CN103601823B - A kind of preparation method of beta-cyclodextrin chiral stationary phase - Google Patents
A kind of preparation method of beta-cyclodextrin chiral stationary phase Download PDFInfo
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- CN103601823B CN103601823B CN201310628374.3A CN201310628374A CN103601823B CN 103601823 B CN103601823 B CN 103601823B CN 201310628374 A CN201310628374 A CN 201310628374A CN 103601823 B CN103601823 B CN 103601823B
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Abstract
The invention discloses a kind of beta-cyclodextrin chiral stationary phase preparation method, is with SiO
2microballoon is raw material, by 3-aminopropyl triethoxysilane (KH550), and trimethylchlorosilane, 4,4 '-diphenylmethanediisocyanate (MDI), is bonded to SiO by beta-cyclodextrin (β-CD)
2microsphere surface, obtains a kind of beta-cyclodextrin chiral stationary phase.The method has continuity, easy and simple to handle, and synthesis cycle is short, and synthetic product is convenient to carry out derivatize; And do not introduce NaOH, NaN
3, CuI (PPh
3) etc. containing the catalyzer of metal ion, can avoid polluting chiral stationary phase, more meet the separation requirement of high-purity liquid chromatography.Present method is applicable to being separated the chirality pharmaceutical intermediate compound containing phenyl ring and pyrethrin compound.
Description
Technical field
The present invention relates to the technology of preparing of high performance liquid chromatography (HPLC) column packing chiral stationary phase, be specifically related to the preparation method of beta-cyclodextrin chiral stationary phase.
Background technology
" Thalidomide " of 1953-1961---" reaction stops " teratogenesis event causes about 12000 sea dog a visit from the storks, and the disaster consequence of " reaction stops " is purified just enter that market causes just because of not carried out chiral separation to the enantiomer in medicine." reaction stops event " causes the great attention of international community, has also caused the research boom of scientific circles for chiral separation.On January 5th, 1992, U.S. food and Drug Administration (FDA) specify: when declaring chiral drug, must know quantity and the relative content of Isomers in the sample being set out in and using in pharmacology, toxicity and clinical study.The high performance liquid chromatography (HPLC) adopting chiral stationary phase not only can separation enantiomer rapidly and efficiently, and has the great potential to lot splitting development, is the study hotspot of chiral chromatography separation field in recent years.Wherein, beta-cyclodextrin chiral stationary phase due to selectivity high, good stability, applied range, receives much concern as multi-mode chiral stationary phase.
In general, in the building-up process of beta-cyclodextrin chiral stationary phase, current research mainly concentrates on the derivatize of cyclodextrin and the mechanism aspect of chiral separation, technology and theory increasingly mature, discuss more.And for the composite part of bonded stationary phase, the report of concrete technology of preparing is few, be summarized as follows now:
Single-(6-O-p-methylphenyl alkylsulfonyl)-beta-cyclodextrin (β-CDOTs) is good 6 single substitution reaction products, can carry out the full derivatize of series.Ning Zhong etc. reports " under the sodium hydroxide solution condition of 10%; synthesized list-(6-O-p-methylphenyl alkylsulfonyl)-beta-cyclodextrin; productive rate reaches 61% " in " Tetrahedron Letters; 1998:2919-2920 "; weak point is to introduce metal ion, can cause the minimizing in the life-span of the hangover of high performance liquid chromatography (HPLC) chromatographic peak and chromatographic column.After this study on the synthesis mostly based on this.Such as; Zhou Ailing etc. report at " SCI; 2003; 24 (9): 1610-1614 " " replaces list-(6-O-p-methylphenyl alkylsulfonyl)-beta-cyclodextrin with quadrol; generate 6-quadrol-beta-cyclodextrin; with the addition of 3-isocyanate group propyl-triethoxysilicane; then with the full derivatize of phenyl isocyanate; be covalently bound on 5 μm of silica gel by transesterification reaction again, successfully synthesized the full derivatized beta of phenylcarbamate-cyclodextrin bonded silica gel chiral fixed phase ".Permitted will just to have waited in " analytical chemistry; 2006; 34(1): 77-79 " " employing epoxy chloropropane is coupling agent; with 6-quadrol-beta-cyclodextrin synthesized 6-monosubstituted-phenylcarbamate derived β-CD ", the method process is simple, be easy to derivatize, but the chemical bond that there is ligation is firm not, and derivatize process isocyanate group can and silica gel on the problem such as residual hydroxyl reaction.
