CN102389782B - Triazole singly-bonded fully-substituted cyclodextrin silica gel chiral fixed phase and preparation method thereof - Google Patents
Triazole singly-bonded fully-substituted cyclodextrin silica gel chiral fixed phase and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a click reaction based preparation method and use of a triazole singly-bonded fully-substituted cyclodextrin silica gel chiral fixed phase. In the method, the triazole singly-bonded fully-substituted cyclodextrin silica gel chiral fixed phase with high chemical stability is prepared by the selective azidation of the position 6 of cyclodextrin and full substitution and alkynylation of silica gel, by using a newly developed catalyst and by a click reaction, and the structural design of cyclodextrin is enriched. The triazole singly-bonded fully-substituted cyclodextrin silica gel chiral fixed phase demonstrates high chiral resolution capacity for amino acid and acidic and neutral racemate medicines and is expected to be used in field of medicine chiral resolution of various chromatographic techniques as a chiral fixed phase.
Description
Technical field
The invention belongs to the chiral resolution field of medicine racemic modification, successfully prepared a class triazolyl singly-bound and closed full substituted cyclodextrin-silica gel chiral fixed phase, can be applicable in the medicine chiral resolution and preparation of various chromatographic techniques.
Background technology
Cyclodextrin (Cyclodextrin, CD) utilizes α-(Isosorbide-5-Nitrae) glycosidic bond to connect by 7 D-Glucose molecules, and shape is the cyclic oligomeric glycan molecule of truncated cone-shaped.Its cavity inner side is by the oxygen atom of two circle hydrogen atoms (H-3 and H-5) and a circle glycosidic bond under the shielding in c h bond, so cyclodextrin inner chamber is hydrophobic, the outside frame of cyclodextrin molecular is because the gathering of hydroxyl is hydrophily.Based on the cave-shaped hydrophobic pocket of cyclodextrin, under three-dimensional effect impact, become the supramolecular system with molecule distinguishability by Van der Waals force, electrostatic attraction, hydrogen bond force, π-π interaction and hydrophobic interaction.Molecular recognition is the intermolecular selectivity combination of similar " lock & key ", can be understood as selective bonding between substrate and given acceptor.Nearest two during the last ten years, and a large amount of chemical modification cyclodextrin are synthesized out, thereby expanded the recognition capability of guest molecule and selective.The two positive center beta-schardinger dextrin-s of two replacements carry out further chemical modification and structure optimization to cyclodextrin just on this basis, make it have better chiral separation performance.
The medicine with chirality often occurs with the form of racemic modification, contains levo form and the d-isomer of equivalent.Enantiomer often has different pharmacological actions: the effect of (1) medicine completely or depend primarily on wherein a kind of enantiomer; The pharmacological action of (2) two kinds of enantiomers is completely contrary; (3) a kind of enantiomer has strong toxic and side effect.Due to these differences, the exploitation of individual isomer medicine develops rapidly, and in the new drug that the world is developing and ratifying to produce at present, having over half is individual isomer.The method of at present desirable synthetic individual isomer medicine not yet forms, and common method is asymmetric syntheses and biological enzyme, these two kinds of problems such as method ubiquity cost is high, yield is low.Therefore, chiral resolution becomes people with solving the main approach that individual isomer is prepared problem.
The analytical instrument such as high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), Capillary Electrophoresis (CE) are widely used in chiral separation.In chromatographic separation technology, HPLC technology is with fastest developing speed, a kind of Analytical Separation of being most widely used at present, the purity testing that is applied to just more and more chirality sample separates with the preparation of chirality sample, has become indispensable efficient, quick, the sensitive Analyze & separate means in biological and chemical laboratory.Utilize HPLC to carry out medicine chiral resolution, the exploitation of chiral chromatographic column is most important, and its core is chiral stationary phase, i.e. the exploitation of filler matrix chemically bonded chiral selective agent.
Cyclodextrin (CD) and derivative thereof occupy an important position in chiral stationary phase (Chiral stationary phase, CSP).Cyclodextrin chiral is fixing to be mainly connected in chiral selector on suitable filler by chemical bond key as CD and derivative thereof by chemical method mutually.CD and derivative thereof are that the difference of its clathration provides the basis of chiral resolution based on forming host-guest complexation thing between CD hydrophobic cavity and enantiomer to the fractionation mechanism of medicine.By replacing the upper single or multiple hydroxyls of CD, a large amount of CD chiral resolving agents are developed, these derivatives have effectively changed the cavity size of CD, increase the inclusion complexation effect between CD and Yao Wu Dui Showing-that-momentum-turning body, also can bring extra electrostatic interaction by introducing charged type group simultaneously, more increase the interaction of CD and chiral molecules, thereby improved chiral Recognition and fractionation ability to chiral molecules.
The development of cyclodextrin CSPs can be traced back to amide groups and the alkyl linked falope ring dextrin of the urea chiral stationary phase of nineteen eighty-three exploitation; These CSPs can realize the effective selectivity of aromatic is separated, but the water-disintegrable of amido and urea alkyl makes it cannot be used for water-based mobile phase.For this reason, Armstrong develops the HP-β-CD chiral stationary phase (USP 4539399) that ether key connects, and has proposed the clathration mechanism of CD CSPs chiral resolution.The CD derivative of these early developments mostly replaces at random hydroxyl on CD ring by substituting group and obtains, substituting group position and quantity are difficult to control, therefore obtain CSPs in chiral separation repeatability and stability be difficult to guarantee, and the CD derivative of different batches structurally there are differences, bring inconvenience to practical application.In addition, the uncertainty of CD structure has limited the further investigation to split process and fractionation mechanism.Therefore structure is determined, individual isomer CD chiral resolving agent just seems particularly important.
Chromatogram worker has developed the definite CD CSPs of various structures in recent years.Wherein the little acute hearing of Wu (Ng Siu-Choon) seminar is devoted to for a long time structure and determines CD CSPs exploitation, by changing chemical bond and the mode between CD derivative and different-grain diameter silica gel, obtain the multiple serial CD CSPs (USP 6017458 that amido and urea groups key connect, USP 6720285, USP 6296768) successfully realize the chiral resolution to multiple aromatic alcohol, beta blocker, alkalescence, neutrality and weak acidic drug.The scientific research institutions such as the Dalian Chemistry and Physics Institute of the Chinese Academy of Sciences of China, the Lanzhou Chemistry and Physics Institute of the Chinese Academy of Sciences, Wuhan University, Beijing Institute of Technology, Nankai University have developed the CSPs that the key such as amide groups, imido grpup connects successively, and some chipal compounds have been obtained to good fractionation effect.
Unstability, chiral resolution medicament categories for the fixing phase bonding of the cyclodextrin chiral of current exploitation are limited, chiral resolution ability has much room for improvement.We have developed the click-reaction synthetic method of cyclodextrin-silica gel chiral fixed phase that the triazolyl singly-bound of chemical stability excellence closes, and utilize HPLC to explore it to amino acids, acidity and neutral racemic drug chiral separation performance for means, verify the chiral resolution ability of its wide spectrum.The present invention is by the selective Azide to 6 of beta-schardinger dextrin-s, the alkynyl of full replacementization and silica gel, utilize catalyst newly developed to pass through click-reaction, and then the triazolyl singly-bound of having prepared chemical stability excellence closes the cyclodextrin-silica gel chiral fixed phase of full replacement, verify its efficient chiral resolution ability to amino acids, acidity and neutral racemic drug within the scope of broad pH.
Summary of the invention
Goal of the invention
The object of the present invention is to provide a kind of to by Azide and the full cyclodextrin replacing and the functionalized silica gel of alkynyl under the catalysis of triphenylphosphine-cupric iodide complex, the method for preparing triazolyl singly-bound and closing full substituted cyclodextrin-silica gel chiral fixed phase by click-reaction.Problem to be solved by this invention is to realize by following technical solution.
Technical scheme
Triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase, it is characterized in that described triazolyl singly-bound closes the structural formula of full substituted cyclodextrin-silica gel chiral fixed phase as follows:
。
Described pore can be 60,100,120,200 or 300.
Triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase, it is characterized in that obtaining according to the following steps:
The first step, obtains product to Methyl benzenesulfonyl base imidazoles by the reaction of p-methyl benzene sulfonic chloride and imidazoles, wherein toluene sulfonyl chloride with imidazoles reaction equivalent than 1:2 ~ 1:3;
Second step, first step products therefrom is placed in to the aqueous solution that dissolves cyclodextrin to Methyl benzenesulfonyl base imidazoles, after stirring, add sodium hydroxide solution, crossing leaching filtrate adds ammonium chloride to regulate pH 6 ~ 9, obtain product 6-to Methyl benzenesulfonyl base-cyclodextrin (Ts-CD), vacuum drying product; Wherein beta-schardinger dextrin-with to Methyl benzenesulfonyl base imidazoles reaction equivalent than 1:1 ~ 1:2;
The 3rd step, is dissolved in deionized water by the product 6-of second step to Methyl benzenesulfonyl base-cyclodextrin (Ts-CD), then in solution, adds sodium azide, stirring and refluxing, concentrated, concentrate adds 1,1, and 2, in 2-tetrachloroethanes, separate out solid, vacuum drying obtains 6-azido-cyclodextrin; Wherein 6-is to Methyl benzenesulfonyl group-beta-cyclodextrin and reaction of sodium azide equivalent proportion 1:15 ~ 1:25;
The 4th step, the product 6-azido-cyclodextrin of the 3rd step is dissolved in to N, dinethylformamide, then in solution, dropwise add sodium hydride, (or 6-azido-cyclodextrin is dissolved in pure pyridine after a small amount of bubble releases, to add lentamente iodomethane to carry out full substitution reaction, add phenyl isocyanate (or halo phenyl isocyanate) to carry out full substitution reaction, decompression distillation is except desolventizing), gained mixture is extracted with ethyl acetate 3 times, getting organic layer washes after 3 times, anhydrous magnesium sulfate drying, after revolving steaming, obtain crude product, after crude product purifying, obtain 6-azido-full replacement-cyclodextrin, wherein with 6-azido-cyclodextrin with full substituted reactant reaction equivalent than 1:20 ~ 1:80,
The 5th step, is dissolved in APTES in anhydrous dichloroethanes, adds propiolic acid, stir, reactant mixture is cooling after, slowly add dicyclohexylcarbodiimide, reaction at the same temperature, filter, get filtrate and steam instrument removal dichloroethanes with revolving, then use dilution with toluene, revolve and boil off except toluene, repeat after twice, vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides; Wherein APTES with propiolic acid reaction equivalent than 1:1 ~ 1:3;
The 6th step, the silica gel of vacuum drying will be added in round-bottomed flask, first vacuumize then and lead to nitrogen twice, under nitrogen protection, successively the 5th step product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides and dry toluene are added to flask, stirring and refluxing, filters, by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying; Wherein N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides and silica gel weight ratio are 1:3 ~ 1:8,
The 7th step, adds cupric iodide and acetonitrile in reaction flask successively, then to the acetonitrile solution that adds triphenylphosphine in solution, stirring reaction, filters, and with acetonitrile washing, vacuum drying obtains product triphenylphosphine-cupric iodide complex; Wherein triphenylphosphine is 1:1 ~ 1:1.5 with cupric iodide reaction equivalent ratio;
The 8th step, the functionalized silica gel of the 6th step product alkynyl is added in reaction flask, first vacuumize then logical nitrogen twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-cyclodextrin, DMF and the 7th step product triphenylphosphine-cupric iodide complex, stirring and refluxing, cold filtration, with DMF washing, adopts methyl alcohol to carry out Soxhlet and extracts purifying, vacuum drying, obtains product: triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase; Wherein 6-azido-full replacement-beta-schardinger dextrin-is 1:1.2 ~ 1:2 with the functionalized silica gel reaction equivalent ratio of alkynyl; 6-azido-full replacement-beta-schardinger dextrin-is 1:0.05 ~ 1:0.15 with the reaction equivalent ratio of triphenylphosphine-cupric iodide complex;
In the first step, solution is carrene, under room temperature and anaerobic anhydrous response system, carries out;
In second step, stir 2 ~ 4 h, the sodium hydroxide solution mass fraction adding is 10 ~ 30%; The CD of described cyclodextrin is alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin;
In second step, add ammonium chloride to regulate pH to 6 ~ 9;
In the 3rd step, stirring and refluxing temperature is 80 ~ 90
oc, the reaction time is 8 ~ 12 h;
Four-step reaction is in room temperature (or 80 ~ 90
oc) under, carry out, the reaction time is 12 ~ 15 h, and crude product is through ethyl acetate/acetone (or ethyl acetate/n-hexane) purifying;
The 5th step is reacted-5 ~ 10
ounder C, carry out, the reaction time is 1 ~ 4 h, crude product through low boiling point solvent as the dilutions such as toluene and purifying;
Stirring and refluxing temperature 70 ~ 140 in the 6th step
oc, reaction is carried out under anaerobic water-less environment;
In the 7th step system first by triphenylphosphine dissolved in acetonitrile, 25
oc reacts 1 ~ 4 h;
In the 8th step, stirring and refluxing temperature is 80 ~ 160
oc, the reaction time is 24 ~ 36 h.
The particle diameter of the silica gel described in the 9th step is 1.8 μ m, 3 μ m, 5 μ m, 10 μ m, 20 μ m, 50 μ m, and its aperture is 60,100,120,200,300.
beneficial effect
The present invention is by carrying out Azide to 6 of beta-schardinger dextrin-hydroxyls, after full replacement, again with the functionalized silica gel of alkynyl under the catalysis of triphenylphosphine-cupric iodide complex by click-reaction, finally prepare triazolyl singly-bound and close full substituted cyclodextrin-silica gel chiral fixed phase.Triazolyl singly-bound closes chiral separation and the preparation field that full substituted cyclodextrin-silica gel chiral fixed phase can be widely used in various chromatographic techniques China and foreign countries racemic drug.
Compared with prior art, its remarkable advantage: (1) passes through click-reaction can be prepared triazolyl singly-bound and close the cyclodextrin-silica gel chiral fixed phase of full replacement on the silica gel of any particle diameter in the present invention; (2) utilize click-reaction to prepare triazolyl singly-bound and close the cyclodextrin of full replacement, wherein cyclodextrin comprises applicable to cyclodextrin and the derivative thereof of any Azide: alpha-cyclodextrin, beta-schardinger dextrin-and gamma-cyclodextrin; (3) triphenylphosphine-cupric iodide complex of preparing in the present invention can successfully be realized the click-reaction of cyclodextrin system, and common click-reaction catalyst can not the above-mentioned reaction of catalysis; (4) preparation that triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase has the chemo-selective of height, and therefore structure has certainty; (5) triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase and has than the fixing more excellent ph stability mutually of the cyclodextrin chiral of other reports, and triazolyl all can keep chemically stable in the normally used buffer solution of chromatogram; (6) triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase in split process, can realize the broad-spectrum high efficacy that the two property compounds of amino acids, acidity and neutral racemic drug are realized in broad pH of buffer scope simultaneously and split; (7) triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase and can utilize the technology such as liquid chromatogram, Supercritical fluid chromatography, gas-chromatography and electrochromatography to obtain extensive use in medicine chiral separation field.
Brief description of the drawings
Fig. 1 is that click-reaction that the present invention reports is prepared triazolyl singly-bound and closed the preparation method's of full substituted cyclodextrin-silica gel chiral fixed phase schematic flow sheet;
Fig. 2,3 close the fractionation effect of full acid amides benzene group-beta-cyclodextrin-silica gel chiral fixed phase (CCP-CSP) to medicine for triazolyl singly-bound.
Detailed description of the invention
Below in conjunction with accompanying drawing, the present invention is described in further detail.
