CN102389782A - 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 one type of triazolyl singly-bound and closed full substituted cyclodextrin-silica gel chiral stationary phase, can be applicable in the medicine chiral resolution and preparation of various chromatographic techniques.
Background technology
(Cyclodextrin is to utilize α-(1,4) glycosidic bond to connect by 7 D-glucose molecules CD) to cyclodextrin, and shape is the cyclic oligomeric glycan molecule of truncated cone-shaped.Its cavity inboard is under the shielding of c h bond by the oxygen atom of two circle hydrogen atoms (H-3 and H-5) and a circle glycosidic bond, so the cyclodextrin inner chamber is hydrophobic, the outside frame of cyclodextrin molecular is then owing to the gathering of hydroxyl is hydrophily.Based on the cave-shaped hydrophobic pocket of cyclodextrin, under influence of space, make it become supramolecular system with molecule distinguishability by Van der Waals force, electrostatic attraction, hydrogen bond force, π-π interaction and hydrophobic interaction.Molecular recognition is that the intermolecular selectivity of similar " lock & key " combines, and is appreciated that to be selectivity 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 recognition capability and selectivity to guest molecule.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.
Medicine with chirality often occurs with the form of racemic modification, promptly contains the levo form and the d-isomer of equivalent.Enantiomer often has different pharmacological actions: the effect of (1) medicine fully perhaps depends primarily on wherein a kind of enantiomer; The pharmacological action of (2) two kinds of enantiomers is opposite fully; (3) a kind of enantiomer has strong toxic and side effect.Because these differences, the exploitation of individual isomer medicine develops rapidly, and having over half in the new drug that the world is developing and ratifying to produce at present is individual isomer.Problems such as the method for at present desirable synthetic individual isomer medicine does not form as yet, and common method is asymmetric syntheses and biological enzyme, and these two kinds of method ubiquity costs are high, yield is low.Therefore, chiral resolution becomes people with solving the main approach that individual isomer prepares problem.
High performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), Capillary Electrophoresis analysis instruments such as (CE) are widely used in chiral separation.In chromatographic separation technology; The HPLC technology is with fastest developing speed at present, the most a kind of Analytical Separation of application; Be applied to the purity testing of chirality sample and the preparation of chirality sample just more and more and separate, become indispensable efficient, quick, the sensitive analysis separation means in biological and chemical laboratory.Utilize HPLC to carry out the 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.
(Chiral stationary phase occupies an important position in CSP) at chiral stationary phase for cyclodextrin (CD) and derivative thereof.Cyclodextrin chiral is fixing mainly to be connected in chiral selector such as CD and derivative thereof on the suitable filler through the chemical bond key through chemical method mutually.CD and derivative thereof are based on formation host-guest complexation thing between CD hydrophobic cavity and enantiomer to the fractionation mechanism of medicine, and the difference of its clathration provides the basis of chiral resolution.By substituting one or more hydroxyl groups on the CD, CD number of chiral resolving agents have been developed, such derivatives effectively change the size of the cavity of the CD, the CD with the drug for increasing body showing that momentum turning inclusion complexation between, while also charging type group by introducing brings additional electrostatic interaction, adds CD interaction with chiral molecules, thereby increasing the chiral chiral recognition and resolution capabilities.
The development of cyclodextrin CSPs can be traced back to the 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 can't be used for water-based flowing phase.For this reason, Armstrong develops the HP-chiral stationary phase (USP 4539399) that the ether key connects, and has proposed the clathration mechanism of CD CSPs chiral resolution.The CD derivative of these early developments replaces hydroxyl on the CD ring at random by substituting group mostly and obtains; Substituting group position and quantity are difficult to control; Therefore the CSPs that obtains repeatability in chiral separation is difficult to assurance with stability; And the CD derivative of different batches structurally there are differences, and brought inconvenience to practical application.In addition, the uncertainty of CD structure has limited the further investigation to split process and fractionation mechanism.So structure is confirmed, the agent of individual isomer CD chiral resolution just seems particularly important.
The chromatogram worker has developed the CD CSPs that multiple structure is confirmed in recent years.Wherein the little acute hearing of Wu (Ng Siu-Choon) seminar is devoted to structure for a long time and confirms CD CSPs exploitation; Through changing chemical bond and the mode between CD derivative and different-grain diameter silica gel; (USP 6017458 to have obtained amido and urea groups key a plurality of serial CD CSPs even; USP 6720285, and USP 6296768) successfully realized chiral resolution to multiple aromatic alcohol, beta blocker, alkalescence, neutrality and weak acidic drug.Scientific research institutions such as the Dalian Chemistry and Physics Institute of China Chinese Academy of Sciences, 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 keys such as amide groups, imido grpup connect successively, some chipal compounds have been obtained split effect preferably.
To the cyclodextrin chiral of present exploitation fixedly limited, the chiral resolution ability of unstability, the chiral resolution drug kinds of phase bonding have much room for improvement.We have developed the click-reaction synthetic method of cyclodextrin-silica gel chiral stationary phase that the excellent triazolyl singly-bound of chemical stability closes; And utilize HPLC to explore it to amino acids, acidity and neutral raceme medicine chiral separation performance for means, verified the chiral resolution ability of its wide spectrum.The present invention is through the selectivity Azide to 6 of beta-schardinger dextrin-s; The alkynylization of full replacementization and silica gel; Utilize catalyst newly developed to pass through click-reaction; And then prepared the excellent triazolyl singly-bound of chemical stability and close complete substituted cyclodextrin-silica gel chiral stationary phase, verified its efficient chiral resolution ability in the pH of broadness scope to amino acids, acidity and neutral raceme medicine.
Summary of the invention
Goal of the invention
The object of the present invention is to provide a kind of to through Azide and complete substituted cyclodextrin and the functionalized silica gel of alkynyl under the catalysis of triphenylphosphine-cupric iodide complex, prepare the method that the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase through click-reaction.Problem to be solved by this invention is to realize through following technical solution.
Technical scheme
The triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase, and it is following to it is characterized in that described triazolyl singly-bound closes the structural formula of full substituted cyclodextrin-silica gel chiral stationary phase:
Described silica gel aperture can be 60,100,120,200 or 300.
The triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase, it is characterized in that obtaining according to the following steps:
The first step obtains product to Methyl benzenesulfonyl base imidazoles with p-methyl benzene sulfonic chloride and imidazoles reaction, wherein Methyl benzenesulfonyl chlorine and imidazoles reaction equivalent proportion 1:2 ~ 1:3;
Second step; First step products therefrom is placed the aqueous solution of dissolving cyclodextrin to Methyl benzenesulfonyl base imidazoles, stir the back and add sodium hydroxide solution, cross leaching filtrating and add ammonium chloride and 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 proportion 1:1 ~ 1:2;
The 3rd the step, with second the step product 6-Methyl benzenesulfonyl base-cyclodextrin (Ts-CD) is dissolved in deionized water, then in solution, add sodium azide, stirring and refluxing; Concentrate, concentrate adds 1,1,2; In the 2-tetrachloroethanes, separate out solid, vacuum drying gets 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 the step, with the 3rd the step product 6-azido-cyclodextrin be dissolved in N, dinethylformamide; Then in solution, dropwise add sodium hydride, add iodomethane after a small amount of bubble has discharged lentamente and carry out full substitution reaction (or 6-azido-cyclodextrin is dissolved in pure pyridine, and adding phenyl isocyanate (or halo phenyl isocyanate) carries out full substitution reaction; Decompression distillation removes and desolvates); The gained mixture is with ethyl acetate extraction 3 times, get organic layer washing 3 times after, anhydrous magnesium sulfate drying; Obtain crude product after revolving steaming; Behind the crude product purifying, get 6-azido-full replacement-cyclodextrin, wherein with 6-azido-cyclodextrin and full substituted reactant reaction equivalent proportion 1:20 ~ 1:80;
The 5th step was dissolved in the 3-aminopropyltriethoxywerene werene in the anhydrous dichloroethanes, added propiolic acid, stirred; After the reactant mixture cooling, slowly add dicyclohexylcarbodiimide, reaction under uniform temp is filtered; Getting filtrates steams appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene; After repeating twice, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides; Wherein 3-aminopropyltriethoxywerene werene and propiolic acid react equivalent proportion 1:1 ~ 1:3;
In the 6th step,, vacuumize logical then nitrogen earlier twice with the silica gel that adds vacuum drying in the round-bottomed flask; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides and dry toluene add flask with the 5th step product N-successively under nitrogen protection; Stirring and refluxing is filtered, and uses toluene wash; Adopt acetone to carry out Suo Shi and extract purifying, get 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 added cupric iodide and acetonitrile in the reaction flask successively, in solution, added the acetonitrile solution of triphenylphosphine again, and stirring reaction filters, and with the acetonitrile washing, vacuum drying gets product triphenylphosphine-cupric iodide complex; Wherein triphenylphosphine and cupric iodide reaction equivalent proportion is 1:1 ~ 1:1.5;
The 8th step added the functionalized silica gel of the 6th step product alkynyl in the reaction flask, vacuumized logical then nitrogen earlier twice; Under nitrogen protection, going on foot product 6-azido-cyclodextrin, N to wherein adding the 4th successively, dinethylformamide and the 7th step product triphenylphosphine-cupric iodide complex, stirring and refluxing; Cold filtration with the DMF washing, adopts methyl alcohol to carry out Suo Shi and extracts purifying; Vacuum drying obtains product: the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase; Wherein 6-azido-full replacement-beta-schardinger dextrin-and the functionalized silica gel reaction of alkynyl equivalent proportion are 1:1.2 ~ 1:2; The reaction equivalent proportion of 6-azido-full replacement-beta-schardinger dextrin-and triphenylphosphine-cupric iodide complex is 1:0.05 ~ 1:0.15;
Solution is carrene in the first step, under room temperature and anaerobic anhydrous response system, carries out;
Stir 2 ~ 4 h in second step, the sodium hydroxide solution mass fraction of adding is 10 ~ 30%; The CD of said cyclodextrin is an alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin;
Add ammonium chloride in second step and regulate pH to 6 ~ 9;
The stirring and refluxing temperature is 80 ~ 90 in the 3rd step
oC, the reaction time is 8 ~ 12 h;
Four-step reaction is in room temperature (or 80 ~ 90
oC) carry out under, the reaction time is 12 ~ 15 h, and crude product is through ethyl acetate/acetone (or ethyl acetate/n-hexane) purifying;
The 5th step was reflected at-5 ~ 10
oCarry out under the C, the reaction time is 1 ~ 4 h, and crude product is through dilution and purifying such as low boiling point solvent such as toluene;
Stirring and refluxing temperature 70 ~ 140 in the 6th step
oC is reflected under the anaerobic water-less environment and carries out;
In the 7th step system earlier with triphenylphosphine dissolved in acetonitrile, 25
oC reacts 1 ~ 4 h;
The stirring and refluxing temperature is 80 ~ 160 in the 8th step
oC, the reaction time is 24 ~ 36 h.
The 9th step particle diameter of described silica gel 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 carries out Azide through 6 hydroxyls to beta-schardinger dextrin-; After full the replacement; Under the catalysis of triphenylphosphine-cupric iodide complex, pass through click-reaction with the functionalized silica gel of alkynyl again, finally prepare the triazolyl singly-bound and close full substituted cyclodextrin-silica gel chiral stationary phase.The triazolyl singly-bound closes chiral separation and the preparation field that full substituted cyclodextrin-silica gel chiral stationary phase can be widely used in racemic modification medicine in the various chromatographic techniques.
The present invention compared with prior art, its remarkable advantage: (1) through click-reaction, can on the silica gel of particle diameter arbitrarily, close complete substituted cyclodextrin-silica gel chiral stationary phase by preparation triazolyl singly-bound; (2) utilize click-reaction to prepare the triazolyl singly-bound and close complete substituted cyclodextrin, wherein cyclodextrin comprises applicable to the cyclodextrin and the derivative thereof of any Azide: alpha-cyclodextrin, beta-schardinger dextrin-and gamma-cyclodextrin; (3) triphenylphosphine for preparing among the present invention-cupric iodide complex 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 of closing full substituted cyclodextrin-silica gel chiral stationary phase of triazolyl singly-bound has the chemo-selective of height, so structure has certainty; (5) the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase and has than the fixing more excellent mutually ph stability of the cyclodextrin chiral of other reports, and triazolyl all can keep chemically stable in the normally used buffer solution of chromatogram; (6) the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase in split process, can realize simultaneously in the pH of buffer scope of broadness the broad-spectrum high efficacy that the two property compounds of amino acids, acidity and neutral raceme medicine are realized is split; (7) the triazolyl singly-bound closes technology such as full substituted cyclodextrin-silica gel chiral stationary phase liquid chromatogram capable of using, overcritical chromatogram, gas-chromatography and electrochromatography and in medicine chiral separation field, obtains extensive use.
Description of drawings
Fig. 1 is that the click-reaction that the present invention reports prepares the schematic flow sheet that the triazolyl singly-bound closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase;
Fig. 2,3 close the fractionation effect of full acid amides phenyl-beta-schardinger dextrin--silica gel chiral stationary phase (CCP-CSP) to medicine for the triazolyl singly-bound.
The specific embodiment
Below in conjunction with accompanying drawing the present invention is described in further detail.
