CN106905486A - The preparation and the application in chiral separation of cyclodextrin SDEB styrene diethylenebenzene microballoon - Google Patents
The preparation and the application in chiral separation of cyclodextrin SDEB styrene diethylenebenzene microballoon Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of cyclodextrin SDEB styrene diethylenebenzene microballoon, the seed microballoon of different-grain diameter size is synthesized using dispersion copolymerization method first, using multi-step swelling polymerization, with styrene as monomer, divinylbenzene is crosslinking agent, the cyclodextrin of modification is added in swelling process, makes to take double bond in its structure, so as to obtain cyclodextrin SDEB styrene diethylenebenzene microballoon.By investigating dispersant, stabilizer and swelling temperature, it is determined that optimal preparation condition, the β CD PS DVB microballoons and γ CD PS DVB microballoons of different-grain diameter size are finally respectively obtained.Contain cyclodextrin, and favorable dispersibility, uniform particle diameter, with complete ball-type degree and pore structure on microballoon；The microballoon can be used for the chiral stationary phase of high performance liquid chromatography.This method prepares chiral chromatographic column, and reagent is cheap, method simple possible, and the microballoon of preparation has certain potentiality in extension chiral separation method and scope.
Description
Technical field
The present invention relates to the preparation and its application in chiral separation of cyclodextrin-styrene-divinylbenzene microballoon.
Background technology
High performance liquid chromatography is one of conventional method of chiral separation, can be divided into two kinds of analytic type and preparative.No matter should
Which kind of chromatographic isolation chiral drug is analyzed with, and chromatographic stationary phases are all its cores.Current most widely used high performance liquid chromatography
Fixing phase can be divided into the silica gel and high molecular polymer of chemical bonding.The filler of high molecular polymer matrix has good chemistry
Stability, preferable chemically stable can be kept under acid, alkalescence and organic solvent effect, this be silica matrix fixing phase not
The advantage for possessing.The microballoon of crosslinking has good mechanical strength simultaneously, can meet the requirement of high performance liquid chromatography.Additionally, poly-
Polymer matrix microballoon is also easy to carry out various chemical modifications, extends its clastotype and range of application.Especially for biology
For macromolecular, because polymer microballoon does not have silicone hydroxyl, surface will not occur non-specific adsorption without electric charge, can greatly limit
Degree is kept by the BA of separation sample.The filling method for preparing polymer substrate has many kinds, the more commonly used at present
Including suspension polymerization, precipitation polymerization method, dispersion copolymerization method, multi-step swelling polymerization etc..Using these methods prepare it is micro-
The characteristics of ball has different, the particle diameter of the microballoon such as prepared, the degree of cross linking of microballoon, preparation technology complexity and cost.
1979 and Ugelstad in 1985 et al. (Ugelstad J, Kaggerud K H, Hansen F K, et
al.Absorption of low molecular weight compounds in aqueous dispersions of
polymer-oligomer particles,a two-step swelling process of polymer particles
giving an enormous increase in absorption capacity[J].Makromolekulare Chemie,
180(3),737-744(1979).),(Ugelstad J,Mfutakamba H R,Mork P C,et al.Preparation
and application of monodisperse polymer particles[J].Journal of Polymer
Science:Polymer Synposium, 72 (1), 225-240 (1985)) multi-step swelling polymerization is developed, prepare
The characteristics of microballoon has homogeneous single dispersing, size tunable, high-crosslinking-degree and cheap preparation cost.This method can use bag
Include styrene, methyl methacrylate, GMA, HEMA, vinylphenol
With 1-chloro-4-methyl-benzene microballoon is prepared in interior various of monomer.Based on this, we apply multi-step swelling polymerization, are with styrene
Monomer, divinylbenzene is crosslinking agent, and the cyclodextrin of modification is added in swelling process, directly obtains single dispersing, uniform in size, ball
Type degree is good, cyclodextrin SDEB styrene diethylenebenzene (CD-PS-DVB) microballoon of controllable hole structure, prepares and can be used for efficient liquid phase
The chiral stationary phase of chromatogram, is applied to the separation and analysis of wider chiral drug.
The content of the invention
The purpose of the present invention is to prepare CD-PS-DVB microballoons, and CD-PS-DVB microballoons are packed into chromatographic column, is applied
In chiral separation.
