CN104130419A - Regioselective beta-cyclodextrin derivative chiral stationary phase as well as preparation method and application thereof - Google Patents
Regioselective beta-cyclodextrin derivative chiral stationary phase as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a regioselective beta-cyclodextrin derivative chiral stationary phase and a preparation method. The method comprises the following steps: reacting triphenylchloromethane with hydroxyl at a C-6 position to protect the hydroxyl at the C-6 position; introducing an R1 carbamate group at a C-2 position and a C-3 position; removing a hydroxyl protecting group at the C-6 position by hydrolyzing; introducing a small amount of isocyanatopropyltriethoxysilane at the C-6 position; introducing another R2 carbamate group to the hydroxyl remaining at the C-6 position; and performing a polymer condensation polymerization reaction on a small quantity of introduced triethoxysilane groups under an acid condition to immobilize a beta-cyclodextrin derivative onto an aminopropyl silica gel surface so as to obtain the regioselective beta-cyclodextrin derivative chiral stationary phase, wherein R1 is different from R2. The method provided by the invention has the advantages of mild reaction condition, short reaction time, catalyst-free process, as well as easiness and convenience in post-treatment purification. The obtained regioselective beta-cyclodextrin derivative chiral stationary phase has high chiral recognition capability, and is wide in the chiral separation range.
Description
Technical field
What the present invention relates to is a kind of regioselectivity beta-cyclodextrin derivative chiral stationary phase and preparation method thereof.
Background technology
Chirality is one of natural essential attribute, comprises that forming the basic chemical substance of vital movement and chiral drug etc. is all chipal compounds.Amino acid, small molecular sugar, Nucleotide and polypeptide, protein, saccharan and DNA etc. have chirality.Between the different optical isomer of chipal compounds, its physicochemical property are almost in full accord, but role but may be just contrary in vivo, as chiral drug, the pharmacologically active in human body, metabolic process and toxicity etc. exist significant difference.These chipal compounds are difficult to separated with conventional separation method, adopt the method for chromatographic separation effectively to address this is that, wherein high performance liquid chromatography (HPLC) method separation efficiency is high, be widely used, can Yin Gaowen when separated and solute configuration is changed and lose biological activity, and column capacities is high, for having a high potential of chiral preparation separation, research has good stability for this reason, HPLC chiral fixed phase (CSP) that separating power is high has actual application value widely.
Beta-cyclodextrin (being called for short β-CD) shape of molecule is similar to the empty cone-shaped body that goes to top in, show inner side hydrophobic, the characteristic that outside is hydrophilic, the amphipathic structure of this uniqueness can make β-CD as different hydrophobicity " object " compound of " main body " inclusion, make it as a kind of novel chiral stationary phase, receive increasing concern, and be mainly used in anti-phase high performance liquid chromatography.People's original adoption carries out hydrocarbylation by the hydroxyl of β-CDs, and (alkyl is methyl, ethyl, butyl, amyl group, isopentyl, hexyl, heptyl, nonyl and decyl etc.) modification, obtain hydrophobicity β-CDs derivative of different alkyl modifications, adopted afterwards urethane modification, as, permitted will and just waited [preparation of the full derivatized cyclodextrin Bonded Phase of phenylcarbamate and chiral separation application, analytical chemistry research notes, 2006, 34 (1): 77-79], Lei Chen et al (Synthesis and chromatographic properties of a novel chiral stationary phase derived from heptakis (6-azido-6-deoxy-2, 3-di-O-phenylcarbamoylated)-β-cyclodextrin immobilized onto amino-functionalized silica gel via multiple urea linkages.J.Chromatogr.A.2002, 950:65-67), Tiham é r Hargitai et al (Preparation and chromatographic evaluation of 3, 5-dimethylphenyl carbamoylated β-cyclodextrin stationary phases for normal-phase high-performance liquid chromatographic separation of enantiomers.J.Chromatogr.A.1993, 628:11-22), Chun Lin et al (Synthesis of a novel cyclodextrin-derived chiral stationary phase with multiple urea linkages and enantioseparation toward chiral osmabenzene complex.J.Chromatogr.A.2013, 1283:68-74) and (number of patent application: 201310293591.1) prepared the ester modified beta-cyclodextrin derivative chiral stationary phase of Multi substituted benzenes aminocarbamic acid such as Chen Xingjuan, but the beta-cyclodextrin derivative chiral stationary phase of these bonding types is at C-2, identical (replacement) phenylcarbamate group is all contained in C-3 and C-6 position, contribution to the chiral recognition ability of racemic modification is limited, because the big opening end of beta-cyclodextrin molecule has the secondary hydroxyl of C-2 and C-3 position, osculum end has the primary hydroxyl of C-6 position, these hydroxyls have different reactive behavioies, therefore can be by controlling different reaction conditionss, obtain in osculum end C-6 position, big opening end C-2 and C-3 position have the beta-cyclodextrin derivative chiral stationary phase of different substituents group, the contribution of the substituting group of giving full play to different positions on beta-cyclodextrin glucose unit to chirality recognition capability, thereby improve its chiral recognition ability, expand the scope of chiral separation, and then the chiral stationary phase of multiaction pattern is prepared in design.
Summary of the invention
The object of the present invention is to provide the regioselectivity beta-cyclodextrin derivative chiral stationary phase that a kind of chiral recognition ability is strong, chiral separation scope is wide.The present invention also aims to provide a kind of chiral stationary phase that can make to obtain to there is the preparation method of the regioselectivity beta-cyclodextrin derivative chiral stationary phase that flow has mutually satisfactory stability and contain difference (replacement) phenylcarbamate group at big opening end, osculum end.