In recent years, along with deepening continuously of research, new synthetic method is constantly had to be seen in report in the synthesis field of chiral stationary phase.Click-reaction " is applied in the synthesis of cyclodextrin bonded chiral stationary phase; directly mono-substituted for 6-position nitrine cyclodextrin is fixed on the beta-cyclodextrin chiral stationary phase that alkynyl-modified Silica Surface prepares novel underivatized by single step reaction " in " Journal of Chromatography A; 2008; 1191 (1/2): 188-192 " by such as Zhang etc. first, the method condition is simple, reaction process is insensitive to water and air, product stable.But same, the method introduces metal ion, copper particle may be generated in reaction and make reaction not easily purifying.
All in all, what obtain most extensive concern at present is the application of isocyanate ester compound in histological cytology.Silica gel and beta-cyclodextrin link up with 3-isocyanate group propyl-triethoxysilicane by such as Kazuo Nakamura etc. in " Journal of Chromatography A; 1995; 694:111-118 ", and the chiral stationary phase of synthesis has good separating power for medicine isomer ".The method does not introduce metal ion, easy and simple to handle, and synthesis cycle is short, is convenient to derivatize, is worthy to be popularized.
Summary of the invention
The present invention seeks to develop a kind of underivatized beta-cyclodextrin histological cytology method, the method synthesis cycle be short, non-metal catalyst introduce and be convenient to carry out later stage derivatize.
The concrete preparation process of underivatized beta-cyclodextrin chiral stationary phase is as follows:
A.3-aminopropyl triethoxysilane (KH550) is modified
Add SiO in the reactor
2microballoon and dry toluene solvent, to dewater 0.5 ~ 1h with water trap, according to 3-aminopropyl triethoxysilane and SiO
2the ratio of microsphere volume mass ratio 0.5 ~ 1mL/g drips 3-aminopropyl triethoxysilane, and under 90-100 DEG C of condition, stirring reaction 4 ~ 6h, is cooled to room temperature, with dry toluene washing 4 ~ 6 times, obtains product 1.Used silica gel microballoon is single dispersing SiO
2microballoon, size distribution is at 5 ~ 8 μm.
Its chemical formula is as follows:
B. trimethylchlorosilane is modified
Dry toluene solvent is added, according to trimethylchlorosilane and SiO in product 1
2the ratio of microsphere volume mass ratio 0.4 ~ 0.6mL/g drips trimethylchlorosilane, and under 50 ~ 60 DEG C of conditions, stirring reaction 4 ~ 6h, is cooled to room temperature, with dry toluene washing 4 ~ 6 times, obtains product 2;
Its chemical formula is as follows:
C. bonding 4,4 '-diphenylmethanediisocyanate (MDI)
According to product 2 and 4,4 '-diphenylmethanediisocyanate reaction mol ratio 1:1, calculates and adds 4, the Theoretical Mass of 4 '-diphenylmethanediisocyanate;
In product 2, add dry toluene, then add 4 of above-mentioned theory quality 2 ~ 3 times, 4 '-diphenylmethanediisocyanate, in product 2, passes into N
2, under 80 ~ 90 DEG C of conditions, stirring reaction 4 ~ 6h, is cooled to room temperature, with dry toluene washing 4-6 time, obtains product 3;
Its chemical formula is as follows:
D. bonding beta-cyclodextrin (β-CD)
React mol ratio 1:1 according to product 3 and beta-cyclodextrin, calculate the Theoretical Mass adding beta-cyclodextrin.In product 3, add dry toluene solvent, take beta-cyclodextrin according to 1 ~ 2 times of Theoretical Mass of above-mentioned calculating and join in product 3, passing into N
2, under 80 ~ 90 DEG C of conditions, stirring reaction 6 ~ 8h, is cooled to room temperature, successively dry toluene washing 1 ~ 2 time, washing with acetone 1 ~ 2 time, and washing with alcohol 2 ~ 3 times, obtains final product 4;
Its chemical formula is as follows:
E. product purification
Product 4 is put into the cable type extractor according being lined with nylon membrane, with pyridine heating and refluxing extraction 4 ~ 6h, till beta-cyclodextrin white solid no longer increases in flask; Product after purifying is 50-60 DEG C of dry 1-2 hour, namely obtains underivatized beta-cyclodextrin chiral stationary phase.
In above-mentioned steps A-D, the add-on of dry toluene solvent accounts for the 1/3-1/2 of reactor.
Get the sample that step e obtains and carry out infrared spectra (IR), nucleus magnetic resonance (
13c-NMR) characterize, result is as shown in Fig. 1, Fig. 2.
