CN102174125A - Preparation and application of novel CH2-N=C-Ar group-modified cyclodextrin derivatives - Google Patents
Preparation and application of novel CH2-N=C-Ar group-modified cyclodextrin derivatives Download PDFInfo
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Abstract
The invention provides a method for synthesizing a novel CH2-N=C-Ar group modified beta-cyclodextrin derivatives by utilizing beta-cyclodextrin and application of the derivative in chiral separation. The principle that a tough and flexible chiral ligand is beneficial to improving the chiral catalysis enantioselectivitiy and obtaining higher substrate adaptability is applied to the design of cyclodextrin chiral stationary phase derived structure molecules; 6-deoxy-6-amino-beta-cyclodextrin is synthesized by the synthesis step which is simpler and is easy for operation; the 6-deoxy-6-amino-beta-cyclodextrin reacts with four different aromatic aldehydes to generate four novel CH2-N=C-Ar group-containing beta-cyclodextrin derivatives; and the aldehyde reacting with cyclodextrin ammonia can be benzaldehyde, 2,4-dihydroxy benzaldehyde, nitro . paratrimethylaminobenzaldehyde and nitro . paraN-methylimidazolylbenzaldehyde. The preparation method provided by the invention has the advantages of simpleness in synthetic route operation, mild reaction condition, easiness in purification of products and high yield. The preparation method provided by the invention is applied to chiral separation and used for carrying out qualitative research on several chiral aromatic alcohols and chiral medicaments.
Description
Affiliated technical field
The present invention relates to utilize the beta-cyclodextrin synthesizing new to contain CH
2The beta-cyclodextrin derivative of-N=C-Ar base group modification, and prepare chiral stationary phase on this basis, belong to the field of chemical synthesis.
Background technology
As everyone knows, chipal compounds is the same with the right hand as people's left hand, each other mirror image and can not overlapping.Along with the increase of chipal compounds, obtain optically pure single chiral isomer and have more and more important meaning in the kind of development of research fields such as medicine, life and catalyzer and demand.
Up to the present, the method for acquisition single enantiomer mainly contains: chiral source synthesis method, asymmetric synthesis method and racemic modification Split Method.The racemize Split Method is because easy and simple to handle, and is not subjected to the restriction of synthesis material and is widely used.Wherein, that the liquid chromatography isolation technique has is quick and convenient, cost is low, the separation efficiency advantages of higher, thereby is subjected to people's generally attention.And in the liquid chromatography, the stationary phase isolating heart of being known as, its character and preparation play important effect to isolating result.
(chiral stationary phase CSP) mainly contains Pirkle type, ligand exchange type, macrocyclic antibiotic class, polyose, chiral crown ether class, cyclodextrin, protein-based and chiral polymer stationary phase to be used for the isolating chiral stationary phase of liquid chromatography at present.And cyclodextrin (CD) has good optical purity and do not disturb the detection of UV spectrum to compound, and the poly-hydroxy structure around the constitutional features of cyclodextrin " interior hydrophobic, outer hydrophilic " and the cavity, make it can be by different linking group by different compound-modified, and then have good chiral Molecular Recognition ability, therefore it is bonded to the last mutually preparation chiral stationary phase of chromatographic stationary and has good development prospect.
Summary of the invention
The objective of the invention is kind, so that better separate more chipal compounds and better study chiral recognition mechanism for the expanded ring dextrin derivative.Here the chiral ligand that will " temper toughness with gentleness " helps improving the chiral catalysis enantioselectivity and obtains the adaptive principle of better substrate, be applied to the design of cyclodextrin chiral stationary phase derived structure molecule, synthesized 6-deoxidation-6-amino-beta--cyclodextrin with synthesis step more simple to operation, and react with four kinds of different aromatic aldehydes on this basis, generated four kinds of novel CH that contain
2The beta-cyclodextrin derivative of-N=C-Ar group, and be bonded to silica gel formation stationary phase.Expectation obtains better molecular recognition effect, and is applicable to effective separation of multiple racemic mixture.Its synthetic route is seen accompanying drawing 1.
