CN102030839B - Beta-cyclodextrin derivative, preparation method and application thereof - Google Patents
Beta-cyclodextrin derivative, preparation method and application thereof Download PDFInfo
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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 description 19
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 55
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 32
- 229960004853 betadex Drugs 0.000 claims abstract description 32
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class 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 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 239000000843 powder Substances 0.000 claims abstract description 10
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 19
- 239000005864 Sulphur Substances 0.000 claims description 18
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 17
- -1 p-methyl benzenesulfonic acid acid anhydride Chemical class 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000011701 zinc Substances 0.000 abstract description 17
- 108090000790 Enzymes Proteins 0.000 abstract description 8
- 102000004190 Enzymes Human genes 0.000 abstract description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 8
- 229910052725 zinc Inorganic materials 0.000 abstract description 8
- 239000002243 precursor Substances 0.000 abstract description 7
- 150000002500 ions Chemical class 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 238000001228 spectrum Methods 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 102000010911 Enzyme Precursors Human genes 0.000 abstract 1
- 108010062466 Enzyme Precursors Proteins 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000010521 absorption reaction Methods 0.000 description 15
- 238000002983 circular dichroism Methods 0.000 description 13
- 238000004448 titration Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000002211 ultraviolet spectrum Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000004455 differential thermal analysis Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 3
- 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 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001142 circular dichroism spectrum Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005557 chiral recognition Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 108010032220 cyclomaltodextrinase Proteins 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 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 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229920002601 oligoester Polymers 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 238000009736 wetting Methods 0.000 description 1
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- Polysaccharides And Polysaccharide Derivatives (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
The invention discloses a cyclodextrin derivative, a preparation method and application thereof. The cyclodextrin derivative that is mono-2-maleonitriledithiolato-beta-cyclodextrin, and a single 2-hydroxy substituted compound on a second hydroxyl surface of beat-cyclodextrin is yellow powder, is soluble in water but not ethanol, has excellent binding capacity with metallic zinc ions, and is easy to form a coordination compound with the metallic zinc ions. An aqueous solution method can be used for synthesizing an intermediate mono-2-p-toluenesulfonates and a product mono-maleonitriledithiolato-beta-cyclodextrin, with simple process, convenient post-processing and higher yield and no need of an organic solvent. A spectrum research shows that mono- maleonitriledithiolato-beta-cyclodextrin has higher binding capacity in aqueous solution and Zn 2+ion and can be used as a metallic zinc enzyme precursor so as to provide a useful precursor material for the fields of metallic zinc enzyme model compound based on the cyclodextrin chemistry and the like.
Description
Technical field
The present invention relates to a kind of cyclodextrin derivative and its preparation method and application, be specifically related to list-2-Malaysia dinitrile two sulphur alkene-beta-cyclodextrins (2-Mnt-β-CD), the preparation method of this material and in the application of metallic zinc enzyme model precursor compound research field.
Background technology
Cyclodextrin (Cyclodextrin) is the naturally occurring alpha-D-glucose macrocyclic oligoesters of a class, wherein α-, β-, γ-cyclodextrin has respectively 6,7,8 glucose structural units, their cavity diameter is slightly different; Comprise on first surface hydroxyl (primary alconol) face 2-on the primary hydroxyl group on the carbon atom of 6-position and second hydroxyl (secondary alcohol) face in the molecular structure, the secondary hydroxyl group on the carbon atom of 3-position.Because the wetting ability of their outside surfaces and the hydrophobicity of cavity, cyclodextrin can inclusion from the organic molecule to the organometallic compound etc. a lot of external guest molecules, this character is so that cyclodextrin is widely used in pharmacopedics, isolation technique, analogue enztme, catalysis, chemical sensor and other field.
Because the solvability of natural cyclodextrin and chemical reactivity are limited, seriously limited their industrial application, so need to carry out highly selective and high efficiency chemically modified to cyclodextrin.Because the second hydroxyl face of cyclodextrin is larger than the first hydroxyl face, guest molecule easier at the second hydroxyl face by inclusion, so the chemically modified of the second hydroxyl face is to more with practical value and prospects for commercial application such as cyclodextrinase catalysis, enzyme simulation and chiral recognition compou nd synthesis; In fact, the cyclodextrin derivative that the cyclodextrin derivative of modifying at the second hydroxyl face first hydroxyl face of comparing is modified shows very special character sometimes.Because the chemically reactive that the second hydroxyl face of cyclodextrin is modified is not high, so technological line in the past will adopt anhydrous organic solvent and highly basic usually, thereby so that a series of subsequent processes such as the aftertreatment of product, yield are not only complicated but also harmful to environment.Therefore, seek a kind of to cyclodextrin the second hydroxyl face carry out green, environmental protection ground chemically modified has important industrial application value and certain theoretical significance.
