CN110028601A - A kind of beta-cyclodextrin derivative, preparation method and the method for preparing supermolecule vesica - Google Patents
A kind of beta-cyclodextrin derivative, preparation method and the method for preparing supermolecule vesica Download PDFInfo
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- CN110028601A CN110028601A CN201910329435.3A CN201910329435A CN110028601A CN 110028601 A CN110028601 A CN 110028601A CN 201910329435 A CN201910329435 A CN 201910329435A CN 110028601 A CN110028601 A CN 110028601A
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- cyclodextrin
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 14
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 84
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 71
- 229960004853 betadex Drugs 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 35
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims abstract description 31
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims abstract description 30
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 11
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 11
- 230000009467 reduction Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 14
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 239000000908 ammonium hydroxide Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 4
- 229940113088 dimethylacetamide Drugs 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 3
- 239000013049 sediment Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 14
- 230000002209 hydrophobic effect Effects 0.000 abstract description 13
- -1 Methyl benzenesulfonyl Chemical group 0.000 abstract description 10
- 238000010521 absorption reaction Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 238000012544 monitoring process Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000010148 water-pollination Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 230000003321 amplification Effects 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910001431 copper ion Inorganic materials 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000001936 parietal effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- CHVZQMAANSUXJU-JJKGCWMISA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanamide;hydrochloride Chemical compound Cl.NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO CHVZQMAANSUXJU-JJKGCWMISA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229950005162 benexate Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- IAXUQWSLRKIRFR-SAABIXHNSA-N chembl2104696 Chemical compound C1C[C@@H](CNC(=N)N)CC[C@@H]1C(=O)OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 IAXUQWSLRKIRFR-SAABIXHNSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
- A61K47/6915—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
-
- 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
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of beta-cyclodextrin derivative, preparation method and the method for preparing supermolecule vesica；With list [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin and Putriscine or 1,6- hexamethylene diamine is that raw material is reacted, and then reacts with ferrocene carboxaldehyde, obtains completely new beta-cyclodextrin derivative through sodium borohydride reduction.The method of the present invention reaction condition is mild, and reaction yield is higher, and reaction route is suitble to large-scale industrial production；Gained beta-cyclodextrin derivative hydrophobic region is effectively expanded, and typical UV absorption is provided with, and is conducive to subsequent applications and monitoring；And has antitumaous effect, be advantageously applied to drug carrying field.Supermolecule vesica can be prepared with beta-cyclodextrin using beta-cyclodextrin derivative obtained by the present invention, gained vesica can effectively deliver hydrophily and hydrophobic drug while having antitumaous effect, there is huge potential using value in terms of drug carrying.
Description
Technical field
The present invention relates to a kind of beta-cyclodextrin derivative, preparation method and the method for preparing supermolecule vesica, belonging to
Work Material synthesis and medical material field.
Background technique
Cyclodextrin (Cyclodextrin, CD) is that starch and malt oligosaccharide are acted on by cyclodextrin glycosyltransferase
The series of annular oligosaccharide for waiting glucose polymers and being formed, is by Villiers earliest in the starch in amylobacter in 1891
It is found in digestive juice.Cyclodextrin is to be formed by D type glucopyranose by α-Isosorbide-5-Nitrae-glucosides key connection, according to glucopyranose
The number of unit is different and is divided into different cyclodextrin, and the cyclodextrin of such as 6 glucopyranose units is named as alpha-cyclodextrin,
The cyclodextrin of 7 glucopyranose units is named as beta-cyclodextrin and the cyclodextrin of 8 glucopyranose units is named
(Tong Linhui Cyclodextrin Chemistry-basis and [M] is applied: Science Press, 2001) for gamma-cyclodextrin etc..Cyclodextrin has cone bucket
The stereochemical structure of shape, chamber external hydrophilicity is intracavitary hydrophobic, therefore can wrap the guest molecule for closing poorly water-soluble, improves by inclusion object
The physicochemical properties (J.Szejtli, Chemical Reviews, 1998,98,1743-1754) of molecule.It is empty compared to cone bucket
The lesser alpha-cyclodextrin of chamber and the higher gamma-cyclodextrin of production cost, beta-cyclodextrin is with its moderate cone bucket cavity size, cheap
Price, good water-soluble and biocompatibility the advantages that and the neck such as be widely used in food, medicine, chemical industry and agricultural
Domain.
