CN106967183A - N‑（N ' oleoyl glycyl）Chitosan oligosaccharide sodium sulfonate and preparation method thereof - Google Patents
N‑（N ' oleoyl glycyl）Chitosan oligosaccharide sodium sulfonate and preparation method thereof Download PDFInfo
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- CN106967183A CN106967183A CN201710219504.6A CN201710219504A CN106967183A CN 106967183 A CN106967183 A CN 106967183A CN 201710219504 A CN201710219504 A CN 201710219504A CN 106967183 A CN106967183 A CN 106967183A
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- Prior art keywords
- oleoyl
- chitosan oligosaccharide
- glycyl
- reaction
- sodium sulfonate
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- 239000011734 sodium Substances 0.000 title claims abstract description 21
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 20
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 20
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 title claims abstract description 19
- RQFQJYYMBWVMQG-IXDPLRRUSA-N chitotriose Chemical compound O[C@@H]1[C@@H](N)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](N)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)[C@@H](CO)O1 RQFQJYYMBWVMQG-IXDPLRRUSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 7
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims abstract description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005642 Oleic acid Substances 0.000 claims abstract description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- 239000004471 Glycine Substances 0.000 claims abstract description 5
- 239000006228 supernatant Substances 0.000 claims abstract description 5
- ZHVSXWCIYWYBQP-QJRAZLAKSA-N N-oleoyl-L-glutamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)N[C@H](C(O)=O)CCC(N)=O ZHVSXWCIYWYBQP-QJRAZLAKSA-N 0.000 claims abstract description 3
- 239000005457 ice water Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000005119 centrifugation Methods 0.000 claims description 5
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 abstract description 21
- 239000000047 product Substances 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 125000004442 acylamino group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 17
- 229920001661 Chitosan Polymers 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 5
- -1 amine group oligosaccharide Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920001542 oligosaccharide Polymers 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000002482 oligosaccharides Chemical class 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 240000008067 Cucumis sativus Species 0.000 description 2
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000002280 amphoteric surfactant Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- HPFXACZRFJDURI-KTKRTIGZSA-N N-oleoylglycine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCC(O)=O HPFXACZRFJDURI-KTKRTIGZSA-N 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FVNBSAFGZDEITN-UHFFFAOYSA-N [Cl-].[NH4+].C(C1CO1)CN(C)CCCCCCCCCCCC Chemical compound [Cl-].[NH4+].C(C1CO1)CN(C)CCCCCCCCCCCC FVNBSAFGZDEITN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229920002892 amber Polymers 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
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- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
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- 238000006555 catalytic reaction Methods 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
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- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
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- 239000000194 fatty acid Substances 0.000 description 1
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- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
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- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
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- 239000004005 microsphere Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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- 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
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
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- Engineering & Computer Science (AREA)
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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Polymers & Plastics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Cosmetics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
N‑（N ' oleoyl glycyl）Chitosan oligosaccharide sodium sulfonate and preparation method thereof, is related to technical field of chemical medicine, and N HOSu NHSs and dicyclohexylcarbodiimide are mixed with the DMF solution of oleic acid, filtrate is obtained；Glycine and potassium carbonate are dissolved in the water, above-mentioned filtrate is added dropwise under the conditions of ice-water bath, reacts at room temperature, N acyl amino acid solutions are obtained；By N oleoyl glutamine solutions be adjusted to after neutrality with chitosan oligosaccharide, 1 (3 dimethylamino-propyl) 3 ethyl-carbodiimide hydrochlorides and N HOSu NHS hybrid reactions, obtain N（N ' oleoyl glycyl）Chitosan oligosaccharide, then sulfonating reaction is carried out after being swelled with DMF, supernatant is taken with filtrate of dialysing to obtain, it is freeze-dried, obtain N（N ' oleoyl glycyl）Chitosan oligosaccharide sodium sulfonate.Product has good biocompatibility, the surfactant of the adjustable environmental protection of efficient, nontoxic, surface-active to be a kind of.
Description
Technical field
The present invention relates to technical field of chemical medicine, and in particular to the preparation method of surfactant.
