CN102225974B - Double-substituted 6-alkyl imidazolium-6-ammonium-beta-cyclodextrin with double positive electricity centers and preparation method thereof - Google Patents
Double-substituted 6-alkyl imidazolium-6-ammonium-beta-cyclodextrin with double positive electricity centers and preparation method thereof Download PDFInfo
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Abstract
The invention discloses double-substituted 6-alkyl imidazolium-6-ammonium-beta-cyclodextrin with double positive electricity centers and a preparation method thereof. The structural formula of double-substituted 6-imidazolidinylnio-6-ammonium-beta-cyclodextrin is as shown in the specification. The preparation method comprises the following steps: adding imidazole in 4-methyl-benzene sulfonyl chloride and then reacting with beta-cyclodextrin so as to obtain 6-p-methyl-benzene-sulfonyl-beta-cyclodextrin (Ts-CD) the 6-hydroxyl of which is substituted; reacting Ts-CD with sodium azide so as to obtain 6-azido-beta-cyclodextrin, namely, N3-CD; reacting N3-CD with 2,4,6-trimethyl benzene sulfonyl chloride so as to obtain 6-azido-6-(2,4,6-trimethyl benzene sulfonyl)-beta-cyclodextrin, namely, N3-Mess-CD; reacting N3-Mess-CD with alkyl imidazole so as to obtain double-substituted 6-azido-6-alkyl imidazolium-beta-cyclodextrin, and reducing azido to amino with triphenylphosphine so as to obtain double-substituted 6-amino-6-alkyl imidazolium-beta-cyclodextrin; and carrying out amino hydrochlorination and ion exchange so as to obtain double-substituted 6-alkyl imidazolium-6-ammonium-beta-cyclodextrin with the double positive electricity centers. The obtained cyclodextrin has good water solubility and effective chiral resolution capacity.
Description
Technical field
The invention belongs to the chiral separation field of racemic modification, particularly a class and be applied to capillary electrophoresis is realized chiral separation to racemic modification two 6-ammonium-6-alkyl imidazole group-beta-cyclodextrins that replace two positive centers.
Background technology
(β-Cyclodextrin, β-CD) utilize α-(1,4) glycosidic link to connect by 7 D-glucose molecules to beta-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 Sauerstoffatom of two circle hydrogen atoms (H-3 and H-5) and a circle glycosidic link, so the cyclodextrin inner chamber is hydrophobic, the outside frame of cyclodextrin molecular is then owing to the gathering of hydroxyl is wetting ability.Based on the cave-shaped hydrophobic pocket of cyclodextrin, under the steric effect influence, make it 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 specificity combination of similar " lock ﹠ key ", can be understood as selectivity bonding between substrate and given acceptor.Nearest two during the last ten years, and a large amount of chemically modified cyclodextrin are synthesized out, thereby expanded recognition capability and selectivity to guest molecule.The two positive center beta-cyclodextrins of two replacements carry out further chemically modified and composition optimizes to cyclodextrin just on this basis, make it have better chiral separation performance.
Medicine with chirality often occurs with the form of racemic modification, namely contains levo form and the dextrorotatory form of equivalent.Enantiomorph often has different pharmacological actions: 1, the effect of medicine fully or depend primarily on wherein a kind of enantiomorph; 2, the pharmacological action of two kinds of enantiomorphs is opposite fully; 3, a kind of enantiomorph has strong toxic 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 the such as at present method of desirable synthetic individual isomer medicine forms as yet, and common method is asymmetric synthesis and biological enzyme, and these two kinds of method ubiquity cost height, yield are low.Therefore, chiral separation 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.Yet, capillary electrophoresis (CE) since its separation efficiency height, plurality of advantages such as velocity of separation is fast, selectivity is high, instrumentation is simple, operator scheme is many be widely used in medicine chiral separation field.Simultaneously, cyclodextrin and derivative thereof are as the chiral separation agent, and the capillary electrophoresis that is applied to by a large amount of carries out chiral separation fast and effectively to various racemies.
As the chiral separation agent, cyclodextrin and derivative thereof are subjected to paying close attention to widely and a large amount of research.Up to the present, many electronegative cyclodextrin are developed, and the cyclodextrin of positively charged report is less by contrast.People are more and more to the research of positive electricity type cyclodextrin in recent years, single cyclodextrin Terabe in 1989 that replaces single positive center is in the news first, its application in capillary electrophoresis medicine chiral separation has caused investigator's extensive concern (S. Terabe, Electrokinetic chromatography:an interface between electrophoresis and chromatography, Trends Anal. Chem. 1989,8,129-134).Compare with the electric neutrality cyclodextrin, positive electricity type cyclodextrin has better water-solubility, can realize multiple raceme medicine is realized splitting faster (T. de Boer with lower concentration, R. A. de Zeeuw, G. J. de Jong, K. Ensing, Recent innovations in the use of charged cyclodextrins in capillary electrophoresis for chiral separations in pharmaceutical analysis, Electrophoresis, 2000,21,3220-3339).Positive electricity type CD mostly is ammonium or imidazolyl list positive center-beta-cyclodextrin greatly, and wherein the almond acids of ammonium positive electricity type CD medicine has excellent fractionation ability, but very limited to the fractionation ability of amino acids; And the amino acids of imidazolyl positive electricity type CD has good fractionation ability, but to weak (the 1. W.H. Tang of the fractionation ability of almond acids medicine, S.C. Ng, Monosubstituted positively charged cyclodextrins:Synthesis and applications in chiral separation, J. Sep. Sci. 2008,31,3246 – 3256; 2. V. Cucinotta, A. Contino, A. Giuffrida, G. Maccarrone, M. Messina, Application of charged single isomer derivatives of cyclodextrins in capillary electrophoresis for chiral analysis, J. Chromatogr. A 2010,1217,953-967.).