But the hydrophobic region of beta-cyclodextrin and catalytic activity etc. are limited, and the derivatization of beta-cyclodextrin can overcome beta-cyclodextrin
The defect of itself, therefore the derivative of many beta-cyclodextrins is synthesized.As Chinese patent literature CN101195662A is disclosed
A kind of 6- (2- glucosyl group amido)-beta-cyclodextrin derivative and preparation method thereof, with 6-O- p-toluenesulfonyl-β-ring paste
Essence, aminoglucose hydrochloride are that 6- (2- glucosyl group amido)-beta-cyclodextrin is prepared in starting material, and gained cyclodextrin spreads out
Biology has good water-soluble and stability.But since the ring-type that beta-cyclodextrin itself is exactly D type glucopyranose is derivative
Object, the introducing of glucosyl group amido can not effectively change the physicochemical property of beta-cyclodextrin, 6- (2- glucosyl group amine
Base)-beta-cyclodextrin derivative hydrophobic region is still limited, and without UV absorption, it is unfavorable for its monitoring and subsequent applications, does not have
Standby anticancer activity, seriously limits it in the application in drug carrying field.Therefore, non-glucose is grafted on beta-cyclodextrin skeleton
Base active group has important theory significance and application value.And ferrocene is a kind of Organometallic with aroma properties
Close object, with certain anticancer activity (L.V.Snegur, V.N.Babin, A.A.Simenel, Y.S.Nekrasov,
L.A.Ostrovskaya and N.S.Sergeeva,Russian Chemical Bulletin,2010,59,2167-
2178) ferrocene is keyed on beta-cyclodextrin by chemistry, is expected to change the physicochemical properties of beta-cyclodextrin, expand
Its application range.
Vesica is the ordered assemblies with closing double-layer structure spontaneously formed when being scattered in aqueous solution by parents' molecule
(D.E.Discher and A.Eisenberg, Science, 2002,297,967-973), in biological film, chemical catalysis
It has a wide range of applications with fields such as drug carryings.The hydrophobic cavity of beta-cyclodextrin can be included water-soluble by hydrophobic effect
Poor guest molecule forms supermolecule parents molecule, to further be self-assembly of structurally ordered Subjective and Objective supermolecule
Vesica.Although the Subjective and Objective supermolecule vesica based on beta-cyclodextrin can effectively deliver hydrophily anticancer drug, it is to thin
The carrying capacity of aqueous anti-tumor drug molecule is extremely limited.
Summary of the invention
In view of the deficienciess of the prior art, the present invention provides a kind of beta-cyclodextrin derivative and preparation method thereof.This hair
Bright that ferrocene group is connected on beta-cyclodextrin by chemical bond, reaction condition is mild, and reaction yield is higher, and reaction route is suitable
Close large-scale industrial production；Gained beta-cyclodextrin derivative hydrophobic region is effectively expanded, and has antitumaous effect,
It is provided with typical UV absorption simultaneously, is conducive to subsequent applications and monitoring, is advantageously applied to drug carrying field.
The present invention also provides a kind of methods for preparing supermolecule vesica using above-mentioned beta-cyclodextrin derivative.Gained vesica
Hydrated diameter is 130-170 nanometers, has antitumaous effect and is easy to be swallowed by cancer cell, can effectively deliver hydrophily and dredge
Aqueous drug has huge potential using value in terms of drug carrying.
Term explanation:
Room temperature: refer to 25 DEG C ± 5 DEG C；
Formula II compound: single [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin；
Formula III compound: single [6- '-deoxy-n-butylamino]-beta-cyclodextrin or single [6- '-deoxy-n-hexyl amido]-β-
Cyclodextrin；
Compound of formula I: single [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin or single [6- deoxidation-
N- hexyl amido-N '-methyl ferrocene]-beta-cyclodextrin, i.e. beta-cyclodextrin derivative.
The compounds of this invention number and formula numbers are completely the same, reference relationship having the same；With compound structure
Formula is foundation.
Technical scheme is as follows:
A kind of beta-cyclodextrin derivative, which is characterized in that there is the structure as shown in following formula I:
Wherein, in structure shown in Formulas I, n is 2 or 3.
It is preferred according to the present invention, the beta-cyclodextrin derivative be using Formula II compound as initial feed, through with Isosorbide-5-Nitrae-
Butanediamine or 1, the reaction of 6- hexamethylene diamine, then reacted with ferrocene carboxaldehyde, then it is prepared through reduction.