Embodiment 1: be example with the beta-schardinger dextrin-
In conjunction with accompanying drawing, triazolyl singly-bound of the present invention closes the preparation method of full replacement-beta-schardinger dextrin--silica gel chiral stationary phase, may further comprise the steps:
The first step obtains p-methyl benzene sulfonic chloride and imidazoles room temperature reaction in carrene to Methyl benzenesulfonyl base imidazoles;
Second step placed the aqueous solution that dissolves beta-schardinger dextrin-with first step products therefrom to Methyl benzenesulfonyl base imidazoles, added sodium hydroxide solution behind stirring at room reaction 2 ~ 4 h, filtered and removed the small amount of precipitate thing that produces; In filtrating, add its pH value to 6 of ammonium chloride adjusting ~ 9 acquisition white solid matter, filter and obtain product Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-CD), vacuum drying product;
The 3rd the step, get the twoport round-bottomed flask, with second the step product 6-Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-CD) is dissolved in deionized water, then in solution, add sodium azide; Stirring and refluxing, reaction is spent the night, with Rotary Evaporators with solution concentration; Concentrate adds 1,1,2; In the 2-tetrachloroethanes, separate out solid, vacuum drying gets 6-azido-beta-cyclodextrin;
The 4th step was dissolved in DMF with the 3rd product 6-azido-beta-cyclodextrin that goes on foot, and then in solution, dropwise added sodium hydride; After having discharged, a small amount of bubble adds iodomethane lentamente, full substitution reaction 12 ~ 15 h, ethyl acetate extraction 3 times of gained mixture; After getting organic layer washing 3 times, anhydrous magnesium sulfate drying obtains crude product after revolving steaming; Crude product gets 6-azido-full replacement-beta-schardinger dextrin-with behind ethyl acetate/acetone purifying;
The 5th step was dissolved in the 3-aminopropyltriethoxywerene werene in the anhydrous dichloroethanes, added propiolic acid, stirred; After the reactant mixture cooling, slowly add dicyclohexylcarbodiimide, reaction under uniform temp is filtered; Getting filtrates steams appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene; After repeating twice, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, the silica gel of adding vacuum drying in round-bottomed flask vacuumizes logical then nitrogen earlier twice; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides and dry toluene add flask with the 5th step product N-successively under nitrogen protection; Stirring and refluxing is filtered, and uses toluene wash; Adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step added cupric iodide and acetonitrile in the reaction flask successively, in solution, added the acetonitrile solution of triphenylphosphine again, and stirring reaction filters, and with the acetonitrile washing, vacuum drying gets product triphenylphosphine-cupric iodide complex;
The 8th step added the functionalized silica gel of the 6th step product alkynyl in the reaction flask, vacuumized logical then nitrogen earlier; Repetitive operation twice is going on foot product 6-azido-full replacement-beta-schardinger dextrin-, DMF and the 7th step product triphenylphosphine-cupric iodide complex, stirring and refluxing to wherein adding the 4th successively under nitrogen protection; Cold filtration with the DMF washing, adopts methyl alcohol to carry out Suo Shi and extracts purifying; Vacuum drying obtains product: the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase;
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, Methyl benzenesulfonyl chlorine and imidazoles reaction equivalent proportion 1:2 ~ 1:3.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, beta-schardinger dextrin-with to Methyl benzenesulfonyl base imidazoles reaction equivalent proportion 1:1 ~ 1:2.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary 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 stationary phase, the reaction equivalent proportion 1:20 ~ 1:35 of 6-azido-beta-cyclodextrin and iodomethane.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, 3-aminopropyltriethoxywerene werene and propiolic acid reaction equivalent proportion 1:1 ~ 1:3.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, and [3-(three ethoxies are silica-based) propyl group-2-propine acid amides and silica gel weight ratio are 1:3 ~ 1:8 to N-, 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 even 50 μ m, 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 stationary phase, and triphenylphosphine and cupric iodide reaction equivalent proportion are 1:1 ~ 1:1.5.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary 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 done further explain.
Triazolyl singly-bound of the present invention closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, may further comprise the steps:
The first step is got 250 mL twoport round-bottomed flasks and is vacuumized logical then nitrogen earlier, takes by weighing p-methyl benzene sulfonic chloride (6.57 g; 34.5 mmol) add in the flask, add 30 mL dry methylene chloride again, the magnetic agitation dissolving; Claim that again imidazoles (5.3 g, 77.8 mmol) is dissolved in the dry dichloromethane solution of 30 mL, is transferred in the dropping funel; Above-mentioned solution is dropwise splashed into (1 ~ 2 droplet/second) in the flask, stirred overnight at room temperature.Reaction finish to be filtered, and filtrating is concentrated into ~ and 10 mL splash in the 40 mL hexane solutions, separate out white solid, filtration under diminished pressure, deposition is with the n-hexane washing, and vacuum drying obtains product to Methyl benzenesulfonyl base imidazoles (7.3 g, productive rate 95%); Its structural characterization data are following, 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:
In second step, beta-schardinger dextrin-needs earlier 50
oC activation 5 h get 250 mL conical flasks, take by weighing dry beta-schardinger dextrin-(4.72 g; 4.16 mmol) join in the 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 room temperature reaction 2 ~ 4 h down.Add the sodium hydroxide solution (8 mL) of mass fraction 20% afterwards again, stirred 0.5 hour, filter, get filtrating, add ammonium chloride, regulate pH value, filter, precipitate vacuum drying and obtain product Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-β-CD) until 6 ~ 9; Its structural characterization data are following, 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 by weighing Methyl benzenesulfonyl group-beta-cyclodextrin (2.57 g; 1.9 mmol) place the twoport flask, add deionized water (150 mL), then take by weighing sodium azide (2.5 g; 38.4 mmol) join in the twoport flask 80 ~ 90
oC refluxes and spends the night, and after reaction finishes, crosses leaching filtrating, and after reaction finished, decompression distillation was concentrated into about 10 mL; Concentrate dropwise splashes into 1,1,2, in the 2-tetrachloroethanes (3 mL); Separate out white solid, filter, the drying precipitated product 6-azido-beta-cyclodextrin (1.9 g, productive rate 85%) that gets; Its structural characterization data are following, 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, and H 6.02, and N 3.18; Found (%): C 43.1, and H 6.21, and N 3.09; Its reaction equation is:
The 4th step, get 100 mL twoport round-bottomed flasks and vacuumize logical then nitrogen earlier, take by weighing 6-azido-beta-cyclodextrin (2.0 g; 1.7 mmol) add in the flask, add the dry DMF of 30 mL again, the magnetic agitation dissolving; Dropwise add the sodium hydride (2.0 g, 84.0 mmol) remove behind the kerosene again, treat to add iodomethane (5 ml lentamente after a small amount of bubble has discharged; 35.0 mmol), stirring at room 12 ~ 15 h.Reaction finishes with ethyl acetate extraction 3 times, after getting organic layer and washing 3 times, anhydrous magnesium sulfate drying, revolve crude product after the steaming with ethyl acetate/acetone purifying after, obtain 6-azido-permethylated-beta-schardinger dextrin-(1.9 g, productive rate 78%); Its structural characterization data are following, Mp:96-99 ℃;
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, and H 7.62, and N 2.92; Found (%): C 52.1, and H 7.97, and N 2.56; Its reaction equation is:
In the 5th step, 50 mL twoport flask reactors are cooled to-10 ~ 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.5 g, 10.8 mmo) and adds in the flask; Add the dry dichloroethanes of 15mL with syringe; Stir, then add propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g successively; 12.0 mmol), same low temperature reacts 2 h down.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, 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 following, 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, get 150 mL twoport flasks, take by weighing 160
oThe 5 μ m silica gel (4 g) of C vacuum drying 12 h add in the flask; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl through vacuum drying; Its structural characterization data are following, FTIR (KBr, cm
-1): 2121 (C ≡ CH str); Anal. found (%): C 5.32, and H 0.99, and N 0.85; Its reaction equation is:
The 7th step, get 25 mL twoport flasks, take by weighing triphenyl phosphorus (0.69 g; 2.63 mmol) join in the flask, then add acetonitrile (10 mL), in reaction system, slowly add CuI (0.50 g of 50 mL afterwards; 2.63 mmol) acetonitrile solution is 20 ~ 40
oC is reaction 1 h down; Filtration is washed through acetonitrile, and vacuum drying gets the complex (0.92 g, productive rate 80%) of triphenyl phosphorus and cupric iodide; Its structural characterization data are following, IR (KBr, cm
-1): 1479,1434,1097,748,695,521,503; Anal. Calcd. (%) for C
18H
15PCuI:C 47.6, and H 3.31; Found (%): C, 47.2; H, 3.29; Its reaction equation is:
In the 8th step, get 100 mL twoport flasks, to wherein adding the functionalized silica gel of alkynyl (4 g); Reaction system is vacuumized logical then nitrogen earlier, and repeatable operation twice is going on foot product 6-azido-full replacement-beta-schardinger dextrin-(3 g to wherein adding the 4th successively under nitrogen protection; 2.47 mmol), DMF (40 mL) and the 7th goes on foot product triphenylphosphine-cupric iodide complex (0.1 g, 0.22 mmol), stirring and refluxing; Cold filtration with the DMF washing, adopts methyl alcohol to carry out Suo Shi and extracts purifying; Vacuum drying obtains product: the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase; Its structural characterization data are following, FTIR (KBr, cm
-1): 2933. Anal. found:C 16.62%, H 2.616%, and N 1.63%; Cyclodextrin is 0.48 μ mol m in the load factor on 5 μ m silica gel surface
-2, its reaction equation is:
Embodiment 2: be example with the beta-schardinger dextrin-
Triazolyl singly-bound with wide spectrum chiral resolution ability closes full methyl flamprop-silica gel chiral stationary phase preparation method, it is characterized in that may further comprise the 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
oThe C reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
In second step, first step products therefrom is placed the aqueous solution that is dissolved with 1 mol beta-schardinger dextrin-, 25 to Methyl benzenesulfonyl base imidazoles 2 mol
oAdding the quality percentage composition behind C stirring reaction 4 h is 30 % sodium hydrate aqueous solutions, filters; In filtrating, add its pH value to 8 acquisition white solid matter of ammonium chloride adjusting, filter, the deposition vacuum drying obtains product to the Methyl benzenesulfonyl group-beta-cyclodextrin;
The 3rd step took by weighing Methyl benzenesulfonyl group-beta-cyclodextrin (2.5 g, 1.9 mmol) is placed the twoport flask, added deionized water (150 mL); Then take by weighing sodium azide (2.5 g, 38.4 mmol) and join in the twoport flask, 80 ~ 90 ℃ of backflows are spent the night, after reaction finishes; Cross leaching filtrating, after reaction finished, decompression distillation was concentrated into about 10 mL, and concentrate dropwise splashes into 1; 1,2, in the 2-tetrachloroethanes (3 mL); Separate out white solid, filter, the drying precipitated product 6-azido-beta-cyclodextrin that gets;
In the 4th step, take by weighing 6-azido-beta-cyclodextrin (2.0 g, 1.7 mmol) and add in the flask; Add the dry DMF of 30 mL again, the magnetic agitation dissolving dropwise adds sodium hydride (2.0 g that remove behind the kerosene again; 84.0 mmol); Treat to add lentamente after a small amount of bubble has discharged iodomethane (7.2 ml, 51.0 mmol), stirring at room 12h ~ 15h.Reaction finishes with ethyl acetate extraction 3 times, get organic layer washing 3 times after, anhydrous magnesium sulfate drying, revolve crude product after the steaming with ethyl acetate/acetone purifying after, obtain the methyl-beta-schardinger dextrin-of 6-azido-entirely;
In the 5th step, reactor is cooled to-10 ~ 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.4 g, 10.8 mmol) and adds in the flask; Add the dry dichloroethanes of 15mL with syringe; Stir, then add propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g successively; 12.0 mmol), same low temperature reacts 2h down.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, take by weighing 160
oThe 5 μ m silica gel (4 g) of C vacuum drying 12 h add in the flask; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step took by weighing triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in the flask, then added acetonitrile (10 mL), in reaction system, slowly added CuI (0.50 g, the 2.63 mmol) acetonitrile solution of 50 mL afterwards, reacted 1 h down at 20 ~ 40 ℃; Filtration is washed through acetonitrile, and vacuum drying gets the complex of triphenyl phosphorus and cupric iodide;
The 8th step took by weighing the functionalized silica gel of alkynyl (4 g), and reaction system is vacuumized logical then nitrogen earlier; Repeatable operation twice is going on foot product 6-azido-full methyl-beta-schardinger dextrin-(3 g, 2.47 mmol), DMF (40 mL) and the 7th step product triphenylphosphine-cupric iodide complex (0.1 g to wherein adding the 4th successively under nitrogen protection; 0.22 mmol), stirring and refluxing, cold filtration; Wash with DMF; Adopt methyl alcohol to carry out Suo Shi and extract purifying, vacuum drying obtains product: the triazolyl singly-bound closes full methyl-beta-schardinger dextrin--silica gel chiral stationary phase;
Embodiment 3With the alpha-cyclodextrin is example
Triazolyl singly-bound with wide spectrum chiral resolution ability closes full methyl flamprop-silica gel chiral stationary phase preparation method, it is characterized in that may further comprise the 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
oThe C reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
In second step, first step products therefrom is placed the aqueous solution that is dissolved with 1 mol alpha-cyclodextrin, 25 to Methyl benzenesulfonyl base imidazoles 2 mol
