CN101766995A - Bonded polysaccharide chiral separation liquid chromatography stationary phase material and synthesis method thereof - Google Patents
Bonded polysaccharide chiral separation liquid chromatography stationary phase material and synthesis method thereof Download PDFInfo
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Abstract
The description of the invention discloses a method for synthesizing a novel bonded polysaccharide chiral separation liquid chromatography stationary phase material, which comprises the following steps: firstly, carrying out the modification and controllable functionalization for polysaccharides; and secondly, fixing polysaccharide molecules on a solid carrier by the bonding method of chemical bonds to obtain a stationary phase material for chromatographic separation. The invention has the advantages that the stationary phase material has wide application range, strong solvent resistance, long service life, industrial production and good separation effect, and is better than the similar bonded stationary phase material.
Description
Technical field
The invention relates to liquid chromatography stationary phase material and corresponding chiral separation technology.Specifically, the stationary phase material among the present invention is based on the poly-polysaccharide material in isocyanate-modified back, and its method with unique chemical bonding is fixed on the inorganic particle.The present invention has also set forth concrete chemical bonding method, comprises chemical modification and functional poly polysaccharide, and further the poly-polysaccharide after the modification is permanently secured on the inorganic particle.The above-mentioned functions particle is used to come in the liquid chromatogram separating technology separating chiral material and medicine.
Background technology
Because the quick growth of many fields demand, it is more and more important that the chiral separation optical isomer is just becoming, especially agricultural and medical aspect.Two optical isomers that studies have shown that same chiral drug have complete difference even opposite drug effect and toxicity: an optical isomer may have some pharmacological action, and another optical isomer may not have drug effect, even toxic side effect is arranged.With the inderal is example, and its left-handed structure is BET-BLOCKER, and left-handed structure has contraceptive efficacy.Another example is a chloromycetin.Its stereoisomer is an antibiotic, and another isomers then can disturb its normal property of medicine.A more famous example is a thalidomide.Its dextrorotation conformation is a kind of sedative safely and effectively, and left-handed conformation then can cause fetal anomaly.The drug effect of chiral drug is by the decision of the protein of cell surface.These protein have chiral structure, must useful effect could take place with the medicine that similar structures is arranged.But common route of synthesis usually generates mixture of isomers; Why now this illustrated also that many medicines all are the mixtures of chiral molecules and mirror image thereof on the market.U.S. medicine inspection office has issued new regulation recently, require in early days necessary quantitative analysis single isomers in vivo the drug effect of medicine manufacturer medicine in the thing exploitation, and with main pharmacology parameter with compare in external result, in the hope of checking independent isomers drug effect and reduce eliminating toxic side effect.
The chiral separation optical isomer especially by chromatographic technique, is subjected to increasing attention; Because chromatographic isolation is relatively gentleer, the separative efficiency height, and can be applied to the large-scale commercial applications separation.Current research emphasis mainly concentrates on the stationary phase material of chiral separation, and just parting material adds the chromatographic stationary phase.Poly-polysaccharide comprises cellulose, amylase, and glucan and starch are the most frequently used parting materials, because these materials have biocompatibility, intrinsic chirality and bigger modification space.The poly-outstanding chiral separation effect of polysaccharide derives from the supramolecular structure and relative more weak active force of height; These active forces comprise π-π active force, hydrogen bond and dipole moment active force.Simultaneously, the chiral separation effect can further improve by suitable modification.Gone out beyond the chiral separation, these material modified other advanced use that are used to, as dialysis membrane, bionical actuator etc.
But because more molecule is interior and intermolecular hydrogen bonding, the poly-solubility of polysaccharide in usual vehicle is lower.This can hinder its chemical modification usually with synthetic heterogeneous materials.Another problem is that the melting point of poly-polysaccharide is higher, is higher than its decomposition temperature.In order to solve the poly-relatively poor dissolubility of polysaccharide, the chemical reaction that people usually introduce a step and alcoholic extract hydroxyl group improves dissolubility.This step modified-reaction also can significantly improve its separating effect usually.