In order to solve the above-mentioned technical problem, the preparation of a kind of cyclodextrin-styrene-divinylbenzene microballoon proposed by the present invention
Method, using multi-step swelling polymerization, with styrene as monomer, divinylbenzene is crosslinking agent, and modification is added in swelling process
Cyclodextrin, so as to obtain cyclodextrin-styrene-divinylbenzene microballoon, the reaction scheme of preparation is as follows：
The preparation method of cyclodextrin of the present invention-styrene-divinylbenzene microballoon, comprises the following steps：
1) preparation of styrene seed microballoon：
Alcohols solvent is added in there-necked flask, the alcohols solvent selects absolute ethyl alcohol or n-butanol, then is burnt to three mouthfuls
Azodiisobutyronitrile and polyvinylpyrrolidone after purification are added in bottle, wherein, azodiisobutyronitrile and polyvinylpyrrolidine
The mass ratio of ketone is 2:15, alcohols solvent and azodiisobutyronitrile with and polyvinylpyrrolidone summation volume mass ratio
1000mL/17g, stirring is completely dissolved, and leads to nitrogen with displaced air, is subsequently adding styrene, wherein, styrene and alcohols solvent
Volume ratio be 1:4, after stirring at normal temperature 0.5-2h, be warming up to 60-90 DEG C, after solution gradually from it is transparent be changed into milky after, after
Stop heating after continuous reaction 18-24h；There is sediment in milky white solution, opalescent solution is poured out, sediment is entered successively
Row centrifugation, ethanol and washing, are then placed within being dried in 60-100 DEG C of vacuum drying chamber after 12h that to obtain styrene seed micro-
Ball；
2) preparation of pi-allyl-cyclodextrin：
Cyclodextrin is weighed in dimethylformamide, the cyclodextrin selects beta-schardinger dextrin or gamma-cyclodextrin, so
After add sodium hydride, wherein, cyclodextrin and dimethylformamide are 25 with the quality volume mass ratio of sodium hydride:200:2, normal temperature
Filtered after lower stirring 0.5-2h, allyl glycidyl ether is added in filtrate, wherein, allyl glycidyl ether and dimethyl
The volume ratio of formamide is 3:80,60-90 DEG C is warming up to, react 18-24h.After reaction terminates, reaction solution is poured into methyl alcohol,
Pi-allyl-cyclodextrin solid is settled out, is filtered, drying is standby；
3) preparation of cyclodextrin-styrene-divinylbenzene microballoon：
Butyl phthalate is added dropwise to the lauryl sodium sulfate water equipped with mass-volume concentration for 0.125-0.5%
In the beaker of solution, wherein, butyl phthalate is 4 with the volume ratio of lauryl sodium sulfate:75, ultrasound is until micro-
Untill no drop obtains emulsion under observation；By step 1) the styrene seed microballoon ultrasonic disperse for preparing is in equipped with matter
During amount volumetric concentration is for the beaker of the lauryl sodium sulfate aqueous solution of 0.125-0.5%, wherein, styrene seed microballoon and ten
The mass volume ratio of the sodium dialkyl sulfate aqueous solution is 7:125, ultrasound 0.5-2h again after the solution in two beakers is merged,
Enter in single port bottle, be put into shaking bath, shake 3-7h to activate bulb；
Azodiisobutyronitrile is dissolved in toluene, the dodecyl that mass-volume concentration is 0.125-0.5% is added to
In aqueous sodium persulfate solution, wherein, azodiisobutyronitrile, toluene, the mass ratio of lauryl sodium sulfate aqueous solution are 21:500:
1250, ultrasound is added in reaction system after mixing, and continuation shakes swelling 10-15h in shaking bath；
Styrene and divinylbenzene are added to the lauryl sodium sulfate that mass-volume concentration is 0.125-0.5% water-soluble
In liquid, wherein, the volume ratio of styrene, divinylbenzene and lauryl sodium sulfate aqueous solution is 1:1:5, ultrasound is mixed；
Weigh step 2) pi-allyl-cyclodextrin for obtaining is added in dimethyl sulfoxide (DMSO), wherein, pi-allyl-cyclodextrin with
The mass volume ratio of dimethyl sulfoxide (DMSO) is 1:5, ultrasonic dissolution；
Above-mentioned solution is all added in reaction system, continuation shakes swelling 10-15h in shaking bath；Will be above-mentioned
Reaction solution is poured into separatory funnel, stands 0.5-2h to be layered, and removes the organic layer of upper strata yellow；
It is the polyvinylpyrrolidonesolution solution of 5-30% to addition mass-volume concentration in reaction solution, wherein, polyethylene pyrrole
The volume of pyrrolidone solution is 1 with the volumetric ratio of reaction solution:10, nitrogen 10-30min is led under stirring at normal temperature, then with gas
The stopper sealing of ball, is put into 60-90 DEG C of shaking bath, and polymerization 10-15h obtains microballoon, and microballoon is washed with water to without poly- second
Alkene pyrrolidone, then dry after being washed with ethanol；Dry microballoon is extracted into 18-24h with toluene, colourless solution is washed till with ethanol,
Drying；Again by dry microballoon with tetrahydrofuran extract 18-24h, be washed till colourless solution with ethanol, dry, that is, obtain cyclodextrin-
Styrene-divinylbenzene microballoon.