Summary of the invention
Goal of the invention: for deficiency of the prior art, the purpose of this invention is to provide a kind of cyclodextrin derivative, be 2-Mnt-β-CD, another object of the present invention provides the preparation method of this 2-Mnt-β-CD, the 3rd purpose of the present invention provides the application of 2-Mnt-β-CD, for provide the precursor substance of usefulness based on metallic zinc enzyme simulation compound of Cyclodextrin Chemistry etc.The technical problem that simultaneously the present invention also will solve provides a kind of easy, green and economic preparation Cyclodextrin Chemistry and modifies important intermediate list-2-p-toluenesulfonic esters-beta-cyclodextrin (method of 2-Ots-β-CD).
Technical scheme: in order to realize the foregoing invention purpose, the technical solution used in the present invention is:
A kind of cyclodextrin derivative, called after: list-2-Malaysia dinitrile two sulphur alkene-beta-cyclodextrins (2-Mnt-β-CD), outward appearance is yellow, pressed powder is water-soluble and be insoluble to ethanolic soln, easily and metallic zinc ion formation coordination compound.
A kind of method for preparing 2-Mnt-β-CD may further comprise the steps:
(1) intermediate 2-Ots-β-CD's is synthetic:
With beta-cyclodextrin (11.5g, 10mmol) and p-methyl benzenesulfonic acid acid anhydride (Ts
2O 4.9g, 15mmol) be mixed in the 250ml water, under the room temperature, stir 2h; The adding mass volume ratio is 10% sodium hydroxide solution, continues stirring reaction 1h, filters and gets rid of unreacted Ts
2O; Add dilute hydrochloric acid solution and regulate pH 3-4, concentrated solution is to 50ml; Then through more than 4 ℃ of cooling 12h, collecting precipitation obtains the thick product of 2-Ots-β-CD, uses the washing with acetone crude product, and vacuum-drying makes intermediate 2-Ots-β-CD, is white powder;
(2) 2-Mnt-β-CD's is synthetic:
3g 2-Ots-β-CD is joined in the aqueous solution of Malaysia dinitrile two sulphur olefin(e) acid disodiums 65 ℃ of temperature controls, stirring reaction 1h; With solution cool to room temperature and filtration, after filtrate is concentrated into 2-5ml, be added drop-wise in the 400ml ethanol of vigorous stirring, be precipitated and be 2-Mnt-β-CD crude product; Thick product is dissolved in the water of 25ml, after filtration, again be added drop-wise in the 500ml ethanol of vigorous stirring after concentrated, leaves standstill more than the 12h, final product is separated out from ethanolic soln, filtration makes 2-Mnt-β-CD, is yellow powder, and output is 2.4g (productive rate 80%).
Employed beta-cyclodextrin comes purifying, Ts by twice recrystallization in water among the above-mentioned preparation method
2O and Malaysia dinitrile two sulphur alkene disodiums are to synthesize according to the method in the document.Used chemical reagent acetone and ethanol are analytically pure.
2-Mnt-β-CD is in the application in metallic zinc enzyme model precursor compound field.
A kind of method for preparing list-2-p-toluenesulfonic esters-beta-cyclodextrin is mixed in 11.5g beta-cyclodextrin and 4.9g p-methyl benzenesulfonic acid acid anhydride in the 250ml aqueous solution, stirs 2h under the room temperature; The adding mass volume ratio is 10% sodium hydroxide solution, behind the 1h, filters and removes unreacted p-methyl benzenesulfonic acid acid anhydride; Add dilute hydrochloric acid solution and regulate pH 3-4, concentrated solution is to 50ml; Then through more than 4 ℃ of cooling 12h, collecting precipitation makes list-thick product of 2-p-toluenesulfonic esters-beta-cyclodextrin; Use the washing with acetone crude product, vacuum-drying makes list-2-p-toluenesulfonic esters-beta-cyclodextrin.