Recent years,, obtained bigger progress based on stationary phase material, the especially cellulose of poly-polysaccharide.The research of this respect mainly is that the method for cellulose by physical absorption is fixed to silica, on zirconia and the alumina particle.Successful example has poly-polysaccharide is reacted the poly-polysaccharide that comes the synthetic ammonia ester bondization by isocyanates in pyridine.Usually, the poly-polysaccharide of about ammonia ester bondization of 20% will be adsorbed onto on many microvoids silica gel particle of amino isopropyl triethoxysilane modification.Silica gel particle after this modification forms suspension with certain solution earlier, adds being charged in the stainless steel pillar again.Y.Okamoto, J Chromatog., 666 (1994), 403-19 has carried out good summary to this method recently.But previous a large amount of work mainly is to concentrate on to rely on more weak physical force method by physical absorption cellulose is fixed on the carrier, as United States Patent (USP) 4,619, and 970,5,268,442,5,589,061 and a day No.1992169595 of the present invention.More weak physical action inevitably causes parting material to run off from fixing going up mutually gradually between cellulose and carrier, has caused short splitter service life and lower separative efficiency.Another problem of this method is the kind that has limited suitable solvents greatly.The good solvent of many medicines often also can dissolving cellulos.The problems referred to above have inevitably increased the cost of drug development, have reduced the scope of application of splitter.
Studies have shown that of past, the chromatographic stationary phase material of developing a kind of long-term stability have uses market widely.
Okamoto etc. are at European patent No.0, and 155,637 (A has introduced in B) and a kind ofly by chemical technology chiral polymer has been keyed to method on the silica gel particle.They have described in detail by the cellulose of triphenylmethyl intermediate with (2,3,6)-triphenyl ammonia ester bondization and have been adsorbed onto on the carrier, with vulcabond cellulose and carrier are bonded to together then.Okamoto etc. are at day No.06 of the present invention, and 206, the imines that generates by amine reduction back among the 893A is bonded to the low molecular weight polycaprolactone polysaccharide chemistry on the silica gel particle, and then is derivatized to amylose, at last alcoholic extract hydroxyl group is changed into urethano group.But the inventor does not provide this splitter of digital proof that stability or long service life are preferably arranged.Francotte etc. have described the method for coming the poly-polysaccharide of chemical bonding by radiation in international monopoly No.WO96/27615A.As everyone knows, radiation often causes the relatively poor repeatability of material structure, because rate of polymerization and radiation intensity have relation; And from outside to inside, radiation intensity is exponential and weakens.This patent does not provide separation example.Francotte etc. have also set forth urethano and the ester group in the poly-polysaccharide of chemical crosslinking in international monopoly Int.Pat.Appl.No.WO97/04011A.According to the inventor, carry out under the crosslinked tangible mercury lamp, and initator is not essential.This patent is not set forth the structure of reaction mechanism and product; The data in relevant separating effect and splitter service life are not provided yet.Olveros etc. introduce the poly-polysaccharide that contains ethyl in international monopoly Int.Pat.Appl.No.WO95/18833A, and itself and surface are had the silica gel particle reaction of two keys.This patent does not provide the data in relevant separating effect and splitter service life.Stuurman etc. are at Chromatogr., Vol.25, and No.4, April 1998, studied the separative efficiency based on the quinine splitter of hydrosilation among the pp.265-271.Wherein the quinine of hydrosilation is chemically bonded on the stationary phase material.Okamoto etc. are at J.Liq.Chromatogr., Vol.10, and 1987, taked another approach different in pp.1613-28 and the U.S. Patent No. 4,619,970 with said method.But the method that they adopt needs too many step, and causes excessively crosslinked easily.House is in U.S. Patent No. 5,811, and 532 have introduced the stable stationary phase material of a class.Wherein poly-polysaccharide or poly-polysaccharide derivates are chemically bonded on the alcoholic extract hydroxyl group of particles of inorganic material by alkyl silane isocyanate.But bonding reaction is to occur in the suspension system of cellulose grain under heterogeneous condition.Although the functionalization degree has arrived 20 moles of %, cellulose is generally speaking insoluble.Therefore, silane group selectively be connected on the surface of particle with noncrystal mutually in, rather than crystal phase, thus caused the uneven distribution of silane group-reduce gradually from outside to inside.Simultaneously, from the angle of actual production, repeatability may be subjected to cellulosic rank, lot number, the size of particle and shape, even the historical influence of being heated.And, particle center zero functionalized will cause its can't with the carrier bonding; And the too much alkoxy silane of particle surface can cause self-crosslinking, thereby has destroyed the peculiar supramolecular structure of separating phase material.The phenomenon of this damage chiral separation ability and efficient also found by other research institutions, as Yashima etc. at J.Chromatogr.A, Vol.677,1994, pp.11-19; Oliveros etc. are at J.Liq.Chromatogr., Vol.18, and 1995, pp.1521.El Seoudand Heinze is at Adv.Polym.Sci., Vol.186,2005, the shortcoming to the out-phase reaction among the pp.103-149 goes through.Duval etc. have studied out-phase in United States Patent (USP) 6342,592 and 09/808,910 crosslinked, run into above-mentioned adverse effect to material structure and separative efficiency equally.