Summary of the invention
The object of the present invention is to provide a kind of 6 hydroxyls to beta-cyclodextrin to carry out the 6-ammonium of disubstituted pair of positive center-6-alkyl imidazole group-beta-cyclodextrin and preparation method thereof.
The technical solution that realizes the object of the invention is: a kind of two 6-alkyl imidazole base-6-ammonium-beta-cyclodextrins that replace two positive centers, and general structure is:
A kind of two preparation method who replaces the 6-alkyl imidazole base-6-ammonium-beta-cyclodextrin of two positive centers may further comprise the steps:
The first step, nucleophilic substitution reaction takes place in p-methyl benzene sulfonic chloride and imidazoles in solvent, obtain product to Methyl benzenesulfonyl base imidazoles;
Second step, the first step product is placed the aqueous solution of dissolving beta-cyclodextrin to Methyl benzenesulfonyl base imidazoles, the stirring back adds sodium hydroxide solution, crosses leaching filtrate adding ammonium chloride adjusting pH value and obtains the Methyl benzenesulfonyl group-beta-cyclodextrin of product 6-Ts-CD, this product of vacuum-drying;
The 3rd step was dissolved in deionized water with the second product Ts-CD that goes on foot, and then added sodiumazide in solution, stirring and refluxing, and with solution concentration, concentrated solution splashes in the sym.-tetrachloroethane, separates out solid, and vacuum-drying obtains 6-azido-beta-cyclodextrin;
The 4th step was dissolved in pyridine with the 3rd step product 6-azido-beta-cyclodextrin, added 2,4, the 6-trimethylbenzene chloride stirs, and reaction back solution adds in the acetone, separate out solid, use washing with acetone, filtering drying obtains product 6-azido--6-(2,4,6-Three methyl Benzene alkylsulfonyl)-beta-cyclodextrin;
The 5th step vacuumized logical nitrogen then earlier with the confined reaction device, with the 4th step product 6-azido--6-(2,4,6-Three methyl Benzene alkylsulfonyl)-and beta-cyclodextrin and N, dinethylformamide---DMF, add in the reaction vessel successively, then in this mixing solutions, add alkyl imidazole, stirring and refluxing, reaction back solution adds in the acetone, separate out solid, use washing with acetone, filtering drying gets product 6-azido--6-alkyl imidazole group-beta-cyclodextrin;
The 6th step, the 5th step product 6-azido--6-alkyl imidazole group-beta-cyclodextrin is dissolved in DMF, in solution, adds triphenylphosphine again, stir, after for some time, add water in reaction soln, then stirring and refluxing adds reacted solution in the acetone at last, separate out solid, use washing with acetone, filtering drying gets product 6-amino-6-alkyl imidazole group-beta-cyclodextrin;
The 7th step was dissolved in dilute hydrochloric acid solution with the 6th step product 6-amino-6-alkyl imidazole group-beta-cyclodextrin, stirred, and with solution concentration, concentrated solution splashes in the acetone, separates out solid, filtration drying; Again drying solid is dissolved in deionized water, adds anionite-exchange resin, leave standstill filtration, filtrate adds in the acetone, separates out solid, and filtration drying obtains product: Cl
-6-ammonium 6-alkyl imidazole group-beta-cyclodextrin for negatively charged ion, the two positive centers of two replacement.
The present invention compared with prior art, its remarkable advantage: therefore the two positive dot center-beta-cyclodextrins of (1) two replacements have more good water-solubility than beta-cyclodextrin because it has ammonium and imidazoles alkali; (2) the two positive center-beta-cyclodextrins of two replacements, its ammonium substituting group makes its excellence that has acidic cpd split ability; (3) amido and the salt of the two positive dot center-beta-cyclodextrins of two replacements and can oneself dissociate, thus in split process, its positive polarity is not subjected to the influence of pH of buffer; (4) imidazolyl makes it have excellent fractionation ability to the amino acids raceme, ammonium has it excellence of acidic cpd is split ability, therefore twoly replaces two positive dot center-beta-cyclodextrins and is expected to realize simultaneously the multiple raceme medicine of dansyl amino acid, alpha hydroxy acid and carboxylic acid is realized splitting efficiently in broader pH scope.
Description of drawings
Accompanying drawing is the preparation method's of the two 6-alkyl imidazole base-6-ammonium-beta-cyclodextrins that replace two positive centers of the present invention schematic flow sheet.
Embodiment
Below in conjunction with accompanying drawing the present invention is described in further detail.