To Fig. 1,2 result be analyzed as follows: in ir data, 1654.9 is relevant with the characteristic absorbance of amido linkage with 1552.9, and 1600.0 and 1514.2 are broad peaks of the skeletal vibration charateristic avsorption band 1109.2 of phenyl ring is SiO
2, ehter bond in cyclodextrin and the coefficient result of-OH.In nuclear magnetic data, 1.701 is-Si-CH3 in trimethylchlorosilane, and 9.977 is the-CH that in KH550, aminopropyl are directly connected with Si
2-peak, 40.277 is the-CH that in KH550, aminopropyl are directly connected with-NH-
2-peak, 21.469 is remaining-CH on aminopropyl in KH550
2-peak, 59.847,72.957,81.466,102.85 is relevant with the absorption of C on cyclodextrin, and 119.22,124.52,129.26,136.81 is the peaks of phenyl ring on MDI, and 157.36 is the peaks of carbonyl on urea groups and acid amides ester bond.The two is confirmation mutually, can reach a conclusion: building-up process respectively walks reaction and all normally carries out, beta-cyclodextrin (β-CD) by 3-aminopropyl triethoxysilane (KH550), 4,4 '-diphenylmethanediisocyanate (MDI), successfully will be bonded to SiO
2microsphere surface.
Beneficial effect of the present invention:
(1) use can with the silane coupling agent 3-aminopropyl triethoxysilane of silicone hydroxyl good combination, produce firmly-Si-O-Si-key, not easily wash-out after coupling, can bonding effect be increased and extend the high performance liquid chromatography chromatographic column life-span;
(2) at bonding after 3-aminopropyl triethoxysilane (KH550), creationaryly small molecules silane coupling agent trimethylchlorosilane (CH is added
3)
3the reaction link of Si-Cl, is compared to former bonding techniques, largely avoid Silica Surface excess silicon hydroxyl to chromatographic separation and 4, the impact of 4 '-diphenylmethanediisocyanate (MDI) bonding reaction;
(3) the creationary main body as connecting arm that have selected containing two-NCO group, connection portion generates firmly amido linkage, not easily wash-out;
(4) method adopted has continuity, easy and simple to handle, and synthesis cycle is short, and synthetic product is convenient to carry out derivatize, does not introduce NaOH, NaN
3, CuI (PPh
3) etc. containing the catalyzer of metal ion, can avoid polluting chiral stationary phase, more meet the separation requirement of high-purity liquid chromatography.
(5) there is very large using value in the compartment analysis field of the synthesis field of chiral stationary phase and high performance liquid chromatography (HPLC), be applicable to being separated the chirality pharmaceutical intermediate compound containing phenyl ring and pyrethrin compound.
Accompanying drawing explanation
Fig. 1 is the infrared spectrogram of embodiment 1 gained beta-cyclodextrin chiral stationary phase
Fig. 2 is the nucleus magnetic resonance of embodiment 2 gained beta-cyclodextrin chiral stationary phase
13c-NMR schemes
Embodiment
Embodiment 1
To in 100mL there-necked flask, add the dry toluene of 7.5g activated silica gel and 70mL, after stirring by water trap reflux the 0.5h that dewaters, drip 4.2mL3-aminopropyl triethoxysilane, stirring reaction 4h under 100 DEG C of conditions.Be cooled to room temperature, after washing 5 times with dry toluene, drip 2.3mL trimethylchlorosilane, stirring reaction 4h under 50 DEG C of conditions.Be cooled to room temperature, wash 5 times with dry toluene, sample and do ultimate analysis.Calculate and take 3.0g4,4 '-diphenylmethanediisocyanate joins in reaction system, passes into N
2, stirring reaction 6h under 80 DEG C of conditions, after being cooled to room temperature, washs 5 times with dry toluene.Calculate and take 5.5g β-CD and join reaction system, pass into N
2, stirring reaction 8h under 80 DEG C of conditions.After being cooled to room temperature, dry toluene washs 2 times successively, washing with acetone 2 times, washing with alcohol 3 times, and is purified by cable type extractor according, obtains β-CD chiral stationary phase.
Embodiment 2
To in 100mL there-necked flask, add the dry toluene of 5g activated silica gel and 70mL, after stirring by water trap reflux the 0.5h that dewaters, drip 3.4mL3-aminopropyl triethoxysilane, stirring reaction 4h under 100 DEG C of conditions.Be cooled to room temperature, after washing 5 times with dry toluene, drip 1.8mL trimethylchlorosilane, stirring reaction 4h under 50 DEG C of conditions.Be cooled to room temperature, wash 5 times with dry toluene, sample and do ultimate analysis.Calculate and take 1.1g4,4 '-diphenylmethanediisocyanate joins in reaction system, passes into N
2, stirring reaction 6h under 80 DEG C of conditions, after being cooled to room temperature, washs 5 times with dry toluene.Calculate and take 3.9g β-CD and join reaction system, pass into N
2, stirring reaction 8h under 80 DEG C of conditions.After being cooled to room temperature, dry toluene washs 2 times successively, washing with acetone 2 times, washing with alcohol 3 times, and is purified by cable type extractor according, obtains β-CD chiral stationary phase.