Embodiment 1: taking beta-schardinger dextrin-as example
By reference to the accompanying drawings, triazolyl singly-bound of the present invention closes the preparation method of full replacement-beta-schardinger dextrin--silica gel chiral fixed phase, comprises the following steps:
The first step, by p-methyl benzene sulfonic chloride and imidazoles, room temperature reaction in carrene obtains Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the first step products therefrom aqueous solution that dissolves beta-schardinger dextrin-to Methyl benzenesulfonyl base imidazoles, after stirring at room temperature reaction 2 ~ 4 h, add sodium hydroxide solution, filters and removes a small amount of sediment producing; In filtrate, add ammonium chloride to regulate its pH value to 6 ~ 9 to obtain white solid matter, filter and obtain product to Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-CD), vacuum drying product;
The 3rd step, gets twoport round-bottomed flask, and the product 6-of second step is dissolved in to deionized water to Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-CD), then in solution, add sodium azide, stirring and refluxing, reaction is spent the night, with Rotary Evaporators, solution is concentrated, concentrate adds 1, in 1,2,2-tetrachloroethanes, separate out solid, vacuum drying obtains 6-azido-beta-cyclodextrin;
The 4th step, the product 6-azido-beta-cyclodextrin of the 3rd step is dissolved in to DMF, then in solution, dropwise add sodium hydride, after a small amount of bubble releases, add lentamente iodomethane, full substitution reaction 12 ~ 15 h, gained mixture is extracted with ethyl acetate 3 times, get after organic layer washing 3 times, anhydrous magnesium sulfate drying, obtains crude product after revolving steaming, after crude product is purified with ethyl acetate/acetone, obtain 6-azido-full replacement-beta-schardinger dextrin-;
The 5th step, is dissolved in APTES in anhydrous dichloroethanes, adds propiolic acid, stir, reactant mixture is cooling after, slowly add dicyclohexylcarbodiimide, reaction at the same temperature, filter, get filtrate and steam instrument removal dichloroethanes with revolving, then use dilution with toluene, revolve and boil off except toluene, repeat after twice, vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, to the silica gel that adds vacuum drying in round-bottomed flask, first vacuumize then and lead to nitrogen twice, under nitrogen protection, successively the 5th step product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides and dry toluene are added to flask, stirring and refluxing, filters, by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, adds cupric iodide and acetonitrile in reaction flask successively, then to the acetonitrile solution that adds triphenylphosphine in solution, stirring reaction, filters, and with acetonitrile washing, vacuum drying obtains product triphenylphosphine-cupric iodide complex;
The 8th step, the functionalized silica gel of the 6th step product alkynyl is added in reaction flask, first vacuumize then logical nitrogen, repeat twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full replacement-beta-schardinger dextrin-, DMF and the 7th step product triphenylphosphine-cupric iodide complex, stirring and refluxing, cold filtration, with DMF washing, adopts methyl alcohol to carry out Soxhlet and extracts purifying, vacuum drying, obtains product: triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase;
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, toluene sulfonyl chloride with imidazoles reaction equivalent than 1:2 ~ 1:3.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, beta-schardinger dextrin-with to Methyl benzenesulfonyl base imidazoles reaction equivalent than 1:1 ~ 1:2.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, and 6-is to Methyl benzenesulfonyl group-beta-cyclodextrin and reaction of sodium azide equivalent proportion 1:15 ~ 1:25.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, 6-azido-beta-cyclodextrin with the reaction equivalent of iodomethane than 1:20 ~ 1:35.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, APTES with propiolic acid reaction equivalent than 1:1 ~ 1:3.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides and silica gel weight ratio are 1:3 ~ 1:8, and the particle diameter of silica gel can be 1.8 μ m, 3 μ m, 5 μ m, 10 μ m, 20 μ m are 50 μ m even, and its aperture can be 60,100,120,200,300.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, and triphenylphosphine is 1:1 ~ 1:1.5 with cupric iodide reaction equivalent ratio.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, 6-azido-full replacement-beta-schardinger dextrin-and the functionalized silica gel weight ratio of alkynyl are 1:1.2 ~ 1:2, and the equivalent proportion of 6-azido-full replacement-beta-schardinger dextrin-and triphenylphosphine-cupric iodide complex is 1:0.05 ~ 1:0.15; .
Below in conjunction with embodiment, the present invention is described in further detail.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, comprises the following steps:
The first step, get 250 mL twoport round-bottomed flasks and first vacuumize then logical nitrogen, take p-methyl benzene sulfonic chloride (6.57 g, 34.5 mmol) and add in flask, then add 30 mL dry methylene chloride, magnetic agitation is dissolved, claim again imidazoles (5.3 g, 77.8 mmol) to be dissolved in the dichloromethane solution that 30 mL are dry, be transferred in dropping funel, above-mentioned solution is dropwise splashed into (1 ~ 2 drop/sec) in flask, stirred overnight at room temperature.Reaction finishes to filter, and be concentrated into ~ 10 mL of filtrate splash in 40 mL hexane solutions, separate out white solid, filtration under diminished pressure, and n-hexane washing for precipitation, vacuum drying obtains product to Methyl benzenesulfonyl base imidazoles (7.3 g, productive rate 95%); Its structural characterization data are as follows, Mp:77-78
oc;
1h NMR (300 MHz, CDCl
3) δ: 8.03 (1H, s, N-CH=N), 7.10 (1H, s, N-CH=C), 7.31 (1H, s, N-CH=C), 7.35 (2H, d, H-Ar), 7.83 (2H, d, H-Ar) 2.46 (3H, s, CH
3);
13cNMR (75 MHz, CDCl
3) δ: 146.5,136.8,134.9,131.6,130.5,127.4,117.9,21.2; FTIR (KBr, cm
-1): 3159,3103,3032,1595,1516,1383,1151; ESI-MS (m/z): 223.03 [M+H]
+, calcd 223.05; Its reaction equation is:
Second step, beta-schardinger dextrin-needs first 50
oc activates 5 h; get 250 mL conical flasks; take dry beta-schardinger dextrin-(4.72 g; 4.16 mmol) join in bottle; inject 100 mL deionized waters, stir 0.5 ~ 2 h, add first step products therefrom to Methyl benzenesulfonyl base imidazoles (1.2 g; 5.40 mmol), stir lower room temperature reaction 2 ~ 4 h.The sodium hydroxide solution (8 mL) that adds again afterwards mass fraction 20%, stirs 0.5 hour, filters, get filtrate, add ammonium chloride, regulate pH value until 6 ~ 9, filter, precipitation vacuum drying obtains product to Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-β-CD); Its structural characterization data are as follows, Mp:165-167
oc; FTIR (KBr, cm
-1): 3400,2935,1647,1367,1159,1080,1031,582;
1hNMR (300 MHz, DMSO-
d6) δ: 7.73-7.76 (2H, d, H-Ar), 7.41-7.44 (2H, d, H-Ar), 5.62-5.84 (14H, m, OH-3 and OH-2), 4.83 (5H, d, H-1), 4.76 (2H, d, H-1), 4.41-4.48 (4H, m, OH-6), 4.28-4.35 (1H, m, OH-6), 4.15-4.2 (1H, m, OH-6), 3.3-3.6 (overlap with HDO, 42H, m, H-2, H-3, H-4, H-5 and H-6), 2.50 (3H, s, CH
3);
13cNMR (75MHz, DMSO-
d6) δ: 144.8,132.7,129.9,127.6,102.1,101.9,80.7,81.5,73.0,72.0,72.4,69.7,68.9,59.9,21.3. ESI-MS (m/z): 1311.2 [M+H]
+, calcd. 1311.6; Its reaction equation is:
The 3rd step; get 100 mL twoport flasks; take Methyl benzenesulfonyl group-beta-cyclodextrin (2.57 g; 1.9 mmol) be placed in twoport flask; add deionized water (150 mL); then take sodium azide (2.5 g, 38.4 mmol) and join in twoport flask 80 ~ 90
