hour；
C, eccentric cleaning, obtain being coated with the microsphere of aldehydedodextrans.
Method for coating the most according to claim 3, it is characterised in that comprise the following steps:
A, at 70 DEG C, the epoxy ethyl microsphere of 500-1500 weight portion is added the quality of 10-30 parts by volume
Mark is the 1 of 10%, in 6-hexamethylene diamine solution, at 90 DEG C stirring reaction 8-16 hour after, through dialysis or in
Hollow fiber pipe cleans and removes unreacted little molecule, obtains ammonification microsphere；
B, the phosphate that the described aldehydedodextrans of 2000-3000 weight portion is dissolved in 40-60 parts by volume delay
Rushing in liquid, the concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer,
Adding described ammonification microsphere, drip three hydrogen boron sodium cyanide solutions after mix homogeneously, described three hydrogen boron Cyanogran .s are molten
Liquid is that three hydrogen boron Cyanogran .s of 400 weight portions are dissolved in the 0.1mol/L phosphate buffer of 2.5 parts by volume
Arrive, react 8-16 hour at 37 DEG C；
C, eccentric cleaning remove unreacted little molecule, obtain being coated with the microsphere of aldehydedodextrans.
5. use a preparation method for the microsphere composition of method for coating described in claim 3, its feature
It is, comprises the following steps:
A, prepared by oxygen microsphere: thioxene, β-two butanone and rare earth compounding are put in microsphere,
Formed by oxygen microsphere；
B, the preparation of oxygen supply microsphere: put into by photosensitizer in microsphere, form oxygen supply microsphere；
C, aldehydedodextrans are coated microsphere: will be added 1 by oxygen microsphere or oxygen supply microsphere, in 6-hexamethylene diamine solution,
React 8-16 hour, obtain ammonification microsphere；Described aldehydedodextrans is dissolved in phosphate buffer, adds
Enter described ammonification microsphere, drip three hydrogen boron sodium cyanide solutions after mix homogeneously, react 8-16 hour；Centrifugal clear
Wash, obtain being coated with aldehydedodextrans by oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
The preparation method of microsphere composition the most according to claim 5, it is characterised in that include with
Lower step:
A, prepared by oxygen microsphere: thioxene, β-two butanone and rare earth compounding are put in microsphere,
Formed by oxygen microsphere；
B, the preparation of oxygen supply microsphere: put into by photosensitizer in microsphere, form oxygen supply microsphere；
C, aldehydedodextrans are coated microsphere: at 70 DEG C, by 500-1500 weight portion by oxygen microsphere or oxygen supply
Microsphere adds mass fraction is 10% the 1 of 10-30 parts by volume, and in 6-hexamethylene diamine solution, at 90 DEG C, stirring is anti-
After answering 8-16 hour, clean through dialysis or hollow fiber conduit and remove unreacted little molecule, obtain ammonification microsphere；
The described aldehydedodextrans of 2000-3000 weight portion is dissolved in the phosphate buffer of 40-60 parts by volume,
The concentration of described phosphate buffer is 0.1mol/L, the pH=6.0 of described phosphate buffer, adds described
Ammonification microsphere, drips three hydrogen boron sodium cyanide solutions after mix homogeneously, described three hydrogen boron sodium cyanide solutions are 400
Three hydrogen boron Cyanogran .s of weight portion are dissolved in the 0.1mol/L phosphate buffer of 2.5 parts by volume and obtaining, 37 DEG C
Lower reaction 8-16 hour；Eccentric cleaning removes unreacted little molecule, obtains being coated with being subject to of aldehydedodextrans
Oxygen microsphere or oxygen supply microsphere；
D, described it is combined as microsphere composition by oxygen microsphere and oxygen supply microsphere.
7. according to the preparation method of the microsphere composition described in claim 5 or 6, it is characterised in that institute
Stating rare earth compounding is europium complex or terbium coordination compound；Described photosensitizer is methylene blue, rose-red, phthalocyanine
One in compound and chlorophyll A or combination.
The preparation method of microsphere composition the most according to claim 7, it is characterised in that described europium
The synthetic method of coordination compound comprises the following steps:
A, adjacent phenyl biphenyl are dissolved in dichloromethane, add aluminum chloride, are cooled to 0 DEG C；Dropping chloroacetic chloride,
Drip complete rear chamber temperature to react 1-2 hour, be dried to obtain solids I；
B, described solids I is dissolved in absolute ether, adds Feldalat NM and Trifluoroacetic Acid Ethyl Ester, room temperature
React 2-3 hour, be dried to obtain solids II；
C, six trichloride hydrate europiums are mixed homogeneously with described solids II, add anhydrous alcohol solution, stirring
Addition ammonia is to pH to 7-9, and room temperature reaction, after 1-2 hour, adds water in system, filters, be dried
To solids III；
D, taking 4,7-diphenyl-1,10-phenanthroline heating for dissolving collects recrystallization crystal after ethanol, cooling；
Taking described recrystallization crystal and 4,7-diphenyl-1,10-phenanthroline adds in toluene, stirs 1-2 hour, cold
But to room temperature, except toluene, europium complex is obtained.