oAdding the quality percentage composition behind C stirring reaction 4 h is 30% sodium hydrate aqueous solution, filters; In filtrating, add its pH value to 8 acquisition white solid matter of ammonium chloride adjusting, filter and obtain product to Methyl benzenesulfonyl base-alpha-cyclodextrin, the vacuum drying product;
The 3rd the step, with second the step product 6-Methyl benzenesulfonyl base-alpha-cyclodextrin (2.7 g, 2.4 mmol) is dissolved in deionized water (150 mL), then in solution, add sodium azide (2.34 g; 36.0 mmol), 80 ~ 90 ℃ of backflows after reaction finishes, are crossed leaching filtrating; Decompression distillation is concentrated into about 10 mL, and concentrate dropwise splashes into 1,1,2; In the 2-tetrachloroethanes (3 mL), separate out white solid, filter, the drying precipitated product 6-azido-alpha-cyclodextrin that gets; The 4th step; The product 6-azido-alpha-cyclodextrin (1.7 g, 1.7 mmol) in the 3rd step is dissolved in dry DMF (30 mL), then in solution, dropwise adds sodium hydride (2.0 g that remove behind the kerosene; 84.0 mmol); Treat to add lentamente after a small amount of bubble has discharged iodomethane (5 ml, 35.0 mmol), stirring at room 12 ~ 15h.Reaction finishes with ethyl acetate extraction 3 times, get organic layer washing 3 times after, anhydrous magnesium sulfate drying, revolve crude product after the steaming with ethyl acetate/acetone purifying after, obtain the methyl-alpha-cyclodextrin of 6-azido-entirely;
In the 5th step, reactor is cooled to 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.4 g, 10.8 mmol) and adds in the flask; Add dry dichloroethanes (15 mL); Stir, then add propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (4.43 g successively; 21.6 mmol), reaction 2 h under the same temperature.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, take by weighing 160
oThe particle diameter of C vacuum drying 12 h is that 5 μ m, aperture are that 100 silica gel (4 g) add in the flask; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl (particle diameter 5 μ m) through vacuum drying;
The 7th step took by weighing triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in the flask, added acetonitrile (10 mL), in reaction system, slowly added CuI (0.50 g, the 2.63 mmol) acetonitrile solution of 50 mL then.There is several seconds deposition to separate out.20 ~ 40
oC is reaction 1 h down, filters through the acetonitrile washing, and vacuum drying gets the complex of triphenyl phosphorus and cupric iodide;
The 8th step took by weighing the functionalized silica gel of alkynyl (4 g), and reaction system is vacuumized logical then nitrogen earlier; Repeatable operation twice is going on foot 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 to wherein adding the 4th successively under nitrogen protection; 0.22 mmol), stirring and refluxing, cold filtration; Wash with DMF; Adopt methyl alcohol to carry out Suo Shi and extract purifying, vacuum drying obtains product: the triazolyl singly-bound closes full methyl-alpha-cyclodextrin silica gel chiral stationary phase;
Embodiment 4With the gamma-cyclodextrin is example
Triazolyl singly-bound with wide spectrum chiral resolution ability closes full methyl flamprop-silica gel chiral stationary phase preparation method, it is characterized in that may further comprise the 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
oThe C reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
In second step, first step products therefrom is placed the aqueous solution that is dissolved with 1 mol gamma-cyclodextrin, 25 to Methyl benzenesulfonyl base imidazoles 2 mol
oAdding the quality percentage composition behind C stirring reaction 4 h is 30 % sodium hydrate aqueous solutions, filters; In filtrating, add its pH value to 8 acquisition white solid matter of ammonium chloride adjusting, filter and obtain product to Methyl benzenesulfonyl base-gamma-cyclodextrin, the vacuum drying product;
The 3rd the step, with second the step product 6-Methyl benzenesulfonyl base-gamma-cyclodextrin (3.5 g, 2.4 mmol) is dissolved in deionized water (150 mL), then in solution, add sodium azide (2.34 g, 36.0 mmol), 80 ~ 90
oC refluxes, and after reaction finishes, crosses leaching filtrating, and decompression distillation is concentrated into about 10 mL, and concentrate dropwise splashes into 1,1,2, in the 2-tetrachloroethanes (3 mL), separates out white solid, filters, drying precipitated product 6-azido-gamma-cyclodextrin;
The 4th step; The product 6-azido-gamma-cyclodextrin (2.2 g, 1.7 mmol) in the 3rd step is dissolved in dry DMF (30 mL), then in solution, dropwise adds sodium hydride (2.0 g that remove behind the kerosene; 84.0 mmol); Treat to add lentamente after a small amount of bubble has discharged iodomethane (5 ml, 35.0 mmol), stirring at room 12 ~ 15 h.Reaction finishes with ethyl acetate extraction 3 times, after getting organic layer and washing 3 times, anhydrous magnesium sulfate drying, revolve crude product after the steaming with ethyl acetate/acetone purifying after, obtain 6-azido-permethylated-gamma-cyclodextrin;
In the 5th step, reactor is cooled to 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.4 g, 10.8 mmol) and adds in the flask; Add dry dichloroethanes (15 mL); Stir, then add propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g successively; 12.0 mmol), react 2h under the same temperature.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, take by weighing 160
oParticle diameter is that 3 μ m, aperture are that 100 silica gel (4 g) add in the flask behind C vacuum drying 12 h; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl (particle diameter 3 μ m) through vacuum drying;
The 7th step took by weighing triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in the flask, added acetonitrile (10 mL), in reaction system, slowly added CuI (0.50 g, the 2.63 mmol) acetonitrile solution of 50 mL then.There is several seconds deposition to separate out.20 ~ 40
oC is reaction 1 h down, filters through the acetonitrile washing, and vacuum drying gets the complex of triphenyl phosphorus and cupric iodide;
The 8th step took by weighing the functionalized silica gel of alkynyl (4 g), and reaction system is vacuumized logical then nitrogen earlier; Repeatable operation twice is going on foot 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 to wherein adding the 4th successively under nitrogen protection; 0.22 mmol), stirring and refluxing, cold filtration; With the DMF washing, adopt methyl alcohol to carry out Suo Shi and extract purifying, vacuum drying; Obtain product: the triazolyl singly-bound closes full methyl-gamma-cyclodextrin-silica gel (3 μ m) chiral stationary phase, and cyclodextrin is 0.59 μ mol m in the load factor on 3 μ m silica gel surface
-2
Embodiment 5With the beta-schardinger dextrin-is example
Triazolyl singly-bound with wide spectrum chiral resolution ability closes full acid amides phenylating cyclodextrin-silica gel chiral stationary phase preparation method, it is characterized in that may further comprise the 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
oThe C reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
In second step, first step products therefrom is placed the aqueous solution that is dissolved with 1 mol beta-schardinger dextrin-, 25 to Methyl benzenesulfonyl base imidazoles 2 mol
oAdding the quality percentage composition behind C stirring reaction 4 h is 30 % sodium hydrate aqueous solutions, filters; Add ammonium chloride in the filtrating and regulate its pH value to 8 and obtain white solid matter, filter, precipitate vacuum drying and obtain product Methyl benzenesulfonyl group-beta-cyclodextrin (Ts-β-CD);