The two 6-alkyl imidazole base-6-ammonium-beta-cyclodextrins that replace two positive centers of the present invention, general structure is:
By reference to the accompanying drawings, the two preparation methods that replace the 6-alkyl imidazole base-6-ammonium-beta-cyclodextrin of two positive centers of the present invention may further comprise the steps:
The first step, based on the mechanism of nucleophilic substitution, the Chang Fashengwen reaction in methylene dichloride of p-methyl benzene sulfonic chloride and imidazoles obtains Methyl benzenesulfonyl base imidazoles;
Second step placed the aqueous solution that dissolves beta-cyclodextrin with the first step products therefrom to Methyl benzenesulfonyl base imidazoles, added 10 ~ 30% aqueous sodium hydroxide solutions behind stirring at normal temperature reaction 2 ~ 4 h, filtered and removed the small amount of precipitate thing that produces; The Ts-CD that utilize to generate is little in neutral or near solubleness when neutral, adds ammonium chloride in the filtrate to regulate its pH value to 6 ~ 8 acquisition white solid matter, and filtration obtains product to Methyl benzenesulfonyl group-beta-cyclodextrin Ts-CD, vacuum-drying product;
The 3rd step, get the twoport round-bottomed flask, the second product Ts-CD that goes on foot is dissolved in deionized water, then in solution, add sodiumazide, stirring and refluxing, with solution concentration, concentrated solution adds 1 with Rotary Evaporators, 1, in 2, the 2-tetrachloroethane, utilize the principle of regulating its polarity, separate out solid, vacuum-drying gets 6-azido-beta-cyclodextrin;
The 4th step was dissolved in pyridine with the 3rd step product 6-azido-beta-cyclodextrin, added 2,4,6-trimethylbenzene chloride stirs, this also is the reaction of a step nucleophilic substitution, reaction back solution adds in the acetone, separates out solid, uses washing with acetone, filtering drying, obtain product 6-azido--6-(2,4,6-Three methyl Benzene alkylsulfonyl)-beta-cyclodextrin;
The 5th step, round-bottomed flask is vacuumized logical nitrogen then earlier, the 4th step product 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin and DMF are added flask successively, then in this mixing solutions, add alkyl imidazole, stirring and refluxing, reaction back solution adds in the acetone, separate out solid, use washing with acetone, filtering drying gets product 6-azido--6-alkyl imidazole group-beta-cyclodextrin;
In the 6th step, the 5th step product 6-azido--6-alkyl imidazole group-beta-cyclodextrin is dissolved in DMF, adds triphenylphosphine again in solution, stir, after for some time, in reaction soln, add water, follow stirring and refluxing, utilize the mechanism of name reaction Stardinger reaction, azido-is reduced to amino, at last reacted solution is added in the acetone, separate out solid, use washing with acetone, filtering drying gets product 6-amino-6-alkyl imidazole group-beta-cyclodextrin;
The 7th step was dissolved in dilute hydrochloric acid with the 6th step product 6-amino-6-alkyl imidazole group-beta-cyclodextrin, stirred, and concentrated with Rotary Evaporators, and concentrated solution adds in the acetone, separates out solid, filtration drying; Again the gained solid is dissolved in deionized water, adds anionite-exchange resin and carry out ion-exchange, leave standstill after-filtration, filtrate adds in the acetone, separates out solid, and filtration drying obtains product-with Cl
-6-ammonium-6-alkyl imidazole group-beta-cyclodextrin for negatively charged ion, the two positive centers of two replacement;
The two preparation methods that replace two positive dot center-beta-cyclodextrins of the present invention, Methyl benzenesulfonyl chlorine and imidazoles reaction equivalence ratio 1:2 ~ 1:3.
The two preparation methods that replace two positive dot center-beta-cyclodextrins of the present invention, beta-cyclodextrin with to Methyl benzenesulfonyl base imidazoles reaction equivalence ratio 1:1 ~ 1:2.
The two preparation methods that replace two positive dot center-beta-cyclodextrins of the present invention, the Methyl benzenesulfonyl group-beta-cyclodextrin of 6-and reaction of sodium azide equivalence ratio 1:15 ~ 1:25.
The two preparation methods that replace two positive dot center-beta-cyclodextrins of the present invention, 6-azido-beta-cyclodextrin and 2,4,6-trimethylbenzene chloride reaction equivalence ratio 1:4 ~ 1:5.
The two preparation methods that replace two positive dot center-beta-cyclodextrins of the present invention, 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin and alkyl imidazole reaction equivalence ratio 1:1 ~ 1:4.
The two preparation methods that replace two positive dot center-beta-cyclodextrins of the present invention, 6-azido--6-alkyl imidazole group-beta-cyclodextrin is 1:1.2 ~ 1:1.5 with triphenylphosphine consumption molar mass ratio.
The present invention passes through twice nucleophilic substitution to two 6 hydroxyl of beta-cyclodextrin, again through a series of chemical reaction, finally prepares two 6-ammonium-6-alkyl imidazole group-beta-cyclodextrins that replace two positive centers, has enriched the structure design of beta-cyclodextrin.Such cyclodextrin has good water-solubility and effective chiral separation ability, can be applicable to capillary electrophoresis broad variety chiral drug racemic modification is realized splitting fast and effectively.
Be described in further detail below in conjunction with the present invention of embodiment.