oc refluxes and spends the night, and after reaction finishes, crosses leaching filtrate, after reaction finishes, decompression distillation is concentrated into 10 mL left and right, and concentrate dropwise splashes into 1,1,2, in 2-tetrachloroethanes (3 mL), separate out white solid, filter, the drying precipitated product 6-azido-beta-cyclodextrin (1.9 g, productive rate 85%) that obtains; Its structural characterization data are as follows, Mp:208
oc; FTIR (KBr, cm
-1): 3,394 (O-H, str), 2,932 (C-H, m), 2,104 (N3, str);
1hNMR (300 MHz, DMSO-
d6 ) δ: 5.62-5.77 (m, 14H), 4.83-4.87 (m, 7H), 4.44-4.54 (m, 6H), 3.55-3.64 (m, 14H), 3.32-3.40 (s, 28H);
13cNMR (75 MHz, DMSO-
d6 ) δ: 102.2,101.6,82.4,81.2,73.4,73.0,72.1,70.7,60.1,51.4; ESI-MS (
m/z): calculated, 1,159; Found, 1,182.5 [M+Na]
+; Anal. Calcd. (%) for C
42h
71o
39n:C 43.6, H 6.02, N 3.18; Found (%): C 43.1, H 6.21, N 3.09; Its reaction equation is:
The 4th step, get 100 mL twoport round-bottomed flasks and first vacuumize then logical nitrogen, take 6-azido-beta-cyclodextrin (2.0 g, 1.7 mmol) and add in flask, then add the DMF that 30 mL are dry, magnetic agitation is dissolved, dropwise add again the sodium hydride (2.0 g, 84.0 mmol) removing after kerosene, after a small amount of bubble releases, add lentamente iodomethane (5 ml, 35.0 mmol), stirring at room temperature 12 ~ 15 h.Reaction finishes to be extracted with ethyl acetate 3 times, gets after organic layer washing 3 times, and anhydrous magnesium sulfate drying, after revolving crude product ethyl acetate/acetone after steaming and purifying, obtains 6-azido-permethylated-beta-schardinger dextrin-(1.9 g, productive rate 78%); Its structural characterization data are as follows, Mp:96-99 DEG C;
1h NMR (300 MHz, CDCl
3) δ: 3.15-3.24 (7H, m, H-5), 3.40 (18H, s, OCH
3), 3.50-3.95 (77H, m, H-2, H-3, H-4, H-6 and OCH
3), 5.05 (1H, d, H-1
a), 5.13 (6H, d, H-1);
13c NMR (75 MHz, CDCl
3) δ: 52.0,58.4,58.6 (2-CH
3), 58.8 (6-CH
3), 61.2,61.3,61.4 (3-CH
3), 70.7,70.8,71.0 (C-5); 71.2,71.3,71.5 (C-6); 79.9,80.0,80.2; 88.3 (C-4), 81.3,81.7 (C-2); 81.8,82.0 (C-3), 98.3; 98.8,99.0,99.2 (C-1); FTIR (KBr, cm
-1): 2930,2104 (N
3str), 1030; ESI-MS (m/z): 1462.7 [M+Na]
+, calcd. 1462.4; Anal. Calcd. (%) for C
62h
109n
3o
34: C 51.7, H 7.62, N 2.92; Found (%): C 52.1, H 7.97, N 2.56; Its reaction equation is:
The 5th step, is cooled to-10 ~ 5 by 50 mL twoport flask reactors
oc, take APTES (2.5 g, 10.8 mmo) add in flask, add the dichloroethanes that 15mL is dry with syringe, stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g, 12.0 mmol), under same low temperature, react 2 h.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, use again dilution with toluene, revolve and boil off except toluene, repeat after twice, vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (2.4 g, productive rate 80%); Its structural characterization data are as follows, FTIR (KBr, cm
-1): 2120 (C ≡ CH, str);
1hNMR (300 MHz, CDCl
3) δ: 7.11 (m, 1H), 3.72-3.79 (s; 6H), 3.21-3.27 (s, 2H); 2.28 (s; 1H), 1.58-1.63 (s, 2H); 1.14-1.19 (s; 9H), 0.56-0.61 (s, 2H); ESI-MS (
m/z): calcld., 273; Found, 296.1 [M+Na]
+; Its reaction equation is:
The 6th step, gets 150 mL twoport flasks, takes 160
o(4 g) add in flask for the 5 μ m silica gel of C vacuum drying 12 h; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying; Its structural characterization data are as follows, FTIR (KBr, cm
-1): 2121 (C ≡ CH str); Anal. found (%): C 5.32, H 0.99, N 0.85; Its reaction equation is:
The 7th step, get 25 mL twoport flasks, take triphenyl phosphorus (0.69 g, 2.63 mmol) join in flask, then add acetonitrile (10 mL), afterwards to CuI (0.50 g, the 2.63 mmol) acetonitrile solution that slowly adds 50 mL in reaction system, 20 ~ 40
ounder C, react 1 h; Filter through acetonitrile washing, vacuum drying obtains the complex (0.92 g, productive rate 80%) of triphenyl phosphorus and cupric iodide; Its structural characterization data are as follows, IR (KBr, cm
-1): 1479,1434,1097,748,695,521,503; Anal. Calcd. (%) for C
18h
15pCuI:C 47.6, H 3.31; Found (%): C, 47.2; H, 3.29; Its reaction equation is:
The 8th step, get 100 mL twoport flasks, (4 g) to add wherein the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full replacement-beta-schardinger dextrin-(3 g, 2.47 mmol), DMF (40 mL) and the 7th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase, its structural characterization data are as follows, FTIR (KBr, cm
-1): 2933. Anal. found:C 16.62%, H 2.616%, N 1.63%, cyclodextrin is 0.48 μ mol m in the load factor of 5 μ m Silica Surfaces
-2, its reaction equation is:
Embodiment 2: taking beta-schardinger dextrin-as example
The triazolyl singly-bound with wide spectrum chiral resolution ability closes full methyl flamprop-silica gel chiral fixed phase preparation method, it is characterized in that comprising the following steps:
The first step, based on the mechanism of nucleophilic displacement of fluorine, p-methyl benzene sulfonic chloride 1 mol and imidazoles 3 mol in carrene, 25
oc reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the aqueous solution that is dissolved with 1 mol beta-schardinger dextrin-, 25 by first step products therefrom to Methyl benzenesulfonyl base imidazoles 2 mol
oafter C stirring reaction 4 h, adding quality percentage composition is 30 % sodium hydrate aqueous solutions, filters; In filtrate, add ammonium chloride to regulate its pH value to 8 acquisition white solid matter, filter, precipitation vacuum drying obtains product to Methyl benzenesulfonyl group-beta-cyclodextrin;
The 3rd step, take Methyl benzenesulfonyl group-beta-cyclodextrin (2.5 g, 1.9 mmol) be placed in twoport flask, add deionized water (150 mL), then take sodium azide (2.5 g, 38.4 mmol) and join in twoport flask, 80 ~ 90 DEG C of backflows are spent the night, after reaction finishes, cross leaching filtrate, after reaction finishes, decompression distillation is concentrated into 10 mL left and right, concentrate dropwise splashes into 1,1,2, in 2-tetrachloroethanes (3 mL), separate out white solid, filter, the drying precipitated product 6-azido-beta-cyclodextrin that obtains;
The 4th step, take 6-azido-beta-cyclodextrin (2.0 g, 1.7 mmol) add in flask, add the DMF that 30 mL are dry, magnetic agitation is dissolved, more dropwise adds sodium hydride (2.0 g that remove after kerosene again, 84.0 mmol), after releasing, a small amount of bubble adds lentamente iodomethane (7.2 ml, 51.0 mmol), stirring at room temperature 12h ~ 15h.Reaction finishes to be extracted with ethyl acetate 3 times, gets after organic layer washing 3 times, and anhydrous magnesium sulfate drying, after revolving crude product ethyl acetate/acetone after steaming and purifying, obtains 6-azido-permethylated-β-CD;
The 5th step, is cooled to reactor-10 ~ 5
oc, take APTES (2.4 g, 10.8 mmol) add in flask, add the dichloroethanes that 15mL is dry with syringe, stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g, 12.0 mmol), under same low temperature, react 2h.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, then use dilution with toluene, revolves and boils off except toluene, repeats after twice, and vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, takes 160
o(4 g) add in flask for the 5 μ m silica gel of C vacuum drying 12 h; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, take triphenyl phosphorus (0.69 g, 2.63 mmol) join in flask, then add acetonitrile (10 mL), afterwards to CuI (0.50 g that slowly adds 50 mL in reaction system, 2.63 mmol) acetonitrile solution reacts 1 h at 20 ~ 40 DEG C; Filter through acetonitrile washing, vacuum drying obtains the complex of triphenyl phosphorus and cupric iodide;
The 8th step, (4 g) to take the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-permethylated-β-CD (3 g, 2.47 mmol), DMF (40 mL) and the 7th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes permethylated-β-CD-silica gel chiral fixed phase,