Claims (2)
1. a preparation method for beta-cyclodextrin chiral stationary phase, concrete preparation process is as follows:
A.3-aminopropyl triethoxysilane is modified
Add activation SiO in the reactor
2microballoon and dry toluene solvent, to dewater 0.5 ~ 1h with water trap, according to 3-aminopropyl triethoxysilane and SiO
2the ratio of microsphere volume mass ratio 0.5 ~ 1mL/g drips 3-aminopropyl triethoxysilane, and under 90-100 DEG C of condition, stirring reaction 4 ~ 6h, is cooled to room temperature, with dry toluene washing 4 ~ 6 times, obtains product 1;
Its chemical formula is as follows:
B. trimethylchlorosilane is modified
Dry toluene solvent is added, according to trimethylchlorosilane and SiO in product 1
2the ratio of microsphere volume mass ratio 0.4 ~ 0.6mL/g drips trimethylchlorosilane, and under 50 ~ 60 DEG C of conditions, stirring reaction 4 ~ 6h, is cooled to room temperature, with dry toluene washing 4 ~ 6 times, obtains product 2;
Its chemical formula is as follows:
C. bonding 4,4 '-diphenylmethanediisocyanate (MDI)
According to product 2 and 4,4 '-diphenylmethanediisocyanate reaction mol ratio 1:1, calculates and adds 4, the Theoretical Mass of 4 '-diphenylmethanediisocyanate;
In product 2, add dry toluene, then add 4 of above-mentioned theory quality 2 ~ 3 times, 4 '-diphenylmethanediisocyanate, in product 2, passes into N
2, under 80 ~ 90 DEG C of conditions, stirring reaction 4 ~ 6h, is cooled to room temperature, with dry toluene washing 4-6 time, obtains product 3;
Its chemical formula is as follows:
D. bonding beta-cyclodextrin (β-CD)
React mol ratio 1:1 according to product 3 and beta-cyclodextrin, calculate the Theoretical Mass adding beta-cyclodextrin;
In product 3, add dry toluene solvent, then the beta-cyclodextrin adding above-mentioned theory quality 1 ~ 2 times is in product 3, passes into N
2, under 80 ~ 90 DEG C of conditions, stirring reaction 6 ~ 8h, is cooled to room temperature, successively dry toluene washing 1 ~ 2 time, washing with acetone 1 ~ 2 time, and washing with alcohol 2 ~ 3 times, obtains final product 4;
Its chemical formula is as follows:
E. product purification
Product 4 is put into the cable type extractor according being lined with nylon membrane, with pyridine heating and refluxing extraction 4 ~ 6h, till beta-cyclodextrin white solid no longer increases in flask; Product after purifying is 50-60 DEG C of dry 1-2 hour, namely obtains underivatized beta-cyclodextrin chiral stationary phase;
In above-mentioned steps A-D, the add-on of dry toluene solvent accounts for the 1/3-1/2 of reactor.
2. the preparation method of beta-cyclodextrin chiral stationary phase according to claim 1, is characterized in that activation SiO used
2microballoon is single dispersing SiO
2microballoon, size distribution is 5 ~ 8 μm.
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| CN104119459A (en) * | 2014-03-03 | 2014-10-29 | 南昌大学 | Preparation method of cyclodextrin hybrid alkyl skeleton chiral stationary phase |
| CN103965484B (en) * | 2014-04-09 | 2017-02-22 | 南昌大学 | Preparation method and application of omega-diamine derivatization beta-cyclodextrin bonded SBA-15 chiral stationary phase |
| CN104151450A (en) * | 2014-08-08 | 2014-11-19 | 北京师范大学 | Chiral pseudo-stationary phase for capillary electrochromatography, and preparation method for chiral pseudo-stationary phase |
| CN105749889A (en) * | 2014-12-15 | 2016-07-13 | 中国科学院兰州化学物理研究所 | Preparation method of cyclodextrin-silicon-based multifunctional chiral stationary phase |
| CN106732475B (en) * | 2016-12-06 | 2019-05-28 | 青岛大学 | A kind of HPLC chiral stationary phase and its preparation method and application |
| CN107233575A (en) * | 2017-06-02 | 2017-10-10 | 河南工程学院 | The preparation method of the composite drug-loaded hydrogel of injectable chitosan grafted cyclodextrin |
| CN107029286A (en) * | 2017-06-02 | 2017-08-11 | 河南工程学院 | The preparation method of PLA grafted cyclodextrin carried stent with multistage slow-release effect |
| CN108181414B (en) * | 2017-12-25 | 2020-03-31 | 齐齐哈尔大学 | Preparation method and application of chiral bonding capillary electrochromatography open tubular column |
| CN113307978B (en) * | 2021-05-07 | 2022-09-27 | 昆明理工大学 | Inorganic microsphere modified by cyclodextrin grafted chiral proline metal complex and preparation method and application thereof |
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