The structure of regioselectivity beta-cyclodextrin derivative chiral stationary phase of the present invention is:
R wherein
1and R
2be respectively phenyl, p-methylphenyl, rubigan, 3, a kind of in 5-3,5-dimethylphenyl or 3,5-dichlorophenyl, and R
1with R
2different.
The preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase of the present invention is:
First the hydroxyl reaction of using triphenylmethyl chloride and C-6 position, gets up the hydroxyl protection of C-6 position, then in C-2, C-3 position, introduces a kind of R
1carbamate groups, removes the hydroxy-protective group hydrolysis of C-6 position subsequently, first introduces a small amount of isocyanic acid propyl-triethoxysilicane, then introduce another kind of R in C-6 position on the residual hydroxyl in C-6 position
2carbamate groups, obtain regioselectivity beta-cyclodextrin derivative, finally under acidic conditions, utilize introduced a small amount of triethoxysilicane groups to carry out polymer polycondensation beta-cyclodextrin derivative is immobilized to aminopropyl Silica Surface, obtain regioselectivity beta-cyclodextrin derivative chiral stationary phase, R
1and R
2be respectively phenyl, p-methylphenyl, rubigan, 3, a kind of in 5-3,5-dimethylphenyl or 3,5-dichlorophenyl, and R
1with R
2different.
The preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase of the present invention can also comprise:
1, the described hydroxyl reaction with triphenylmethyl chloride and C-6 position specifically comprises: the beta-cyclodextrin of complete drying is dissolved in anhydrous pyridine under inert nitrogen gas protection, the massfraction of beta-cyclodextrin is 10～30%, then the triphenylmethyl chloride of 0.5～1 times of amount of beta-cyclodextrin hydroxyl mole number is added wherein, under nitrogen atmosphere, keep 60～100 ℃ of isothermal reaction 24～72h, generate the thick product of 6-O-trityl-beta-cyclodextrin, with the sherwood oil of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings are to constant weight, obtain 6-O-trityl-beta-cyclodextrin.
2, describedly in C-2, C-3 position, introduce a kind of R
1carbamate groups specifically comprises: dry 6-O-trityl-beta-cyclodextrin is dissolved in anhydrous pyridine, the massfraction of 6-O-trityl-beta-cyclodextrin is 10～30%, then with the R of 1～3 times of amount of 6-O-trityl-beta-cyclodextrin hydroxyl mole number
1isocyanic ester is at 60～90 ℃ of reaction 24～96h, and stopped reaction, is down to room temperature, with the methanol aqueous solution of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain 2,3-, bis-R
1carbamate-6-O-trityl-beta-cyclodextrin.
3, the hydrolysis of the described hydroxy-protective group by C-6 position is removed specifically and is comprised: by dry 2, and 3-bis-R
1carbamate-6-O-trityl-beta-cyclodextrin is dissolved in tetrahydrofuran (THF), 2,3-, bis-R
1the massfraction of carbamate-6-O-trityl-beta-cyclodextrin is 1～5%, then 1～3% the dense HCl that adds tetrahydrofuran (THF) volume fraction, 0～40 ℃ of reaction 12～36h, removes trityl hydrolysis stopped reaction, be down to room temperature, with the sherwood oil of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings are to constant weight, obtain 2,3-, bis-R
1carbamate-beta-cyclodextrin.
4, a small amount of isocyanic acid propyl-triethoxysilicane is first introduced in described C-6 position, on the residual hydroxyl in C-6 position, introduces another kind of R
2carbamate groups specifically comprises: by 2,3-, bis-R
1carbamate-beta-cyclodextrin is dissolved in anhydrous pyridine, 2,3-, bis-R
1the massfraction of carbamate-beta-cyclodextrin is 10～30%, then by 2,3-, bis-R
1the isocyanic acid propyl-triethoxysilicane of 0.3～0.8 times of amount of carbamate-beta-cyclodextrin hydroxyl mole number adds wherein, 60～90 ℃ of reaction 24-48h, then add another kind of R
2isocyanic ester, its consumption is 2,3-, bis-R
10.5～1 times of carbamate-beta-cyclodextrin hydroxyl mole number, at 60～90 ℃ of reaction 24～48h, stopped reaction, cooling, with the methanol aqueous solution of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain containing a small amount of triethoxysilicane groups and contain different R in C-6 position from C-2, C-3 position
1the beta-cyclodextrin derivative of carbamate.
5, describedly to aminopropyl Silica Surface, specifically comprise beta-cyclodextrin derivative is immobilized: beta-cyclodextrin derivative is dissolved in tetrahydrofuran solvent, the shared massfraction of beta-cyclodextrin derivative is 5～10%, then according to aminopropyl silica gel: beta-cyclodextrin derivative mass ratio is 3～5:1, the tetrahydrofuran solution of beta-cyclodextrin derivative is coated in to aminopropyl Silica Surface, and repeatedly revolve and steam to solvent evaporates, during polymer polycondensation, press the aminopropyl silica gel after coating: dehydrated alcohol: deionized water=1g:10～20ml:10～20ml, with ultrasonic concussion, make the aminopropyl silica gel after coating in aqueous ethanolic solution, become suspension, be heated to after 90～120 ℃, add trimethylchlorosilane, its consumption is 1～3% of deionized water volume, under acidic conditions, there is polymer polycondensation, being stirred to liquid all volatilizees, be cooled to after room temperature, washing with alcohol by the product after polycondensation with 50～100 times of volume equivalents, remove unreacted beta-cyclodextrin derivative and impurity, at 60～80 ℃, vacuum-drying is to constant weight, obtain regioselectivity beta-cyclodextrin derivative chiral stationary phase.