Embodiment 1: the two preparation methods that replace two positive center 6-ammoniums-6-Methylimidazole group-beta-cyclodextrin chiral separation agent of the present invention may further comprise the steps:
The first step, get 250 mL twoport round-bottomed flasks and vacuumize logical nitrogen then earlier, take by weighing p-methyl benzene sulfonic chloride (6.57 g, 34.5 mmol) and add in the flask, add 30 mL dry methylene chloride again, the magnetic agitation dissolving, claim imidazoles (5.3 g, 77.8 mmol) to be dissolved in the dichloromethane solution of 30 mL dryings again, be transferred in the dropping funnel, above-mentioned solution is dropwise splashed into (1 ~ 2 droplet/second) in the flask, stirred overnight at room temperature.Reflection finish to be filtered, and filtrate is concentrated into ~ 10 mL splash in the 40 mL hexane solutions, separate out white solid, filtration under diminished pressure, and precipitation is with the normal hexane washing, and vacuum-drying obtains product to Methyl benzenesulfonyl base imidazoles;
Second step; beta-cyclodextrin needs earlier at 50 ℃ of activation 5 h; get 250 mL Erlenmeyer flasks; take by weighing dry beta-cyclodextrin (4.72 g, 4.16 mmol) and join in the bottle, inject 100 mL deionized waters; stir 0.5 h; add the first step products therefrom to Methyl benzenesulfonyl base imidazoles (1.2g, 5.40 mmol), stir room temperature reaction 4 h down.The sodium hydroxide solution (8 mL) that adds massfraction 20% afterwards again stirs half an hour, filters, and gets filtrate, adds an amount of ammonium chloride, regulates pH value to 8.0, filters, and precipitation vacuum-drying obtains product to the Methyl benzenesulfonyl group-beta-cyclodextrin, Ts-β-CD;
The 3rd step; get 500 mL twoport flasks; take by weighing Methyl benzenesulfonyl group-beta-cyclodextrin (3.1 g; 2.4 mmol), place the twoport flask, add 200 mL deionized waters; stir half an hour; then take by weighing sodiumazide (3.1 g, 47.7 mmol) and join in the twoport flask, 80 ℃ of backflows are spent the night.After reaction finishes, cross leaching filtrate, underpressure distillation is concentrated into about 15 mL, and concentrated solution dropwise splashes in the sym.-tetrachloroethane (3 mL), separates out white solid, filters, the drying precipitated product 6-azido-beta-cyclodextrin that gets;
The 4th step, get 50 mL twoport flasks and vacuumize logical nitrogen then earlier, take by weighing 6-azido-beta-cyclodextrin (2 g, 1.72 mmol) and add in the flask, add the pyridine of 30mL drying with syringe, stir, then add 2,4,6-trimethylbenzene chloride (1.7 g, 7.77 mmol), react 9h under the room temperature.Solution filters, and filtrate dropwise splashes into 100 mL acetone, separates out white solid, filters, the drying precipitated product 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin that gets; Its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, DMSO-
D6) δ: 7.11 (s, 2H, aromatic), 5.83-5.70 (m, 14H, OH-2 and OH-3), 4.88-4.82 (m, 7H, H-1), and 4.51-4.45 (m, 5H, OH-6), (4.21 br, 1H, H-3 ' CD), (4.09 s, 1H, H-5 ' CD), 3.64-3.55 (m, 26H, H-5
CD, H-3
CDAnd H-6
CD), 3.36-3.26 (m, 14H, H-2
CDAnd H-4
CD), 2.29 (s, 6H, Ar-
o-CH
3), 2.17 (s, 3H, Ar-
p-CH
3), its chemical structural formula is:
The 5th step, get 25 mL twoport flasks, take by weighing 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin (2 g; 1.5 mmol) add in the flask, add DMF (10 mL) again, add Methylimidazole (0.367 g with syringe; 4.5 mmol) in flask, 90 ℃ of 48 h that reflux.After reflection finishes, filter, filtrate dropwise splashes in the 30 mL acetone, separates out white solid, filters, and drying solid gets product 6-azido--6-Methylimidazole group-beta-cyclodextrin; Its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, DMSO-
D6) δ: 8.75 (s, 1H, CH-2
Im), 7.58 (s, 1H, CH-4
Im), 7.47 (s, 1H, CH-5
Im), 7.10 (s, 2H, aromatic), 5.93-5.59 (m, 14H, OH-2 and OH-3), 4.94-4.76 (m, 7H, H-1), 4.51-4.45 (m, 5H, OH-6), 3.94 (br, 1H, H-3 ' CD), 3.88 (s, 1H, H-5 ' CD), 3.82 (s, 3H, CH
3-
Im), 3.71-3.50 (m, 26H, H-5
CD, H-3
CDAnd H-6
CD), 3.49-3.21 (m, 14H, H-2
CDAnd H-4
CD), 2.32 (s, 6H, Ar-
o-CH
3), 2.27 (s, 3H, Ar-
p-CH
3), its chemical structural formula is:
The 6th step, get 25 mL twoport flasks, take by weighing 6-azido--6-Methylimidazole group-beta-cyclodextrin (1 g, 0.7 mmol) and join in the flask, add DMF (5 mL), then add triphenylphosphine (0.2 g, 0.77 mmol), reaction 2 h under the room temperature.Then, add 0.8 mL water in reaction system, the rising system temperature is at 80 ℃ of reaction 3 h.Filter, filtrate dropwise splashes into 20mL acetone, separates out white solid, filters, the drying precipitated product 6-amino-6-Methylimidazole group-beta-cyclodextrin that gets, and its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, DMSO-