The concrete synthetic method of 6 deoxidations-6-amino-beta--cyclodextrin is: under nitrogen protection, in will being dissolved in the anhydrous pyridine through the beta-cyclodextrin that three recrystallizations are crossed under the room temperature, slowly be added dropwise to the anhydrous pyridine solution of the Tosyl chloride of 0.71 molar equivalent again, dropwise the back room temperature and continue reaction more than 12 hours, soak after-filtration with ether, filter cake obtains compound (2) with drying behind the distilled water recrystallization 3 times; With compound (2) is substrate, dissolves in exsiccant DMF, adds the NaN of 1.2 molar equivalents
3, in 105-110 ℃ of down reaction 3 hours, be cooled to room temperature after, reaction solution is splashed in the acetone, the gained white solid is compound (3); The triphenyl phosphorus of compound (3) and 3 molar equivalents is placed the single port flask, and, continue reaction 2 hours under the room temperature, after acetone treatment, obtain compound (4) with after the exsiccant DMF dissolving; Compound (4) with behind the ammonia solvent in stirring at room 6 hours, the adularescent suspension liquid generates (be triphenylphosphinc oxide), filtration, filtrate obtains purpose product compound (5) after acetone treatment.
The concrete synthetic method of cyclodextrin derivative (6): under the nitrogen protection, in reaction flask, add compound (5), after the anhydrous pyridine dissolving; add the aromatic aldehyde based compound; reaction added reaction solution in the acetone after 4 days under the room temperature, and suction filtration obtains solids washed with acetone, obtains containing CH after the drying
2The beta-cyclodextrin derivative of-N=C-Ar group.With the compound of cyclodextrin ammonia react be respectively phenyl aldehyde, 2, to N-Methylimidazole benzaldehyde, its structural formula is seen accompanying drawing 2 to trimethylammonium aminobenzaldehyde and nitro for 4-Dihydroxy benzaldehyde, nitro.
Contain CH
2The preparation of the beta-cyclodextrin derivative stationary phase of-N=C-Ar group: compound (6) is dissolved among the DMF, the NaH that adds 5 molar equivalents, after being stirred to no bubble generation, add 1.6 molar equivalent KH-560 coupling agents,, continue reaction 24 hours down at 110 ℃ behind the adding silica gel in 90 ℃ of reactions 4 hours, after the cooling, filter, filter cake is fixed phase through DMF, methyl alcohol, redistilled water and ether washing by soaking.
Advantage of the present invention:
(1) synthesized intermediate 6-deoxidation-6-amino-beta--cyclodextrin with a kind of method simple and easy to operate;
(2) synthesize the cyclodextrin derivative that a kind of novel group links, enlarged the kind of cyclodextrin derivative;
(3) will contain CH
2The beta-cyclodextrin derivative of-N=C-Ar group is bonded to the silica gel surface, makes the liquid chromatography chiral stationary phase, is applied in the chiral separation.Amino acid, medicine, aromatic alcohol chirality etc. have been carried out chiral separation, for obtaining pure optical isomer, and then prepare the pure medicine that physiologically active is arranged and effectively catalyst ligand etc. lay a good foundation.
Below be that some chirality aromatic alcohols and chiral drug are respectively at 6-deoxidation-6-benzimide-beta-cyclodextrin (BCD) and 6-deoxidation-6-(2,4-dihydroxyl-benzimide)-separate instance on beta-cyclodextrin (MDHBCD) chiral column, separate data is seen accompanying drawing 3 (separation condition: under the room temperature, flow rate of mobile phase is 0.6mol/ml, (a) methanol=40/60; (b) methanol=70/30).
Description of drawings
Fig. 1 is the synthetic route of novel beta-cyclodextrin derivative and stationary phase thereof.
Fig. 2 is four kinds of structural formulas with the compound of cyclodextrin ammonia react.
Fig. 3 is some chirality aromatic alcohols and the chiral drug separate data on BCD and MDHBCD chiral column respectively.
Embodiment
Specify the present invention below by embodiment, but the present invention has more than and is confined to following Example.