The 3rd step took by weighing Methyl benzenesulfonyl group-beta-cyclodextrin (2.5 g, 1.9 mmol) is placed the twoport flask, added deionized water (150 mL), then took by weighing sodium azide (2.5 g, 38.4 mmol) and joined in the twoport flask 80 ~ 90
oC refluxes and to spend the night, and after reaction finishes, crosses leaching filtrating, and after reaction finished, decompression distillation was concentrated into about 10 mL, and concentrate dropwise splashes into 1,1,2, in the 2-tetrachloroethanes (3 mL), separates out white solid, filters, drying precipitated product 6-azido-beta-cyclodextrin;
The 4th step, get 100 mL twoport round-bottomed flasks and vacuumize logical then nitrogen earlier, take by weighing 6-azido-beta-cyclodextrin (2.23 g; 1.92 mmol) add in the flask; Add the dry pyridine of 35 mL again, the magnetic agitation dissolving dropwise adds phenyl isocyanate (13.44 g again; 35.0 mmol), stirred overnight under 85 ℃ of temperature.Reaction finishes decompression distillation and obtains the yellowish-brown gel except that desolvating; Add ethyl acetate (140 mL), add deionized water (60 mL) after stirring 2 h, cross leaching organic layer anhydrous magnesium sulfate drying; Filter; Revolve crude product after the steaming with ethyl acetate/n-hexane purifying after, obtain 6-azido-full acid amides phenyl-beta-schardinger dextrin-(3.3 g, productive rate 49%); Its structural characterization data are following, Mp:225-227 ℃;
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, and H 4.65, and N 8.85, and found (%): C 61.3, and H 68, and N 8.85; Its reaction equation is:
In the 5th step, reactor is cooled to-10 ~ 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.4 g, 10.8 mmo) and adds in the flask; Add the dry dichloroethanes of 15mL with syringe; Stir, then add propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g successively; 12.0 mmol), same low temperature reacts 2h down.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, take by weighing 160
oThe 5 μ m silica gel (4 g) of C vacuum drying 12 h add in the flask; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step took by weighing triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in the flask, then added acetonitrile (10 mL), in reaction system, slowly added CuI (0.50 g, the 2.63 mmol) acetonitrile solution of 50 mL afterwards, 20 ~ 40
oC is reaction 1 h down; Filtration is washed through acetonitrile, and vacuum drying gets the complex of triphenyl phosphorus and cupric iodide;
The 8th step took by weighing the functionalized silica gel of alkynyl (4 g), and reaction system is vacuumized logical then nitrogen earlier; Repeatable operation twice is going on foot product 6-azido-full acid amides phenyl-beta-schardinger dextrin-(3 g, 2.47 mmol), DMF (40 mL) and the 7th step product triphenylphosphine-cupric iodide complex (0.1 g to wherein adding the 4th successively under nitrogen protection; 0.22 mmol), stirring and refluxing, cold filtration; Wash with DMF; Adopt methyl alcohol to carry out Suo Shi and extract purifying, vacuum drying obtains product: the triazolyl singly-bound closes full acid amides benzyl ring dextrin-silica gel chiral stationary phase; Its structural characterization data are following, FTIR (KBr, cm
-1): 1725,1448. Anal. found (%): C 12.49, and H 1.79, and N 1.98; Cyclodextrin is 0.48 μ mol m in the load factor on 5 μ m silica gel surface
-2, its reaction equation is:
Embodiment 6With the alpha-cyclodextrin is 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
oThe C reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
In second step, first step products therefrom is placed the aqueous solution that is dissolved with 1 mol alpha-cyclodextrin, 25 to Methyl benzenesulfonyl base imidazoles 2 mol
oAdding the quality percentage composition behind C stirring reaction 4 h is 30 % sodium hydrate aqueous solutions, filters; In filtrating, add its pH value to 8 acquisition white solid matter of ammonium chloride adjusting, filter and obtain product to Methyl benzenesulfonyl base-alpha-cyclodextrin, the vacuum drying product;
The 3rd the step, with second the step product 6-Methyl benzenesulfonyl base-alpha-cyclodextrin (10.0 g, 7.8 mmol) is dissolved in deionized water (150 mL), then in solution, add sodium azide (10.0 g; 154.0 mmol), 80 ~ 90 ℃ of backflows after reaction finishes, are crossed leaching filtrating; Decompression distillation is concentrated into about 10 mL, and concentrate dropwise splashes into 1,1,2; In the 2-tetrachloroethanes (5 mL), separate out white solid, filter, the drying precipitated product 6-azido-alpha-cyclodextrin that gets;
In the 4th step, the product 6-azido-alpha-cyclodextrin (2.0 g, 2.0 mmol) that took by weighing for the 3rd step adds in the flask; Add the dry pyridine of 35 mL again, the magnetic agitation dissolving dropwise adds phenyl isocyanate (14 g again; 115.0 mmol), stirred overnight under 85 ℃ of temperature.Reaction finishes decompression distillation and removes to desolvate and obtain the yellowish-brown gel, adds ethyl acetate (140 mL), adds deionized water (60 mL) after stirring 2 h; Cross leaching organic layer anhydrous magnesium sulfate drying; Filter, revolve crude product after the steaming with ethyl acetate/n-hexane purifying after, obtain the acid amides phenylating-alpha-cyclodextrin of 6-azido-entirely; Its structural characterization data are following, and 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, and H 4.80, and N 9.27; Found (%): C 62.02, and H 4.85, and N 9.19; Its reaction equation is:
In the 5th step, reactor is cooled to 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.4 g, 10.8 mmol) and adds in the flask; Add dry dichloroethanes (15 mL); Stir, then add propiolic acid (0.87 g, 11.9 mmol) and dicyclohexylcarbodiimide (4.43 g successively; 21.6 mmol), reaction 2 h under the same temperature.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, take by weighing 160
oThe particle diameter of C vacuum drying 12 h is that 5 μ m, aperture are that 100 silica gel (4 g) add in the flask; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step took by weighing triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in the flask, added acetonitrile (10 mL), in reaction system, slowly added CuI (0.50 g, the 2.63 mmol) acetonitrile solution of 50 mL then.There is several seconds deposition to separate out.20 ~ 40
oC is reaction 1 h down, filters through the acetonitrile washing, and vacuum drying gets the complex of triphenyl phosphorus and cupric iodide;
The 8th step took by weighing the functionalized silica gel of alkynyl (4 g), and reaction system is vacuumized logical then nitrogen earlier; Repeatable operation twice is going on foot 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 to wherein adding the 4th successively under nitrogen protection; 0.22 mmol), stirring and refluxing, cold filtration; Wash with DMF; Adopt methyl alcohol to carry out Suo Shi and extract purifying, vacuum drying obtains product: the triazolyl singly-bound closes full substituted cyclodextrin silica gel chiral stationary phase;
Embodiment 7With the gamma-cyclodextrin is example
Triazolyl singly-bound with wide spectrum chiral resolution ability closes full substituted cyclodextrin-silica gel chiral stationary phase preparation method, it is characterized in that may further comprise the 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
oThe C reaction is spent the night and is obtained Methyl benzenesulfonyl base imidazoles;