Step 1 of the present invention) in, when the alcohols solvent selects absolute ethyl alcohol, the particle diameter of the styrene seed microballoon for obtaining
It is 2 μm；When alcohols solvent selects n-butanol, the particle diameter of the cyclodextrin for obtaining-styrene-divinylbenzene microballoon is 5 μm.
Step 3 of the present invention) in, during with 2 μm of styrene seed microballoons as bulb, 5 μm of cyclodextrin-styrene-two can be obtained
Ethenylbenzene microballoon；During with 5 μm of styrene seed microballoons as bulb, 10 μm of cyclodextrin-styrene-divinylbenzene microballoon can be obtained.
Cyclodextrin obtained above-styrene-divinylbenzene microballoon is applied in high performance liquid chromatography, using high pressure
Homogenate method loads cyclodextrin-styrene-divinylbenzene microballoon, has respectively obtained 5 μm of β-CD-PS-DVB microballoons, 5 μm of γ-CD-
PS-DVB microballoons, the reversed-phase HPLC column of 10 μm of CD-PS-DVB microballoons filling and 5 μm of CD-PS-DVB microballoons fillings
Positive HPLC chromatogram post, then these chiral chromatographic columns being applied, different chiral drugs are separated in high performance liquid chromatography.
Compared with prior art, the beneficial effects of the invention are as follows：
(1) cyclodextrin-styrene-divinylbenzene microballoon is packed into chromatographic column by the present invention first, is applied in chiral separation
In.
(2) present invention prepares chiral chromatographic column, and reagent is cheap, method simple possible.
(3) microballoon prepared by the present invention has certain potentiality in terms of extension chiral separation method and scope.
Brief description of the drawings
Fig. 1 (a) schemes for the SEM of PS-DVB, and Fig. 1 (b) is the partial enlarged drawing of Fig. 1 (a)；
Fig. 1 (c) schemes for the SEM of β-CD-PS-DVB, and Fig. 1 (d) is the partial enlarged drawing of Fig. 1 (c)；
Fig. 1 (e) schemes for the TEM of β-CD-PS-DVB, and Fig. 1 (f) is the partial enlarged drawing of Fig. 1 (e)；
Fig. 2 is the infared spectrum of PS-DVB microballoons and β-CD-PS-DVB microballoons.
Fig. 3 is 5 μm of chromatograms of γ-CD-PS-DVB post separation chiral drug Propranolols.
Fig. 4 is 5 μm of chromatograms of γ-CD-PS-DVB post separation chiral drug warfarins.
Fig. 5 is 10 μm of chromatograms of γ-CD-PS-DVB post separation chiral drug chlorpheniramines.
Fig. 6 is 5 μm of chromatograms of γ-CD-PS-DVB post separation chiral drug Ofloxacins.
Specific embodiment
Technical solution of the present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings, described is specific
Embodiment is only explained to the present invention, is not intended to limit the invention.
Mentality of designing of the invention is：The seed microballoon of different-grain diameter size is synthesized using dispersion copolymerization method first, together
When cyclodextrin is modified, make to take double bond in its structure；Then, the method using multi-step swelling and polymerization is molten by cyclodextrin
It is swollen enter PS-DVB microballoons inside, by investigating dispersant, stabilizer and swelling temperature, it is determined that optimal synthesis condition, final point
β-CD-PS-DVB the microballoons and γ-CD-PS-DVB microballoons of different-grain diameter size are not obtained.