Under nitrogen protection; 6-deoxidation-6-amino-beta--cyclodextrin 2.00g (1.765mmol) is dissolved in the 35mL anhydrous pyridine; add phenyl aldehyde 2.5g (23.585mmol); behind the room temperature reaction 4 days, reaction solution dropwise splashed in the 400mL acetone obtains faint yellow solid, behind the suction filtration with washing with acetone filter cake 3-4 time; place vacuum drying oven in 80 ℃ of dry 4-5h; obtain list-6-benzimide-β-CD1.98g, productive rate: 95.96%, fusing point: 250 ℃.IR(KBr)v：3389.74，2928.14，2105.50，1660.38，1388.55，1255.02，1155.83，1081.03，1031.29，945.39，847.23，756.57，707.44，663.66，580.29cm
-1。
1HNMR?(500MHz，DMSO-d
6)δ：8.333(s，1H)，7.625-7.935(t，2H)，7.348-7.453(d，3H)，5.734-5.793(d，21H)，4.837-5.001(m，7H)，4.485(s，13H)，3.111-3.946(m，28H)，2.511(s，DMSO-d
6)。MS：M/Z(M+K)
+：1260.8。
Reactions steps and condition are identical with embodiment 1, and used substrate is 6-deoxidation-6-amino-beta--cyclodextrin and 2, the 4-Dihydroxy benzaldehyde, and the productive rate of products therefrom is: 89.51%, fusing point: 269-270 ℃.IR(KBr)v：3368.47，2929.16，1702.56，1636.40，1531.96，1367.93，1333.00，1300.79，1259.10，1156.25，1079.05，1029.25，947.06，857.39，758.86，707.70，580.15，533.37cm
-1。
1H?NMR(500MHz，DMSO-d
6)δ：8.290(s，1H)，7.763(t，1H)，7.383(d，1H)，7.135(d，1H)，6.097(s，21H)，4.832(s，7H)，4.418(s，13H)，3.296-3.659(m，28H)，2.503(s，DMSO-d
6)。MS：M/Z(M+Na)
+：1276.3。
Reactions steps and condition are identical with embodiment 1, used substrate be 6-deoxidation-6-amino-beta--cyclodextrin and nitro to the trimethylammonium aminobenzaldehyde, the productive rate of products therefrom is: 76.32%, fusing point: 220-225 ℃.IR(KBr)v：3368.61，2928.00，2105.14，1656.09，1384.73，1155.39，1080.11，1031.36，945.51，846.84，754.81，708.64，582.53cm
-1。
1H?NMR(500MHz，DMSO-d
6)δ：8.415(s，1H)，8.177(m，2H)，8.020(m，2H)，5.679-5.794(d，21H)，4.842(s，7H)，4.331-4.487(d，13H)，3.567-3.660(m，28H)，2.505(s，DMSO-d
6)，1.046-1.081(t，6H)。MS:M/Z (M
Positively charged ion)
+: 1256.3.
Reactions steps and condition are identical with embodiment 1, used substrate be 6-deoxidation-6-amino-beta--cyclodextrin and nitro to N-Methylimidazole benzaldehyde, the productive rate of products therefrom is: 91.21%, fusing point: 262-264 ℃.IR(KBr)v：3390.16，2927.79，1707.48，1645.48，1575.47，1384.65，1165.08，1080.36，1031.77，945.36，848.92，755.58，706.40，581.40，527.81cm
-1。
1H?NMR(500MHz，DMSO-d
6)δ：8.582(s，1H)，8.344(s，1H)，8.177(m，2H)，8.020(m，2H)，7.721-7.975(m，4H)，7.383-7.467(m，2H)，5.693-5.815(d，21H)，4.921-4.928(d，2H)，4.835(s，7H)，4.434-4.461(d，13H)，3.585-3.947(m，31H)，2.503(s，DMSO-d
6)。MS:M/Z (M
Positively charged ion)
+: 1316.8.
Claims (3)
1. a class is novel contains CH
2The preparation of the cyclodextrin derivative of-N=C-Ar base group modification and application is characterized in that: introduced CH in the synthetic route
2The flexible group of-N=C-Ar, concrete route is seen Figure of description 1.