D6) δ: 9.05 (s, 1H, CH-2
Im), 7.98 (s, 1H, CH-4
Im), 7.37 (s, 1H, CH-5
Im), 7.10 (s, 2H, aromatic), 5.98-5.59 (m, 14H, OH-2 and OH-3), 5.06-4.72 (m, 7H, H-1), 4.61-4.38 (m, 5H, OH-6), 4.25 (m, 2H, NH
2), 3.92 (m, 1H, H-3 ' CD), 3.82 (s, 1H, H-5 ' CD), 3.64 (s, 3H, CH
3-
Im), 3.72-3.48 (m, 26H, H-5
CD, H-3
CDAnd H-6
CD), 3.47-3.15 (m, 14H, H-2
CDAnd H-4
CD), 2.34 (s, 6H, Ar-
o-CH
3), 2.17 (s, 3H, Ar-
p-CH
3), its chemical structural formula is:
The 7th step, get 100 mL small beakers, to the dilute hydrochloric acid solution that wherein adds 0.1 mol/L (10 mL), product 6-amino-6-Methylimidazole group-beta-cyclodextrin with the 6th step, stir halfhour clear solution, with solution concentration, dropwise splash into 30 mL acetone, separate out white solid, the filtration drying precipitation.Then get a dropping funnel, add about semicanal anionite-exchange resin.Above-mentioned precipitation is dissolved in appropriate amount of deionized water, is transferred in the dropping funnel standing over night.Emit clear liquor, it concentrated, after dropwise splash into 30 mL acetone, separate out white solid, drying precipitated final product-with Cl
-Be the 6-ammonium 6-Methylimidazole group-beta-cyclodextrin of negatively charged ion, the two positive centers of two replacement, its chemical structural formula is:
Embodiment 2: the two preparation methods that replace two positive center 6-ammoniums-6-ethyl imidazol(e) group-beta-cyclodextrin chiral separation agent of the present invention may further comprise the steps:
The first step is with example 1 the first step;
Second step is with 1 second step of example;
The 3rd step is with the 3rd step of example 1;
The 4th step is with the 4th step of example 1
In the 5th step, at first prepare ethyl imidazol(e): get 50 mL twoport flasks and vacuumize logical nitrogen earlier again, take by weighing imidazoles (4 g, 58.8 mmol) and add in the flask, the ethanol of measuring 20 mL dryings again injects flask, stirs a moment.Then add sodium ethylate (4.4 g, 64.6 mmol) in flask, be warming up to 40 ℃, stir half an hour.Measure monobromethane (7.04 g, 64.6 mmol) to dropping funnel, dropwise splash in the flask, reaction backflow 2 h.Filter, with the washed with dichloromethane precipitation, get filtrate, Rotary Evaporators goes out desolventizing, and 68 ~ 70 ℃ of cuts are collected in underpressure distillation, get the colourless liquid ethyl imidazol(e), and its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, CDCl
3) δ: 7.41 (s, 1H, CH-2
Im), 6.97 (s, 1H, CH-4
Im), 6.86 (s, 1H, CH-5
Im), 3.93-3.88 (m, 2H, CH
2-
Im), 1.36 (t, 3H, CH
3).
Then get 25 mL twoport flasks; take by weighing 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin (2 g; 1.5 mmol) add in the flask; add DMF (10 mL) again; add above-mentioned product ethyl imidazol(e) (0.43 g, 4.5 mmol) in flask with syringe afterwards, 100 ℃ of 48 h that reflux.After reflection finishes, filter, filtrate dropwise splashes in the 30 mL acetone, separates out white solid, filters, and drying solid gets product 6-azido--6-ethyl imidazol(e) group-beta-cyclodextrin, and its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, DMSO-
D6) δ: 9.01 (s, 1H, CH-2
Im), 8.15 (s, 1H, CH-4
Im), 8.13 (s, 1H, CH-5
Im), 7.10 (s, 2H, aromatic), 6.08-5.54 (m, 14H, OH-2 and OH-3), 5.01-4.62 (m, 7H, H-1), 4.50-4.28 (m, 5H, OH-6), 4.09 (m, 2H, CH
2-
Im), 3.90 (m, 1H, H-3 ' CD), 3.84 (s, 1H, H-5 ' CD), 3.80-3.50 (m, 26H, H-5
CD, H-3
CDAnd H-6
CD), 3.50-3.19 (m, 14H, H-2
CDAnd H-4
CD), 2.38 (s, 6H, Ar-
o-CH
3), 2.27 (s, 3H, Ar-
p-CH
3), 1.05 (t, 3H, CH
3), its chemical structural formula is:
The 6th step, get 25 mL twoport flasks, take by weighing 6-azido--6-ethyl imidazol(e) group-beta-cyclodextrin (1 g, 0.7 mmol) and join in the flask, add DMF (5 mL), then add triphenylphosphine (0.2 g, 0.77 mmol), reaction 2 h under the room temperature.Then, add water (1 mL) in reaction system, the rising system temperature is at 85 ℃ of reaction 3 h.Filter, filtrate dropwise splashes into 20 mL acetone, separates out white solid, filters, the drying precipitated product 6-amino-6-ethyl imidazol(e) group-beta-cyclodextrin that gets, and its chemical structural formula is:
The 7th step, get 100 mL small beakers, to the dilute hydrochloric acid solution that wherein adds 0.1 mol/L (10 mL), product 6-amino-6-ethyl imidazol(e) group-beta-cyclodextrin with the 6th step, stir halfhour clear solution, with solution concentration, dropwise splash into 30 mL acetone, separate out white solid, the filtration drying precipitation.Then get a dropping funnel, add about semicanal anionite-exchange resin.Above-mentioned precipitation is dissolved in appropriate amount of deionized water, is transferred in the dropping funnel standing over night.Emit clear liquor, it concentrated, after dropwise splash into 30 mL acetone, separate out white solid, drying precipitated final product-with Cl
-Be the 6-ammonium-6-ethyl imidazole group-beta-cyclodextrin of negatively charged ion, the two positive centers of two replacement, its chemical structural formula is:
Embodiment 3: the two preparation methods that replace two positive center 6-ammoniums-6-propyl imidazole group-beta-cyclodextrin chiral separation agent of the present invention may further comprise the steps:
The first step is with example 1 the first step;
Second step is with 1 second step of example;
The 3rd step is with the 3rd step of example 1;
The 4th step is with the 4th step of example 1
In the 5th step, at first prepare propyl imidazole: get 50 mL twoport flasks and vacuumize logical nitrogen earlier again, take by weighing imidazoles (4 g, 58.8 mmol) and add in the flask, the ethanol of measuring 20 mL dryings again injects flask, stirs a moment.Then add sodium ethylate (4.4 g, 64.6 mmol) in flask, be warming up to 40 ℃, stir half an hour.Measure 1-N-PROPYLE BROMIDE (7.95 g, 64.6 mmol) to dropping funnel, dropwise splash in the flask, reaction backflow 2 h.Filter, with the washed with dichloromethane precipitation, get filtrate, Rotary Evaporators goes out desolventizing, and 75 ~ 78 ℃ of cuts are collected in underpressure distillation, get the colourless liquid propyl imidazole.Its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, CDCl
3) δ: 7.31 (s, 1H, CH-2
Im), 6.94 (s, 1H, CH-4
Im), 6.76 (s, 1H, CH-5
Im), 3.74 (t, 2H, CH
2-
Im), 1.68-1.60 (m, 2H, CH
2), 0.78 (t, 3H, CH
3).
Then get 25 mL twoport flasks; take by weighing 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin (2 g; 1.5 mmol) add in the flask; then add DMF (10 mL); add above-mentioned product n-propyl imidazoles (0.50 g with syringe afterwards; 4.5 mmol) in flask, 110 ℃ of 48 h that reflux.After reflection finishes, filter, filtrate dropwise splashes in the 30 mL acetone, separates out white solid, filters, and drying solid gets product 6-azido--6-propyl imidazole group-beta-cyclodextrin, and its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, DMSO-
D6) δ: 9.19 (s, 1H, CH-2
Im), 8.22 (s, 1H, CH-4
Im), 8.13 (s, 1H, CH-5
Im), 7.45 (s, 2H, aromatic), 5.97-5.62 (m, 14H, OH-2 and OH-3), 4.87 (s, 1H, H-6), 4.82 (s, 6H, H-1), 4.63-4.37 (m, 5H, OH-6), 4.09 (t, 2H, CH
2-
Im), 3.93 (m, 1H, H-3 ' CD), 3.88 (m, 1H, H-5 ' CD), 3.72-3.48 (m, 26H, H-5
CD, H-3
CDAnd H-6
CD), 3.48-3.16 (m, 14H, H-2
CDAnd H-4
CD), 2.39 (s, 6H, Ar-
o-CH
3), 2.18 (s, 3H, Ar-
p-CH
3), 1.82-1.78 (m, 2H, CH
2), 0.84 (t, 3H, CH
3), its chemical structural formula is:
The 6th step, get 25 mL twoport flasks, take by weighing 6-azido--6-propyl imidazole group-beta-cyclodextrin (1 g, 0.68 mmol) and join in the flask, add DMF (5mL), then add triphenylphosphine (0.19 g, 0.75 mmol), reaction 3 h under the room temperature.Then, add water (1 mL) in reaction system, the rising temperature of reaction system is at 85 ℃ of reaction 4 h.Filter, filtrate dropwise splashes into 20 mL acetone, separates out white solid, filters, the drying precipitated product 6-amino-6-propyl imidazole group-beta-cyclodextrin that gets, and its chemical structural formula is:
The 7th step, get 100 mL small beakers, to the dilute hydrochloric acid solution that wherein adds 0.15 mol/L (10 mL), product 6-amino-6-propyl imidazole group-beta-cyclodextrin with the 6th step, stir halfhour clear solution, with solution concentration, dropwise splash into 30 mL acetone, separate out white solid, the filtration drying precipitation.Then get a dropping funnel, add about semicanal anionite-exchange resin.Above-mentioned precipitation is dissolved in appropriate amount of deionized water, is transferred in the dropping funnel standing over night.Emit clear liquor, it concentrated, after dropwise splash into 30 mL acetone, separate out white solid, drying precipitated final product-with Cl
-Be the 6-ammonium-6-propyl imidazole group-beta-cyclodextrin of negatively charged ion, the two positive centers of two replacement, its chemical structural formula is:
Embodiment 4: the two preparation methods that replace two positive center 6-ammoniums-6-butyl imidazole group-beta-cyclodextrin chiral separation agent of the present invention may further comprise the steps:
The first step is with example 1 the first step;
Second step is with 1 second step of example;
The 3rd step is with the 3rd step of example 1;
The 4th step is with the 4th step of example 1
In the 5th step, at first prepare butyl imidazole: get 50 mL twoport flasks and vacuumize again logical nitrogen earlier, take by weighing imidazoles (4 g, 58.8 mmol) and add in the flask, measure dry ethanol (20 mL) again and inject flask, stir a moment.Then add sodium ethylate (4.4 g, 64.6 mmol) in flask, be warming up to 40 ℃, stir half an hour.Measure n-butyl bromide (8.85 g, 64.6 mmol) to dropping funnel, dropwise splash in the flask, reaction backflow 2 h.Filter, with the washed with dichloromethane precipitation, get filtrate, Rotary Evaporators goes out desolventizing, and 84 ~ 86 ℃ of cuts are collected in underpressure distillation, get the colourless liquid butyl imidazole.Its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, CDCl
3) δ: 7.38 (s, 1H, CH-2
Im), 7.01 (s, 1H, CH-4
Im), 6.83 (s, 1H, CH-5
Im), 3.85 (t, 2H, CH
2), 1.70-1.64 (m, 2H, CH
2-
Im), 1.26-1.22 (m, 2H, CH
2), 0.86 (t, 3H, CH
3).
Then get 25 mL twoport flasks; get 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin (2 g; 1.5 mmol) add in the flask; measure DMF (10 mL) solution and inject the twoport flask; add above-mentioned product butyl imidazole (0.56 g with syringe; 4.5 mmol) in flask, 110 ℃ of 48 h that reflux.After reflection finishes, filter, filtrate dropwise splashes in the 30 mL acetone, separates out white solid, filters, and drying solid gets product 6-azido--6-butyl imidazole group-beta-cyclodextrin, and its nuclear-magnetism characterizes as follows:
1HNMR (500 MHz, DMSO-
D6) δ: 9.03 (s, 1H, CH-2
Im), 8.32 (s, 1H, CH-4
Im), 8.13 (m, 1H, CH-5
Im), 7.54 (s, 2H, aromatic), 5.92-5.60 (m, 14H, OH-2 and OH-3), 4.86 (s, 1H, H-6), 4.84 (s, 6H, H-1), 4.63-4.27 (m, 5H, OH-6), 4.11 (t, 2H, CH
2-
Im), 3.90 (m, 1H, H-3 ' CD), 3.83 (m, 1H, H-5 ' CD), 3.74-3.49 (m, 26H, H-5
CD, H-3
CDAnd H-6
CD), 3.48-3.20 (m, 14H, H-2
CDAnd H-4
CD), 2.32 (s, 6H, Ar-
o-CH
3), 2.16 (s, 3H, Ar-
p-CH
3), 1.78-1.71 (m, 2H, CH
2), 1.25-1.20 (m, 2H, CH
2), 0.88 (t, 3H, CH
3), its chemical structural formula is:
The 6th step, get 25 mL twoport flasks, take by weighing 6-azido--6-butyl imidazole group-beta-cyclodextrin (1 g, 0.7 mmol) and join in the flask, add DMF (5 mL), then add triphenylphosphine (0.2 g, 0.77 mmol), reaction 3 h under the room temperature.Then, add water (1mL) in reaction system, the rising system temperature is at 90 ℃ of reaction 4 h.Filter, filtrate dropwise splashes into 20 mL acetone, separates out white solid, filters, the drying precipitated product 6-amino-6-butyl imidazole group-beta-cyclodextrin that gets, and its chemical structural formula is:
The 7th step, get 100 mL small beakers, to the dilute hydrochloric acid solution that wherein adds 0.2 mol/L (10 mL), product 6-amino-6-butyl imidazole group-beta-cyclodextrin with the 6th step, stir halfhour clear solution, with solution concentration, dropwise splash into 30 mL acetone, separate out white solid, the filtration drying precipitation.Then get a dropping funnel, add about semicanal anionite-exchange resin.Above-mentioned precipitation is dissolved in appropriate amount of deionized water, is transferred in the dropping funnel standing over night.Emit clear liquor, it concentrated, after dropwise splash into 30 mL acetone, separate out white solid, drying precipitated final product-with Cl
-Be the 6-ammonium-6-butyl imidazole group-beta-cyclodextrin of negatively charged ion, the two positive centers of two replacement, its chemical structural formula is:
More than, we have developed the two cyclodextrin derivative that replace two positive centers that have ammonium and imidazolyl concurrently, in order to explore its in capillary electrophoresis as the chiral separation performance of chiral separation agent to acidic drug and amino acid drug, verify the chiral separation ability of its wide spectrum.The present invention replaces 2 six hydroxyl of beta-cyclodextrin respectively, prepare two 6-ammonium 6-alkyl imidazole group-beta-cyclodextrins that replace two positive centers through a series of chemical reaction again, it has chiral separation ability efficiently to polytype raceme medicines such as dansyl amino acid, alpha hydroxy acid and carboxylic acids in the pH of broadness scope.
