CN1315874C - Process for synthesizing alpha-Schiff base derivatized beta-cyclodextrin - Google Patents
Process for synthesizing alpha-Schiff base derivatized beta-cyclodextrin Download PDFInfo
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- CN1315874C CN1315874C CNB2005100514519A CN200510051451A CN1315874C CN 1315874 C CN1315874 C CN 1315874C CN B2005100514519 A CNB2005100514519 A CN B2005100514519A CN 200510051451 A CN200510051451 A CN 200510051451A CN 1315874 C CN1315874 C CN 1315874C
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Abstract
The present invention provides a synthetic method which utilizes beta-cyclodextrin aldehyde to obtain novel alpha-schiff base derivatization beta-cyclodextrin. The method introduces an alpha-schiff base group into a synthetic route and utilizes the reaction of cyclodextrin aldehyde and various amino compounds. The amino compounds reacting with the cyclodextrin aldehyde can be aniline, isopropylamine, R-(+)-phenyl ethylamine, S-(-)-phenyl ethylamine, R-binaphthalene phenol diamine, S-binaphthalene phenol diamine, S-binaphthalene phenol monoamine, diphenylphosphine ferrocenylethylamine and various fatty groups, aromatic groups and heterocyclic compounds containing mono-amino groups and multi-amino groups. The present invention has the advantages of simple synthetic routes, high yield, simple and convenient operation, and easy purification, is applied to chiral separation for qualitative and quantitative research to optical isomers of amino acid, ferrocene amino compounds, drugs, sulfur-containing compounds, alcohol compounds, amino compounds and various chiral compounds. Simultaneously, if applied to asymmetric catalysts, the present invention can solve the problems of catalyst recovery and cyclic utilization.
Description
Affiliated technical field
The present invention relates to utilize beta-cyclodextrin aldehyde to obtain the synthetic method of novel alpha-Schiff base derivatized beta-cyclodextrin bonded silica gel chiral stationary phase, belong to the field of chemical synthesis.
Background technology
In recent years, the emergence of chiral drug industry has driven the development of chiral separation.Chiral chromatography is analyzed accurately because it is easy and simple to handle, and velocity of separation is fast, has obtained people's generally approval, becomes the focus of chiral separation research.In the chiral chromatography, chiral stationary phase is isolating key, and it often is called as the heart of chromatographic separation.Therefore, the research of different sorts chiral stationary phase, to promoting the development of chiral separation, constantly advancing and driving expanding economy of promotion asymmetric synthesis and related discipline thereof all has profound significance.
(β-CDs) is connected and the ring-type oligosaccharides cavity compounds formed through α-1,4 glycosidic link by 7 D (+)-glucopyranose units beta-cyclodextrin, and the inside of its cavity is hydrophobic hydrogen atom and glycosyloxy atom, and the outside is hydrophilic hydroxyl.Because its particular structure, cyclodextrin and derivative thereof are widely used in aspects such as chiral separation.
At present, mostly the commodity chiral column is to be bonded on the silica gel by some small molecules and makes.This kind stationary phase molecular structure is simple, and identification sample kind is single during chiral separation, the range of application relative narrower.In addition, some polymer chiral stationary phase commodity posts, though abundant as chiral environment such as cyclodextrin commodity posts, because its molecular structure complexity, commercial chiral column kind is single, the design of novel high polymer chiral column and a synthetic bottleneck that has become chiral separation.Along with pharmaceutical chemistry and development of life science, the appearance of a large amount of novel chiral medicines, chiral catalyst, synthesize more novel, the cyclodextrin derivative stationary phase is very important more easily.
For remedying the existing single deficiency of chiral stationary phase kind, enlarge the range of application of cyclodextrin derivative, alleviate a large amount of novel chiral medicines, the separation contradiction that the appearance of chiral catalyst brings, we are according to charge transfer, dipole-dipole, the hydrogen bond action principle, utilize rigidity C=N key, invented the synthetic method of alpha-Schiff base derivatized beta-cyclodextrin, be about to chirality Schiff alkali and (comprise a chirality, planar chiral) is incorporated in the cyclodextrin, synthetic cyclodextrin α-Schiff alkali, and this compounds is applied in the chiral separation as chiral stationary phase, this will increase the π-π effect between bonded stationary phase and separated material, hydrogen bond action and dipole-dipole interaction, the separation selectivity of change beta-cyclodextrin bonded stationary phase.