6, in regioselectivity beta-cyclodextrin derivative chiral stationary phase: the ratio of mixed solvent: whiteruss=1g:20～30ml:5～10ml, regioselectivity beta-cyclodextrin derivative chiral stationary phase is joined in mixed solvent and whiteruss, the ultrasonic suspension slurry that shakes into, with packing column machine, under 30～40MPa, pack in stainless steel liquid phase chromatographic column, obtain beta-cyclodextrin derivative chiral chromatographic column.
The regioselectivity cyclodextrin derivative chiral chromatographic column of preparation is mainly used in the high performance liquid chromatography under positive, anti-phase and polar organic solvent pattern, and partially racemic compound is had to certain Chiral Separation Ability.
The present invention be directed to existing beta-cyclodextrins chiral stationary phase weak point, a kind of synthesis technique that can be applicable to the regioselectivity beta-cyclodextrin derivative chiral stationary phase of multiaction pattern is provided.Its major advantage is embodied in:
(1) utilize (replacement) phenyl isocyanate to carry out derivatize modification to the hydroxyl on beta-cyclodextrin glucose unit, this reaction conditions is gentle, the reaction times is short, does not need catalyzer, and aftertreatment is purified easy.
(2) utilize the hydroxyl reaction of different positions on beta-cyclodextrin glucose unit active different, first the hydroxyl of the higher osculum end C-6 position of reactive behavior is carried out to regioselectivity protection, subsequently at beta-cyclodextrin big opening end C-2, a kind of (replacement) phenylcarbamate group is introduced in C-3 position, then the blocking group of the C-6 position of osculum end is hydrolyzed, in C-6 position, introduce a small amount of silane coupling agent isocyanic acid propyl-triethoxysilicane, and with the residual hydroxyl reaction of another kind of (replacement) phenyl isocyanate and osculum end C-6 position, in the preparation process of chiral stationary phase, there is polymer polycondensation in a small amount of triethoxysilicane groups wherein, between beta-cyclodextrin derivative molecule, by silicon-oxygen-silicon bound, couple together, make beta-cyclodextrin derivative form inclusion reticulated structure, thereby obtain the beta-cyclodextrin derivative chiral stationary phase of high immobilized rate and high stability.By introducing different substituted radicals at the different positions of beta-cyclodextrin, can increase hydrophobic interaction, dipole-dipole effect, π-π effect and the hydrogen bond action etc. of stationary phase and solute molecule, to improve its chiral recognition ability, and then design and prepare the beta-cyclodextrin derivative class chiral stationary phase that performance is better, split wider novel multiaction pattern.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 6-O-trityl-beta-cyclodextrin.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of 2,3-bis-(3,5-dichlorophenyl carbamate)-6-O-trityl-beta-cyclodextrin.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of 2,3-bis-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of 2,3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Fig. 5 adopts the chromatographic fractionation figure of 2,3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column to Chao Geer alkali (troger ' s base) racemic modification.Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.), moving phase normal hexane/Virahol=90/10 (v/v), flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Fig. 6 adopts 2,3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column to flavanone (flavanone) racemic modification chromatographic fractionation figure.Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.), moving phase normal hexane/Virahol=90/10 (v/v), flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Fig. 7 adopts 2,3-bis-(3,5-dichlorophenyl carbamate)-6-(3,5-3,5-dimethylphenyl the carbamate)-chromatographic fractionation figure of beta-cyclodextrin chiral chromatographic column to flavanone (flavanone).Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.); Moving phase normal hexane/Virahol=90/10 (v/v); Flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Fig. 8 adopts 2,3-bis-(3,5-dichlorophenyl carbamate)-6-(3,5-3,5-dimethylphenyl the carbamate)-chromatographic fractionation figure of beta-cyclodextrin chiral chromatographic column to bitter almond oil camphor (benzoin).Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.); Moving phase normal hexane/Virahol=99/1 (v/v); Flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Fig. 9 adopts the chromatographic fractionation figure of 2,3-bis-(3,5-dichlorophenyl carbamate)-6-p-methylphenyl carbamate-beta-cyclodextrin chiral chromatographic column to γ-phenyl-gamma-butyrolactone (γ-phenyl-γ-butyrolactone).Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.); Moving phase normal hexane/Virahol=90/10 (v/v); Flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Figure 10 is process route chart of the present invention.
Embodiment
Preparation method's step of regioselectivity beta-cyclodextrin derivative chiral stationary phase of the present invention is as follows:
(1) beta-cyclodextrin of complete drying is dissolved in anhydrous pyridine under inert nitrogen gas protection; the massfraction of beta-cyclodextrin is 10～30%; then the triphenylmethyl chloride of 0.5～1 times of amount of beta-cyclodextrin hydroxyl mole number is added wherein; under nitrogen atmosphere, keep 60～100 ℃ of isothermal reaction 24～72h, generate the thick product of 6-O-trityl-beta-cyclodextrin.With the sherwood oil of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain 6-O-trityl-beta-cyclodextrin (a).
(2) dry 6-O-trityl-beta-cyclodextrin (a) is dissolved in anhydrous pyridine, the massfraction of 6-O-trityl-beta-cyclodextrin is 10～30%.At 60～90 ℃, react 24～96h with (replacement) phenyl isocyanate of 1～3 times of amount of 6-O-trityl-beta-cyclodextrin hydroxyl mole number again, stopped reaction, is down to room temperature.With the methanol aqueous solution of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain 2,3-bis-(replacement) phenylcarbamate-6-O-trityl-beta-cyclodextrin (b).