In second step, first step products therefrom is placed the aqueous solution that is dissolved with 1 mol gamma-cyclodextrin, 25 to Methyl benzenesulfonyl base imidazoles 2 mol
oAdding the quality percentage composition behind C stirring reaction 4 h is 30% sodium hydrate aqueous solution, filters; In filtrating, add its pH value to 8 acquisition white solid matter of ammonium chloride adjusting, filter and obtain product to Methyl benzenesulfonyl base-gamma-cyclodextrin, the vacuum drying product;
The 3rd the step, with second the step product 6-Methyl benzenesulfonyl base-gamma-cyclodextrin (10.0 g, 7.8 mmol) is dissolved in deionized water (400 mL), then in solution, add sodium azide (10.0 g, 154.0 mmol), 80 ~ 90
oC refluxes, and after reaction finishes, crosses leaching filtrating, and decompression distillation is concentrated into about 10 mL, and concentrate dropwise splashes into 1,1,2, in the 2-tetrachloroethanes (5 mL), separates out white solid, filters, drying precipitated product 6-azido-gamma-cyclodextrin;
In the 4th step, the product 6-azido-gamma-cyclodextrin (2.65 g, 2.0 mmol) that took by weighing for the 3rd step adds in the flask; Add the dry pyridine of 35 mL again, the magnetic agitation dissolving dropwise adds phenyl isocyanate (14 g again; 115.0 mmol), stirred overnight under 85 ℃ of temperature.Reaction finishes decompression distillation and removes to desolvate and obtain the yellowish-brown gel, adds ethyl acetate (140 mL), adds deionized water (60 mL) after stirring 2 h; Cross leaching organic layer anhydrous magnesium sulfate drying; Filter, revolve crude product after the steaming with ethyl acetate/n-hexane purifying after, obtain the acid amides phenyl-gamma-cyclodextrin of 6-azido-entirely; Its structural characterization data are following, and 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, and H 4.81, and N 8.97; Found (%): C 62.13, and H 4.95, and N 8.84; Its reaction equation is:
In the 5th step, reactor is cooled to 5
oC takes by weighing 3-aminopropyltriethoxywerene werene (2.4 g, 10.8 mmo) and adds in the flask; Add dry dichloroethanes (15mL), stir, then add propiolic acid (0.87 g successively; 11.9 mmol) and dicyclohexylcarbodiimide (2.46 g, 12.0 mmol), react 2h under the same temperature.Solution filters, and filters, and getting filtrating and steaming appearance removal dichloroethanes with revolving, and uses dilution with toluene again, revolves to boil off except that toluene, repeat twice after, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides;
In the 6th step, take by weighing 160
oParticle diameter is that 5 μ m, aperture are that 100 silica gel (4 g) add in the flask behind C vacuum drying 12 h; Reaction system is vacuumized logical then nitrogen earlier; Twice of repeatable operation; [3-(three ethoxies are silica-based) propyl group-2-propine acid amides (1 g, 3.66 mmol) adds flask with dry toluene (50 mL), 120 with N-successively under nitrogen protection
oStirring and refluxing 12 ~ 20 h under the C filter, and use toluene wash, adopt acetone to carry out Suo Shi and extract purifying, get the functionalized silica gel of product alkynyl through vacuum drying;
The 7th step took by weighing triphenyl phosphorus (0.69 g, 2.63 mmol) and joins in the flask, added acetonitrile (10 mL), in reaction system, slowly added CuI (0.50 g, the 2.63 mmol) acetonitrile solution of 50 mL then.There is several seconds deposition to separate out.20 ~ 40
oC is reaction 1 h down, filters through the acetonitrile washing, and vacuum drying gets the complex of triphenyl phosphorus and cupric iodide;
The 8th step took by weighing the functionalized silica gel of alkynyl (4 g), and reaction system is vacuumized logical then nitrogen earlier; Repeatable operation twice is going on foot 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 to wherein adding the 4th successively under nitrogen protection; 0.22 mmol), stirring and refluxing, cold filtration; Wash with DMF; Adopt methyl alcohol to carry out Suo Shi and extract purifying, vacuum drying obtains product: the triazolyl singly-bound closes full acid amides phenyl-gamma-cyclodextrin-silica gel chiral stationary phase;
Embodiment 8Acquisition triazolyl singly-bound among the embodiment 1-7 is closed full substituted cyclodextrin-silica gel chiral stationary phase carries out the chromatographic column filling test:
1, with the sealing of empty stainless steel chromatogram post (Φ 4.6 * 250 a mm) end, the other end is connected with pre-column, pre-column one end is connected with the HPLC pump through a storage tank afterwards again;
2, (wherein the silica gel particle diameter is 3 μ m or 5 μ m the triazolyl singly-bound to be closed full substituted cyclodextrin-silica gel chiral stationary phase; The aperture is 100) be scattered in the methyl alcohol fixedly phase slurry of preparation; The slurry that stirs is added in the above-mentioned storage tank; Open the HPLC pump, impose pressure 30 min of 8,000 psi to chromatographic column filling system.
3, close the 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 9Acquisition triazolyl singly-bound among the embodiment 1-7 is closed full substituted cyclodextrin-silica gel chiral stationary phase chromatography post medicine is carried out the test of HPLC chiral resolution:
1,1% triethyl group ammonium acetate (TEAA) buffer solution is formulated by the 1% triethylamine aqueous solution; Its pH value is regulated through adding glacial acetic acid; The TEAA/MeOH buffer solution is prepared through 1% TEAA and the MeOH that adds the different volumes ratio, and other flowing phases are by acetonitrile and water (ACN/H
2Or first alcohol and water (MeOH/H O),
2O) carry out mixed configuration according to a certain volume, all buffer solutions and flowing phase are all existing with join at present, through filtration, and utilize DEGASYS DG-2410 degasser to get rid of air wherein.
2, selected raceme compound is dissolved in methanol (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 raceme medicine that splits is following:
3, utilize by Waters 2695 HPLC pumps; The HPLC system that 2996 pairs of permutation pipe detectors of Waters (254 nm) are formed; Adopt the triazolyl singly-bound to close full methyl-beta-schardinger dextrin--silica gel (3 μ m and 5 μ m) chiral stationary phase chromatography post (CCM-CSP), 10 kinds of racemies are carried out chiral resolution, under different pH, all alcohols, beta-Blocking agent raceme have been represented excellent chiral resolution; The 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). annotate: separation selectivity (α), separating degree (
R s )
The triazolyl singly-bound closes full acid amides phenyl-beta-schardinger dextrin--silica gel chiral stationary phase (CCP-CSP) medicine has also been represented excellent chiral resolution ability, wherein fractionation effect such as Fig. 2, shown in 3:
Embodiment 10Acquisition triazolyl singly-bound among the embodiment 1-7 is closed full substituted cyclodextrin-silica gel chiral stationary phase chromatography post medicine is carried out the test of capillary electric chromatogram (CEC) chiral resolution:
1, flowing phase is made up of acetonitrile and phosphate buffer solution: concrete preparation as follows; Sodium dihydrogen phosphate is dissolved in the high purity water; Its pH value is regulated through adding 1M NaOH; All buffer solutions and flowing phase are all existing with join at present, through filtration, and utilize DEGASYS DG-2410 degasser to get rid of air wherein.