embodiment 3taking alpha-cyclodextrin as example
The triazolyl singly-bound with wide spectrum chiral resolution ability closes full methyl flamprop-silica gel chiral fixed phase preparation method, it is characterized in that comprising the following steps:
The first step, based on the mechanism of nucleophilic displacement of fluorine, p-methyl benzene sulfonic chloride 1 mol and imidazoles 3 mol in carrene, 25
oc reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the aqueous solution that is dissolved with 1 mol alpha-cyclodextrin, 25 by first step products therefrom to Methyl benzenesulfonyl base imidazoles 2 mol
oafter C stirring reaction 4 h, adding quality percentage composition is 30% sodium hydrate aqueous solution, filters; In filtrate, add ammonium chloride to regulate its pH value to 8 acquisition white solid matter, filter and obtain product to Methyl benzenesulfonyl base-alpha-cyclodextrin, vacuum drying product;
The 3rd step, by the product 6-of second step to Methyl benzenesulfonyl base-alpha-cyclodextrin (2.7 g, 2.4 mmol) be dissolved in deionized water (150 mL), then in solution, add sodium azide (2.34 g, 36.0 mmol), 80 ~ 90 DEG C of backflows, after reaction finishes, cross leaching filtrate, decompression distillation is concentrated into 10 mL left and right, concentrate dropwise splashes into 1,1,2, in 2-tetrachloroethanes (3 mL), separate out white solid, filter, the drying precipitated product 6-azido-alpha-cyclodextrin that obtains; The 4th step, by product 6-azido-alpha-cyclodextrin (1.7 g of the 3rd step, 1.7 mmol) be dissolved in dry DMF (30 mL), then in solution, dropwise add sodium hydride (2.0 g that remove after kerosene, 84.0 mmol), after releasing, a small amount of bubble adds lentamente iodomethane (5 ml, 35.0 mmol), stirring at room temperature 12 ~ 15h.Reaction finishes to be extracted with ethyl acetate 3 times, gets after organic layer washing 3 times, and anhydrous magnesium sulfate drying, after revolving crude product ethyl acetate/acetone after steaming and purifying, obtains 6-azido-methyl-alpha-cyclodextrin entirely;
The 5th step, is cooled to 5 by reactor
oc, take APTES (2.4 g, 10.8 mmol) add in flask, add dry dichloroethanes (15 mL), stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (4.43 g, 21.6 mmol), at same temperature, react 2 h.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, then use dilution with toluene, revolves and boils off except toluene, repeats after twice, and vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, takes 160
othe particle diameter of C vacuum drying 12 h is that 5 μ m, aperture are that (4 g) add in flask 100 silica gel; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, and (particle diameter 5 μ m) to obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, take triphenyl phosphorus (0.69 g, 2.63 mmol) and join in flask, add acetonitrile (10 mL), then to CuI (0.50 g, the 2.63 mmol) acetonitrile solution that slowly adds 50 mL in reaction system.There is Precipitation several seconds.20 ~ 40
ounder C, react 1 h, filter through acetonitrile washing, vacuum drying obtains the complex of triphenyl phosphorus and cupric iodide;
The 8th step, (4 g) to take the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full methyl-alpha-cyclodextrin (3 g, 2.3 mmol), DMF (40 mL) and the 6th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes full methyl-alpha-cyclodextrin silica gel chiral fixed phase,
embodiment 4taking gamma-cyclodextrin as example
The triazolyl singly-bound with wide spectrum chiral resolution ability closes full methyl flamprop-silica gel chiral fixed phase preparation method, it is characterized in that comprising the following steps:
The first step, based on the mechanism of nucleophilic displacement of fluorine, p-methyl benzene sulfonic chloride 1 mol and imidazoles 3 mol in carrene, 25
oc reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the aqueous solution that is dissolved with 1 mol gamma-cyclodextrin, 25 by first step products therefrom to Methyl benzenesulfonyl base imidazoles 2 mol
oafter C stirring reaction 4 h, adding quality percentage composition is 30 % sodium hydrate aqueous solutions, filters; In filtrate, add ammonium chloride to regulate its pH value to 8 acquisition white solid matter, filter and obtain product to Methyl benzenesulfonyl base-gamma-cyclodextrin, vacuum drying product;
The 3rd step; the product 6-of second step is dissolved in to deionized water (150 mL) to Methyl benzenesulfonyl base-gamma-cyclodextrin (3.5 g, 2.4 mmol), then in solution, adds sodium azide (2.34 g; 36.0 mmol), 80 ~ 90
oc backflow, after reaction finishes, crosses leaching filtrate, and decompression distillation is concentrated into 10 mL left and right, and concentrate dropwise splashes in 1,1,2,2-tetrachloroethanes (3 mL), separates out white solid, filters, the drying precipitated product 6-azido-gamma-cyclodextrin that obtains;
The 4th step, by product 6-azido-gamma-cyclodextrin (2.2 g of the 3rd step, 1.7 mmol) be dissolved in dry DMF (30 mL), then in solution, dropwise add sodium hydride (2.0 g that remove after kerosene, 84.0 mmol), after releasing, a small amount of bubble adds lentamente iodomethane (5 ml, 35.0 mmol), stirring at room temperature 12 ~ 15 h.Reaction finishes to be extracted with ethyl acetate 3 times, gets after organic layer washing 3 times, and anhydrous magnesium sulfate drying, after revolving crude product ethyl acetate/acetone after steaming and purifying, obtains 6-azido-permethylated-gamma-cyclodextrin;
The 5th step, is cooled to 5 by reactor
oc, take APTES (2.4 g, 10.8 mmol) add in flask, add dry dichloroethanes (15 mL), stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g, 12.0 mmol), at same temperature, react 2h.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, then use dilution with toluene, revolves and boils off except toluene, repeats after twice, and vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, takes 160
oafter C vacuum drying 12 h, particle diameter is that 3 μ m, aperture are that (4 g) add in flask 100 silica gel; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, and (particle diameter 3 μ m) to obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, take triphenyl phosphorus (0.69 g, 2.63 mmol) and join in flask, add acetonitrile (10 mL), then to CuI (0.50 g, the 2.63 mmol) acetonitrile solution that slowly adds 50 mL in reaction system.There is Precipitation several seconds.20 ~ 40
ounder C, react 1 h, filter through acetonitrile washing, vacuum drying obtains the complex of triphenyl phosphorus and cupric iodide;
The 8th step, (4 g) to take the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full methyl-gamma-cyclodextrin (3 g, 2.3 mmol), DMF (40 mL) and the 6th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes full methyl-gamma-cyclodextrin-silica gel (m) chiral stationary phase of 3 μ, cyclodextrin is 0.59 μ mol m in the load factor of 3 μ m Silica Surfaces
-2,
embodiment 5taking beta-schardinger dextrin-as example
The triazolyl singly-bound with wide spectrum chiral resolution ability closes full acid amides phenylating cyclodextrin-silica gel chiral fixed phase preparation method, it is characterized in that comprising the following steps:
The first step, based on the mechanism of nucleophilic displacement of fluorine, p-methyl benzene sulfonic chloride 1 mol and imidazoles 3 mol in carrene, 25
oc reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the aqueous solution that is dissolved with 1 mol beta-schardinger dextrin-, 25 by first step products therefrom to Methyl benzenesulfonyl base imidazoles 2 mol
oafter C stirring reaction 4 h, adding quality percentage composition is 30 % sodium hydrate aqueous solutions, filters; In filtrate, add ammonium chloride to regulate its pH value to 8 acquisition white solid matter, filter, precipitation vacuum drying obtains product to Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-β-CD);