(3) by dry 2,3-bis-(replacement) phenylcarbamate-6-O-trityl-beta-cyclodextrin (b) is dissolved in tetrahydrofuran (THF), the massfraction of 2,3-bis-(replacement) phenylcarbamate-6-O-trityl-beta-cyclodextrin is 1～5%.Then add dense HCl (tetrahydrofuran (THF) volume fraction 1～3%), 0～40 ℃ of reaction 12～36h, removes trityl hydrolysis.Stopped reaction, is down to room temperature, with the sherwood oil of 100～200 times of volume equivalents, precipitates, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain 2,3-bis-(replacement) phenylcarbamate-beta-cyclodextrin (c).
(4) by 2, 3-bis-(replacement) phenylcarbamate-beta-cyclodextrin (c) is dissolved in anhydrous pyridine, 2, the massfraction of 3-bis-(replacement) phenylcarbamate-beta-cyclodextrin is 10～30%, then by 2, the isocyanic acid propyl-triethoxysilicane of 0.3～0.8 times of amount of 3-bis-(replacement) phenylcarbamate-beta-cyclodextrin hydroxyl mole number adds wherein, 60～90 ℃ of reaction 24-48h, (its consumption is 2 to add another kind (replacement) phenyl isocyanate again, 0.5～1 times of 3-bis-(replacement) phenylcarbamate-beta-cyclodextrin hydroxyl mole number), at 60～90 ℃ of reaction 24～48h, stopped reaction, cooling.With the methanol aqueous solution of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain the beta-cyclodextrin derivative (d) that contains a small amount of triethoxysilicane groups and contain different (replacement) phenylcarbamate in C-6 position and C-2, C-3 position.
(5) beta-cyclodextrin derivative (d) is dissolved in tetrahydrofuran solvent, the shared massfraction of beta-cyclodextrin derivative (d) is 5～10%, then according to aminopropyl silica gel: beta-cyclodextrin derivative (d) is (3～5): 1 (mass ratio), the tetrahydrofuran solution of beta-cyclodextrin derivative (d) is coated in to aminopropyl Silica Surface, and repeatedly revolves and steam to solvent evaporates.During polymer polycondensation, press the aminopropyl silica gel after coating: dehydrated alcohol: deionized water=1g:(10～20) ml:(10～20) ml, with ultrasonic concussion, make the aminopropyl silica gel after coating in aqueous ethanolic solution, become suspension, be heated to after 90～120 ℃, add trimethylchlorosilane (its consumption be deionized water volume 1～3%), polymer polycondensation occurs under acidic conditions.Being stirred to liquid all volatilizees, be cooled to after room temperature, washing with alcohol by the product after polycondensation with 50～100 times of volume equivalents, remove unreacted beta-cyclodextrin derivative (d) and impurity, at 60～80 ℃, vacuum-drying, to constant weight, obtains regioselectivity beta-cyclodextrin derivative chiral stationary phase (e).
(6) in beta-cyclodextrin derivative chiral stationary phase (e): mixed solvent: the whiteruss=1g:(20～30) ml:(5～10) ratio of ml, beta-cyclodextrin derivative chiral stationary phase (e) is joined in mixed solvent and whiteruss, the ultrasonic suspension slurry that shakes into, with packing column machine, under 30～40MPa, pack in stainless steel liquid phase chromatographic column, obtain beta-cyclodextrin derivative chiral chromatographic column.
R in (replacement) phenylcarbamate group that in beta-cyclodextrin glucose unit, introduce C-6 position
1for phenyl, p-methylphenyl, rubigan, 3,5-3,5-dimethylphenyl, 3, five kinds of 5-dichlorophenyls a kind of, C-2, R in (replacement) phenylcarbamate group of introducing on C-3 position
2also be phenyl, p-methylphenyl, rubigan, 3,5-3,5-dimethylphenyl, 3, five kinds of 5-dichlorophenyls a kind of, but R
1≠ R
2.
Described acidic conditions is by trimethylchlorosilane hydrolysis, to produce hydrogenchloride to obtain.
Described 2, when 3-bis-(replacement) phenylcarbamate-6-O-trityl-beta-cyclodextrin C-6 position hydroxyl removes blocking group, dense HCl massfraction used is 37%.
Methanol aqueous solution volume ratio used is methanol/water=(2～4)/1.
The particle diameter of aminopropyl silica gel used is 5～10 μ m, and aperture is 100nm.
Mixed solvent used is normal hexane/Virahol=90/10 (v/v).
The regioselectivity cyclodextrin derivative chiral chromatographic column of preparation is mainly used in the high performance liquid chromatography under positive, anti-phase and polar organic solvent pattern, and partially racemic compound is had to certain Chiral Separation Ability.
For example the present invention is described in more detail below.