A kind of preparation method of cyclodextrin-styrene-divinylbenzene microballoon proposed by the present invention, is polymerized using multi-step swelling
Method, with styrene as monomer, divinylbenzene is crosslinking agent, and the cyclodextrin of modification is added in swelling process, so as to obtain ring paste
Essence-styrene-divinylbenzene microballoon, the reaction scheme of preparation is as follows：
As a example by preparing beta-schardinger dextrin-styrene-divinylbenzene (β-CD-PS-DVB) microballoon, preparation of the invention is illustrated
Method, comprises the following steps：
1) preparation of styrene seed microballoon：In the there-necked flask of 250mL add 100mL absolute ethyl alcohols, absolute ethyl alcohol with
There-necked flask volume ratio is 2:5.Poly- second after being purified to the azodiisobutyronitrile and 1.5g after adding 0.2g to purify in there-necked flask again
Alkene pyrrolidone (PVP), the mechanical agitation of 190r/min is completely dissolved AIBN and PVP, leads to nitrogen with displaced air.Then plus
Enter the styrene of 25mL, after stirring at normal temperature 0.5h, be warming up to 75 DEG C, question response solution gradually from it is transparent be changed into milky after, after
Stop heating after continuous reaction 24h；There is microspheroidal sediment in milky white solution, opalescent solution is poured out, with the side of centrifugation
Method washs microballoon, washes microballoon with ethanol to remove unreacted styrene, PVP is washed with water, then by the microballoon after washing
It is placed in 60 DEG C of vacuum drying chamber and is dried overnight, obtains a diameter of 2 μm of styrene seed microballoon, it is standby.According to above-mentioned
Method prepares a diameter of 5 μm of styrene seed microballoon, and absolute ethyl alcohol therein is replaced with into n-butanol.
2) preparation of allyl group-beta-cyclodextrin (β-ACD)：The beta-schardinger dextrin (β-CD) for weighing 10g is dissolved in the two of 80mL
In NMF (DMF), the sodium hydride (NaH) of 0.8g is added, filtered after 0.5h is stirred under normal temperature, 3mL is added in filtrate
Allyl glycidyl ether (AGE), be warming up to 70 DEG C, react 10h.After reaction terminates, reaction solution is poured into a large amount of methyl alcohol,
β-ACD solids are settled out, are filtered, drying is standby；
3) preparation of beta-schardinger dextrin-styrene-divinylbenzene (β-CD-PS-DVB) microballoon：By 4mL butyl phthalates
It is added dropwise in the beaker equipped with the lauryl sodium sulfate aqueous solution that 75mL mass-volume concentrations are 0.25%, ultrasound is until aobvious
It is microcosmic to examine untill lower no drop obtains emulsion；By 1.4g by step 1) the styrene seed microballoon ultrasonic disperse for preparing
In the beaker equipped with the SDS aqueous solution that 25mL mass-volume concentrations are 0.25%, the above-mentioned beaker for being loaded with emulsion is added
In, two-phase merge after ultrasound 0.5h again, pour into 500mL single port bottles, be put into shaking bath, 150rpm stirring 4h are activating kind
Ball.0.42g azodiisobutyronitriles are dissolved in 10mL toluene, are added in the SDS aqueous solution of 25mL 0.25% (m/v), surpassed
Sound is added in reaction system after mixing, and is continued the 150rpm in shaking bath and is stirred swelling 12h.By 5mL styrene (St) and
5mL divinylbenzenes are added in the SDS aqueous solution of 25mL 0.25% (m/v), and ultrasound is uniformly mixed so as to obtain solution A；2g is weighed by step
2) β-ACD for obtaining are added in 10mL dimethyl sulfoxide (DMSO)s (DMSO), and ultrasonic dissolution obtains solution B；By above-mentioned solution A and solution
B is all added in reaction system, is continued the 150rpm in shaking bath and is stirred swelling 12h；Above-mentioned reaction solution is poured into a point liquid
In funnel, stand 1h to be layered, remove the organic layer of upper strata yellow.Added in the solution of the organic layer for eliminating upper strata yellow
Polyvinylpyrrolidone (PVP) solution of 50mL20% (m/v), leads to nitrogen 30min under stirring at normal temperature, then use with balloon
Stopper is sealed, and is put into 75 DEG C of shaking bath, and 150rpm polymerizations 12h obtains microballoon, microballoon is washed with water to without PVP, then used
Ethanol is dried after washing；Dry microballoon is extracted into 24h with toluene, colourless solution is washed till with ethanol, dried；Again by dry microballoon
24h is extracted with tetrahydrofuran (THF), colourless solution is washed till with ethanol, dried, that is, obtain the ring paste of monodisperse porous high-crosslinking-degree
Essence-β-styrene-divinylbenzene microballoon.
In the present embodiment, in step 2) in, if what is added is a diameter of 2 μm of styrene seed microballoon, finally give
A diameter of 5 μm of β-CD-PS-DVB microballoons；If what is added is a diameter of 5 μm of styrene seed microballoon, finally give
A diameter of 10 μm of β-CD-PS-DVB microballoons.
In the present invention, gamma-cyclodextrin-styrene-divinylbenzene (γ-CD-PS-DVB) microballoon, including step 1 are prepared) benzene
The preparation of ethene seed microballoon, step 2) γ-ACD preparation, 3) preparation of γ-CD-PS-DVB microballoons, preparation method with it is above-mentioned
The method of β-CD-PS-DVB microballoons is essentially identical, simply in step 2) β-CD are replaced with into γ-CD.