Admittedly problem and the challenge of recognizing that this field exists of above-mentioned achievement in research, and propose to have adopted rational solution.But these work also only rest on the primary stage, and exist significant problem, the especially chemical bonding destruction in various degree to poly-polysaccharide supramolecular structure, and then cause the decline of chiral separating efficiency.Simultaneously, from industrialized angle, these methods have relatively poor controllability and repeatability.Key challenge to the current research producers is to find the life-span of splitter and the optimum balance of separative efficiency.Therefore, current relevant research and development also mainly concentrate on adopts novel bonding method, and the chiral separation ability of effective simultaneously maintenance or the poly-polysaccharide of raising is to peak.
Summary of the invention
Main purpose of the present invention is the chiral stationary phase material that has the following advantages of exploitation: bigger separating ranges, solvent resistance preferably, longer service life, high separating efficiency and effect, low-cost and simpler production technology.Although chemical bonding is the correct direction of research of technique by generally acknowledging, this method can cause the decline of separative efficiency, shows as previous document result.The invention provides the new technology that a cover addresses the above problem, and kept all advantages of chemical bonding.The present invention has also taked novel chemical reaction that poly-polysaccharide has been carried out different chemical modifications in the system of homogeneous phase.Comprise the poly-polysaccharide of synthetic ammonia esterification, then it is chemically bonded on the inorganic particle.This scheme comprises the poly-polysaccharide of the ammonia esterification that has different functional groups, and these functional groups comprise alkene, mercaptan, ammonia, (methyl) acrylate, alkene ketone, oxirane, acid anhydrides, carboxylic acid and aldehyde.Containing hydroxyl on the inorganic particle, can be silica gel, scandium oxide or aluminium oxide.Particle surface has following functional group after modification: alkene, mercaptan, ammonia, (methyl) acrylate, alkene ketone, oxirane, acid anhydrides, carboxylic acid and aldehyde.
The invention provides a kind of method of synthetic bonded polysaccharide chiral separation liquid chromatography stationary phase material, it comprises the following steps:
1) the ammonia esterified cellulose is synthetic
Cellulosic microcrystal grain is joined in the pyridine; With syringe the alkylbenzene isocyanates is injected above-mentioned suspension afterwards; Under nitrogen protection, reaction temperature is increased to 90-100 ℃ and stirred 12 hours; Reaction finishes the back and forms slightly yellow viscous solution; To obtain isocyanate-modified cellulose after above-mentioned solution precipitation, filtration, the drying;
2) have the synthetic of unsaturated double-bond ammonia esterified cellulose
At room temperature in reactor, add alkyl phenylamino ester fiber element, dimethyl formamide, sodium hydride; After the reaction, the halid dimethyl formamide solution that will have unsaturated double-bond with syringe joins in the flask, and at room temperature stirs 12 hours; The pH of solution is adjusted to 5, then macromolecule is precipitated, filter, obtain having the isocyanate-modified cellulose of two keys after the drying;
3) have the synthetic of alkoxy silane ammonia esterified cellulose
At room temperature in the tetrahydrofuran solution that has two key ammonia esterified celluloses, add alkoxy silane and rare metal catalyst, at 40 ℃ mixture was stirred 6 hours afterwards; At last reaction solution is concentrated to generate and have the isocyanate-modified cellulose of alkoxyl silicone;
4) chiral stationary phase
Having the dissolving of alkoxy silane ammonia esterified cellulose, in solution, add solid fine grained and the formed suspension system of vigorous stirring with dry tetrahydrofuran then; Glacial acetic acid/deionized water/the ethanol that adds 5 times of volumes to this system comes the alkoxy grp on the catalyse cellulose and the polycondensation reaction on fine grained surface; Ultrasonic processing mixture continues after 15 minutes to stir a whole night under vacuum; After reaction finishes, particle is filtered out, and with oxolane flush away free-fiber element, more at room temperature with its vacuum drying; These fine graineds after cellulose modified will separate the purification chiral molecules as liquid chromatogram chiral separation phase material.