The preparation method of above-mentioned beta-cyclodextrin derivative, comprising steps of
(1) in solvent 1, in the presence of catalyst of triethylamine, Formula II compound and Putriscine or 1,6- hexamethylene diamine
The preparation formula that reacts III compound；
Wherein, in formula III structural formula of compound, n is 2 or 3；
(2) in solvent 2, under nitrogen protection, formula III compound and ferrocene carboxaldehyde are protected from light；Then in nitrogen
Under gas shielded, through sodium borohydride reduction；It is finally separating purifying and compound of formula I is prepared.
Preferred according to the present invention, in step (1), the solvent 1 is N-Methyl pyrrolidone, N, N- dimethyl formyl
Amine, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide；Preferably N-Methyl pyrrolidone；The quality and solvent of the Formula II compound
1 volume ratio is 0.01-0.1g/mL；Preferably, the quality of the Formula II compound and the volume ratio of solvent 1 are 0.05-
0.07g/mL。
Preferred according to the present invention, in step (1), the quality of the catalyst of triethylamine is Formula II compound quality
25-30%.
Preferred according to the present invention, in step (1), the Formula II compound and Putriscine or 1,6- hexamethylene diamine rub
You are than being 1:1-3；Preferably, the Formula II compound and Putriscine or 1, the molar ratio of 6- hexamethylene diamine are 1:2.
It is preferred according to the present invention, in step (1), the Formula II compound and Putriscine or 1,6- hexamethylene diamine it is anti-
Answering temperature is 60-80 DEG C；Preferably, the Formula II compound and Putriscine or 1, the reaction temperature of 6- hexamethylene diamine are 70
℃.The reaction time of Formula II compound and 1,4- butanediamine or 1,6- hexamethylene diamine is 8-12 hours；Preferably, Formula II compound and
The reaction time of 1,4- butanediamine or 1,6- hexamethylene diamine is 10 hours.
It is preferred according to the present invention, in step (1), Formula II compound and Putriscine or 1, after the reaction of 6- hexamethylene diamine,
Gained reaction solution is cooled to room temperature, and is subsequently poured into acetone, and formula III compound crude product is made through acetone washing in gained precipitating,
And it is directly used in step (2).
Preferred according to the present invention, in step (2), the solvent 2 is N-Methyl pyrrolidone, N, N- dimethyl formyl
Amine, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide；Preferably N-Methyl pyrrolidone；The quality of the formula III compound and molten
The volume ratio of agent 2 is 0.05-0.3g/mL.
Preferred according to the present invention, in step (2), the molar ratio of the formula III compound and ferrocene carboxaldehyde is 1:
0.5-2；Preferably, the molar ratio of formula III compound and ferrocene carboxaldehyde is 1:1.
Preferred according to the present invention, in step (2), the formula III compound and ferrocene carboxaldehyde are protected from light temperature
It is 50-70 DEG C；Preferably, the temperature that is protected from light of the formula III compound and ferrocene carboxaldehyde is 60 DEG C.It is protected from light the time
It is 3-7 hours；Preferably, being protected from light the time is 5 hours.
Preferred according to the present invention, in step (2), the molar ratio of the sodium borohydride and formula III compound is 1-3:1；
Preferably, the molar ratio of the sodium borohydride and formula III compound is 2:1.
Preferred according to the present invention, in step (2), the reduction reaction temperature is room temperature.The reduction reaction time is that 1-4 is small
When；Preferably, the reduction reaction time is 2 hours.
It is preferred according to the present invention, in step (2), after the reduction reaction is complete, with acetone quenching reaction.
Preferred according to the present invention, in step (2), described isolate and purify is isolated and purified using silica gel chromatographic column；
Eluant, eluent used is the mixed solution of isopropanol, water and 30wt% ammonium hydroxide, the volume ratio of the isopropanol, water and 30wt% ammonium hydroxide
For 5:3:2.
The method for preparing supermolecule vesica using above-mentioned beta-cyclodextrin derivative, comprising steps of
Beta-cyclodextrin derivative and beta-cyclodextrin are dissolved in steam in water three times and obtain mixed liquor；At 20-30 DEG C, ultrasonic wave
Mixing 20-50 minutes, obtains supermolecule vesica.
Preferred according to the present invention, the molar ratio of the beta-cyclodextrin derivative and beta-cyclodextrin is 1:1.