Summary of the invention
Mostly original cyclodextrin derivative is that with the cyclodextrin p-toluenesulfonic esters be intermediate, so with the synthetic corresponding cyclodextrin derivative of different raw material reaction.The synthetic method of cyclodextrin p-toluenesulfonic esters mainly contains two kinds, and its productive rate is up to 30%, so the cyclodextrin p-toluenesulfonic esters has become cyclodextrin derivative synthetic bottleneck as intermediate.In order to address this problem, the synthetic kind of expanded ring dextrin derivative simultaneously, the inventor has invented a kind of method of utilizing cyclodextrin aldehyde to synthesize α-schiff bases-beta-cyclodextrin derivative through research.The advantage of this method is that synthetic route is simple, and productive rate height (overall yield almost reaches more than 90%) is easy and simple to handle, is easy to purifying.Alpha-Schiff base derivatized beta-cyclodextrin is bonded to the silica gel surface, make the liquid chromatography chiral stationary phase, be applied in the chiral separation, to amino acid, the ferrocene amino-complex, medicine, sulfocompound, alcohol compound, the optical isomer of amino-complex and multiple chipal compounds carries out chiral separation, carry out the research of qualitative and quantitative simultaneously, and obtain pure optical isomer, thereby obtain to have the medicine of physiologically active, nonlinear optical material, advanced function materials such as liquid crystal are alleviated chiral drug greatly, the separation that a large amount of appearances of chiral catalyst and various chipal compounds bring, the contradiction of purifying; Alpha-Schiff base derivatized beta-cyclodextrin is applied in the asymmetry catalysis, can be with high e.e. value catalyzed reaction substrate, and because α-schiff bases-beta-cyclodextrin derivative solubleness in common solvent is lower, can also realize the recovery and the recycle problem of catalyzer, reduce cost greatly, remedy the environmental pollution that catalyst treatment causes well, for realizing that Green Chemistry lays the foundation.With all cpds of cyclodextrin aldehyde reaction can be aniline, Isopropylamine, R-(+)-phenyl-ethyl amine, S-(-)-phenyl-ethyl amine, R-binaphthol diamines, S-binaphthol diamines, S-binaphthol monoamine, diphenylphosphine ferrocene ethamine and various aliphatics, aromatic series or the heterogeneous ring compound that contains mono amino, polyamino.R structural formula in the alpha-Schiff base derivatized beta-cyclodextrin is preferably as follows:
Concrete synthetic method is: the exsiccant beta-cyclodextrin is dissolved in the anhydrous dimethyl sulphoxide (DMSO), anhydrous dimethyl sulphoxide (DMSO) solution that adds 2 molar equivalent 2-iodoxybenzene formic acid (IBX), under the room temperature behind the stirring reaction 6h, dropwise splash in the acetone, place ice bath (0～5 ℃) cooling 4h, suction filtration.Product is dissolved in the pure water, stirs 1h, and suction filtration after the filtrate lyophilize, obtains cyclodextrin list aldehyde.Productive rate reaches more than 98%.In reaction flask, add cyclodextrin aldehyde and pyridine; start magnetic agitation; nitrogen protection; the amino-complex that adds 2 molar equivalents; control reaction temperature is 25-30 ℃, reacts after 4-6 days reaction solution to be splashed in the acetone freezing suction filtration; obtain solid and wash 2 times, obtain α-schiff bases cyclodextrin derivative solid with acetone.Transformation efficiency 100%, productive rate is more than 90%.NaH gives a baby a bath on the third day after its birth under nitrogen protection time in 80 ℃ with dry toluene, adds dry DMF, adds α-schiff bases-beta-cyclodextrin derivative; room temperature reaction 1h, suction filtration adds γ-(2 in the filtrate; the 3-glycidoxy) propyl trimethoxy silicane (KH-560) behind 80-90 ℃ of reaction 5h, adds dry silica gel; in 110 ℃ of reaction 24h; after being cooled to room temperature, suction filtration is washed 3 times with DMF, pure water, methyl alcohol, ether successively; place vacuum drying oven in 90 ℃ of dry 12h, be fixed phase CSPs.Wherein, the compound with the cyclodextrin aldehyde reaction comprises aniline, Isopropylamine, R-(+)-phenyl-ethyl amine, S-(-)-phenyl-ethyl amine, R-binaphthol diamines, S-binaphthol diamines, S-binaphthol monoamine, diphenylphosphine ferrocene ethamine and various aliphatics, aromatic series or the heterogeneous ring compound that contains mono amino, polyamino.