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, carrying out the HPLC pillar according to following step fills: thin of the silica gel after cellulose modified is suspended in the methyl alcohol, and 50 ℃ down with ultrasonic processing mixture 60 minutes, with high pressure this suspension system is injected in the stainless steel pillar at last.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has; preferably; the described alkylbenzene isocyanates that can react with the alcoholic extract hydroxyl group on the poly-polysaccharide is a phenyl isocyanate; the Alpha-Methyl phenyl isocyanate; the tosyl based isocyanate is fluoridized phenyl isocyanate, the Benzene Chloride based isocyanate; the bromination phenyl isocyanate; the iodinated phenyl isocyanates, ethylphenyl isocyanates, cumene based isocyanate; the tert-butyl benzene based isocyanate; the alkoxyphenyl radical isocyanates, (trifluoromethyl) phenyl isocyanate, nitrobenzophenone isocyanates; the fluorinated methyl phenyl isocyanate; the methyl chloride phenyl isocyanate, Diethylaminoethyl phenyl isocyanate, two trifluoromethylbenzene based isocyanates; dimethylphenyl isocyanate, at least a in difluorophenyl isocyanate and the dichlorophenyl isocyanate.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, described halide with unsaturated double-bond is 6-bromo-1-hexene, 7-bromo-1-heptene, 8-bromo-1-decene, 10-bromo-1-decene and 11-bromo-1-endecatylene at least a.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, employed alkoxy silane is HSi (OC
2H
5)
3, HSiCH
3(OC
2H
5)
2, HSi (OCH
3)
3And HSiCl
3In at least a.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, employed catalyst is H
2PtCl
66H
2O, Cp
2PtCl
66H
2At least a in O and other palladium class catalyst.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, employed fine grained is a silica, at least a in zirconia and the aluminium oxide.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, employed particle is between 0.05 and 500 micron.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, employed granule surface area is greater than 20m
2/ g.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, employed particle is a porous system.
According to the above-mentioned synthetic unsaturated double-bond ammonia esterified cellulose method that has, preferably, the aperture of employed particle is between 20 Hes
Between.
The invention advantage
Inventor of the present invention has proposed a kind of novel chemical bonding method at this and has prepared bonding type HPLC chiral stationary phase material.This method has controllability, the repeatability and low-cost of high bonding efficiency, excellence, and stationary phase material has solvent resistance preferably.This method at first makes it have complete resolvability with the poly-polysaccharide of isocyanate ester compound modification.Then, carrying out functionalizedly reaching the even distribution of functional group in poly-polysaccharide under the condition of homogeneous phase to the poly-polysaccharide of ammonia ester bondization, and functionalized degree can be controlled accurately, guarantees the influence of chiral separating efficiency is minimized.Functionalization is efficient, novel, is not in the news.Compare with the out-phase modification, the homogeneous phase modification can be controlled preferably, and higher repeatability is arranged.Therefore, the chiral separation stationary phase material among the present invention has excellent stability in each kind solvent, has kept the chiral separating efficiency of similar physics coating material simultaneously to greatest extent, as the ChiralCel OD of Daicel Co..These performances have been compared significant raising than like product or the result of study delivered, and proper checking.Our scheme provides macroscopical thinking of the poly-polysaccharide of effective modification, and detail has been carried out detailed elaboration.
The specific embodiment
Embodiment 1: ammonia esterified cellulose synthetic
Adopt phenyl isocyanate with isocyanate-modified cellulose, and the synthetic method of the corresponding document of reference.Cellulosic microcrystal grain (10.0 grams, 61.7 mM polysaccharide repetitives) is joined (200 milliliters) in the pyridine; At room temperature fed nitrogen then 15 minutes; Afterwards with syringe with 3,5-dimethyl benzene isocyanates (30.0 milliliters, 210 mMs) injects above-mentioned suspension.Under nitrogen protection, reaction temperature is increased to 90-100 ℃ and stirred 12 hours. with above-mentioned solution precipitation, filter; Cellulose (91% productive rate) (I) to obtain 30.0 grams, three (3,5-dimethyl phenylamino ester) after the drying.According to nmr spectrum, functionalization is quantitatively to carry out basically.The number-average molecular weight of ammonia esterified cellulose approximately is 90,000 gram/moles, and molecular weight distribution is 2.5 (with respect to the polystyrene standard samples).