Embodiment 1
0.9674g is added in the reactor that fills 18ml anhydrous pyridine through the beta-cyclodextrin of complete drying, under nitrogen atmosphere, be warming up to 80 ℃, after solid all dissolves, add wherein 4.9832g triphenylmethyl chloride, keep 80 ℃ of constant temperature, stirring reaction 72h, stop heating.The cooled pyridine solution that contains product is dropwise added in the sherwood oil of 300ml of vigorous stirring, now produce a large amount of light-yellow precipitate.Continue to stop stirring after vigorous stirring 15min, after standing 15min, by supernatant liquor sucking-off, the suspension liquid that a large amount of solids are contained in bottom is through high speed centrifugation separate solid product.After centrifugal, add 30ml petroleum ether, continue centrifugation solid.Repeat above operation 6 times, guarantee the pure inclusion-free of product.Solid product after purification is vacuum-drying 12h at 60 ℃, obtains yellow powder powder solid matter, is 6-O-trityl-beta-cyclodextrin, and its hydrogen nuclear magnetic resonance spectrogram as shown in Figure 1.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Get above-mentioned through the pressed powder 6-O-of super-dry trityl-beta-cyclodextrin 2.0888g, add in the reaction flask that fills 40ml anhydrous pyridine, under nitrogen atmosphere, be warming up to 80 ℃, after solid all dissolves, add wherein white solid 3,5-dichlorophenyl isocyanate 2.2229g, keeps 80 ℃ of constant temperature, stirring reaction 24h, stops heating.By cooled above-mentioned solution dropwise add the 500ml of vigorous stirring methanol aqueous solution (methanol/water=4/1, v/v) in, produce a large amount of white precipitates.Continue to stop stirring after vigorous stirring 30min, after standing 30min, by the suspension liquid centrifugation solid product that contains a large amount of solids.Solid after centrifugal is added to 30ml methanol aqueous solution, and (methanol/water=4/1, v/v) washing, continues centrifugation solid, repeats above operation 5 times, guarantees the pure inclusion-free of product.Solid product after purification is vacuum-drying 12h at 60 ℃, obtains light brown powdered solid substance, is 2,3-bis-(3,5-dichlorophenyl carbamate)-6-O-trityl-beta-cyclodextrin, and its hydrogen nuclear magnetic resonance spectrogram as shown in Figure 2.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Get above-mentioned dry light brown pressed powder 2,3-bis-(3,5-dichlorophenyl carbamate)-6-O-trityl-beta-cyclodextrin 2.5034g is placed in reaction flask, add wherein 450ml tetrahydrofuran (THF), stirring is after it dissolves, adding massfraction is 37% dense HCl8.1ml, stirring reaction 24h at 25 ℃ of room temperatures, stopped reaction.Revolve and steam liquid to about 20ml, it is dropwise added in the sherwood oil of 200ml of vigorous stirring, now produce a large amount of light brown precipitations.Continue to stop stirring after vigorous stirring 30min, after standing 30min, supernatant liquor is poured out.The suspension liquid that a large amount of solids are contained in bottom is through high speed centrifugation separate solid product.After centrifugal, add 30ml petroleum ether, continue centrifugation solid, repeat above washing operation 6 times, guarantee that product is pure.Solid product after purification is vacuum-drying 12h at 60 ℃, obtains light brown powdered solid substance, and 2,3-bis-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin, its hydrogen nuclear magnetic resonance spectrogram is as shown in Figure 3.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Get above-mentioned 2,3-bis-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin powder 0.6104g is placed in reaction flask, under nitrogen atmosphere, add anhydrous pyridine 12ml, be warming up to 80 ℃ and stir it is dissolved, then add 0.15ml isocyanic acid propyl-triethoxysilicane, keep 80 ℃ of constant temperature, stirring reaction 24h, then add 0.14ml phenylisocyanate, keep 80 ℃, stirring reaction 24h, stop heating.By cooled above-mentioned solution dropwise add the 250ml of vigorous stirring methanol aqueous solution (methanol/water=4/1, v/v) in, produce a large amount of light brown precipitations, continue after vigorous stirring 30min, stop stirring, after static 30min, by the suspension liquid centrifugation solid product that contains a large amount of solids.After centrifugal, (methanol/water=4/1, v/v) washing, continues centrifugation solid, repeats above operation 5 times, guarantees the pure inclusion-free of product to add 30mL methanol aqueous solution.Solid product after purification is vacuum-drying 12h at 60 ℃, obtain light brown powdered solid substance, must contain 2 of a small amount of triethoxy propyl carbamate group, 3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin (a), its hydrogen nuclear magnetic resonance spectrogram as shown in Figure 4.Test condition: 500MHz nuclear magnetic resonance spectrometer, solvent deuterated dimethyl sulfoxide; 20 ℃ of temperature; Tetramethylsilane is done interior mark.
Get above-mentioned pressed powder (a) 0.2000g, add 5ml tetrahydrofuran (THF), to dissolving completely.The tetrahydrofuran solution of the above-mentioned beta-cyclodextrin derivative (a) taking a morsel, dropwise join 0.8000g aminopropyl silica gel (particle diameter 7 μ m, aperture 100nm), vibrate and make uniform liquid be dispersed in aminopropyl Silica Surface, then with Rotary Evaporators, tetrahydrofuran solvent wherein being steamed.Repeat the above tetrahydrofuran solution that is operated to beta-cyclodextrin derivative (a) that drips, revolves steaming and be completely evenly coated in aminopropyl Silica Surface.
To adding 20ml aqueous ethanolic solution in the aminopropyl silica gel having applied, (ethanol/deionized water=1/1, v/v), ultrasonic concussion 2min, makes the aminopropyl silica gel that is coated with beta-cyclodextrin derivative (a) in aqueous ethanolic solution, become suspension.Be heated to subsequently 90 ℃, add 1ml trimethylchlorosilane, stirring reaction 12h, finally all volatilizees liquid, obtains crude product regioselectivity beta-cyclodextrin derivative chiral stationary phase.After being cooled to room temperature, above-mentioned thick product adds 30ml dehydrated alcohol, ultrasonic concussion 2min, and suction filtration suspension liquid, washs this chiral stationary phase with 100ml ethanolic soln.Chiral stationary phase product after filtration vacuum-drying 12h at 60 ℃, obtain light brown solid product, this is regioselectivity 2,3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral stationary phase, the bonding efficiency of testing this chiral stationary phase with thermogravimetic analysis (TGA) is 91.2%.