UV absorption test is carried out to the mixed liquor of beta-cyclodextrin derivative and beta-cyclodextrin, controls beta-cyclodextrin derivative
It is constant with the total concentration of beta-cyclodextrin, change the molar ratio of beta-cyclodextrin derivative and beta-cyclodextrin in mixed liquor, with β-
The UV absorption of the mixed liquor of the increase of cyclodextrine derivatives concentration, beta-cyclodextrin derivative and beta-cyclodextrin gradually increases, root
Job ' s curve is made according to result above, it is found that the inclusion molar ratio between beta-cyclodextrin derivative and beta-cyclodextrin is 1:1.
Preferred according to the present invention, the concentration of beta-cyclodextrin derivative is 5 × 10 in the mixed liquor-3-8×10-3mol/
L。
Preferred according to the present invention, the ultrasonic wave mixing temperature is 25 ± 1 DEG C, and Sonic mixing time is 30 minutes.
Preferred according to the present invention, the average grain diameter of the supermolecule vesica is 130-170nm.
The synthesis equation of beta-cyclodextrin derivative of the present invention is as follows:
Wherein, n is 2 or 3.
It technical characterstic of the invention and has the beneficial effect that:
1, the present invention is using list [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin and 1,4- butanediamine or 1,6- hexamethylene diamine as raw material
Single [6- '-deoxy-n-butylamino]-beta-cyclodextrin or single [6- '-deoxy-n-hexyl amido]-beta-cyclodextrin are synthesized, it is then luxuriant with two
Armor aldehyde reaction, through sodium borohydride reduction obtain list [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin or
Both completely new beta-cyclodextrin derivatives of single [6- '-deoxy-n-hexyl amido-N '-methyl ferrocene]-beta-cyclodextrin.The present invention
Ferrocene group is keyed on beta-cyclodextrin by chemistry through two-step reaction, preparation method is simple, easily operated, reacts item
Part is mild；Reaction site is single-minded, and by-product is less, and reaction yield is higher, is suitble to large-scale industrial production.
2, ferrocene group is keyed on beta-cyclodextrin by the present invention by chemistry, makes beta-cyclodextrin derivative hydrophobic region
Domain is effectively expanded, while assigning beta-cyclodextrin derivative antitumaous effect, is advantageously applied to drug carrying field；And make institute
It obtains beta-cyclodextrin derivative and has ultraviolet absorption characteristic (beta-cyclodextrin is without ultraviolet absorption characteristic), conducive to subsequent monitoring and answer
With.There is amino and ferrocene group simultaneously, amino has preferable thorn to copper ion in gained beta-cyclodextrin derivative structure
Swash responding ability, and ferrocene group has preferable stimuli responsive ability to oxidant.Thus, have applied to load medical instrument quick
The stimulating responsive of sense transports conducive to the active targeting of anticancer drug.
3, present invention gained beta-cyclodextrin derivative can be used for preparing supermolecule vesica, can be effective as guest molecule
Ground is included to form supermolecule parents' molecule by L-phenylalanine, is assembled into Subjective and Objective oversubscription ascus under certain condition
Bubble.The hydrated diameter of gained vesica is 130-170 nanometers, so that the vesica is easy to be trapped in cancerous issue portion by EPR effect
Position, and be easy to be swallowed by cancer cell；Simultaneously there is the ferrocene group of anticancer activity to be embedded in the parietal layer of vesica,
Hydrophobic region is expanded while assigning vesica certain antitumaous effect；The hydrophobic region of beta-cyclodextrin cavity and parietal layer in vesica
Domain can wrap a little hydrophobic drugs of unification, and the inner cavity of vesica can be with some hydrophilic drug molecules of carrying, to realize
Triple carryings to ferrocene, hydrophilic medicament molecule and hydrophobic drug, greatly increase drug carrying capacity.Cause
This Subjective and Objective supermolecule vesica according to the present invention has huge potential using value in terms of drug carrying.In addition, β-
There is amino and ferrocene group simultaneously, amino has preferable stimuli responsive energy to copper ion in cyclodextrine derivatives structure
Power, and ferrocene group has preferable stimuli responsive ability to oxidant；Thus, gained Subjective and Objective supermolecule vesica has quick
The stimulating responsive of sense transports conducive to the active targeting of anticancer drug.
Detailed description of the invention
Fig. 1 is [two cyclopentadienyl of 6- '-deoxy-n-butylamino-N '-methyl single in the supermolecule vesica of the preparation of the embodiment of the present invention 1
Iron]-two-dimentional nuclear-magnetism (2D NMR ROSEY) spectrogram between beta-cyclodextrin and beta-cyclodextrin.