The 3rd step, takes Methyl benzenesulfonyl group-beta-cyclodextrin (2.5 g, 1.9 mmol) is placed in to twoport flask; add deionized water (150 mL); then take sodium azide (2.5 g, 38.4 mmol) and join in twoport flask 80 ~ 90
oc refluxes and spends the night, and after reaction finishes, crosses leaching filtrate, after reaction finishes, decompression distillation is concentrated into 10 mL left and right, and concentrate dropwise splashes into 1,1,2, in 2-tetrachloroethanes (3 mL), separate out white solid, filter, the drying precipitated product 6-azido-beta-cyclodextrin that obtains;
The 4th step, get 100 mL twoport round-bottomed flasks and first vacuumize then logical nitrogen, take 6-azido-beta-cyclodextrin (2.23 g, 1.92 mmol) add in flask, add the pyridine that 35 mL are dry, magnetic agitation is dissolved, more dropwise adds phenyl isocyanate (13.44 g again, 35.0 mmol), stirred overnight at 85 DEG C of temperature.Reaction end decompression distillation removes desolventizing and obtains yellowish-brown gel, add ethyl acetate (140 mL), after stirring 2 h, add deionized water (60 mL), cross leaching organic layer anhydrous magnesium sulfate drying, filter, after revolving crude product ethyl acetate/n-hexane after steaming and purifying, obtain 6-azido-full acid amides benzene group-beta-cyclodextrin (3.3 g, productive rate 49%); Its structural characterization data are as follows, Mp:225-227 DEG C;
1h NMR (300 MHz, CDCl
3) δ: 3.98 (7H, m, H-4); 4.44-4.63 (21H, m, H-1; H-5 and H-6), 5.15-5.22 (14H, m; H-2), 5.59 (7H, m; H-3), 6.88-7.45 (120H, m; NHCO, H-Ar);
13c NMR (75 MHz, CDCl
3) δ: 54.0,60.1 (C-6), 9.5-69.8 (C-2), 70.4-70.7 (C-5), 72.3 (C-3), 98.4 (C-1), 118.0-128.2 (C-Ar); FTIR (cm
-1, KBr): 3396,3317,2106 (N
3str), 1739,1602,1500; ESI-MS (m/z): 3676.2 [M+K]
+, calcd 3677.1; Anal. Calcd (%) for C
187h
175n
23o
56: C 61.7, H 4.65, N 8.85, found (%): C 61.3, H 68, N 8.85; Its reaction equation is:
The 5th step, is cooled to reactor-10 ~ 5
oc, take APTES (2.4 g, 10.8 mmo) add in flask, add the dichloroethanes that 15mL is dry with syringe, stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g, 12.0 mmol), under same low temperature, react 2h.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, then use dilution with toluene, revolves and boils off except toluene, repeats after twice, and vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, takes 160
o(4 g) add in flask for the 5 μ m silica gel of C vacuum drying 12 h; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, takes triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in flask, then add acetonitrile (10 mL), afterwards to CuI (0.50 g, the 2.63 mmol) acetonitrile solution that slowly adds 50 mL in reaction system, 20 ~ 40
ounder C, react 1 h; Filter through acetonitrile washing, vacuum drying obtains the complex of triphenyl phosphorus and cupric iodide;
The 8th step, (4 g) to take the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full acid amides benzene group-beta-cyclodextrin (3 g, 2.47 mmol), DMF (40 mL) and the 7th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes full acid amides benzyl ring dextrin-silica gel chiral fixed phase, its structural characterization data are as follows, FTIR (KBr, cm
-1): 1725,1448. Anal. found (%): C 12.49, H 1.79, N 1.98, cyclodextrin is 0.48 μ mol m in the load factor of 5 μ m Silica Surfaces
-2, its reaction equation is:
embodiment 6taking alpha-cyclodextrin as example
The first step, based on the mechanism of nucleophilic displacement of fluorine, p-methyl benzene sulfonic chloride 1 mol and imidazoles 3 mol in carrene, 25
oc reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the aqueous solution that is dissolved with 1 mol alpha-cyclodextrin, 25 by first step products therefrom to Methyl benzenesulfonyl base imidazoles 2 mol
oafter C stirring reaction 4 h, adding quality percentage composition is 30 % sodium hydrate aqueous solutions, filters; In filtrate, add ammonium chloride to regulate its pH value to 8 acquisition white solid matter, filter and obtain product to Methyl benzenesulfonyl base-alpha-cyclodextrin, vacuum drying product;
The 3rd step, by the product 6-of second step to Methyl benzenesulfonyl base-alpha-cyclodextrin (10.0 g, 7.8 mmol) be dissolved in deionized water (150 mL), then in solution, add sodium azide (10.0 g, 154.0 mmol), 80 ~ 90 DEG C of backflows, after reaction finishes, cross leaching filtrate, decompression distillation is concentrated into 10 mL left and right, concentrate dropwise splashes into 1,1,2, in 2-tetrachloroethanes (5 mL), separate out white solid, filter, the drying precipitated product 6-azido-alpha-cyclodextrin that obtains;
The 4th step, take product 6-azido-alpha-cyclodextrin (2.0 g of the 3rd step, 2.0 mmol) add in flask, add again the pyridine that 35 mL are dry, magnetic agitation is dissolved, dropwise add again phenyl isocyanate (14 g, 115.0 mmol), stirred overnight at 85 DEG C of temperature.Reaction end decompression distillation removes desolventizing and obtains yellowish-brown gel, add ethyl acetate (140 mL), after stirring 2 h, add deionized water (60 mL), cross leaching organic layer anhydrous magnesium sulfate drying, filter, after revolving crude product ethyl acetate/n-hexane after steaming and purifying, obtain 6-azido-acid amides phenylating-alpha-cyclodextrin entirely, its structural characterization data are as follows, m.p 198 ~ 202
oc; IR (KBr, cm
-1): 3398,3310 (
n-C=O, m); 3052 (sp
2c-H, m); 2946 (sp
3c-H, m); 1733 (C=O, s); 1610,1538,1443 (arom C=C ring, s); 1224,1080 (C-O-C, s);
13cNMR (75 MHz, DMSO-
d6 ) δ: 53.99 (C-6 '-N
3), 60.01 (C-6), 69.40-69.78 (C-2), 70.43-70.69 (C-5), 72.30 (C-3), 98.41 (C-1), (118.10-128.17 aromatic C), 148.52-152.49 (
c=O); Anal. Calcd. (%) for C
155h
144o
46n
20: C 61.59, H 4.80, N 9.27; Found (%): C 62.02, H 4.85, N 9.19; Its reaction equation is:
The 5th step, is cooled to 5 by reactor
oc, take APTES (2.4 g, 10.8 mmol) add in flask, add dry dichloroethanes (15 mL), stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (4.43 g, 21.6 mmol), at same temperature, react 2 h.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, then use dilution with toluene, revolves and boils off except toluene, repeats after twice, and vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, takes 160
othe particle diameter of C vacuum drying 12 h is that 5 μ m, aperture are that (4 g) add in flask 100 silica gel; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, take triphenyl phosphorus (0.69 g, 2.63 mmol) and join in flask, add acetonitrile (10 mL), then to CuI (0.50 g, the 2.63 mmol) acetonitrile solution that slowly adds 50 mL in reaction system.There is Precipitation several seconds.20 ~ 40
ounder C, react 1 h, filter through acetonitrile washing, vacuum drying obtains the complex of triphenyl phosphorus and cupric iodide;
The 8th step, (4 g) to take the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full replacement-alpha-cyclodextrin (3 g, 2.3 mmol), DMF (40 mL) and the 6th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes full substituted cyclodextrin silica gel chiral fixed phase,
embodiment 7taking gamma-cyclodextrin as example
The triazolyl singly-bound with wide spectrum chiral resolution ability closes full substituted cyclodextrin-silica gel chiral fixed phase preparation method, it is characterized in that comprising the following steps:
The first step, based on the mechanism of nucleophilic displacement of fluorine, p-methyl benzene sulfonic chloride 1 mol and imidazoles 3 mol in carrene, 25
oc reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
Second step, is placed in the aqueous solution that is dissolved with 1 mol gamma-cyclodextrin, 25 by first step products therefrom to Methyl benzenesulfonyl base imidazoles 2 mol