Background technology
Because surfactant has excellent application performance, have in industrial production and daily life extensive
Application.All the time, people never stopped the R and D to novel surfactant.Particularly raw material sources are wide
It is general, good biocompatibility, the exploitation of the unique surfactant of function is always one of focus of research.
Chitosan oligosaccharide is called Chitosan poly oligosaccharide, chitosan oligomer, is through special biological enzyme technology by chitosan（Also there is useization
Learn degraded, the report of microwave degradation technology）A kind of obtained degree of polymerization of degrading oligosaccharide product between 2~20, molecular weight≤
3200Da, is the water-soluble preferable, low molecular weight product that function is big, bioactivity is high.It has chitosan unexistent
Higher solubility, is dissolved in water entirely, easily many unique functions such as absorbs by organism, it act as the 14 of chitosan
Times.Chitosan oligosaccharide is unique positively charged cation basic amine group oligosaccharide in nature, is animal fiber element.At present both at home and abroad
It is more to chitin modified surfactant research, chitosan anionic, cationic and the amphoteric surfactants of preparation
Agent all has been reported that.Such as chitosan and the alkyl glycidyl ether of different length carbochain can synthesize a series of new in the basic conditions
Type amphoteric surfactant；By chitosan graft glycidyl dodecyldimethylamine ammonium chloride, further sulfonation is introduced
Sulfonic group and synthesized a kind of extremely strong high molecular surfactant of hygroscopicity；Utilize chitosan and 2,3- epoxies
Ammonium chloride reacts, and can synthesize HACC cationic surface active agent.Also have chitosan in addition
The report for the surfactant being combined with organosilicon.
Amino acid is the basis for constituting protein, is the primitive material for constituting life.Usual amino acid surface activity
Agent mainly introduces long chain fatty acyl on the amino of amino acid, then neutralizes into and corresponding surface-active is can obtain after salt
Agent.Conventional amino acid has methyl amimoacetic acid, glutamic acid, serine, alanine, propylhomoserin, leucine etc. is picked, wherein with methyl amimoacetic acid, paddy
Propylhomoserin is the most commonly used.Used aliphatic acid is divided into saturation and unsaturated two kinds, such as oleic acid, oleic acid, cocinic acid, palm oil
Acid, hard fatty acids, octanoic acid, capric acid etc..
Because surfactant can be aligned in incompatible two-phase interface, this causes surfactant being related to two-phase
Some properties at interface（Identification, catalysis, the sustained release performance at such as interface etc.）Aspect has advantageous advantage.Shell gathers
Sugar surfactant has certain filming performance, but poor to the specific effect of Cucumber；Amino acid surfactant
There is certain specific effect to Cucumber（Such as some metal ions）, but film forming is relatively weak.In addition, being lived using surface
Property agent molecule in the performance of hydrophobic side chain regulation surfactant be also one of key content in surfactant research.
The content of the invention
The defect existed for both the above surfactant, the present invention proposes a kind of water-soluble preferably N-（N '-oleoyl
Glycyl）- chitosan oligosaccharide sodium sulfonate.
The N- of the present invention（N '-oleoyl glycyl）The molecular structural formula of-chitosan oligosaccharide sodium sulfonate is as follows：
Wherein n=6~15.
The surface-active available amino acid of the amino acid chitosan oligosaccharide surfactant of good water solubility of the present invention is different
Hydrophobic side chain be finely adjusted.
Product of the present invention is a kind of with good biocompatibility, the adjustable environmental protection of efficient, nontoxic, surface-active
Surfactant, such surfactant has good filming performance, and property is gentle, except with general surfactant
Outside feature, it may also be used for fat-soluble medicine is sustained the structure of microbody, extensive in field of medicaments application prospect.
It is another object of the present invention to propose the preparation method of above product.