Fig. 2 is TEM image of the supermolecule vesica of the preparation of the embodiment of the present invention 1 in water phase under different amplification.
Fig. 3 is SEM image of the supermolecule vesica of the preparation of the embodiment of the present invention 1 in water phase under different amplification.
Fig. 4 is dynamic hydrated diameter figure of the supermolecule vesica of the preparation of the embodiment of the present invention 1 in water phase.
Fig. 5 is TEM image of the supermolecule vesica of the preparation of the embodiment of the present invention 2 in water phase under different amplification.
Fig. 6 is dynamic hydrated diameter figure of the supermolecule vesica of the preparation of the embodiment of the present invention 2 in water phase.
Specific embodiment
The present invention is further elaborated combined with specific embodiments below, but the present invention is not limited in following implementation
Example.
Method described in embodiment is conventional method unless otherwise instructed, and the reagent is commercially available unless otherwise specified
It obtains.
Embodiment 1
A kind of system of beta-cyclodextrin derivative (single [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin)
Preparation Method, comprising steps of
(1) single [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin (II, 0.6445g, 0.5mmol) is added to 10 at room temperature
In milliliter N-Methyl pyrrolidone, stirs to being completely dissolved, above-mentioned list [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin is then added
The Putriscine (0.088g, 1mmol) of 2 times of moles, then be added dropwise to the triethylamine of 0.25mL and make catalyst, it is anti-at 70 DEG C
It answers 10 hours, TLC detects fully reacting, and cooling reaction solution to room temperature pours into reaction solution in acetone, generates a large amount of whites
Grain, filter and with acetone washing filter cake 3 times, obtain list [6- '-deoxy-n-butylamino]-beta-cyclodextrin (III) crude product；
(2) at room temperature by list obtained above [6- '-deoxy-n-butylamino]-beta-cyclodextrin (III, 0.6025g,
It 0.5mmol) is dissolved in 5 milliliters of N-Methyl pyrrolidones, the ferrocene carboxaldehyde of 0.107g (0.5mmol) is then added, at 60 DEG C
Under, it is protected from light, nitrogen protection is reacted 5 hours, and TLC detects fully reacting；Stop heating, reaction is cooled to room temperature, and points 3 batches at 10 points
The sodium borohydride of 0.03783g (1mmol) is added in clock into reaction solution, continues room temperature reaction 2 hours, TLC inspection under nitrogen protection
It surveys fully reacting and obtains list [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-β-ring with 1 milliliter of acetone quenching reaction
Dextrin crude product；Above-mentioned cyclodextrine derivatives crude product is used into silica gel chromatograph column separating purification, eluant, eluent is that volume ratio is 5:
The mixed liquor of the isopropanol of 3:2, water and 30wt% ammonium hydroxide, obtains list [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-β-
Cyclodextrin, i.e. beta-cyclodextrin derivative.
The yield of beta-cyclodextrin derivative of the present invention is 65% (yield on the basis of starting material), is bright orange toner
End.
The nuclear magnetic data of products therefrom of the present invention is as follows:
1H NMR(300MHz,DMSO-D6,300K,TMS,δppm):5.97-5.61(m,9H,C5H5),4.92-4.81(m,
4H,H1),4.27-4.17(m,3H,H1),3.94-3.37(m,28H,H3,H5,H6),3.36-3.20(m,14H,H2,H4),
2.70-2.68(s,2H,CH2),2.31-2.15(m,2H,CH2),2.10-2.06(s,2H,CH2),2.02-1.74(m,2H,
CH2),1.27-1.17(m,2H,CH2).13C NMR(75MHz,DMSO-D6,300K,δppm):17.06,20.80,28.97,
30.04,30.62,48.39,60.19,68.52,72.42,73.00,101.94,125.25,127.93.FT-IR(KBr
pellet,υcm-1):3236.44(vN-H),2928.42(vC-H),1657.16(vC=C),618.49(δC=C).ESI-MS:
Calcd.for C57H92N2O34Fe2+, m/z=702.1850, found m/z=702.2503.
The method for preparing supermolecule vesica using above-mentioned gained beta-cyclodextrin derivative, comprising steps of
By single [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin and beta-cyclodextrin according to 1:1 molar ratio
It is dissolved in and steaming in water three times, being prepared into beta-cyclodextrin derivative concentration is 6 × 10-3The mixed liquor of mol/L；At 25 ± 1 DEG C, ultrasound
Wave mixes 30 minutes, obtains the supermolecule vesica that average diameter is 150nm or so.