Beneficial effect: the present invention studies synthetic, structural characterization and the application prospect that discloses 2-Mnt-β-CD.Aqua-solution method is adopted in the preparation of 2-Ots-β-CD, utilizes beta-cyclodextrin and Ts
2O reacts generation under alkaline condition; Preparation technology is simple, without the need for the machine solvent, and convenient post-treatment, productive rate higher (51.4%).2-Mnt-β-CD is synthetic also to adopt aqueous process, 2-Ots-β-CD solution is joined in the aqueous solution of Malaysia dinitrile two sulphur olefin(e) acid disodiums, and mixed solution got final product 65 ℃ of lower stirrings in 1 hour; Product after filtration, concentrated after, drip in the ethanolic soln and obtain crude product.From ethanolic soln, separate out again after thick product dissolves in a small amount of water, be yellow powder (productive rate 80%).Show that 2-Mnt-β-CD is in the aqueous solution and Zn through Spectroscopy Study
2+Ion has very strong binding ability, might be as the precursor of metallic zinc enzyme mimics.This result of study is true and reliable, green, the environmental protection of experimental technique, and convenient product separation, yield are higher, for provide the precursor substance of usefulness based on the metallic zinc enzyme mimics field of Cyclodextrin Chemistry.
Description of drawings
Fig. 1 a is the RPLC figure of 2-Ots-β-CD.Detecting wavelength is 221.4nm.
Fig. 1 b is the RPLC figure of 6-Ots-β-CD.Detecting wavelength is 221.4nm.
Fig. 2 a is thermogravimetric and the differential thermal curve figure of 2-Ots-β-CD, 6-Ots-β-CD and beta-cyclodextrin.
Fig. 2 b is thermogravimetric and the differential thermal curve figure of 2-Mnt-β-CD and 6-Mnt-β-CD.
Fig. 3 a be 2-Ots-β-CD and 6-Ots-β-CD ultraviolet (on) and circular dichroism (descending) (in 298K and 1.40 * 10
-4Under the concentration of mol/L).
Fig. 3 b be 2-Mnt-β-CD and 6-Mnt-β-CD ultraviolet (on) and circular dichroism (descending) (in 298K and 1.33 * 10
-4Under the concentration of mol/L).
Fig. 4 a is dripping Zn continuously
2+During solution, the ultraviolet of 6-Mnt-β-CD (on) and circular dichroism (descending) figure.
Fig. 4 b is dripping Zn continuously
2+During solution, the ultraviolet of 2-Mnt-β-CD (on) and circular dichroism (descending) figure.
Embodiment
Below in conjunction with specific embodiment to the most further explanation of the present invention.
What high performance liquid chromatography used is Agilent 1200 highly effective liquid phase chromatographic systems with UV-detector, and separator column is Thermo Hypersil-Keystone AQUASILC18 chromatographic column (4.6mm * 150mm).The gradient elution of high performance liquid chromatography was finished in 40 minutes, MeCN and H in the elutriant
2The ratio of O changes to 100: 0 from 0: 100 linearity, and flow velocity is 1.0 ml/min.
Infrared detection is used Bruker IFS66V FT-IR spectrophotometer, measures by the method for KBr compressing tablet.
UV spectrum is carried out record with Shimadzu UV-3100 spectrograph.
All
13C and
1The H-NMR spectrogram all records at Bruker AVANCE-500 spectrometer, and measuring temperature is 15 ℃, and solvent is deuterium generation-methyl-sulphoxide or heavy water.
The thermogravimetric analysis curve records at U.S.'s SDT-2960 thermal analyzer.The circular dichroism record records with JASCOJ-810 circular dichroism instrument.
Beta-cyclodextrin comes purifying, Ts by twice recrystallization in water
2O and Malaysia dinitrile two sulphur alkene disodiums be according to literature method (
G.and Schleitzer G., Chem.Ber.[J], 1957,90,438-443.) synthetic.((6-Mnt-β-CD) also is according to literature method (1.Lu C.S., Ren X.M., Hu C.J. to list-6-p-toluenesulfonic esters-beta-cyclodextrin for 6-Ots-β-CD) and list-6-Malaysia dinitrile two sulphur alkene-beta-cyclodextrins, et al..Chem.Pharm.Bull.[J], 2001,49,818-821.2.Lu C.S., Zhang W.W., Ren X.M., et al..J.Chem.Soc.-Dalton Trans.[J], 2001,3052-3055.) synthetic, acetone and ethanol are analytical pure.