By regioselectivity 2,3-bis-(3,5-dichlorophenyl carbamate) in-6-phenylcarbamate-beta-cyclodextrin chiral stationary phase, add successively 20ml normal hexane/Virahol (90/10, v/v), 5ml whiteruss, the ultrasonic suspension of shaking into, pour in homogenate tank, with packing column machine at 40MPa, under 3.8ml/min flow velocity, be packed in stainless steel liquid phase chromatographic column (25 * 0.2cm, i.d.), obtain regioselectivity 2,3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column.
Embodiment 2
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dichlorophenyl isocyanate, its consumption is 2.2229g, C-6 position derivatization reagent is 4-aminomethyl phenyl isocyanic ester, and its consumption is 0.18ml, finally obtains 2,3-bis-(3,5-dichlorophenyl carbamate)-6-(4-methyl phenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 3
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dichlorophenyl isocyanate, its consumption is 2.2229g, C-6 position derivatization reagent is 4-chloro-phenyl-isocyanic ester, and its consumption is 0.1913g, finally obtains 2,3-bis-(3,5-dichlorophenyl carbamate)-6-(4-chloro-phenyl-carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 4
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dichlorophenyl isocyanate, its consumption is 2.2229g, C-6 position derivatization reagent is 3,5-dimethylphenyl isocyanate, its consumption is 0.20ml, finally obtains 2,3-bis-(3,5-dichlorophenyl carbamate)-6-(3,5-3,5-dimethylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 5
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-aminomethyl phenyl isocyanic ester, its consumption is 1.56mL, it is 0.20mL that C-6 position adds coupling agent isocyanic acid propyl-triethoxysilicane consumption, C-6 position derivatization reagent is phenyl isocyanate, its consumption is 0.19mL, finally obtains 2,3-bis-(4-methyl phenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column.
Embodiment 6
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-aminomethyl phenyl isocyanic ester, its consumption is 1.56mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.20mL, C-6 position derivatization reagent is 4-chloro-phenyl-isocyanic ester, its consumption is 0.2503g, finally obtains 2,3-bis-(4-methyl phenyl carbamate)-6-(4-chloro-phenyl-carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 7
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-aminomethyl phenyl isocyanic ester, its consumption is 1.56mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.20mL, and C-6 position derivatization reagent is 3,5-dimethylphenyl isocyanate, its consumption is 0.23mL, finally obtain 2,3-bis-(4-methyl phenyl carbamate)-6-(3,5-3,5-dimethylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 8
[0032] reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-aminomethyl phenyl isocyanic ester, its consumption is 1.56mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.20mL, C-6 position derivatization reagent is 3,5-dichlorophenyl isocyanate, its consumption is 0.3061g, finally obtain 2,3-bis-(4-methyl phenyl carbamate)-6-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 9
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-chloro-phenyl-isocyanic ester, its consumption is 1.9036g, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.18mL, C-6 position derivatization reagent is phenyl isocyanate, its consumption is 0.16mL, finally obtains 2,3-bis-(4-chloro-phenyl-carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column.
Embodiment 10
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-chloro-phenyl-isocyanic ester, its consumption is 1.9036g, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.18mL, C-6 position derivatization reagent is 4-aminomethyl phenyl isocyanic ester, its consumption is 0.19mL, finally obtains 2,3-bis-(4-chloro-phenyl-carbamate)-6-(4-methyl phenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 11
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-chloro-phenyl-isocyanic ester, its consumption is 1.9036g, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.18mL, and C-6 position derivatization reagent is 3,5-dimethylphenyl isocyanate, its consumption is 0.21mL, finally obtain 2,3-bis-(4-chloro-phenyl-carbamate)-6-(3,5-3,5-dimethylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 12
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 4-chloro-phenyl-isocyanic ester, its consumption is 1.9036g, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.18mL, and C-6 position derivatization reagent is 3,5-dichlorophenyl isocyanate, its consumption is 0.2795g, finally obtain 2,3-bis-(4-chloro-phenyl-carbamate)-6-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 13
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dimethylphenyl isocyanate, its consumption is 1.75mL, and C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.19mL, and C-6 position derivatization reagent is phenyl isocyanate, its consumption is 0.17mL, finally obtain 2,3-bis-(3,5-3,5-dimethylphenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column.
Embodiment 14
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dimethylphenyl isocyanate, its consumption is 1.75mL, and C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.19mL, and C-6 position derivatization reagent is 4-aminomethyl phenyl isocyanic ester, its consumption is 0.19mL, finally obtain 2,3-bis-(3,5-3,5-dimethylphenyl carbamate)-6-(4-methyl phenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 15
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dimethylphenyl isocyanate, its consumption is 1.75mL, and C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.19mL, and C-6 position derivatization reagent is 4-chloro-phenyl-isocyanic ester, its consumption is 0.2347g, finally obtain 2,3-bis-(3,5-3,5-dimethylphenyl carbamate)-6-(4-chloro-phenyl-carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 16
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are 3,5-dimethylphenyl isocyanate, its consumption is 1.75mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.19mL, C-6 position derivatization reagent is 3,5-dichlorophenyl isocyanate, its consumption is 0.2873g, finally obtain 2,3-bis-(3,5-3,5-dimethylphenyl carbamate)-6-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 17
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are phenyl isocyanate, its consumption is 1.35mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.22mL, C-6 position derivatization reagent is 4-aminomethyl phenyl isocyanic ester, its consumption is 0.22mL, finally obtains 2,3-bis-(phenylcarbamate)-6-(4-methyl phenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 18
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are phenyl isocyanate, its consumption is 1.35mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.22mL, C-6 position derivatization reagent is 4-chloro-phenyl-isocyanic ester, its consumption is 0.2676g, finally obtains 2,3-bis-(phenylcarbamate)-6-(4-chloro-phenyl-carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 19
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are phenyl isocyanate, its consumption is 1.35mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.22mL, and C-6 position derivatization reagent is 3,5-dimethylphenyl isocyanate, its consumption is 0.25mL, finally obtain 2,3-bis-(phenylcarbamate)-6-(3,5-3,5-dimethylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Embodiment 20
Reactions steps and condition are identical with embodiment 1, substrate C-2 used, C-3 position derivatization reagent are phenyl isocyanate, its consumption is 1.35mL, C-6 position coupling agent isocyanic acid propyl-triethoxysilicane consumption is 0.22mL, and C-6 position derivatization reagent is 3,5-dichlorophenyl isocyanate, its consumption is 0.3276g, finally obtain 2,3-bis-(phenylcarbamate)-6-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin chiral chromatographic column.