Embodiment 2: have the synthetic of two key ammonia esterified celluloses
At room temperature in a single port flask, add three (3,5-dimethyl phenylamino ester) cellulose (I, 15.0 grams, 25.0 mM polysaccharide repetitive or 75.0 mM urethano groups), dimethyl formamide (120 milliliters), (60% in mineral oil for sodium hydride, 0.1 gram, 2.5 mMs).After 60 minutes, be incorporated in the flask with the dimethyl formamide solution (30 milliliters) of syringe, and at room temperature stirred 12 hours 10-bromo-1-decene (165 milligrams, 0.75 mM).With 6 mol hydrochloric acid the pH of solution is adjusted to 5, then macromolecule is precipitated, after the drying 14.1g (94% productive rate) have two key ammonia esterified celluloses (II).To the analysis showed that of nmr spectrum, there are two keys of 1mol% to be bonded to cellulose.
Embodiment 3: have the synthetic of alkoxy silane ammonia esterified cellulose
At room temperature (II, 7.2 grams, the two keys of 0.36 mM, 100 milliliters of oxolanes) adds HSi (OC in the tetrahydrofuran solution that has two key ammonia esterified celluloses (II)
2H
5)
3(73.8 milligrams, 0.45 mM) and chloroplatinic acid (H
2PtCl
66H
2O, 9.3 milligrams, 5 moles of %).At 40 ℃ mixture was stirred 6 hours afterwards; At last reaction solution is concentrated to generate and has alkoxy silane ammonia esterified cellulose (III).
Embodiment 4: the preparation of chiral stationary phase and HPLC pillar
Having alkoxy silane ammonia esterified cellulose (III, 200 milligrams) dissolving, in solution, add silica gel fine grained (7 grams, 5 microns of average diameters, average empty footpath 20 nanometers) and the formed suspension system of vigorous stirring with dry tetrahydrofuran then.Glacial acetic acid/deionized water/the ethanol (1/50/75) that adds 5 times of volumes to this system comes the alkoxy grp on the catalyse cellulose and the polycondensation reaction on silica gel fine grained surface.Ultrasonic processing mixture continues after 15 minutes to stir a whole night under vacuum.After reaction finishes, particle is filtered out, and with oxolane flush away free-fiber element, more at room temperature with its vacuum drying.The cellulose that is bonded on the silica gel fine grained is quantitatively determined by elementary analysis.These silica gel fine graineds after cellulose modified will separate the purification chiral molecules as liquid chromatogram chiral separation phase material.
Thin of silica gel after cellulose modified (4 gram) is suspended in 18 ml methanol, and at 50 ℃ down with ultrasonic processing mixture 60 minutes.Use high pressure (7000 atmospheric pressure) that this suspension system is injected into (100 * 4.6 millimeters) in the stainless steel pillar at last.
Embodiment 5: to the separation of typical chiral drug
The separative efficiency of the separation pillar that seven kinds of typical chiral drugs are used to test invent among the present invention.Two major parameters, separation factor (λ) and retention factors (κ) are recorded and are summarised in the table 1.These results also compare with the performance of bonding ChiralCel OD pillar non-chemically.
Retention factors (κ) is the retention volume (V that drenches the peak
X) with the dead volume (V of pillar itself
0) poor, divided by the dead volume (V of pillar itself
0) value (formula 1).Retention time depends mainly on polarity of solvent.
Separation factor (λ) is defined as two ratios (formula 2) of drenching the κ at peak, and it represents two peak-to-peak relative separation speed.λ=1 shows that these two kinds of compounds can not be separated.
Separation pillar among table 1. the present invention is to the separating resulting of several chiral drugs
(pillar size: 100 * 4.6 millimeters; Phase flows: hexane/different propane 90/10)
Separation pillar among the present invention is to 2,2, and separating resulting and the result in the House/Duval patent, the commercially available pillar of 2-three fluoro-1-(9-anthryl) ethanol compare.The results are shown in Table 2.Obviously, the separation factor of the separation pillar among the present invention has kept the separating effect of ChiralCel (physics) pillar of Daicel, even has surpassed the result of the chemical bonding pillar of Daicel, and considerably beyond House or Duval inventive result.Simultaneously, the retention factors (κ) of the separation pillar among the present invention is minimum in above-mentioned pillar, shows that the separation pillar among the present invention has the highest chiral separating efficiency.