With beta-cyclodextrin (11.5g, 10mmol) and Ts
2O (4.9g, 15mmol) is mixed in the 250ml water, under the room temperature, and stirring reaction 2h (stir speed (S.S.) is 200-400 rev/min); The adding mass volume ratio is 10% sodium hydroxide solution 50ml, behind the reaction 1h, filters the unreacted Ts of removal with sand core funnel
2O; The dilute hydrochloric acid solution that adds the about 0.5-1mol/L of concentration is adjusted to pH 3-4, adopts decompression rotary evaporation method concentrated solution to 50ml; 4 ℃ of temperature controls, more than the non-shock chilling 12h, collecting precipitation obtains the thick product of 2-Ots-β-CD; Use the washing with acetone crude product, vacuum-drying makes intermediate 2-Ots-β-CD, is white powder (7.4g, 51.4%).2-Ots-β-CD is characterized, and concrete data are as follows:
Results of elemental analyses: C, 42.54; H, 5.84.According to molecular formula C
49H
76O
37S5H
2The constituent content calculated value of O is: C, 42.67; H, 6.28%.
Infrared absorption peak position: v
Max/ cm
-1: 1178,1368,1600.
Uv-absorbing peak position: λ
Max(H
2O)/nm 221 (ε/dm
3Mol
-1Cm
-1): 9550.
1H-NMR nuclear magnetic resonance data: δ
H(500MHz, D
2O): 4.94 (7H, s, 1-H), 3.81-3.65 (28H, m, 3,5,6-H), and 3.53-3.44 (14H, m, 2,4-H), 7.57 (2H, d, phenyl-H), 7.23 (2H, d, phenyl-H), 2.29 (3H, s, methyl-H) ppm.
13C-NMR nuclear magnetic resonance data: δ
C(500MHz, DMSO-d
6): 145.18 (phenyl-C), 138.09 (phenyl-C), 128.24 (phenyl-C), 125.59 (phenyl-C), 102.00 (1-C), 81.62 (4-C), 73.13 (3-C), 72.48 (5-C), 72.11 (2-C), 60.01 (6-C), 20.87 (methyl-C) ppm.
Embodiment 32-Mnt-β-CD's is synthetic
After getting 3g 2-Ots-β-CD and being dissolved in 5ml water, this solution is joined among the aqueous solution 10ml that contains 1.2g Malaysia dinitrile two sulphur olefin(e) acid disodiums, 65 ℃ of temperature controls stir 1h; The solution cool to room temperature is also used filter paper filtering, after filtrate adopts the decompression rotary evaporation to be concentrated into 2-5ml, be added drop-wise to 0.5 drops/sec speed in the 400ml dehydrated alcohol of vigorous stirring (about 500 rev/mins of stir speed (S.S.)), be precipitated and be 2-Mnt-β-CD crude product; Thick product is dissolved in the water of 25ml, again is added drop-wise to through filter paper filtering, after concentrated in the 500ml dehydrated alcohol of vigorous stirring (about 500 rev/mins of stir speed (S.S.)); Leave standstill more than the 12h after dripping end, final product is separated out from ethanolic soln; Filter paper filtering, vacuum-drying make 2-Mnt-β-CD, are yellow powder, and output is 2.4g (productive rate 80%).2-Mnt-β-CD is characterized, and the embodiments data are as follows:
Results of elemental analyses: C, 37.70; H, 6.15.According to molecular formula C
46H
69O
34N
2S
2Na10H
2The constituent content calculated value of O is: C, 38.28; H, 6.08%.
Infrared absorption peak position: v
Max/ cm
-1: 2189 (CN).
Uv-absorbing peak position: λ
Max(H
2O)/nm 376 (ε/dm
3Mol
-1Cm
-1): 6150.
1H-NMR nuclear magnetic resonance data: δ
H(500MHz, D
2O): 4.98 (7H, s, 1-H), 3.90-3.86 (7H, t, 3-H), 3.79 (21H, m, 5,6-H), 3.53-3.44 (7H, d, C2-H), 3.52-3.49 (7H, t, 4-H) ppm.
13C-NMR nuclear magnetic resonance data: δ
C(500MHz, DMSO-d
6): 101.89 (1-C), 81.54 (4-C), 73.01 (3-C), 72.38 (5-C), 71.99 (2-C), 59.92 (6-C), 118.99 (double bond-C), 117.96 (doublebond-C) ppm.