Claims (3)
1. two 6-alkyl imidazole base-6-ammonium-beta-cyclodextrin that replaces two positive centers is characterized in that general structure is:
2. two preparation methods that replace the 6-alkyl imidazole base-6-ammonium-beta-cyclodextrin of two positive centers as claimed in claim 1 is characterized in that may further comprise the steps:
The first step, nucleophilic substitution reaction takes place in p-methyl benzene sulfonic chloride and imidazoles in solvent, obtain product to Methyl benzenesulfonyl base imidazoles; Solvent for use is methylene dichloride, and reaction conditions is room temperature and anhydrous and oxygen-free, and the reaction molar equivalent of p-methyl benzene sulfonic chloride and imidazoles is than being 1:2 ~ 1:3;
Second step, the first step product is placed the aqueous solution of dissolving beta-cyclodextrin to Methyl benzenesulfonyl base imidazoles, the stirring back adds sodium hydroxide solution, crosses leaching filtrate adding ammonium chloride adjusting pH value to 6 ~ 9 and obtains the Methyl benzenesulfonyl group-beta-cyclodextrin of product 6-Ts-CD, this product of vacuum-drying; Churning time is 2 ~ 4h, and the sodium hydroxide solution massfraction of adding is 10 ~ 30%, beta-cyclodextrin with to the reaction molar equivalent of Methyl benzenesulfonyl base imidazoles than being 1:1 ~ 1:2;
The 3rd step was dissolved in deionized water with the second product Ts-CD that goes on foot, and then added sodiumazide in solution, stirring and refluxing, and with solution concentration, concentrated solution splashes in the sym.-tetrachloroethane, separates out solid, and vacuum-drying obtains 6-azido-beta-cyclodextrin; The stirring and refluxing temperature is 80 ~ 90 ℃, and the reaction times is 8 ~ 12 h, and the Methyl benzenesulfonyl group-beta-cyclodextrin of 6-is 1:15 ~ 1:20 with the reaction molar equivalent ratio of sodiumazide;
The 4th step was dissolved in pyridine with the 3rd step product 6-azido-beta-cyclodextrin, added 2,4, the 6-trimethylbenzene chloride stirs, and reaction back solution adds in the acetone, separate out solid, use washing with acetone, filtering drying obtains product 6-azido--6-(2,4,6-Three methyl Benzene alkylsulfonyl)-beta-cyclodextrin; Reaction conditions is normal temperature and anhydrous and oxygen-free, and the reaction molar equivalent of 6-azido-beta-cyclodextrin and 2,4,6-trimethylbenzene chloride is than being 1:4 ~ 1:5;
The 5th step vacuumized logical nitrogen then earlier with the confined reaction device, with the 4th step product 6-azido--6-(2,4,6-Three methyl Benzene alkylsulfonyl)-and beta-cyclodextrin and N, dinethylformamide---DMF, add in the reaction vessel successively, then in this mixing solutions, add alkyl imidazole, stirring and refluxing, reaction back solution adds in the acetone, separate out solid, use washing with acetone, filtering drying gets product 6-azido--6-alkyl imidazole group-beta-cyclodextrin; 90 ℃ ~ 120 ℃ of stirring and refluxing temperature, 6-azido--6-Three methyl Benzene sulphonyl group-beta-cyclodextrin is 1:1 ~ 1:4 with the reaction molar equivalent ratio of alkyl imidazole;
The 6th step, the 5th step product 6-azido--6-alkyl imidazole group-beta-cyclodextrin is dissolved in DMF, in solution, adds triphenylphosphine again, stir, after for some time, add water in reaction soln, then stirring and refluxing adds reacted solution in the acetone at last, separate out solid, use washing with acetone, filtering drying gets product 6-amino-6-alkyl imidazole group-beta-cyclodextrin; System is reacted earlier 3-4 h at normal temperatures in the 6th step, after the amount that adds water be 0.8 ~ 1.0 mL, then at 80 ~ 90 ℃ of reaction 2-3 h down, the reaction molar equivalent of 6-azido--6-alkyl imidazole group-beta-cyclodextrin and triphenylphosphine is than being 1:1.2 ~ 1:1.5;
The 7th step was dissolved in dilute hydrochloric acid solution with the 6th step product 6-amino-6-alkyl imidazole group-beta-cyclodextrin, stirred, and with solution concentration, concentrated solution splashes in the acetone, separates out solid, filtration drying; Again drying solid is dissolved in deionized water, adds anionite-exchange resin, leave standstill filtration, filtrate adds in the acetone, separates out solid, and filtration drying obtains product: Cl
-6-ammonium 6-alkyl imidazole group-beta-cyclodextrin for negatively charged ion, the two positive centers of two replacement.
3. two preparation method who replaces the 6-alkyl imidazole base-6-ammonium-beta-cyclodextrin of two positive centers according to claim 2, it is characterized in that: the concentration of dilute hydrochloric acid is 0.1 ~ 0.2 mol/L in the 7th step.
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