The present invention comprises the following steps：
1）By n-hydroxysuccinimide（NHS）And dicyclohexylcarbodiimide（DCC）Mixed with the DMF solution of oleic acid anti-
Should, obtain filtrate；
2）Glycine and potassium carbonate are dissolved in the water, above-mentioned filtrate is added dropwise under the conditions of ice-water bath, drip it is rearmounted at room temperature
Reaction, is made N- acyl amino acid solutions；
3）The pH value of N- oleoyl glutamine solutions is adjusted to after neutrality and chitosan oligosaccharide, 1- (3- dimethylamino-propyls) -3- ethyls
Carbodiimide hydrochloride and n-hydroxysuccinimide mixing are reacted, and generate N-（N '-oleoyl glycyl）- chitosan oligosaccharide；
4）By N-（N '-oleoyl glycyl）- chitosan oligosaccharide is swelled rear and chlorosulfonic acid with DMF and carries out sulfonating reaction, and reaction will after terminating
The pH value of reaction solution is adjusted to neutrality, centrifugation, takes supernatant to be dialysed with bag filter；
5）By the dialysate filter in bag filter, filtrate is obtained, it is freeze-dried, obtain N-（N '-oleoyl glycyl）- chitosan oligosaccharide sulphur
Sour sodium.
The reaction equation of the present invention is as follows：
Wherein n=6~15.
It is an advantage of the invention that：Synthetic reaction is simple, and reaction condition is gentle, and high income, reaction can be quantified.Due to first step reaction
NHS is used（N-hydroxysuccinimide）NHS is discharged after activation aliphatic acid, with amino acid couplings, is coupled with chitosan oligosaccharide
When can be directly added into aqueous condensation reagent EDC（1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides）Just can be in water
It is middle to complete reaction, therefore second step reacts（With amino acid couplings）Three-step reaction can be carried out without separation.It so can be achieved one
Pot method reaction, greatlys save reaction cost.
Reaction alkali selection potassium carbonate used, this is due to that the carboxylic acid of potassium carbonate and glycine acts on forming saleratus,
Reaction need not add alkali again in addition, so as to simplify technique.
The present invention by the pH value of N- oleoyl glycine solutions be adjusted to after neutrality with chitosan oligosaccharide, 1- (3- dimethylamino-propyls)-
3- ethyl-carbodiimide hydrochloride mixing is reacted, and what is obtained is to contain N-（N '-oleoyl glycyl）The reaction of-chitosan oligosaccharide is molten
Liquid.Due to the system that this reaction system is aqueous phase, using water miscible 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
Hydrochlorate is condensing agent, and reaction can be made to be completed in one pot, eliminates the trouble of intermediate separation.
The present invention is also by step 3）The reaction solution that reaction is obtained carries out centrifugal treating, and the precipitation that centrifuging and taking is obtained is used into second
30 DEG C of vacuum drying after alcohol mixing extracting, obtain N-（N '-oleoyl glycyl）- chitosan oligosaccharide.Purpose is to remove the boiling carried secretly in product
The higher DMF of point so that product is easy to vacuum drying, while can also remove partial impurities.
The present invention is by through dry N-（N '-oleoyl glycyl）After-chitosan oligosaccharide is swelled with DMF, at room temperature with it is a certain amount of
Chlorosulfuric acid, the side reaction that can so avoid violent reaction condition from bringing.React after certain time, reaction solution is neutralized
To neutral, so the highly acid of sulfonic acid can be avoided to cause the degraded of chitosan oligosaccharide（Or the hydrolysis to amido link）Effect.
In addition, the cutoff of bag filter of the present invention is 2000~3000Mw.Because target product is flat
Average molecular weight is retained more than 2000 in dialysis, and the molecular weight of the accessory substance produced in course of reaction is all 2000
Hereinafter, can all it be removed in dialysis procedure.
Brief description of the drawings
Fig. 1 is N-（N '-oleoyl glycyl）The infrared spectrum of-chitosan oligosaccharide sodium sulfonate.
Fig. 2 is XPS elementary analysis energy spectrum diagrams.
Embodiment
（1）First by 0.2g（1.0mmol）Oleic acid is dissolved in dry DMF, adds 0.12g（1.05mmol）NHS（N- hydroxyl ambers
Amber acid imide）And 0.226g（1.1mmol）Dicyclohexylcarbodiimide（DCC）, stirring reaction 10~12 hours, reaction 10h after
Filtering, obtains filtrate（Ⅰ）.