Several separation pillars of table 2. are to 2,2,2, the separating resulting of-three fluoro-1-(9-anthryl) ethanol
(pillar size: 100 * 4.6 millimeters; Phase flows: hexane/isopropyl alcohol 90/10)
| The chiral separation parameter | Splitter among the embodiment 4 | ChiralCel OD among the embodiment 5 | The House splitter | ??ChiralCel??OD(House) | ??Covalent??OD(House) | ??Whelk-O?1??(House) | The Duval splitter |
| Separation factor (λ) | ??3.65 | ??3.33 | ??1.57 | ??3.06 | ??2.32 | ??1.12 | ??1.70 |
| Retention factors (κ) | ??0.95 | ??2.07 | ??4.36 | ??2.58 | ??- | ??1.50 | ??- |
Embodiment 6: the stability test that separates pillar
Add 10% oxolane at hexane/different propane (90/10) mixture, separate pillar with the HPLC among the drip washing the present invention at room temperature of this mixture then.This separation pillar in drip washing the separating effect after 7300 times do not have obvious variation, the result is as shown in table 3.
HPLC among table 3. the present invention separates the separating resulting of pillar before and after drip washing relatively
(pillar size: 100 * 4.6 millimeters; Phase flows: hexane/isopropyl alcohol 90/10)
Claims (25)
1. a chromatogram chiral stationary phase comprises: (a) poly-polysaccharide; (b) inorganic oxide carrier; (c) the chemical bonds structure between poly-polysaccharide and inorganic oxide carrier.
Wherein the L representative gathers polysaccharide;
Wherein Z represents inorganic oxide carrier;
M=1-3 wherein;
Wherein A=Si, Ti or Zr;
X wherein
1Comprise hydrogen, halogen, alcoholic extract hydroxyl group, alkoxyl, acetyl group, siloxy, replacement or unsubstituted alkyl, replacement or unsubstituted alkylene, replacement or unsubstituted aryl, replacement or unsubstituted alkyl and aryl mixture, substituted radical wherein can be following group: halogen, aryl, alkoxyl, acetyl group or silicyl;
R wherein
1And R
2Comprise replacement or unsubstituted alkyl, replacement or unsubstituted alkylene, replacement or unsubstituted aryl, replacement or unsubstituted alkyl and aryl mixture respectively, substituted radical wherein can be following group: halogen, aryl, alkoxyl, oxirane, acetyl group, cyano group or nitro.
2. the poly-polysaccharide in the chiral stationary phase material in the claim 1 can be cellulose, amylose, amylopectin, glucan, insulin, levulan, angle shell element, amylopectin, agarose, starch, and their mixture.
3. the poly-polysaccharide in the chiral stationary phase material in the claim 2 can be cellulose or amylose.
4. the inorganic oxide carrier in the chiral stationary phase material in the claim 1 can be aluminium oxide, titanium oxide, magnesia, zirconia, zinc oxide, chromium oxide, silica, silicate, glass, boron oxide, iron oxide or their mixture.
5. the inorganic oxide carrier in the chiral stationary phase material in the claim 4 is silica, zirconia and aluminium oxide.
6. the inorganic oxide carrier in the chiral stationary phase material in the claim 5 is a silica.
7. the size of the inorganic oxide carrier particle in the chiral stationary phase material in the claim 1 is between 0.05 and 500 micron.
8. the surface area of the inorganic oxide carrier particle in the chiral stationary phase material in the claim 1 is greater than 20 square metres of every grams.
9. the inorganic oxide carrier particle in the chiral stationary phase material in the claim 1 is a porous system.
10. the aperture of the inorganic oxide carrier particle in the chiral stationary phase material in the claim 9 is between 2 and 400 nanometers.