The preparation method of microsphere composition the most according to claim 8, it is characterised in that described europium
The synthetic method of coordination compound comprises the following steps
A, the adjacent phenyl biphenyl of 4500-5000 weight portion is dissolved in the anhydrous methylene chloride of 30-50 parts by volume
In, add the aluminum chloride of 5500-6000 weight portion, be cooled to 0 DEG C；The second of dropping 3500-4500 weight portion
Acyl chlorides, drips complete rear chamber temperature and reacts 1-2 hour, after the organic phase washed with water in system three times, uses
Anhydrous sodium sulfate is dried to obtain 5000-6000 parts by weight solids thing I；
B, the described solids I taking 3000-3500 weight portion are dissolved in the absolute ether of 30-50 parts by volume,
Add Feldalat NM and the Trifluoroacetic Acid Ethyl Ester of 3000-5000 weight portion, the room temperature reaction of 1500-2500 weight portion
2-3 hour, after the organic phase washed with water in system three times, it is dried to obtain 1000-2000 with anhydrous sodium sulfate
The solids II of weight portion；
C, by the described solid of six trichloride hydrate europiums of 2800-3200 weight portion Yu 6000-6800 weight portion
Thing II mix homogeneously, adds the anhydrous alcohol solution of 30-50 parts by volume, and stirring adds 1500-2500 parts by volume
Ammonia to pH to 7-9, room temperature reaction is after 1 hour, adds the water of 600-1000 parts by volume in system,
Precipitation is collected by filtration, and precipitation is dried to obtain solids III；
D, taking the 4 of 3000-5000 weight portion, 7-diphenyl-1,10-phenanthroline heating for dissolving is in 100-150
The ethanol of parts by volume, collects recrystallization crystal after cooling；The described recrystallization taking 2500-3500 weight portion is brilliant
Body and the 4 of 800-1200 weight portion, 7-diphenyl-1,10-phenanthroline adds the toluene of 200-400 parts by volume
In, stir 1-2 hour at 62 DEG C, be cooled to room temperature, except toluene, obtain europium complex.
The preparation method of microsphere composition the most according to claim 7, it is characterised in that described
The synthetic method of thioxene and β-two butanone comprises the following steps:
A, bromoaniline is dissolved in DMF, adds bromotetradecane and diisopropylethylamine, 100 DEG C
After reacting 10-14 hour, in reactant liquor add dichloromethane, recrystallization obtain N, N-bis-replacement to bromobenzene
Amine；
B, by described N, the dibasic para-bromoaniline of N-, magnesium rod and iodine are dissolved in wiring solution-forming in THF,
Under the conditions of maintaining the reflux for, being added drop-wise in THF by solution, after liquid feeding, back flow reaction 1 hour, is cooled to
0 DEG C, in system, add benzoyl hydroperoxide and THF, react 2-3 hour under room temperature；Salt is added in system
After the acid salt with hydrolysis generation, in system, add dichloromethane, be dried chromatography isolated intermediate；
C, being dissolved in toluene solution by described intermediate, add zinc chloride and 2 mercapto ethanol, backflow is anti-
Answer 3-5 hour, except toluene chromatography obtains thioxene and β-two butanone.
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| CN110736738A (en) * | 2018-07-18 | 2020-01-31 | 博阳生物科技（上海）有限公司 | microsphere composition for chemiluminescence detection and application thereof |
| CN113045684A (en) * | 2021-03-11 | 2021-06-29 | 山西奥睿基赛生物科技有限公司 | Solid-phase metal ion chelating agent, preparation method and application thereof |
| CN113621139A (en) * | 2021-08-24 | 2021-11-09 | 濮阳市盛源石油化工（集团）有限公司 | Glucan-based amphiphilic block copolymer and preparation method thereof |
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| WO2004007560A1 (en) * | 2002-07-12 | 2004-01-22 | Centre National De La Recherche Scientifique | Method for obtaining modified polysaccharides by oxidation of hydroxyl groups |
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| CN113621139A (en) * | 2021-08-24 | 2021-11-09 | 濮阳市盛源石油化工（集团）有限公司 | Glucan-based amphiphilic block copolymer and preparation method thereof |
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