2. a class as claimed in claim 1 is novel contains CH
2The preparation of the cyclodextrin derivative of-N=C-Ar base group modification and application, it is characterized in that: with the aromatic aldehyde based compound of cyclodextrin ammonia react can be phenyl aldehyde, 2,4-Dihydroxy benzaldehyde, nitro to trimethylammonium aminobenzaldehyde and nitro to N-Methylimidazole benzaldehyde, CH
2The structural formula of R is seen Figure of description 2 in the cyclodextrin derivative of-N=C-Ar base group modification.
3. a class as claimed in claim 1 is novel contains CH
2The preparation of the cyclodextrin derivative of-N=C-Ar base group modification and application, it is characterized in that: it is bonded to is prepared into stationary phase on the silica gel, some chirality aromatic alcohols and drug molecule have been carried out good separation, its separate data on 6-deoxidation-6-benzimide-beta-cyclodextrin (BCD) and 6-deoxidation-6-(2,4-dihydroxyl-benzimide)-beta-cyclodextrin (MDHBCD) post is seen Figure of description 3.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102921193A (en) * | 2012-11-13 | 2013-02-13 | 郑州大学 | Preparation method of capillary electro-chromatography column taking beta-cyclodextrin as bonded stationary phase and application in chiral drug separation |
| CN103288982A (en) * | 2013-06-17 | 2013-09-11 | 福建省北理展华医药技术研发有限公司 | Preparation method and application of diphenylphosphonate-beta-cyclodextrin |
| CN109158087A (en) * | 2018-09-21 | 2019-01-08 | 天津科技大学 | A kind of cyclodextrin based on microcellular structure constructs the preparation method of adsorbent material |
| GB2568550A (en) * | 2017-11-21 | 2019-05-22 | Univ Cape Town | Method of synthesising 6-deoxy-6-amino-ß-d-glucopyranoside-containing polymers |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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| EP1595936A1 (en) * | 2003-01-27 | 2005-11-16 | Mitsubishi Corporation | Antioxidative composition and composition for external use |
| CN101481355A (en) * | 2009-02-20 | 2009-07-15 | 中山大学 | Preparation of 2-substituted benzimidazole |
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| EP1595936A1 (en) * | 2003-01-27 | 2005-11-16 | Mitsubishi Corporation | Antioxidative composition and composition for external use |
| CN101481355A (en) * | 2009-02-20 | 2009-07-15 | 中山大学 | Preparation of 2-substituted benzimidazole |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102921193A (en) * | 2012-11-13 | 2013-02-13 | 郑州大学 | Preparation method of capillary electro-chromatography column taking beta-cyclodextrin as bonded stationary phase and application in chiral drug separation |
| CN102921193B (en) * | 2012-11-13 | 2015-03-18 | 郑州大学 | Preparation method of capillary electro-chromatography column taking beta-cyclodextrin as bonded stationary phase and application in chiral drug separation |
| CN103288982A (en) * | 2013-06-17 | 2013-09-11 | 福建省北理展华医药技术研发有限公司 | Preparation method and application of diphenylphosphonate-beta-cyclodextrin |
| GB2568550A (en) * | 2017-11-21 | 2019-05-22 | Univ Cape Town | Method of synthesising 6-deoxy-6-amino-ß-d-glucopyranoside-containing polymers |
| US11021547B2 (en) | 2017-11-21 | 2021-06-01 | University Of Cape Town | Method of synthesising 6-deoxy-6-amino-β-D-glucopyranoside-containing polymers and their precursors |
| GB2568550B (en) * | 2017-11-21 | 2021-06-30 | Univ Cape Town | Method of synthesising 6-deoxy-6-amino-ß-d-glucopyranoside-containing polymers |
| CN109158087A (en) * | 2018-09-21 | 2019-01-08 | 天津科技大学 | A kind of cyclodextrin based on microcellular structure constructs the preparation method of adsorbent material |
| CN109158087B (en) * | 2018-09-21 | 2021-03-12 | 天津科技大学 | Preparation method of cyclodextrin constructed adsorption material based on microporous structure |
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