In supermolecule vesica prepared by the present invention, single [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin
Two-dimentional nuclear-magnetism (2D NMR ROSEY) spectrogram between beta-cyclodextrin is as shown in Figure 1, as shown in Figure 1, single [6- '-deoxy-n-fourth
Base amido-N '-methyl ferrocene] H in-beta-cyclodextrin on ferrocene group10With the H of beta-cyclodextrin inner cavity3、H5Between have
Apparent coherent signal illustrates single [6- '-deoxy-n-butylamino-N '-methyl the ferrocene]-beta-cyclodextrin of beta-cyclodextrin inclusion compound
Middle ferrocene group forms supermolecule parents' molecule.
TEM, the SEM image such as Fig. 2 and 3 of supermolecule vesica manufactured in the present embodiment in water phase under different amplification
Shown, by Fig. 2 and 3 it is found that supermolecule vesica is spherical in shape, size is uniform, and average diameter is in 150nm or so, vesica wall thickness 3.5nm
Left and right, it is suitable with list [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin/Benexate Hydrochloride size.
Dynamic hydrated diameter figure of the supermolecule vesica manufactured in the present embodiment in water phase as shown in figure 4, surpass as shown in Figure 4
Molecule vesica dynamic hydrated diameter is in 150nm or so.
Embodiment 2
A kind of system of beta-cyclodextrin derivative (single [6- '-deoxy-n-hexyl amido-N '-methyl ferrocene]-beta-cyclodextrin)
Preparation Method, comprising steps of
(1) single [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin (II, 0.6445g, 0.5mmol) is added to 10 at room temperature
In milliliter N-Methyl pyrrolidone, stirs to being completely dissolved, above-mentioned list [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin is then added
1, the 6- hexamethylene diamine (0.116g, 1mmol) of 2 times of moles, then be added dropwise to the triethylamine of 0.25mL and make catalyst, it is anti-at 70 DEG C
It answers 10 hours, TLC detects fully reacting, and cooling reaction solution to room temperature pours into reaction solution in acetone, generates a large amount of whites
Grain, filter and with acetone washing filter cake 3 times, obtain list [6- '-deoxy-n-hexyl amido]-beta-cyclodextrin (III) crude product；
(2) at room temperature by list obtained above [6- '-deoxy-n-hexyl amido]-beta-cyclodextrin (III, 0.6165g,
It 0.5mmol) is dissolved in 5 milliliters of N-Methyl pyrrolidones, the ferrocene carboxaldehyde of 0.107g (0.5mmol) is then added, at 60 DEG C
Under, it is protected from light, nitrogen protection is reacted 5 hours, and TLC detects fully reacting；Stop heating, reaction is cooled to room temperature, and points 3 batches at 10 points
The sodium borohydride of 0.03783g (1mmol) is added in clock into reaction solution, continues room temperature reaction 2 hours, TLC inspection under nitrogen protection
It surveys fully reacting and obtains list [6- '-deoxy-n-hexyl amido-N '-methyl ferrocene]-β-ring with 1 milliliter of acetone quenching reaction
Dextrin crude product；Above-mentioned cyclodextrine derivatives crude product is used into silica gel chromatograph column separating purification, eluant, eluent is that volume ratio is 5:
The mixed liquor of the isopropanol of 3:2, water and 30wt% ammonium hydroxide, obtains list [6- '-deoxy-n-hexyl amido-N '-methyl ferrocene]-β-
Cyclodextrin, i.e. beta-cyclodextrin derivative.
The yield of beta-cyclodextrin derivative of the present invention is 68% (yield on the basis of starting material), is bright orange toner
End.
The nuclear magnetic data of products therefrom of the present invention is as follows:
1H NMR(300MHz,DMSO-D6,300K,TMS,δppm):6.08-5.58(m,9H,C5H5),4.89-4.79(m,
4H,H1),4.29-4.18(m,3H,H1),4.12-3.36(m,28H,H3,H5,H6),3.35-3.09(m,14H,H2,H4),
3.02-2.56(m,4H,CH2),2.40-1.76(m,2H,CH2),1.73-0.84(m,8H,CH2).13C NMR(75MHz,DMSO-
D6,300K,δppm):17.58,20.78,21.22,25.94,29.41,30.49,31.09,49.01,60.41,62.36,
69.04,73.68,73.60,82.08,102.43,125.93,128.38.FT-IR(KBr pellet,υcm-1):3248.80
(vN-H),2938.66(vC-H),1662.28(vC=C),618.50(δC=C).ESI-MS:Calcd.for C59H96N2O34Fe2+,m/
Z=716.1100, found m/z=716.2684.