The sign of the CD-PS-DVB microballoons that the present invention is prepared, including：
(1) microsphere surface Morphological Characterization：Appropriate CD-PS-DVB microballoons are taken, distilled water ultrasonic disperse is used, biomicroscope is used
Observe size, dispersiveness and the uniformity of CD-PS-DVB microballoons；Microballoon is observed with ESEM (SEM) and transmission electron microscope (TEM)
Surface and aperture pattern.
(2) functional group of microballoon characterizes：Take appropriate CD-PS-DVB microballoons carries out Fourier infrared spectrum with pressing potassium bromide troche
Analysis (FTIR).
By application of the CD-PS-DVB microballoons in high performance liquid chromatography obtained in the present invention, filled out using high-pressure homogenization
Dress cyclodextrin-styrene-divinylbenzene microballoon, has obtained different chiral chromatographic columns, then by these chiral chromatographic column applications
Different chiral drugs are separated in high performance liquid chromatography.Comprise the following steps：
(1) by cyclodextrin obtained in the present invention-styrene-divinylbenzene microballoon sieving, 2.5g microballoons are weighed, with anhydrous second
Alcohol is homogenate, and the microballoon of the 2.5g after sieving is dispersed in homogenate using ultrasound, and ring is dispersed with using high-pressure homogenization
The homogenate of dextrin-styrene-divinylbenzene microballoon is filled in stainless steel tube, obtains chiral chromatographic column；
(2) chiral separation experiment is carried out at room temperature, and Flow Injection Chemiluminescence Method used is mutually methanol-water or acetonitrile-water system, positive
Mobile phase is ethanol-n-hexane system, Flow Injection Chemiluminescence Method phase and positive mobile phase using preceding by 0.45 μm of membrane filtration,
And the method using vacuum outgas is de-gassed.
Embodiment 1
The investigation of CD-PS-DVB microballoon preparation conditions and optimization, comprise the following steps：
(1) optimization of dispersant dosage：Dispersant can not only improve or improve solid or liquid in emulsion point
The situation of dissipating, while the generation that particle is settled and built up can be prevented.SDS is a kind of good dispersant, and intramolecular has simultaneously
Hydrophily and lipophilic group.Attempt changing the content of SDS in experiment to improve the influence due to adding cyclodextrin to bring.Point
Do not carry out swelling seed microballoon using 0.5%SDS 100mL and 200mL, CD-PS-DVB microballoons are obtained after swollen-state polymerization.SDS is molten
The volume of liquid refers to the summation of SDS liquor capacities in seed microspheres swell.Found out by microscope figure, by the body for increasing SDS
The concentration of product, dilution PS seeds microballoon and cyclodextrin, monodispersed CD-PS-DVB microballoons, also many microballoons are not obtained
The phenomenon of adhesion occurs.SDS belongs to small molecule dispersant, and its solution viscosity is small, it is impossible to reach the purpose of the microballoon that scatter.Foundation
The principle of reduces cost, finally still selects addition 100mLSDS solution to participate in swelling.
(2) optimization of stabilizer concentration：By changing the concentration of stabilizer, change the viscosity of reaction solution, reaching prevents
The effect of microballoon adhesion.The PVP solution of various concentrations is added before the polymerization, when PVP mass-volume concentrations are 5% and 10%
When, because viscosity is not enough, there is different degrees of microballoon to be sticked together in product, when PVP mass-volume concentrations increase to
After 20%, CD-PS-DVB microballoons show good monodispersity.
(3) optimization of swelling temperature：During swelling, the swelling process of seed microballoon can be accelerated by heating,
More monomers, crosslinking agent and perforating agent etc. are made to participate in the swelling of seed microballoon.But due to being added in swelling process
AIBN is initiator, and AIBN will start at relatively high temperatures decompose, therefore swelling temperature can not be too high.Selected in experiment
Compare normal temperature swelling and be heated to 43 DEG C of swelling modes, the influence that reduced temperature is prepared to microballoon.Can from microscope figure
Go out, the swelling microballoon size of the heating microballoon more swelling than normal temperature is larger, illustrates that swelling temperature is have shadow for microspherulite diameter
Loud.Can be found in experimentation simultaneously, heat swelling seed microspheres solution, when standing, the organic phase on upper strata is obvious
Less than dissolved swollen seed microspheres solution.In addition, it is swelling to keep equilibrium temperature to carry out, it is also possible to exclude because room temperature is different
The different influence of microspherulite diameter between the different batches for bringing, is conducive to the reappearance of microballoon between different batches.