Advantage of the present invention is: (1) utilizes rigidity C=N key, synthesizes cyclodextrin α-Schiff alkali, has enlarged the kind of cyclodextrin derivative; (2) chirality Schiff alkali (comprising a chirality, planar chiral) is incorporated in the cyclodextrin, has increased the chiral environment of cyclodextrin derivative, increased effects such as charge transfer, dipole-dipole, hydrogen bond, π-π simultaneously; (3) advantage of this method is that synthetic route is simple, and productive rate height (overall yield almost reaches more than 90%) is easy and simple to handle, is easy to purifying; (4) alpha-Schiff base derivatized beta-cyclodextrin is bonded to the silica gel surface, make the liquid chromatography chiral stationary phase, be applied in the chiral separation, to amino acid, the ferrocene amino-complex, medicine, sulfocompound, alcohol compound, the optical isomer of amino-complex and multiple chipal compounds carries out chiral separation, carry out the research of qualitative and quantitative simultaneously, and obtain pure optical isomer, thereby obtain to have the medicine of physiologically active, nonlinear optical material, advanced function materials such as liquid crystal are alleviated chiral drug greatly, the separation that a large amount of appearances of various chipal compounds such as chiral catalyst bring, the contradiction of purifying; (5) alpha-Schiff base derivatized beta-cyclodextrin is applied in the asymmetry catalysis, can be with high e.e. value catalyzed reaction substrate, and because α-schiff bases-beta-cyclodextrin derivative solubleness in common solvent is lower, can also realize the recovery and the recycle problem of catalyzer, reduce cost greatly, remedy the environmental pollution that catalyst treatment causes well, for realizing that Green Chemistry lays the foundation.
Figure of description:
Accompanying drawing one: the composite diagram that contains α-schiff bases group chiral stationary phase;
Accompanying drawing two: the composite diagram of alpha-Schiff base derivatized beta-cyclodextrin.
Embodiment
Specify the present invention below by embodiment, but the present invention has more than and is limited to following Example.
Embodiment 1
In the 100ml reaction flask, add cyclodextrin aldehyde 3g and pyridine 45ml; start magnetic agitation; open the nitrogen protection valve, add aniline solution 4.4ml, control indirect heating device temperature is 25-30 ℃; react and stop heating and nitrogen protection after 4 days; reaction solution is splashed into acetone, cooled off suction filtration 4 hours; obtain solid and wash 2 times, obtain 6-benzene imines-beta-cyclodextrin solid with acetone.Cyclodextrin aldehyde transformation efficiency 100%, 6-benzene imines-beta-cyclodextrin productive rate 94%.In each comparative example NM reaction conditions and
Embodiment 1 is identical:
Embodiment 2
Condition only will add aniline solution and change into the adding Isopropylamine with embodiment 1, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, the different tetrahydroform of 6--beta-cyclodextrin productive rate 96%.
Embodiment 3
Condition only will add aniline solution and change into adding R-(+)-phenyl-ethyl amine with embodiment 1, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, 6-R-(+)-phenylethyl-beta-cyclodextrin imines productive rate 93%.
Embodiment 4
Condition only will add aniline solution and change into adding S-(-)-phenyl-ethyl amine with embodiment 1, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, 6-S-(-)-phenylethyl-beta-cyclodextrin imines productive rate 95%.
Embodiment 5
Condition only will add aniline solution and change into adding 6 with embodiment 1,6 '-R-naphthyl naphthalene diamines, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, 6,6 '-R-naphthyl naphthalene-two-beta-cyclodextrin imines productive rate 96%.