Weigh glycine 0.075g（1.0mmol）With potassium carbonate 0.138g（1.0 mmol）, add suitable quantity of water dissolving, frozen water
Filtrate is slowly added dropwise in bath（Ⅰ）, rearmounted reaction 24 hours at room temperature are dripped, N- acylglycine acid solutions are made.
（2）The pH for adjusting N- oleoyl glycyl solution with 3N hydrochloric acid adds 0.17g chitosan oligosaccharides to neutrality（Can be in advance with few
Measure water dissolving）、0.201g（1.05mmol）EDAC（1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides）, room temperature
Lower reaction 24h, obtains containing N-（N '-oleoyl glycyl）The reaction solution of-chitosan oligosaccharide.Reaction solution is centrifuged, precipitation is taken out with ethanol
Carry 2 times, 30 DEG C of vacuum drying 8h obtain N-（N '-oleoyl glycyl）- chitosan oligosaccharide.
（3）Weigh 0.15gN-（N '-oleoyl glycyl）- chitosan oligosaccharide 5mLDMF（DMF）It was swelled
At night, add the DMF solution of 1.2mL chlorosulfonic acids（The mixed volume ratio of DMF and chlorosulfonic acid is 1:3）, react stay overnight at room temperature, use
The 10% NaOH aqueous solution is neutralized to neutrality, centrifugation, the bag filter dialysis 3 that supernatant cutoff is 2000~3000Mw
My god（Water is changed for every eight hours once）, take dialysate filter, remove precipitation, take filtrate to be freeze-dried, products obtained therefrom be it is water-soluble compared with
Good N-（N '-oleoyl glycyl）- chitosan oligosaccharide sodium sulfonate.
（4）N- prepared by this method（N '-oleoyl glycyl）- chitosan oligosaccharide sodium sulfonate infrared spectrum, as shown in Figure 1.
In Fig. 1 in 3505cm-1Neighbouring broad peak is mainly O-H on hydroxyl on chitosan oligosaccharide, N-H stretching vibrations on amide groups
Peak, 2928 cm-1、2856 cm-1The stretching vibration peak of c h bond on methyl and methylene nearby is absorbed as, therefore confirms long-chain
The presence of alkane structure；1662 cm-1Place's absorption is the stretching vibration peak of mainly carbonyl；1141cm-1Place is absorbed as sulfonate
Strong absworption peak.
（5）Target compound XPS elementary analyses, as shown in Figure 2.
Fig. 2 is XPS elementary analysis energy spectrum diagrams.
Constituent content as seen from Figure 2：
| Element | Atom content（%） |
| C | 66.83 |
| O | 22.55 |
| Na | 3.71 |
| S | 4 |
| N | 2.91 |
By（4）、（5）It can be seen that：N- is achieved using this method（N '-oleoyl glycyl）- chitosan oligosaccharide sodium sulfonate.
（6）Target compound surface tension test in different pH solution：
By N-（N '-oleoyl glycyl）- chitosan oligosaccharide sodium sulfonate is soluble in water, ultrasound 0.5 hour, high speed centrifugation（Rotating speed：
12000r/min）, take supernatant to determine surface tension（Sessile drop method）It see the table below：
Surface tension in the various concentrations aqueous solution of table 1
| Solution concentration（Mass percent, %） | Surface tension（ 10-3N·m-1） |
| 0.5 | 38.7 |
| 1 | 35.9 |
| 1.5 | 28.7 |
| 2 | 25.5 |
As seen from the above table, raised with the concentration of solution, N-（N '-oleoyl glycyl）The surface tension table of-chitosan oligosaccharide sodium sulfonate
Reveal obvious decline, it is seen that N '-oleoyl glycyl chitosan oligosaccharide sodium sulfonate can be used as surfactant.
（6）Applicating example：
The present invention can be used for new drug controlled release Transmission system（Such as PLA（PLA）Microballoon drug-loading system）Preparation,
Method is as follows.