11. a system is prepared the method for chiral chromatogram stationary phase material, comprises following five continuous step operations:
(1) the poly-polysaccharide of modification will gather polysaccharide and isocyanate compound (molecular formula: R
1-NCO) reaction generates carbamate poly-polysaccharide, wherein R
1Comprise replacement or unsubstituted alkyl, replacement or unsubstituted alkylene, replacement or unsubstituted aryl, replacement or unsubstituted alkyl aryl mixture, and these mixtures are replaced by following group: halogen, aryl, alkoxyl, oxirane, acetyl group, cyano group or nitro;
(2) carry out the dehydrogenation reaction with the poly-polysaccharide of alkali after with above-mentioned modification;
(3) on the poly-polysaccharide of the carbamate behind the above-mentioned dehydrogenation, use the compound (molecular formula: X that has unsaturated bond
2-J～CH=CH-R
8Or X
2-J-C ≡ C-R
8) carry out chemical graft, wherein X
2Can be Cl, Br, I, TsO-, MsO-, TfO-; J can be the two a mixture of alkyl, aryl or alkylaryl; R
8It can be the two mixture of hydrogen base, alkyl, aryl or alkylaryl;
(4) with unsaturated bond and silane (molecular formula: HSiX on the poly-polysaccharide of above-mentioned carbamate
3 nX
4 3-n) carry out hydrosilylation; X wherein
3And X
4Can be halogen, alcoholic extract hydroxyl group, alkoxyl, acetyl group, siloxy, replacement or unsubstituted alkyl, replacement or unsubstituted alkylene, replacement or unsubstituted aryl, replacement or unsubstituted alkyl and aryl mixture, substituted radical wherein can be following group: halogen, aryl, alkoxyl, acetyl group or silicyl; N=1-3 wherein;
(5) above-mentioned carbamate is gathered polysaccharide coating and chemical bonds to the inorganic oxide carrier surface.
12. the method for a preparative chromatography chiral stationary phase comprises following continuous four-step reaction operation:
(1) the poly-polysaccharide of modification generates the poly-polysaccharide of carbamate with itself and isocyanate compound reaction, and wherein the molecular formula of isocyanate compound is R
1-NCO; R wherein
1Comprise replacement or unsubstituted alkyl, replacement or unsubstituted alkylene, replacement or unsubstituted aryl, replacement or unsubstituted alkyl aryl mixture and these mixtures are replaced by following group: halogen, aryl, alkoxyl, oxirane, acetyl group, cyano group or nitro;
(2) carry out the dehydrogenation reaction with the poly-polysaccharide of alkali after with above-mentioned modification;
(3) on the poly-polysaccharide of the carbamate behind the above-mentioned dehydrogenation, be X with molecular formula
2-T-AX
3 nX
4 3-nCompound carry out chemical graft; X wherein
2Be a leaving group, comprise: Cl, Br, I, TsO-, MsO-, TfO-; T comprises aryl, alkyl, alkylene or alkylaryl mixture; A is Si, Ti or Zr; X
3And X
4Can be halogen, alcoholic extract hydroxyl group, alkoxyl, acetyl group, siloxy, replacement or unsubstituted alkyl, replacement or unsubstituted alkylene, replacement or unsubstituted aryl, replacement or unsubstituted alkyl and aryl mixture, substituted radical wherein can be following group: halogen, aryl, alkoxyl, acetyl group or silicyl; N=1-3;
(4) above-mentioned carbamate is gathered polysaccharide coating and chemical bonds to the inorganic oxide carrier surface.
13. the method for the poly-polysaccharide of the modification in claim 11 and 12 is dissolved poly-polysaccharide fully.
14. employed isocyanate compound comprises aromatic isocyanate, cyclisation alkyl isocyanate or the mixture of the two in claim 11 and 12.
15. the aromatic isocyanate in the claim 14 comprises phenyl isocyanate; the Alpha-Methyl phenyl isocyanate; the tosyl based isocyanate; fluoridize phenyl isocyanate; the Benzene Chloride based isocyanate; smelling phenyl isocyanate; the iodinated phenyl isocyanates; the ethylphenyl isocyanates; the cumene based isocyanate; the tert-butyl benzene based isocyanate; the alkoxyphenyl radical isocyanates; (trifluoromethyl) phenyl isocyanate; the nitrobenzophenone isocyanates; the fluorinated methyl phenyl isocyanate; the methyl chloride phenyl isocyanate; smelling aminomethyl phenyl isocyanates; two trifluoromethylbenzene based isocyanates; dimethylphenyl isocyanate; difluorophenyl isocyanate; dichlorophenyl isocyanate.
16. the aromatic isocyanate in the claim 15 is 3,5-dimethylphenyl isocyanate, 3,5-dichlorophenyl isocyanate, 3-fluoro-5-aminomethyl phenyl isocyanates, 2-methyl-5-fluoridize phenyl isocyanate, 4-aminomethyl phenyl isocyanates, 4-chlorphenyl isocyanates, Alpha-Methyl phenyl isocyanate or phenyl isocyanate.