Embodiment 6
Condition only will add aniline solution and change into adding 6-S-naphthyl naphthalene diamines with embodiment 1, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, 6,6 '-S-naphthyl naphthalene-two-beta-cyclodextrin imines productive rate 96%.
Embodiment 7
Condition only will add aniline solution and change into adding 6-S-naphthyl naphthalene monoamine with embodiment 1, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, 6-S-naphthyl naphthalene-beta-cyclodextrin imines productive rate 92%.
Embodiment 8
Condition only will add aniline solution and change into adding diphenylphosphine ferrocene ethamine with embodiment 1, and reaction result is: cyclodextrin aldehyde transformation efficiency 100%, 6-S-diphenylphosphine ferrocene ethyl-beta-cyclodextrin imines productive rate 92%.
Claims (4)
1. the synthetic method of an alpha-Schiff base derivatized beta-cyclodextrin is characterized in that: introduced α-schiff bases group in synthetic route, concrete route is as follows:
Concrete synthetic method about beta-cyclodextrin aldehyde is: the exsiccant beta-cyclodextrin is dissolved in the anhydrous dimethyl sulphoxide (DMSO), anhydrous dimethyl sulphoxide (DMSO) solution that adds 2 molar equivalent 2-iodoxybenzene formic acid (IBX), behind the stirring reaction 6h, dropwise splash in the acetone under the room temperature, place ice bath to cool off 4h, suction filtration, product is dissolved in the pure water, stirs 1h, and suction filtration, after the filtrate lyophilize, obtain cyclodextrin list aldehyde; Synthetic method about α-schiff bases-beta-cyclodextrin derivative is: add cyclodextrin aldehyde and pyridine in reaction flask, start magnetic agitation, nitrogen protection adds the amino-complex of 2 molar equivalents down, 25-30 ℃ of reaction splashed into reaction solution in the acetone after 4-6 days, freezing suction filtration, obtain solids washed with acetone 2 times, obtain α-schiff bases cyclodextrin derivative solid at last; With the compound of cyclodextrin aldehyde reaction be aliphatics, aromatic series or the heterogeneous ring compound that contains mono amino or polyamino.
2. the alpha-Schiff base derivatized beta-cyclodextrin of a kind of synthetic method of alpha-Schiff base derivatized beta-cyclodextrin preparation according to claim 1.
3. the purposes of a kind of alpha-Schiff base derivatized beta-cyclodextrin as claimed in claim 2, it is characterized in that: alpha-Schiff base derivatized beta-cyclodextrin is bonded to the silica gel surface, make the liquid chromatography chiral stationary phase, be applied in the chiral separation, the optical isomer of amino acid, ferrocene amino-complex, medicine, sulfocompound, alcohol compound, amino-complex and multiple chipal compounds is carried out chiral separation.
4. the purposes of an alpha-Schiff base derivatized beta-cyclodextrin as claimed in claim 2 is characterized in that: alpha-Schiff base derivatized beta-cyclodextrin is applied in the asymmetry catalysis.
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| CN103288983B (en) * | 2013-06-17 | 2015-04-29 | 福建省北理展华医药技术研发有限公司 | Cyclodextrin derivative modified by oxazoline group as well as preparation method and application thereof |
| CN116693715B (en) * | 2023-08-03 | 2023-10-27 | 东营市宝泽能源科技有限公司 | High-temperature-resistant modified guar gum and synthetic method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001323002A (en) * | 2000-05-12 | 2001-11-20 | Coletica | Cyclodextrin having first face side priorly substituted with acid or amine functional group |
| WO2003072637A1 (en) * | 2002-02-22 | 2003-09-04 | Insert Therapeutics, Inc. | Carbohydrate-modified polymers, compositions and uses related thereto |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001323002A (en) * | 2000-05-12 | 2001-11-20 | Coletica | Cyclodextrin having first face side priorly substituted with acid or amine functional group |
| WO2003072637A1 (en) * | 2002-02-22 | 2003-09-04 | Insert Therapeutics, Inc. | Carbohydrate-modified polymers, compositions and uses related thereto |
Non-Patent Citations (1)
| Title |
|---|
| 环湖精及其衍生物功能研究进展 万军民 胡智文 陈文兴 陈海相，化学试剂，第26卷第1期 2004 * |
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