The efficient liquid phase chromatographic analysis of embodiment 42-Ots-β-CD
Primary hydroxyl (the first hydroxyl) in the cyclodextrin on the 6-position carbon atom of glucose unit is that chemical reactivity is the strongest in all hydroxyls, the acidity of the secondary hydroxyl on the carbon atom of 2-position is the strongest, secondary hydroxyl on the carbon atom of 3-position is the most inaccessible, and these character have been applied on preparation intermediate 2-Ots-β-CD.With the purity of RPLC test 2-Ots-β-CD, analytical results illustrates as shown in Figure 1a: 2-Ots-β-CD is principal product; Under experiment condition of the present invention, its purity is up to more than 90%.(retention time of 6-Ots-β-CD) is 10.520min, shown in Fig. 1 b by beta-cyclodextrin the first hydroxyl face list replace being modified the list that obtains-6-p-toluenesulfonic esters-beta-cyclodextrin; And the retention time of 2-Ots-β-CD is 5.039min, so can infer that it is stronger than the polarity of its isomers 6-Ots-β-CD.The peak of retention time about 5.130min among Fig. 1 b may be the by product at synthetic 6-Ots-β-CD, i.e. 2-Ots-β-CD.
Three charateristic avsorption bands are arranged in the infrared spectra of 2-Ots-β-CD, lay respectively at 1178,1368 and 1600cm
-1, the existence that tosylate is arranged in the compound is described.And it
1H-NMR spectrum and
13The C-NMR spectrum has all proved the existence of tosylate equally.In the beta-cyclodextrin (4.94ppm) on the glucose unit integral area of the proton peak of C-1 position as reference, product
1Phenyl ring proton peak integral area meets the single monobasic feature of its p-toluenesulfonic esters in the H-NMR spectrum.
In addition, the solubleness of 2-Ots-β-CD (＞35g/100ml water) is more much larger than 6-Ots-β-CD and beta-cyclodextrin, and both solubleness in water are respectively 0.04g/100ml and 1.89g/100ml afterwards.More than all experimental datas show, be pure substance by the resulting 2-Ots-β-CD of this preparation technology, and be different from its isomer 6-Ots-β-CD.
The thermogravimetric analysis of embodiment 52-Mnt-β-CD
2-Mnt-β-CD is solvable in water, and is insoluble in dehydrated alcohol, but can be dissolved in 90% aqueous ethanolic solution.Infrared spectra shows the existence that dinitrile two sulphur alkene in Malaysia are arranged among 2-Mnt-β-CD, at 2189cm
-1The eigen vibration frequency peak of the itrile group of observing (C ≡ N).In addition, 2-Mnt-β-CD
1H-NMR spectrum and
13The C-NMR spectrum is consistent with the structure of expectation.
Shown in Fig. 2 a, shown 2-Ots-β-CD (Compound1), the thermogravimetric of 6-Ots-β-CD and beta-cyclodextrin and differential thermal analysis curve.The differential thermal curve of 2-Ots-β-CD has shown two peaks, near the dehydration of the corresponding compound in the peak of temperature 53 ℃, near the decomposition course of corresponding its skeleton in peak 208 ℃; For 6-Ots-β-CD, it is 42 ℃ and 190 ℃ that corresponding dehydration and skeleton decomposition temperature are respectively.By thermogravimetric and differential thermal curve, confirmed that 2-Ots-β-CD can not be the physical mixed of raw material, and should be a new chemical substance different with its parent beta-cyclodextrin.
Shown in Fig. 2 b, be thermogravimetric and the differential thermal analysis curve of 2-Mnt-β-CD (Compound2) and 6-Mnt-β-CD.Can be observed two peaks on the differential thermal analysis curve of 2-Mnt-β-CD, near the dehydration of the corresponding compound in the peak of temperature 61 ℃, near the decomposition course of corresponding its skeleton in peak 313 ℃.For 6-Mnt-β-CD, corresponding dehydration and skeleton decomposition temperature are 56 ℃ and 280 ℃.These data declarations are similar to the transition process from 6-Ots-β-CD to 6-Mnt-β-CD, the transformation from 2-Ots-β-CD to 2-Mnt-β-CD, the framework modification process of similar beta-cyclodextrin have occured also.