(4) selection of optimal conditions：By investigating dispersant, stabilizer and swelling temperature prepared by CD-PS-DVB microballoons
The influence of process, it is seed microballoon finally to determine with 2 μm of polystyrene microspheres, and SDS solution total amounts are added when preparing emulsion
It is 100mL, and keeps swelling temperature for 43 DEG C, PVP solution that mass-volume concentration is 20% is added before polymerization to obtain 5 μm
γ-CD-PS-DVB the microballoons of single dispersing crosslinking high.CD-PS-DVB microballoons to obtain bigger particle diameter, then need to use bigger
Seed microballoon carry out it is swelling and polymerization.When using 5 μm polystyrene microsphere be seed microballoon when, by identical it is swelling and
Polymerization, can obtain 10 μm of γ-CD-PS-DVB microballoons.The method is equally applicable to the preparation of β-CD-PS-DVB microballoons,
β-ACD are dissolved when swelling in DMSO, is added in reaction system, participate in swelling and polymerization, you can obtain single dispersing
10 μm of β-CD-PS-DVB microballoons.
Embodiment 2
The sign of CD-PS-DVB microballoons, comprises the following steps：
(1) microsphere surface Morphological Characterization：Appropriate CD-PS-DVB microballoons are taken, distilled water ultrasonic disperse is used, biomicroscope is used
Observe size, dispersiveness and the uniformity of CD-PS-DVB microballoons；Microballoon is observed with ESEM (SEM) and transmission electron microscope (TEM)
Surface and aperture pattern.
Add after cyclodextrin, by optimizing reaction condition, end product form and pore structure are not subject to very big
Influence, not there is destruction or fragmentation in microballoon, cyclodextrin do not block the pore structure of microballoon yet, and CD-PS-DVB microballoons are in
Single dispersing, microspherulite diameter is uniform, with good ball-type degree and complete pore structure (Fig. 1 (a) to Fig. 1 (f)).
(2) functional group of microballoon characterizes：Take appropriate CD-PS-DVB microballoons carries out Fourier infrared spectrum with pressing potassium bromide troche
Analysis (FTIR).
3500cm-1The peak at place represents the stretching vibration of O-H, and the stretching vibration of-OH is significantly stronger than Fig. 2's in (B) of Fig. 2
(A)-OH stretching vibrations in, show that cyclodextrin is successfully aggregated in CD-PS-DVB microballoons.3000 to 3100cm-1It
Between three peaks, 1602cm-1And 1492cm-1The peak at place, is all the characteristic peak of phenyl ring vibration.In 700 and 759cm-1Peak at two
Also it is relevant with C-H stretching vibrations on monosubstituted phenyl ring (Fig. 2).
By with SEM, TEM and infrared spectrum CD-PS-DVB microballoons are characterized, it was demonstrated that the CD-PS- of high-crosslinking-degree
Contain cyclodextrin, and favorable dispersibility, uniform particle diameter, with complete ball-type degree and pore structure on DVB microballoons.
Embodiment 3
The application of 5 μm of β-CD-PS-DVB microballoons in reversed-phase HPLC chiral separation：
Propranolol is a kind of antagonistic of the beta-2 adrenoceptor of commercialization, is widely used in treatment cardiovascular
Disease.But commercially available Propranolol is racemic modification, its enantiomer shows visibly different pharmacodynamics and medicine for power
Characteristic is learned, S- enantiomers are more more effective than R- enantiomer.Propranolol can use β-CD-PS-DVB chromatograms post separation (Fig. 3).
Embodiment 4
The application of 5 μm of γ-CD-PS-DVB microballoons in reversed-phase HPLC chiral separation：
It is model chiral drug with warfarin, verifies the Chiral Separation Ability of γ-CD-PS-DVB chromatographic columns.Warfarin is
A kind of conventional anti-coagulants, is generally used for pre- preventing thrombosis and thrombotic disease.Commercially available warfarin is a kind of racemic
Mixture, in terms of prevention of thromboembolic disorders, the activity of S- enantiomers is 5 times of R enantiomers, therefore separates the magnificent method of analysis
Woods also has very important significance (Fig. 4).
Embodiment 5
The application of 10 μm of CD-PS-DVB microballoons in reversed-phase HPLC chiral separation：
Organic amine medicine chlorpheniramine is a kind of typical H1 receptor antagonists, is usually used in the symptoms such as treatment allergy, at it
There is chiral centre in chemical constitution.The research that acceptor is combined in various tissues shows that the activity of d- isomers is l- isomeries
100 times of body.Chlorpheniramine can be used to prove the Chiral Separation Ability of big particle diameter γ-CD-PS-DVB chromatographic columns, contain buffering
Under the flowing phase separation of salt, chlorpheniramine shows separation trend (Fig. 5) on 10 μm of γ-CD-PS-DVB chiral columns.