Use 500MHz hydrogen nuclear magnetic resonance spectrometer to carry out structural characterization to each product in embodiment 1 as follows, its proton nmr spectra is shown in Fig. 1～Fig. 4.
6-O-trityl-beta-cyclodextrin (
1h NMR, 500MHz, DMSO-d
6, ppm): 8.00～8.90 (Pyridine-H, 3.3H), 6.50～7.50 (Ph-H, 14.8H), 3.30～5.00 (glucose-H, 9.0H).
2,3-bis-(3,5-dichlorophenyl carbamate)-6-O-trityl-beta-cyclodextrin (
1h NMR, 500MHz, DMSO-d
6, ppm): 9.47,9.56 (NH-H, 2.0H), 6.50～7.80 (Ph-H, 21.4H), 3.30～5.00 (glucose-H, 7.0H).
2,3-bis-(3,5-dichlorophenyl carbamate)-beta-cyclodextrin (
1h NMR, 500MHz, DMSO-d
6, ppm): 9.87,9.92 (NH-H, 2.0H), 6.50～7.70 (Ph-H, 6.4H), 3.30～5.50 (glucose-H, 8.0H).
Contain 2 of a small amount of triethoxy propyl carbamate silane group, 3-bis-(3,5-dichlorophenyl carbamate)-6-phenylcarbamate-beta-cyclodextrin (
1h NMR, 500MHz, DMSO-d
6, ppm): 9.78,10.12 (NH-H, 2.4H), 6.50～7.80 (Ph-H, 7.3H), 3.73 (SiOCH
2, 1.4H), 3.50～5.60 (glucose-H, 7.0H), 1.49 (SiCH
2cH
2, 0.9H), 1.12 (SiOCH
2cH
3, 3.4H), 0.55 (SiCH
2, 1.0H).
Use embodiment 1 prepared 2,3-bis-(3,5-dichlorophenyl carbamate) the separated Chao Geer alkali of-6-phenylcarbamate-beta-cyclodextrin chiral chromatographic column (troger ' s base) and flavanone (flavanone) racemic modification, the chromatographic fractionation figure of two compounds is distinguished as shown in Figure 5 and Figure 6.Chromatographic condition: chromatographic column 25 * 0.2cm (i.d.), moving phase normal hexane/Virahol=90/10 (v/v), flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Use embodiment 4 prepared 2,3-bis-(3,5-dichlorophenyl carbamate) separated flavanone (flavanone) racemic modification of-6-(3,5-3,5-dimethylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column, its chromatographic fractionation figure as shown in Figure 7.Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.); Moving phase normal hexane/Virahol=90/10 (v/v); Flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Use embodiment 4 prepared 2,3-bis-(3,5-dichlorophenyl carbamate) separated bitter almond oil camphor (benzoin) racemic modification of-6-(3,5-3,5-dimethylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column, its chromatographic fractionation figure as shown in Figure 8.Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.); Moving phase normal hexane/Virahol=99/1 (v/v); Flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Use embodiment 2 prepared 2,3-bis-(3,5-dichlorophenyl carbamate)-6-(p-methylphenyl carbamate)-beta-cyclodextrin chiral chromatographic column separating gamma-phenyl-gamma-butyrolactone (γ-phenyl-γ-butyrolactone) racemic modification, its chromatographic fractionation figure as shown in Figure 9.Chromatographic condition used: chromatographic column 25 * 0.2cm (i.d.); Moving phase normal hexane/Virahol=90/10 (v/v); Flow velocity 0.1ml/min; UV detects wavelength 254nm; 25 ℃ of column temperatures.
Claims (9)
1. a regioselectivity beta-cyclodextrin derivative chiral stationary phase of the present invention, is characterized in that structure is:
R wherein
1and R
2be respectively phenyl, p-methylphenyl, rubigan, 3, a kind of in 5-3,5-dimethylphenyl or 3,5-dichlorophenyl, and R
1with R
2different.
2. the preparation method of a regioselectivity beta-cyclodextrin derivative chiral stationary phase claimed in claim 1; it is characterized in that: the hydroxyl reaction of first using triphenylmethyl chloride and C-6 position; the hydroxyl protection of C-6 position is got up, then in C-2, C-3 position, introduce a kind of R
1carbamate groups, removes the hydroxy-protective group hydrolysis of C-6 position subsequently, first introduces a small amount of isocyanic acid propyl-triethoxysilicane, then introduce another kind of R in C-6 position on the residual hydroxyl in C-6 position
2carbamate groups, obtain regioselectivity beta-cyclodextrin derivative, finally under acidic conditions, utilize introduced a small amount of triethoxysilicane groups to carry out polymer polycondensation beta-cyclodextrin derivative is immobilized to aminopropyl Silica Surface, obtain regioselectivity beta-cyclodextrin derivative chiral stationary phase, R
1and R
2be respectively phenyl, p-methylphenyl, rubigan, 3, a kind of in 5-3,5-dimethylphenyl or 3,5-dichlorophenyl, and R
1with R
2different.