By a certain amount of medicine（Such as felodipine）It is dissolved in 100 mg PLA in 5 mL chloroforms, forms solution；Then
Add and 50 mL, 1% N- are housed（N '-oleoyl glycyl）In 100 mL beakers of-chitosan oligosaccharide sodium sulfonate solution；Use again afterwards
Cell pulverization instrument ultrasonic emulsification（900 W）6 min formation oil-in-water emulsions；The h of magnetic agitation 8 makes chloroform volatilize completely under normal temperature
Form the suspension of PLA microballoons.PLA microballoons are collected with the min of suspension 45 of 25,000 rpm centrifugation microballoon.Then
With distilled water again dispersion microsphere, centrifugation, suspending 3 times removes remaining BASDE and the medicine do not encapsulated into.Finally to micro-
Ball carry out be freeze-dried obtain dry PLA microballoons and save it in 4 DEG C under conditions of it is standby.Microballoon prepared by this method
Particle diameter is in 100nm~2000nm.
Claims (4)
1.N-（N '-oleoyl glycyl）- chitosan oligosaccharide sodium sulfonate, molecular structural formula is as follows：
Wherein n=6~15.
2. N- as claimed in claim 1（N '-oleoyl glycyl）The preparation method of-chitosan oligosaccharide sodium sulfonate, it is characterised in that including
Following steps：
1）The DMF solution of n-hydroxysuccinimide and dicyclohexylcarbodiimide and oleic acid is mixed into reaction, filter is obtained
Liquid；
2）Glycine and potassium carbonate are dissolved in the water, above-mentioned filtrate is added dropwise under the conditions of ice-water bath, drip it is rearmounted at room temperature
Reaction, is made N- acyl amino acid solutions；
3）The pH value of N- oleoyl glutamine solutions is adjusted to after neutrality and chitosan oligosaccharide, 1- (3- dimethylamino-propyls) -3- ethyls
Carbodiimide hydrochloride and n-hydroxysuccinimide mixing are reacted, and generate N-（N '-oleoyl glycyl）- chitosan oligosaccharide；
4）By N-（N '-oleoyl glycyl）- chitosan oligosaccharide is swelled rear and chlorosulfonic acid with DMF and carries out sulfonating reaction, and reaction will after terminating
The pH value of reaction solution is adjusted to neutrality, centrifugation, takes supernatant to be dialysed with bag filter；
5）By the dialysate filter in bag filter, filtrate is obtained, it is freeze-dried, obtain N-（N '-oleoyl glycyl）- chitosan oligosaccharide sulphur
Sour sodium.
3. N- according to claim 2（N '-oleoyl glycyl）The preparation method of-chitosan oligosaccharide sodium sulfonate, it is characterised in that：Will
Step 3）The reaction solution that reaction is obtained carries out centrifugal treating, and the precipitation that centrifuging and taking is obtained is true using 30 DEG C after ethanol mixing extracting
Sky is dried, and obtains N-（N '-oleoyl glycyl）- chitosan oligosaccharide.
4. the N- according to Claims 2 or 3（N '-oleoyl glycyl）The preparation method of-chitosan oligosaccharide sodium sulfonate, its feature exists
In：The cutoff of the bag filter is 2000~3000Mw.
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| CN108309875A (en) * | 2018-05-07 | 2018-07-24 | 杨恒智 | Moisten moisturizing face cream and preparation method thereof |
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| CN108309874A (en) * | 2018-05-07 | 2018-07-24 | 杨恒智 | Skin whitening, moisturizing face cream |
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| CN110577480A (en) * | 2019-07-16 | 2019-12-17 | 成都医学院 | Preparation method and application of compound with anti-beta amyloid activity |
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| CN111040003B (en) * | 2019-12-20 | 2023-03-14 | 扬州工业职业技术学院 | Chitosan oligosaccharide derivative molecular imprinting functional monomer and preparation method thereof |
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| CN113214442B (en) * | 2021-05-18 | 2022-03-04 | 扬州工业职业技术学院 | Anionic-nonionic dispersant and preparation method thereof |
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