2, selected raceme compound is dissolved in 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 raceme medicine that splits is following:
3, utilize by Waters 2695 HPLC pumps; The HPLC system that 2996 pairs of permutation pipe detectors of Waters (254 nm) are formed; Adopt the triazolyl singly-bound to close full acid amides phenyl-beta-schardinger dextrin--silica gel (3 μ m and 5 μ m) chiral stationary phase chromatography post (CCP-CSP), 8 kinds of racemies are carried out chiral resolution, under different pH, all the aromatic alcohol raceme has been represented excellent chiral resolution; The result is as shown in table 1
Table .2 is based on the fractionation data of 5 μ m silica gel CCP-CSP to the 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. annotate: separation selectivity (α), separating degree (Rs);
In sum; We have developed the click-reaction preparation method that the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase; Explored its in high performance liquid chromatography as the chiral resolution agent to amino acids raceme, acidity and neutral medicine chiral separation performance, it has the excellent chiral resolution ability of wide spectrum experiment proof to amino acids raceme, acidity and neutral medicine.The present invention closes 6 Azides-full replacement-cyclodextrin and different-grain diameter alkynyl silica gel through click-reaction through the excellent triazolyl singly-bound of chemical stability; Finally prepare the triazolyl singly-bound and close full substituted cyclodextrin-silica gel chiral stationary phase, and in the pH of broadness scope, two-way compound of several amino acids and acid raceme medicine have been represented wide spectrum chiral resolution ability efficiently.This chiral resolution agent can be widely used in HPLC, CE, SFC even the SMB technology, realizes the wide spectrum of amino acids raceme, acidity and neutral raceme medicine is split.
Claims (4)
1. the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary phase, and it is following to it is characterized in that described triazolyl singly-bound closes the structural formula of full substituted cyclodextrin-silica gel chiral stationary phase:
。
2. triazolyl singly-bound according to claim 1 closes full substituted cyclodextrin-silica gel chiral stationary phase, it is characterized in that described silica gel aperture can be 60,100,120,200 or 300.
3. the triazolyl singly-bound closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, it is characterized in that obtaining according to the following steps:
The first step obtains product to Methyl benzenesulfonyl base imidazoles with p-methyl benzene sulfonic chloride and imidazoles reaction, wherein Methyl benzenesulfonyl chlorine and imidazoles reaction equivalent proportion 1:2 ~ 1:3;
Second step; First step products therefrom is placed the aqueous solution of dissolving cyclodextrin to Methyl benzenesulfonyl base imidazoles, stir the back and add sodium hydroxide solution, cross leaching filtrating and add ammonium chloride and regulate pH 6 ~ 9; Obtain product 6-to the Methyl benzenesulfonyl group-beta-cyclodextrin, the vacuum drying product; Wherein cyclodextrin with to Methyl benzenesulfonyl base imidazoles reaction equivalent proportion 1:1 ~ 1:2;
The 3rd the step, with second the step product 6-Methyl benzenesulfonyl base-cyclodextrin is dissolved in deionized water, then in solution, add sodium azide, stirring and refluxing; Concentrate, concentrate adds 1,1,2; In the 2-tetrachloroethanes, separate out solid, vacuum drying gets 6-azido-cyclodextrin; Wherein 6-is to Methyl benzenesulfonyl base-cyclodextrin and reaction of sodium azide equivalent proportion 1:15 ~ 1:25;
The 4th the step, with the 3rd the step product 6-azido-cyclodextrin be dissolved in N, dinethylformamide; Then in solution, dropwise add sodium hydride, add iodomethane lentamente after a small amount of bubble has discharged and carry out full substitution reaction, or 6-azido-cyclodextrin is dissolved in the pyridine of new distillation; Add phenyl isocyanate or halo phenyl isocyanate and carry out full substitution reaction, remove and desolvate, the gained mixture is used ethyl acetate extraction; Get organic layer washing,, obtain crude product after revolving steaming through anhydrous magnesium sulfate drying; Behind the crude product purifying, get 6-azido-full replacement-cyclodextrin, wherein with 6-azido-cyclodextrin and full substituted reactant reaction equivalent proportion 1:20 ~ 1:80;
The 5th step was dissolved in the 3-aminopropyltriethoxywerene werene in the anhydrous dichloroethanes, added propiolic acid, stirred; After the reactant mixture cooling, slowly add dicyclohexylcarbodiimide, reaction under uniform temp is filtered; Remove dichloroethanes, use dilution with toluene again, remove toluene; After repeating twice, vacuum drying obtains yellow oil product N-[3-(three ethoxies are silica-based) propyl group-2-propine acid amides; Wherein 3-aminopropyltriethoxywerene werene and propiolic acid react equivalent proportion 1:1 ~ 1:3;
The 6th step; With the silica gel that adds vacuum drying in the round-bottomed flask, [3-(three ethoxies are silica-based) propyl group-2-propine acid amides and dry toluene add flask, stirring and refluxing with the 5th step product N-successively under nitrogen protection; Filter; Use toluene wash, adopt the acetone purifying, get 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 added cupric iodide and acetonitrile in the reaction flask successively, in solution, added the acetonitrile solution of triphenylphosphine again, and stirring reaction filters, and with the acetonitrile washing, vacuum drying gets product triphenylphosphine-cupric iodide complex; Wherein triphenylphosphine and cupric iodide reaction equivalent proportion is 1:1 ~ 1:1.5;
The 8th step added the functionalized silica gel of the 6th step product alkynyl in the reaction flask, under nitrogen protection, was going on foot product 6-azido-full replacement-cyclodextrin, N to wherein adding the 4th successively; Dinethylformamide and the 7th step product triphenylphosphine-cupric iodide complex; Stirring and refluxing, cold filtration washs with DMF; Adopt the methyl alcohol purifying, obtain product: the triazolyl singly-bound closes full substituted cyclodextrin-silica gel chiral stationary 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.
4. triazolyl singly-bound according to claim 3 closes the preparation method of full substituted cyclodextrin-silica gel chiral stationary phase, it is characterized in that solution is carrene in the first step, under room temperature and anaerobic anhydrous response system, carries out; Stir 2 ~ 4 h in second step, the sodium hydroxide solution mass fraction of adding is 10 ~ 30%, and said cyclodextrin is an alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin; The stirring and refluxing temperature is 80 ~ 90 ℃ in the 3rd step, and the reaction time is 8 ~ 12 h; Four-step reaction is in room temperature or 80 ~ 90
oCarry out under the C, the reaction time is 12 ~ 15 h, and crude product is through ethyl acetate/acetone or ethyl acetate/n-hexane purifying; The 5th step was reflected at-5 ~ 10
oCarry out under the C, the reaction time is 1 ~ 4 h, and crude product is through low boiling point solvent dilution and purifying; Stirring and refluxing temperature 70 ~ 140 in the 6th step
oC is reflected under the anaerobic water-less environment and carries out; 1 ~ 4 h in acetonitrile, react triphenylphosphine dissolved at 25 ℃ in system elder generation in the 7th step; The stirring and refluxing temperature is 80 ~ 160 in the 8th step
oC, the reaction time is 24 ~ 36 h.
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