Owing among 2-Ots-β-CD and the 2-Mnt-β-CD chromophoric group (being respectively phenyl and Malaysia dinitrile two sulphur thiazolinyl groups) is arranged, thus their UV spectrum and circular dichroism is studied, as shown in Figure 3.Wherein the maximum absorption peak of 6-Ots-β-CD in visible absorption spectra appears at the 227nm place, the absorption peak blue shift of 2-Ots-β-CD 6nm appear at the 221nm place; The aromaticity chromophoric group number that exists in the molar absorption coefficient of 2-Ots-β-CD and 6-Ots-β-CD and the molecule is proportional, yet the Cotton effect of these two kinds of materials in circular dichroism spectrum is diverse.There is one to absorb by force trough at the 227nm place in the circular dichroism spectrum of 6-Ots-β-CD, then do not observe obvious absorption signal among 2-Ots-β-CD, this and identical (the Ma X. of data in literature, Wang Q.C.and Tian H., Tetrahedron Lett.[J], 2007,48,7112-7116.).
The UV spectrum of 2-Mnt-β-CD has more by force absorption at the 376nm place, its isomers 6-Mnt-β-CD has strong absorption peak at the 369nm place, shown in Fig. 3 b.Although their ultraviolet absorption curve is similar, molar absorptivity has a great difference; 2-Mnt-β-CD is ε=6.15 * 10
3Cm
3Mol
-1Cm
-1, and 6-Mnt-β-CD is ε=1.21 * 10
4Cm
3Mol
-1Cm
-1Find that from the research of another relevant Malaysia dinitrile two sulphur alkene disodium-cyclodextrin encapsulated objects system along with the increase of the used cyclodextrin soln concentration of titration, the maximum absorption of object (Malaysia dinitrile two sulphur alkene disodiums) will strengthen.Thereby the difference of two isomerss aspect molecular configuration can be explained the difference of both molar absorption coefficients in the solution.Be likely because Malaysia dinitrile two sulphur thiazolinyl chromophoric grouies buried in the cavity of 6-Mnt-β-CD, and the Malaysia dinitrile two sulphur thiazolinyls among 2-Mnt-β-CD only have the part or not by embedding.This part has explained with 2-Mnt-β-CD and has compared that the ultraviolet absorption peak of 6-Mnt-β-CD obviously strengthens.
Embodiment 7ZnCl
2The solution titration experiments
In order further to determine 6-Mnt-β-CD and the configuration of 2-Mnt-β-CD in solution, the present invention Zn
2+Solution carries out titration experiments.
Concrete grammar is: 2-Mnt-β-CD and 6-Mnt-β-CD dissolving are obtained 1.33 * 10
-4The aqueous solution of mol/L, and then the ZnCl that increases successively with concentration
2Solution carries out titration, ZnCl
2Concentration is followed successively by 0,1.33, and 2.66,3.99,5.32,6.65,7.98,9.31,10.64,11.97,13.3 * 10
-5Mol/L.
ZnCl
2The solution titration experiments
Shown in Fig. 4 a, as the Zn that increases gradually with concentration
2+When solution carried out titration, the maximum absorption wavelength of 6-Mnt-β-CD had only increased a bit with respect to baseline, but did not have the variation of wavelength, did not also observe the variation of circular dichroism signal simultaneously.Because circular dichroism is very responsive to molecular configuration, be usually used to do the change of configuration that detects chromophore in the cyclodextrin inclusion complexes, so experimental data shows that 6-Mnt-β-CD is at Zn
2+Coordination interaction had not both occured in the titration process does not have change of configuration to occur yet.The cavity of beta-cyclodextrin has stoped by the Malaysia dinitrile two sulphur thiazolinyls of inclusion group and zinc ion coordination.
Shown in Fig. 4 b, the maximum absorption wavelength of 2-Mnt-β-CD changes to 381 and 396nm from 376nm in titration process, a new absorption peak occurred at the 279nm place; Use in addition Zn
2+Two new circular dichroism fignal centers have appearred after the titration.Data show that 2-Mnt-β-CD has generated coordination compound with zine ion in titration process, formed the characteristic signal of the circular dichroism among Fig. 4.In addition, when 2-Mnt-β-CD concentration is low (1.33 * 10
-4Mol/L), also can observe the dropping trace Zn
2+(1.33 * 10
-5Mol/L) variation of caused UV, visible light and circular dichroism spectral signal shows that 2-Mnt-β-CD has the very strong ability that forms title complex with the metallic zinc ion coordination.