17. the cyclisation alkyl isocyanate in the claim 14 is ring five alkyl isocyanates, cyclohexyl isocyanates, cycloheptane based isocyanate, cyclooctane based isocyanate, cyclododecane based isocyanate, cyclohexyl methyl isocyanate, norborny isocyanates or adamantane isocyanates.
18. the cyclisation alkyl isocyanate in the claim 17 is ring five alkyl isocyanates, cyclohexyl isocyanates, norborny isocyanates or adamantane isocyanates.
19. the alkali that uses comprises metal hydride, metal alkoxide, alkali metal ammonia compound, alkali metal alkyl compound or their mixture in claim 11 and 12.
20. employed alkali is sodium hydride in the claim 19.
21. poly-polysaccharide-modified in claim 11 and 12 finished under the homogeneous reaction condition.
22. be connected to 1 to 50 functional group on the poly-polysaccharide of the modification in claim 11 and 12.
23. be connected to 1 to 20 functional group on the poly-polysaccharide of the modification in the claim 22.
24. be connected to 1 to 10 functional group on the poly-polysaccharide of the modification in the claim 23.
25. the alcoholic extract hydroxyl group of chemical bonding is arranged on the inorganic oxide carrier surface in claim 11 and 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810220537A CN101766995A (en) | 2008-12-30 | 2008-12-30 | Bonded polysaccharide chiral separation liquid chromatography stationary phase material and synthesis method thereof |
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| CN103097887A (en) * | 2010-09-09 | 2013-05-08 | 株式会社大赛璐 | Method for separating water-soluble biological material |
| CN103172755A (en) * | 2013-03-21 | 2013-06-26 | 哈尔滨工程大学 | Cellulose derivative simultaneously containing cyclohexyl carbamate and phenyl carbamate and preparation method of cellulose derivative |
| CN103172756A (en) * | 2013-03-21 | 2013-06-26 | 哈尔滨工程大学 | Method for preparing side-chain amylose with different carbamates and chiral stationary phase |
| CN105131132A (en) * | 2015-07-24 | 2015-12-09 | 哈尔滨工程大学 | Synthetic method of cellulose derivatives having long alkoxyl side chain |
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| JP2019059912A (en) * | 2017-06-28 | 2019-04-18 | フンダシオン セントロ デ インベスティガシオン コオペラティバ デ エネルヒアス アルテルナティバス セイセ エネルヒグネ フンダツィオアＦｕｎｄａｃｉｏｎ Ｃｅｎｔｒｏ Ｄｅ Ｉｎｖｅｓｔｉｇａｃｉｏｎ Ｃｏｏｐｅｒａｔｉｖａ Ｄｅ Ｅｎｅｒｇｉａｓ Ａｌｔｅｒｎａｔｉｖａｓ Ｃｉｃ Ｅｎｅｒｇｉｇｕｎｅ Ｆｕｎｄａｚｉｏａ | Solid polymer electrolyte based on modified cellulose, and application thereof in lithium or sodium secondary battery |
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| JP2019059912A (en) * | 2017-06-28 | 2019-04-18 | フンダシオン セントロ デ インベスティガシオン コオペラティバ デ エネルヒアス アルテルナティバス セイセ エネルヒグネ フンダツィオアＦｕｎｄａｃｉｏｎ Ｃｅｎｔｒｏ Ｄｅ Ｉｎｖｅｓｔｉｇａｃｉｏｎ Ｃｏｏｐｅｒａｔｉｖａ Ｄｅ Ｅｎｅｒｇｉａｓ Ａｌｔｅｒｎａｔｉｖａｓ Ｃｉｃ Ｅｎｅｒｇｉｇｕｎｅ Ｆｕｎｄａｚｉｏａ | Solid polymer electrolyte based on modified cellulose, and application thereof in lithium or sodium secondary battery |
| JP7308580B2 (en) | 2017-06-28 | 2023-07-14 | フンダシオン セントロ デ インベスティガシオン コオペラティバ デ エネルヒアス アルテルナティバス セイセ エネルヒグネ フンダツィオア | Solid polymer electrolyte based on modified cellulose and its use in lithium or sodium secondary batteries |
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