oafter C stirring reaction 4 h, adding quality percentage composition is 30% sodium hydrate aqueous solution, filters; In filtrate, add ammonium chloride to regulate its pH value to 8 acquisition white solid matter, filter and obtain product to Methyl benzenesulfonyl base-gamma-cyclodextrin, vacuum drying product;
The 3rd step; the product 6-of second step is dissolved in to deionized water (400 mL) to Methyl benzenesulfonyl base-gamma-cyclodextrin (10.0 g, 7.8 mmol), then in solution, adds sodium azide (10.0 g; 154.0 mmol), 80 ~ 90
oc backflow, after reaction finishes, crosses leaching filtrate, and decompression distillation is concentrated into 10 mL left and right, and concentrate dropwise splashes in 1,1,2,2-tetrachloroethanes (5 mL), separates out white solid, filters, the drying precipitated product 6-azido-gamma-cyclodextrin that obtains;
The 4th step, take product 6-azido-gamma-cyclodextrin (2.65 g of the 3rd step, 2.0 mmol) add in flask, add again the pyridine that 35 mL are dry, magnetic agitation is dissolved, dropwise add again phenyl isocyanate (14 g, 115.0 mmol), stirred overnight at 85 DEG C of temperature.Reaction end decompression distillation removes desolventizing and obtains yellowish-brown gel, add ethyl acetate (140 mL), after stirring 2 h, add deionized water (60 mL), cross leaching organic layer anhydrous magnesium sulfate drying, filter, after revolving crude product ethyl acetate/n-hexane after steaming and purifying, obtain 6-azido-acid amides phenyl-gamma-cyclodextrin entirely, its structural characterization data are as follows, Mp 212 ~ 215
oc; IR (KBr, cm
-1): 3392,3307 (
n-C=O, m); 3055 (sp
2c-H, m); 2948 (sp
3c-H, m); 1743 (C=O, s); 1614,1546,1449 (arom C=C ring, s); 1220,1083 (C-O-C, s);
13cNMR (75MHz, DMSO-
d 6 ) δ: 53.80 (C-6 '-N
3), 60.32 (C-6), 69.53-69.82 (C-2), 71.04-71.26 (C-5), 72.43 (C-3), 99.56 (C-1), (119.35-128.73 aromatic C), 148.46-153.61 (
c=O); Ana. Calcd (%) for C
209h
194o
62n
26: C 61.80, H 4.81, N 8.97; Found (%): C 62.13, H 4.95, N 8.84; Its reaction equation is:
The 5th step, is cooled to 5 by reactor
oc, take APTES (2.4 g, 10.8 mmo) add in flask, add dry dichloroethanes (15mL), stir, then add successively propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g, 12.0 mmol), react 2h at same temperature.Solution filter, filters, and gets filtrate and steams instrument removal dichloroethanes with revolving, then use dilution with toluene, revolves and boils off except toluene, repeats after twice, and vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
The 6th step, takes 160
oafter C vacuum drying 12 h, particle diameter is that 5 μ m, aperture are that (4 g) add in flask 100 silica gel; reaction system is first vacuumized to then logical nitrogen; repeatedly operate twice; under nitrogen protection successively by N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g; 3.66 mmol) add flask with dry toluene (50 mL), 120
ostirring and refluxing 12 ~ 20 h under C, filter, and by toluene wash, adopt acetone to carry out Soxhlet and extract purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step, take triphenyl phosphorus (0.69 g, 2.63 mmol) and join in flask, add acetonitrile (10 mL), then to CuI (0.50 g, the 2.63 mmol) acetonitrile solution that slowly adds 50 mL in reaction system.There is Precipitation several seconds.20 ~ 40
ounder C, react 1 h, filter through acetonitrile washing, vacuum drying obtains the complex of triphenyl phosphorus and cupric iodide;
The 8th step, (4 g) to take the functionalized silica gel of alkynyl, reaction system is first vacuumized to then logical nitrogen, repeatedly operate twice, under nitrogen protection, adding wherein successively the 4th step product 6-azido-full replacement-gamma-cyclodextrin (3 g, 2.3 mmol), DMF (40 mL) and the 6th step product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing, cold filtration, wash with DMF, adopt methyl alcohol to carry out Soxhlet and extract purifying, vacuum drying, obtain product: triazolyl singly-bound closes full acid amides phenyl-gamma-cyclodextrin-silica gel chiral fixed phase,
embodiment 8close full substituted cyclodextrin-silica gel chiral fixed phase and carry out chromatographic column filling test obtaining triazolyl singly-bound in embodiment 1-7:
1, by the sealing of empty stainless steel chromatogram post (Φ 4.6 × 250 mm) one end, the other end is connected with pre-column, pre-column one end is connected with HPLC pump by a storage tank afterwards again;
2, (wherein silica gel particle diameter is 3 μ m or 5 μ m triazolyl singly-bound to be closed to full substituted cyclodextrin-silica gel chiral fixed phase, aperture is 100) be scattered in methyl alcohol and prepare and fix phase slurry, the slurry stirring is added in above-mentioned storage tank, open HPLC pump, impose pressure 30 min of 8,000 psi to chromatographic column filling system.
3, close HPLC pump, wait system pressure to be kept to zero, take off populated chromatographic column, seal up for safekeeping at two ends, and this chromatographic column can be preserved 6 months under sealing state.
embodiment 9close full substituted cyclodextrin-silica gel chiral fixed phase chromatographic column medicine carried out to the test of HPLC chiral resolution obtaining triazolyl singly-bound in embodiment 1-7:
1,1% triethyl group ammonium acetate (TEAA) buffer solution is formulated by the 1% triethylamine aqueous solution, its pH value regulates by adding glacial acetic acid, TEAA/MeOH buffer solution is prepared by 1% TEAA and the MeOH that add different volumes ratio, and other mobile phases are by acetonitrile and water (ACN/H
2, or first alcohol and water (MeOH/H O)
2o) carry out according to a certain volume mixed configuration, the equal matching while using of all buffer solutions and mobile phase, after filtration, and utilizes DEGASYS DG-2410 degasser to get rid of air wherein.
2, selected raceme compound is dissolved in to methanol/water (50/50 v/v) preparation 0.2 g/mL standard liquid, adopts other all raceme solution of preparation that use the same method, the selected racemic drug splitting is as follows:
3, utilize by Waters 2695 HPLC pumps, the HPLC system of 2996 pairs of permutation pipe detectors of Waters (254 nm) composition, (3 μ m and 5 μ are chiral stationary phase chromatography post (CCM-CSP) m) to adopt triazolyl singly-bound to close permethylated-β-CD-silica gel, 10 kinds of racemies are carried out to chiral resolution, under different pH, all alcohols, beta-Blocking agent raceme are represented to excellent chiral resolution, result is as shown in table 1
Table 1. is based on the fractionation data of 5 μ m silica gel CCM-CSP to alcohols, beta-Blocking agent raceme
Splitting condition: flow velocity 0.7 mL/min; A, MeOH/H
2o 50/50 (v/v); B, ACN/H
2o 20/80 (v/v); C, 1% TEAA buffer solution (pH 6.5)/MeOH 70/30 (v/v); C, 1% TEAA buffer solution (pH 6.5)/MeOH 50/50 (v/v); D, 1% TEAA buffer solution (pH 6.5)/MeOH 80/20 (v/v). note: separation selectivity (α), separating degree (
r s )
Triazolyl singly-bound closes full acid amides benzene group-beta-cyclodextrin-silica gel chiral fixed phase (CCP-CSP) medicine has also been represented to excellent chiral resolution ability, and fractionation effect is wherein as Fig. 2, shown in 3:
embodiment 10close full substituted cyclodextrin-silica gel chiral fixed phase chromatographic column medicine carried out to capillary electric chromatogram (CEC) chiral resolution test obtaining triazolyl singly-bound in embodiment 1-7:
1, mobile phase is made up of acetonitrile and phosphate buffer solution: be specifically formulated as follows, sodium dihydrogen phosphate is dissolved in high purity water, its pH value regulates by adding 1M NaOH, the equal matching while using of all buffer solutions and mobile phase, after filtration, and utilize DEGASYS DG-2410 degasser to get rid of air wherein.