The method for preparing supermolecule vesica using above-mentioned gained beta-cyclodextrin derivative, comprising steps of
By single [6- '-deoxy-n-hexyl amido-N '-methyl ferrocene]-beta-cyclodextrin and beta-cyclodextrin according to 1:1 molar ratio
It is dissolved in and steaming in water three times, being prepared into beta-cyclodextrin derivative concentration is 6 × 10-3Mixed liquor；At 25 ± 1 DEG C, ultrasonic wave is mixed
It closes 30 minutes, obtains the supermolecule vesica that average diameter is 160nm or so.
TEM image of the supermolecule vesica manufactured in the present embodiment in water phase under different amplification as shown in figure 5, by
Fig. 5 is it is found that supermolecule vesica is spherical in shape, and size is uniform, and average diameter is in 160nm or so.
Dynamic hydrated diameter figure of the supermolecule vesica manufactured in the present embodiment in water phase as shown in fig. 6, it will be appreciated from fig. 6 that
Supermolecule vesica dynamic hydrated diameter is in 160nm or so.
Embodiment 3
A kind of system of beta-cyclodextrin derivative (single [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin)
Preparation Method, comprising steps of
(1) single [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin (II, 0.6445g, 0.5mmol) is added to 10 at room temperature
In milliliter N-Methyl pyrrolidone, stirs to being completely dissolved, above-mentioned list [6- is to Methyl benzenesulfonyl base]-beta-cyclodextrin is then added
The Putriscine (0.088g, 1mmol) of 2 times of moles, then be added dropwise to the triethylamine of 0.23mL and make catalyst, it is anti-at 80 DEG C
It answering 8 hours, TLC detects fully reacting, and reaction solution is poured into acetone, generates a large amount of white particles by cooling reaction solution to room temperature,
It filters and uses acetone washing filter cake 3 times, obtain list [6- '-deoxy-n-butylamino]-beta-cyclodextrin (III) crude product；
(2) at room temperature by list obtained above [6- '-deoxy-n-butylamino]-beta-cyclodextrin (III, 0.6025g,
It 0.5mmol) is dissolved in 3 milliliters of N-Methyl pyrrolidones, the ferrocene carboxaldehyde of 0.107g (0.5mmol) is then added, at 50 DEG C
Under, it is protected from light, nitrogen protection is reacted 7 hours, and TLC detects fully reacting；Stop heating, reaction is cooled to room temperature, and points 3 batches at 10 points
The sodium borohydride of 0.03783g (1mmol) is added in clock into reaction solution, continues room temperature reaction 3 hours, TLC inspection under nitrogen protection
It surveys fully reacting and obtains list [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-β-ring with 1 milliliter of acetone quenching reaction
Dextrin crude product；Above-mentioned cyclodextrine derivatives crude product is used into silica gel chromatograph column separating purification, eluant, eluent is that volume ratio is 5:
The mixed liquor of the isopropanol of 3:2, water and 30wt% ammonium hydroxide, obtains list [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-β-
Cyclodextrin, i.e. beta-cyclodextrin derivative.
The method for preparing supermolecule vesica using above-mentioned gained beta-cyclodextrin derivative, comprising steps of
By single [6- '-deoxy-n-butylamino-N '-methyl ferrocene]-beta-cyclodextrin and beta-cyclodextrin according to 1:1 molar ratio
It is dissolved in and steaming in water three times, being prepared into beta-cyclodextrin derivative concentration is 5 × 10-3The mixed liquor of mol/L；At 25 ± 1 DEG C, ultrasound
Wave mixes 25 minutes, obtains supermolecule vesica.
Claims (10)
1. a kind of beta-cyclodextrin derivative, which is characterized in that have the structure as shown in following formula I:
Wherein, in structure shown in Formulas I, n is 2 or 3.
2. beta-cyclodextrin derivative according to claim 1, which is characterized in that the beta-cyclodextrin derivative is with Formula II
Compound is initial feed, through with Putriscine or 1, the reaction of 6- hexamethylene diamine then reacts with ferrocene carboxaldehyde, then through restoring
It is prepared.