Embodiment 6
Application of 5 μm of CD-PS-DVB microballoons in positive HPLC chiral separations：
CD-PS-DVB chromatographic columns not only in reversed-phase liquid chromatography can with separating chiral medicine, in positive form and aspect chromatogram,
CD-PS-DVB chromatographic columns equally show certain chiral separation potentiality.Racemic Ofloxacin is a kind of quinolones
Antibacterials, its stereochemical structure significantly affects its pharmacological activity.Some researchs show, S- enantiomers (lavo-ofloxacin)
It is bigger 8-128 times than its R- enantiomer activity.The use of ethanol and n-hexane is mobile phase, diethylamine adjusts mobile phase acid-base value,
Ofloxacin just illustrates separation trend (Fig. 6) in γ-CD-PS-DVB chromatographic columns in short time.
These CD-PS-DVB microballoons that the present invention is prepared are packed into chromatographic column, are applied in chiral separation, it was demonstrated that
It has certain potentiality in terms of chiral Recognition.Be can be seen that of the invention with ring by above method the result
Dextrin SDEB styrene diethylenebenzene microballoon has feasibility as HPLC chiral stationary phase separation methods, and result is relatively stable.
This method prepares chiral chromatographic column, and reagent is cheap, method simple possible, and the microballoon of preparation is in chiral point of extension
There are certain potentiality from method and scope.
By above-mentioned Binding experiment accompanying drawing, invention has been described, but specific implementation case is only part reality above
Test, be not for limiting practical range of the invention.The person skilled of this area is according to the present invention or does not depart from this hair
In the case of bright objective, the equivalent deformation and relevant modifications for being carried out, these are all within protection of the invention.
Claims (6)
1. the preparation method of a kind of cyclodextrin-styrene-divinylbenzene microballoon, it is characterised in that apply multi-step swelling polymerization,
With styrene as monomer, divinylbenzene is crosslinking agent, and the cyclodextrin of modification is added in swelling process, thus obtain cyclodextrin-
Styrene-divinylbenzene microballoon, the reaction scheme of preparation is as follows：
2. the preparation method of cyclodextrin-styrene-divinylbenzene microballoon according to claim 1, it is characterised in that including such as
Lower step：
1) preparation of styrene seed microballoon：
Alcohols solvent, the alcohols solvent is added to select absolute ethyl alcohol or n-butanol in there-necked flask, then in there-necked flask
The azodiisobutyronitrile and polyvinylpyrrolidone after purification are added, wherein, azodiisobutyronitrile and polyvinylpyrrolidone
Mass ratio is 2:15, alcohols solvent and azodiisobutyronitrile with and the volume mass of polyvinylpyrrolidone summation compare 1000mL/
17g, stirring is completely dissolved, and leads to nitrogen with displaced air, is subsequently adding styrene, wherein, the volume of styrene and alcohols solvent
Than being 1:4, after stirring at normal temperature 0.5-2h, be warming up to 60-90 DEG C, after solution gradually from it is transparent be changed into milky after, continue react
Stop heating after 18-24h；Have sediment in milky white solution, opalescent solution poured out, sediment is carried out successively from
The heart, ethanol and washing, are then placed within obtaining styrene seed microballoon after drying 12h in 60-100 DEG C of vacuum drying chamber；
2) preparation of pi-allyl-cyclodextrin：
Cyclodextrin is weighed in dimethylformamide, the cyclodextrin selects beta-schardinger dextrin or gamma-cyclodextrin, Ran Houjia
Enter sodium hydride, wherein, cyclodextrin is 25 with the quality volume mass ratio of sodium hydride with dimethylformamide:200:2, stirred under normal temperature
Mix and filter after 0.5-2h, allyl glycidyl ether is added in filtrate, wherein, allyl glycidyl ether and dimethyl formyl
The volume ratio of amine is 3:80,60-90 DEG C is warming up to, react 18-24h；After reaction terminates, reaction solution is poured into methyl alcohol, precipitated
Go out pi-allyl-cyclodextrin solid, filter, drying is standby；
3) preparation of cyclodextrin-styrene-divinylbenzene microballoon：
Butyl phthalate is added dropwise to the lauryl sodium sulfate aqueous solution equipped with mass-volume concentration for 0.125-0.5%
Beaker in, wherein, the volume ratio of butyl phthalate and lauryl sodium sulfate is 4:75, ultrasound is until in microexamination