3. the preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase according to claim 2, it is characterized in that the described hydroxyl reaction with triphenylmethyl chloride and C-6 position specifically comprises: the beta-cyclodextrin of complete drying is dissolved in anhydrous pyridine under inert nitrogen gas protection, the massfraction of beta-cyclodextrin is 10～30%, then the triphenylmethyl chloride of 0.5～1 times of amount of beta-cyclodextrin hydroxyl mole number is added wherein, under nitrogen atmosphere, keep 60～100 ℃ of isothermal reaction 24～72h, generate the thick product of 6-O-trityl-beta-cyclodextrin, with the sherwood oil of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings are to constant weight, obtain 6-O-trityl-beta-cyclodextrin.
4. the preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase according to claim 3, introduces a kind of R in C-2, C-3 position described in it is characterized in that
1carbamate groups specifically comprises: dry 6-O-trityl-beta-cyclodextrin is dissolved in anhydrous pyridine, the massfraction of 6-O-trityl-beta-cyclodextrin is 10～30%, then with the R of 1～3 times of amount of 6-O-trityl-beta-cyclodextrin hydroxyl mole number
1isocyanic ester is at 60～90 ℃ of reaction 24～96h, and stopped reaction, is down to room temperature, with the methanol aqueous solution of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain 2,3-, bis-R
1carbamate-6-O-trityl-beta-cyclodextrin.
5. the preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase according to claim 4, is characterized in that the described hydrolysis of the hydroxy-protective group by C-6 position is removed specifically to comprise: by dry 2, and 3-bis-R
1carbamate-6-O-trityl-beta-cyclodextrin is dissolved in tetrahydrofuran (THF), 2,3-, bis-R
1the massfraction of carbamate-6-O-trityl-beta-cyclodextrin is 1～5%, then 1～3% the dense HCl that adds tetrahydrofuran (THF) volume fraction, 0～40 ℃ of reaction 12～36h, removes trityl hydrolysis stopped reaction, be down to room temperature, with the sherwood oil of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings are to constant weight, obtain 2,3-, bis-R
1carbamate-beta-cyclodextrin.
6. the preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase according to claim 5, is characterized in that described C-6 position first introduces a small amount of isocyanic acid propyl-triethoxysilicane, on the residual hydroxyl in C-6 position, introduces another kind of R
2carbamate groups specifically comprises: by 2,3-, bis-R
1carbamate-beta-cyclodextrin is dissolved in anhydrous pyridine, 2,3-, bis-R
1the massfraction of carbamate-beta-cyclodextrin is 10～30%, then by 2,3-, bis-R
1the isocyanic acid propyl-triethoxysilicane of 0.3～0.8 times of amount of carbamate-beta-cyclodextrin hydroxyl mole number adds wherein, 60～90 ℃ of reaction 24-48h, then add another kind of R
2isocyanic ester, its consumption is 2,3-, bis-R
10.5～1 times of carbamate-beta-cyclodextrin hydroxyl mole number, at 60～90 ℃ of reaction 24～48h, stopped reaction, cooling, with the methanol aqueous solution of 100～200 times of volume equivalents, precipitate, and repeatedly washing, last 60～80 ℃ of vacuum-dryings, to constant weight, obtain containing a small amount of triethoxysilicane groups and contain different R in C-6 position from C-2, C-3 position
1the beta-cyclodextrin derivative of carbamate.
7. the preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase according to claim 6, it is characterized in that describedly to aminopropyl Silica Surface, specifically comprising beta-cyclodextrin derivative is immobilized: beta-cyclodextrin derivative is dissolved in tetrahydrofuran solvent, the shared massfraction of beta-cyclodextrin derivative is 5～10%, then according to aminopropyl silica gel: beta-cyclodextrin derivative mass ratio is 3～5:1, the tetrahydrofuran solution of beta-cyclodextrin derivative is coated in to aminopropyl Silica Surface, and repeatedly revolve and steam to solvent evaporates, during polymer polycondensation, press the aminopropyl silica gel after coating: dehydrated alcohol: deionized water=1g:10～20ml:10～20ml, with ultrasonic concussion, make the aminopropyl silica gel after coating in aqueous ethanolic solution, become suspension, be heated to after 90～120 ℃, add trimethylchlorosilane, its consumption is 1～3% of deionized water volume, under acidic conditions, there is polymer polycondensation, being stirred to liquid all volatilizees, be cooled to after room temperature, washing with alcohol by the product after polycondensation with 50～100 times of volume equivalents, remove unreacted beta-cyclodextrin derivative and impurity, at 60～80 ℃, vacuum-drying is to constant weight, obtain regioselectivity beta-cyclodextrin derivative chiral stationary phase.
8. the preparation method of regioselectivity beta-cyclodextrin derivative chiral stationary phase according to claim 7, it is characterized in that in regioselectivity beta-cyclodextrin derivative chiral stationary phase: the ratio of mixed solvent: whiteruss=1g:20～30ml:5～10ml, regioselectivity beta-cyclodextrin derivative chiral stationary phase is joined in mixed solvent and whiteruss, the ultrasonic suspension slurry that shakes into, with packing column machine, under 30～40MPa, pack in stainless steel liquid phase chromatographic column, obtain beta-cyclodextrin derivative chiral chromatographic column.
9. the application of a regioselectivity beta-cyclodextrin derivative chiral stationary phase claimed in claim 1, it is characterized in that: regioselectivity cyclodextrin derivative chiral chromatographic column is mainly used in the high performance liquid chromatography under positive, anti-phase and polar organic solvent pattern, and partially racemic compound is had to certain Chiral Separation Ability.
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