Product of the present invention is a kind of Novel ring dextrin derivative, 2-Mnt-β-CD, and its outward appearance is yellow solid, and is water-soluble and be insoluble to ethanol, has strong and ability metallic ion coordination.Compare the easier and metallic zinc ion formation coordination compound of 2-Mnt-β-CD with 6-Mnt-β-CD; In addition, when forming coordination compound with the metallic zinc ion, although two sulphur atoms among 2-Mnt-β-CD are on same group, but one to be form with free negatively charged ion exist, another then is that form with thioesters exists, this characteristic makes 2-Mnt-β-CD and metal complexes have more adjustability, can become the useful precursor substances in field such as metallic zinc enzyme mimics based on cyclodextrin.
Claims (3)
1. cyclodextrin derivative, it is characterized in that: be list-2-Malaysia dinitrile two sulphur alkene-beta-cyclodextrins, it is hydroxyl list monobasic compound in 2-position on beta-cyclodextrin the second hydroxyl face, yellow powder, water-soluble and be insoluble to ethanol, have the good combination ability with the metallic zinc ion, be easy to form coordination compound with the metallic zinc ion.
2. a method for preparing cyclodextrin derivative claimed in claim 1 is characterized in that, may further comprise the steps:
(1) 11.5g beta-cyclodextrin and 4.9g p-methyl benzenesulfonic acid acid anhydride are mixed in the 250ml aqueous solution, stir 2h under the room temperature; The adding mass volume ratio is 10% sodium hydroxide solution, behind the 1h, filters and removes unreacted p-methyl benzenesulfonic acid acid anhydride; Add dilute hydrochloric acid solution and regulate pH 3-4, concentrated solution to 50 ml; Then through more than 4 ° of C cooling 12h, collecting precipitation makes list-thick product of 2-p-toluenesulfonic esters-beta-cyclodextrin; Use the washing with acetone crude product, vacuum-drying, making end product is white powder;
(2) get in the aqueous solution that 3g list-2-p-toluenesulfonic esters-beta-cyclodextrin solution joins Malaysia dinitrile two sulphur alkene disodiums, mixed solution is at 65 ℃ of lower 1h that stir; With solution cool to room temperature and filtration, after filtrate is concentrated into 2-5 ml, be added drop-wise in the 400 ml ethanol of vigorous stirring, be precipitated and be list-2-Malaysia dinitrile two sulphur alkene-beta-cyclodextrin crude product; Thick product is dissolved in the water of 25 ml, after filtration, again be added drop-wise in the 500 ml ethanol of vigorous stirring after concentrated, leaves standstill more than the 12h, and final product is separated out from ethanolic soln, filters, and makes yellow powder.
3. a method for preparing list-2-p-toluenesulfonic esters-beta-cyclodextrin is characterized in that: 11.5g beta-cyclodextrin and 4.9g p-methyl benzenesulfonic acid acid anhydride are mixed in the 250ml aqueous solution, stir 2h under the room temperature; The adding mass volume ratio is 10% sodium hydroxide solution, behind the 1h, filters and removes unreacted p-methyl benzenesulfonic acid acid anhydride; Add dilute hydrochloric acid solution and regulate pH 3-4, concentrated solution to 50 ml; Then through more than 4 ° of C cooling 12h, collecting precipitation makes list-thick product of 2-p-toluenesulfonic esters-beta-cyclodextrin; Use the washing with acetone crude product, vacuum-drying makes list-2-p-toluenesulfonic esters-beta-cyclodextrin.
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| Chang-Sheng Lu et.al.Intramolecular photo-substitution in the inclusion compound of mono[6-deoxy-6-(2-butenedinitrile-2,3-dimercapto sodium salt)]– ┃┌-cyclodextrin with cyclopentadienyl manganese tricarbonyl in DMF solution.《Journal of the chemical society, Dalton》.2001,3052-3055. * |
| Chang-Sheng LU et.al.The Inclusion Compound of a New Ionizable Derivative of b-Cyclodextrin with Ferrocenium Drug.《Chemical and Pharmaceutical bulletin》.2001,第49卷(第7期),818-821. * |
| Yoshihisa Matsui et.al.The binding and catalytic properies of a positively charged cyclodextrin.《Bulletin of the chemical society of Japan》.1978,第51卷3030-3034. * |
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