Under untill no drop obtains emulsion；By step 1) the styrene seed microballoon ultrasonic disperse for preparing is in equipped with mass body
During product concentration is for the beaker of the lauryl sodium sulfate aqueous solution of 0.125-0.5%, wherein, styrene seed microballoon and dodecane
The mass volume ratio of base aqueous sodium persulfate solution is 7:125, ultrasound 0.5-2h again after the solution in two beakers is merged, pour into list
In mouth bottle, it is put into shaking bath, shakes 3-7h to activate bulb；
Azodiisobutyronitrile is dissolved in toluene, the dodecyl sulphate that mass-volume concentration is 0.125-0.5% is added to
In sodium water solution, wherein, azodiisobutyronitrile, toluene, the mass ratio of lauryl sodium sulfate aqueous solution are 21:500:1250,
Ultrasound is added in reaction system after mixing, and continuation shakes swelling 10-15h in shaking bath；
Styrene and divinylbenzene are added to the lauryl sodium sulfate aqueous solution that mass-volume concentration is 0.125-0.5%
In, wherein, the volume ratio of styrene, divinylbenzene and lauryl sodium sulfate aqueous solution is 1:1:5, ultrasound is mixed；
Weighing step 2) pi-allyl-cyclodextrin for obtaining is added in dimethyl sulfoxide (DMSO), wherein, pi-allyl-cyclodextrin and diformazan
The mass volume ratio of base sulfoxide is 1:5, ultrasonic dissolution；
Above-mentioned solution is all added in reaction system, continuation shakes swelling 10-15h in shaking bath；By above-mentioned reaction
Liquid is poured into separatory funnel, stands 0.5-2h to be layered, and removes the organic layer of upper strata yellow；
It is the polyvinylpyrrolidonesolution solution of 5-30% to addition mass-volume concentration in reaction solution, wherein, polyvinylpyrrolidine
The volume of ketone solution is 1 with the volumetric ratio of reaction solution:10, nitrogen 10-30min is led under stirring at normal temperature, then use with balloon
Stopper is sealed, and is put into 60-90 DEG C of shaking bath, and polymerization 10-15h obtains microballoon, and microballoon is washed with water to without polyethylene pyrrole
Pyrrolidone, then dry after being washed with ethanol；Dry microballoon is extracted into 18-24h with toluene, colourless solution is washed till with ethanol, dried；
Dry microballoon is extracted into 18-24h with tetrahydrofuran again, colourless solution is washed till with ethanol, dried, that is, obtain cyclodextrin-benzene second
Alkene-divinylbenzene microspheres.
3. the preparation method of cyclodextrin-styrene-divinylbenzene microballoon according to claim 2, it is characterised in that prepare benzene
During ethene seed microballoon, alcohols solvent selects absolute ethyl alcohol, and the particle diameter of the styrene seed microballoon for obtaining is 2 μm；Alcohols solvent
From n-butanol, the particle diameter of the styrene seed microballoon for obtaining is 5 μm.
4. the preparation method of cyclodextrin-styrene-divinylbenzene microballoon according to claim 3, it is characterised in that with 2 μm
When styrene seed microballoon is bulb, 5 μm of cyclodextrin-styrene-divinylbenzene microballoon can be obtained；It is micro- with 5 μm of styrene seeds
When ball is bulb, 10 μm of cyclodextrin-styrene-divinylbenzene microballoon can be obtained.
5. the cyclodextrin that the preparation method of cyclodextrin-styrene-divinylbenzene microballoon is prepared according to claim 2-
Application of the styrene-divinylbenzene microballoon in high performance liquid chromatography, it is characterised in that ring paste is loaded using high-pressure homogenization
Essence-styrene-divinylbenzene microballoon, respectively obtained 5 μm of β-CD-PS-DVB microballoons, 5 μm of γ-CD-PS-DVB microballoons, 10 μm
The reversed-phase HPLC column of CD-PS-DVB microballoons filling and 5 μm of positive HPLC chromatogram posts of CD-PS-DVB microballoons filling, so
These chiral chromatographic columns are applied afterwards different chiral drugs are separated in high performance liquid chromatography.
6. cyclodextrin-application of the styrene-divinylbenzene microballoon in high performance liquid chromatography according to claim 5, its
It is characterised by, comprises the following steps：Flow Injection Chemiluminescence Method used mutually be methanol-water or acetonitrile-water system, positive mobile phase be ethanol-
N-hexane system, Flow Injection Chemiluminescence Method phase and positive mobile phase, by 0.45 μm of membrane filtration, and are taken off using preceding using vacuum
The method of gas is de-gassed.
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