3. the preparation method of beta-cyclodextrin derivative as claimed in claim 1 or 2, comprising steps of
(1) in solvent 1, in the presence of catalyst of triethylamine, Formula II compound and Putriscine or 1,6- hexamethylene diamine occur
React preparation formula III compound；
Wherein, in formula III structural formula of compound, n is 2 or 3；
(2) in solvent 2, under nitrogen protection, formula III compound and ferrocene carboxaldehyde are protected from light；Then it is protected in nitrogen
Under shield, through sodium borohydride reduction；It is finally separating purifying and compound of formula I is prepared.
4. the preparation method of beta-cyclodextrin derivative according to claim 1, which is characterized in that in step (1), including with
It is one or more in lower condition:
A, the solvent 1 is N-Methyl pyrrolidone, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide；
Preferably N-Methyl pyrrolidone；The quality of the Formula II compound and the volume ratio of solvent 1 are 0.01-0.1g/mL；It is preferred that
, the quality of the Formula II compound and the volume ratio of solvent 1 are 0.05-0.07g/mL；
B, the quality of the catalyst of triethylamine is the 25-30% of Formula II compound quality.
5. the preparation method of beta-cyclodextrin derivative according to claim 1, which is characterized in that in step (1), including with
It is one or more in lower condition:
A, the molar ratio of the Formula II compound and 1,4- butanediamine or 1,6- hexamethylene diamine is 1:1-3；Preferably, the Formula II
The molar ratio for closing object and 1,4- butanediamine or 1,6- hexamethylene diamine is 1:2；
B, the reaction temperature of the Formula II compound and 1,4- butanediamine or 1,6- hexamethylene diamine is 60-80 DEG C；Preferably, the formula
The reaction temperature of II compound and 1,4- butanediamine or 1,6- hexamethylene diamine is 70 DEG C.
6. the preparation method of beta-cyclodextrin derivative according to claim 1, which is characterized in that in step (1), Formula II
Object and Putriscine or 1 are closed, after the reaction of 6- hexamethylene diamine, gained reaction solution is cooled to room temperature, and is subsequently poured into acetone, and gained is heavy
It forms sediment and formula III compound crude product is made through acetone washing, and be directly used in step (2).
7. the preparation method of beta-cyclodextrin derivative according to claim 1, which is characterized in that in step (2), including with
It is one or more in lower condition:
A, the solvent 2 is N-Methyl pyrrolidone, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide；
Preferably N-Methyl pyrrolidone；The quality of the formula III compound and the volume ratio of solvent 2 are 0.05-0.3g/mL；
B, the molar ratio of the formula III compound and ferrocene carboxaldehyde is 1:0.5-2；Preferably, formula III compound and ferrocene
The molar ratio of formaldehyde is 1:1；
C, the temperature that is protected from light of the formula III compound and ferrocene carboxaldehyde is 50-70 DEG C；Preferably, the formula III chemical combination
The temperature that is protected from light of object and ferrocene carboxaldehyde is 60 DEG C.
8. the preparation method of beta-cyclodextrin derivative according to claim 1, which is characterized in that in step (2), including with
It is one or more in lower condition:
A, the molar ratio of the sodium borohydride and formula III compound is 1-3:1；Preferably, the sodium borohydride and formula III chemical combination
The molar ratio of object is 2:1；
B, the reduction reaction temperature is room temperature；
C, after the reduction reaction is complete, with acetone quenching reaction；
D, described isolate and purify is isolated and purified using silica gel chromatographic column；Eluant, eluent used is isopropanol, water and 30wt%
The mixed solution of ammonium hydroxide, the volume ratio of the isopropanol, water and 30wt% ammonium hydroxide are 5:3:2.
9. the method for preparing supermolecule vesica using beta-cyclodextrin derivative described in as claimed in claim 1 or 22, comprising steps of
Beta-cyclodextrin derivative and beta-cyclodextrin are dissolved in steam in water three times and obtain mixed liquor；At 20-30 DEG C, ultrasonic wave mixing
20-50 minutes, obtain supermolecule vesica.
10. the method according to claim 9 for preparing supermolecule vesica, which is characterized in that including one in the following conditions
Item is multinomial:
A, the molar ratio of the beta-cyclodextrin derivative and beta-cyclodextrin is 1:1；
B, the concentration of beta-cyclodextrin derivative is 5 × 10 in the mixed liquor-3-8×10-3mol/L；
C, the ultrasonic wave mixing temperature is 25 ± 1 DEG C, and Sonic mixing time is 30 minutes；
D, the average grain diameter of the supermolecule vesica is 130-170nm.
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