2, selected raceme compound is dissolved in to acetonitrile/water (40/60 v/v) preparation 0.2 g/mL standard liquid, adopts other all raceme solution of preparation that use the same method, the selected racemic drug splitting is as follows:
3, utilize by Waters 2695 HPLC pumps, the HPLC system of 2996 pairs of permutation pipe detectors of Waters (254 nm) composition, (3 μ m and 5 μ are chiral stationary phase chromatography post (CCP-CSP) m) to adopt triazolyl singly-bound to close full acid amides benzene group-beta-cyclodextrin-silica gel, 8 kinds of racemies are carried out to chiral resolution, under different pH, all aromatic alcohol raceme is represented to excellent chiral resolution, result is as shown in table 1
Table .2 is based on the fractionation data of 5 μ m silica gel CCP-CSP to aromatic alcohol raceme
Splitting condition: NaH
2pO
4buffer (5 mM, pH 7)/ACN (60/40 v/v); A, voltage, 10 kV; B, voltage, 5 kV. notes: separation selectivity (α), separating degree (Rs);
In sum, we have developed the click-reaction preparation method that triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase, explored its in high performance liquid chromatography as chiral resolving agent to amino acids raceme, acidity and neutral medicine chiral separation performance, experimental results show that it has the excellent chiral resolution ability of wide spectrum to amino acids raceme, acidity and neutral medicine.The present invention closes 6 Azides-full replacement-cyclodextrin and different-grain diameter alkynyl silica gel by click-reaction by the triazolyl singly-bound of chemical stability excellence, finally prepare triazolyl singly-bound and close full substituted cyclodextrin-silica gel chiral fixed phase, and within the scope of broad pH, several amino acids Two-way compound and acid racemic drug have been represented to efficient wide spectrum chiral resolution ability.This chiral resolving agent can be widely used in HPLC, CE, SFC even in SMB technology, realizes the wide spectrum fractionation to amino acids raceme, acidity and neutral racemic drug.
Claims (1)
1. triazolyl singly-bound closes the preparation method of full substituted cyclodextrin-silica gel chiral fixed phase, it is characterized in that obtaining according to the following steps:
The first step, obtains product to Methyl benzenesulfonyl base imidazoles by the reaction of p-methyl benzene sulfonic chloride and imidazoles, wherein p-methyl benzene sulfonic chloride with imidazoles reaction equivalent than 1:2 ~ 1:3;
Second step, first step products therefrom is placed in to the aqueous solution that dissolves cyclodextrin to Methyl benzenesulfonyl base imidazoles, after stirring, adds sodium hydroxide solution, cross leaching filtrate and add ammonium chloride to regulate pH 6 ~ 9, obtain product 6-to Methyl benzenesulfonyl group-beta-cyclodextrin, vacuum drying product; Wherein cyclodextrin with to Methyl benzenesulfonyl base imidazoles reaction equivalent than 1:1 ~ 1:2;
The 3rd step, is dissolved in deionized water by the product 6-of second step to Methyl benzenesulfonyl group-beta-cyclodextrin, then in solution, adds sodium azide, stirring and refluxing, concentrated, concentrate adds 1,1, and 2, in 2-tetrachloroethanes, separate out solid, vacuum drying obtains 6-azido-cyclodextrin; Wherein 6-is to Methyl benzenesulfonyl group-beta-cyclodextrin and reaction of sodium azide equivalent proportion 1:15 ~ 1:25;
The 4th step, the product 6-azido-cyclodextrin of the 3rd step is dissolved in to N, dinethylformamide, then in solution, dropwise add sodium hydride, after releasing, a small amount of bubble add lentamente iodomethane to carry out full substitution reaction, or 6-azido-cyclodextrin is dissolved in the pyridine of new distillation, add phenyl isocyanate or halo phenyl isocyanate to carry out full substitution reaction, except desolventizing, gained mixture is extracted with ethyl acetate, get organic layer washing, through anhydrous magnesium sulfate drying, after revolving steaming, obtain crude product, after crude product purifying, obtain 6-azido-full replacement-cyclodextrin, wherein 6-azido-cyclodextrin with full substituted reactant reaction equivalent than 1:20 ~ 1:80,
The 5th step, is dissolved in APTES in anhydrous dichloroethanes, adds propiolic acid, stir, reactant mixture is cooling after, slowly add dicyclohexylcarbodiimide, reaction at the same temperature, filter, remove dichloroethanes, then use dilution with toluene, remove toluene, repeat after twice, vacuum drying, obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group]-2-propine acid amides; Wherein APTES with propiolic acid reaction equivalent than 1:1 ~ 1:3;
The 6th step, the silica gel of vacuum drying will be added in round-bottomed flask, under nitrogen protection successively by the 5th step product N-[3-(three ethoxies are silica-based) propyl group]-2-propine acid amides and dry toluene add flask, stirring and refluxing, filter, by toluene wash, adopt acetone purifying, obtain the functionalized silica gel of product alkynyl through vacuum drying; Wherein N-[3-(three ethoxies are silica-based) propyl group]-2-propine acid amides and silica gel weight ratio be 1:3 ~ 1:8,
The 7th step, adds cupric iodide and acetonitrile in reaction flask successively, then to the acetonitrile solution that adds triphenylphosphine in solution, stirring reaction, filters, and with acetonitrile washing, vacuum drying obtains product triphenylphosphine-cupric iodide complex; Wherein triphenylphosphine is 1:1 ~ 1:1.5 with cupric iodide reaction equivalent ratio;
The 8th step, the functionalized silica gel of the 6th step product alkynyl is added in reaction flask, under nitrogen protection, add wherein successively again the 4th step product 6-azido-full replacement-cyclodextrin, N, dinethylformamide and the 7th step product triphenylphosphine-cupric iodide complex, stirring and refluxing, cold filtration, washs with DMF, adopt methyl alcohol purifying, obtain product: triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral fixed phase; Wherein 6-azido-full replacement-cyclodextrin and the functionalized silica gel equivalent proportion of alkynyl are 1:1.2 ~ 1:2; The equivalent proportion of 6-azido-full replacement-cyclodextrin and triphenylphosphine-cupric iodide complex is 1:0.05 ~ 1:0.15.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4318820A (en) * | 1980-02-25 | 1982-03-09 | Uop Inc. | Chiral supports for resolution of racemates |
| CN101259406A (en) * | 2007-12-17 | 2008-09-10 | 南京工业大学 | Preparation of bonding- affinity composite type polysaccharides chiral stationary phase |
| CN101372516A (en) * | 2008-08-14 | 2009-02-25 | 广州研创生物技术发展有限公司 | Beta-cyclodextrin derivative, preparation thereof and use as chiral selector |
| CN101745371A (en) * | 2008-12-17 | 2010-06-23 | 中国科学院大连化学物理研究所 | Preparation method of cyclodextrin bonded stationary phase |
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| US4318820A (en) * | 1980-02-25 | 1982-03-09 | Uop Inc. | Chiral supports for resolution of racemates |
| CN101259406A (en) * | 2007-12-17 | 2008-09-10 | 南京工业大学 | Preparation of bonding- affinity composite type polysaccharides chiral stationary phase |
| CN101372516A (en) * | 2008-08-14 | 2009-02-25 | 广州研创生物技术发展有限公司 | Beta-cyclodextrin derivative, preparation thereof and use as chiral selector |
| CN101745371A (en) * | 2008-12-17 | 2010-06-23 | 中国科学院大连化学物理研究所 | Preparation method of cyclodextrin bonded stationary phase |
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