CN102174125B - 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
- Publication number
- CN102174125B CN102174125B CN 201110006332 CN201110006332A CN102174125B CN 102174125 B CN102174125 B CN 102174125B CN 201110006332 CN201110006332 CN 201110006332 CN 201110006332 A CN201110006332 A CN 201110006332A CN 102174125 B CN102174125 B CN 102174125B
- Authority
- CN
- China
- Prior art keywords
- cyclodextrin
- chiral
- beta
- preparation
- novel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
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 bebenzaldehyde, 2, 4-dihydroxy benzaldehyde, nitro. aratrimethylaminobenzaldehyde and nitro. Para N-methylimidazolylbenzaldehyde. The preparation method provided by the invention has the advantages ofsimpleness 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=CH-R base group modification, and prepare on this basis chiral stationary phase, belong to the field of chemical synthesis.
Background technology
As everyone knows, chipal compounds is the same with the right hand such as people's left hand, each other mirror image and can not overlapping.Along with the increase of chipal compounds in the kind of the development of the research fields such as medicine, life and catalyzer and demand, obtain optically pure single chiral isomer and have more and more important meaning.
Up to the present, the method for acquisition single enantiomer mainly contains: chiral source synthesis method, dissymmetric synthesis 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 subject to people's generally attention.And in the liquid chromatography, the heart that stationary phase is known as and is separated, its character and preparation play very important effect to the result who separates.
The chiral stationary phase (chiral stationary phase, CSP) that is used at present the liquid chromatography separation mainly contains Pirkle type, ligand exchange type, macrocyclic antibiotic class, polyose, chiral crown ether class, cyclodextrin, protein-based and Polymer-based Chiral Stationary Phases.And cyclodextrin (CD) has good optical purity and do not disturb UV spectrum to the detection of 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 a good chiral Molecular Recognition ability, therefore it is bonded to that the preparation chiral stationary phase has good development prospect on the chromatographic stationary phases.
Summary of the invention
The objective of the invention is the kind for the expanded ring dextrin derivative, in order to better separate more chipal compounds and better study chiral recognition mechanism.Here the chiral ligand that will " temper toughness with gentleness " is conducive to improve 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 containing-CH
2The beta-cyclodextrin derivative of-N=CH-R group, and be bonded to silica gel formation stationary phase.Expectation obtains better molecular recognition effect, and is applicable to the effective separation of multiple racemic mixture.Its synthetic route is seen accompanying drawing 1.
The concrete synthetic method of 6-deoxidation-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 again the anhydrous pyridine solution of the Tosyl chloride of 0.71 molar equivalent, dropwise rear room temperature and continue reaction more than 12 hours, filter after soaking with ether, filter cake obtains compound (2) with distilled water recrystallization 3 times by oven dry; Take compound (2) as substrate, in the DMF of drying, dissolve, add the NaN of 1.2 molar equivalents
3, in 105-110 ℃ of lower 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 with after the dry DMF dissolving, continue reaction 2 hours under the room temperature, after acetone treatment, obtain compound (4); 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; suction filtration obtains solids washed with acetone, is contained after the drying-CH
2The beta-cyclodextrin derivative of-N=CH-R group.With the compound of cyclodextrin ammonia react be respectively phenyl aldehyde, 2,4-Dihydroxy benzaldehyde, nitro to trimethylammonium aminobenzaldehyde and nitro to N-Methylimidazole benzaldehyde, corresponding-R is respectively phenyl, 2, to N-methylimidazolyl phenyl, structural formula is seen accompanying drawing 2 to trimethylammonium aminophenyl and nitro for 4-dihydroxy phenyl, nitro.
Contain-CH
2The preparation of the beta-cyclodextrin derivative stationary phase of-N=CH-R group: compound (6) is dissolved among the DMF, the NaH that adds 5 molar equivalents, be stirred to without behind the Bubble formation, add 1.6 molar equivalent KH-560 coupling agents, in 90 ℃ of reactions 4 hours, reacted 24 hours 110 ℃ of lower continuation behind the adding silica gel, 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=CH-R group is bonded to Silica 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 5 kinds of chiral aromatic alcohols and chiral drug loxoprofen, metoprolol and atenolol USP 23 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/water=40/60; (b) methanol/water=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 the respectively separate data on BCD and MDHBCD chiral column of 5 kinds of chiral aromatic alcohols and chiral drug loxoprofen, metoprolol and atenolol USP 23.
Embodiment
Specify the present invention below by embodiment, but the present invention has more than and is confined to following example.
Embodiment 1
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。
1H?NMR(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。
Embodiment 2
Reactions steps and condition are identical with embodiment 1, and used substrate is 6-deoxidation-6-amino-beta--cyclodextrin and 2,4-Dihydroxy benzaldehyde, and the productive rate of products therefrom is: 89.51%, and 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。
Embodiment 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 ℃.IP(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.
Embodiment 4
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。
1HNMR(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 (2)
1. a class contains-CH
2The preparation of the cyclodextrin derivative of-N=CH-R base group modification is characterized in that: introduced in the synthetic route-CH
2The flexible group of-N=CH-R, concrete route is as follows
2. a class as claimed in claim 1 contains-CH
2The application of the cyclodextrin derivative of-N=CH-R base group modification is characterized in that: it is bonded to is prepared into stationary phase on the silica gel, concrete route is as follows
1-phenyl-2-nitroethyl alcohol, 1-o-bromophenyl-2-nitroethyl alcohol, 1-o-methoxyphenyl-2-nitroethyl alcohol, 1-betanaphthyl-2-nitroethyl alcohol and 1-α-furyl base-2-nitroethyl alcohol and drug molecule loxoprofen, metoprolol and atenolol USP 23 have been carried out good the 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 as follows
Separation condition: under the room temperature, flow rate of mobile phase is 0.6mol/ml, (a) methanol/water=40/60; (b) methanol/water=70/30
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110006332 CN102174125B (en) | 2011-01-13 | 2011-01-13 | Preparation and application of novel CH2-N=C-Ar group-modified cyclodextrin derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110006332 CN102174125B (en) | 2011-01-13 | 2011-01-13 | Preparation and application of novel CH2-N=C-Ar group-modified cyclodextrin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102174125A CN102174125A (en) | 2011-09-07 |
| CN102174125B true CN102174125B (en) | 2013-01-02 |
Family
ID=44517404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110006332 Expired - Fee Related CN102174125B (en) | 2011-01-13 | 2011-01-13 | Preparation and application of novel CH2-N=C-Ar group-modified cyclodextrin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102174125B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288983A (en) * | 2013-06-17 | 2013-09-11 | 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 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103288982B (en) * | 2013-06-17 | 2015-09-02 | 福建省北理展华医药技术研发有限公司 | The preparation method of diphenylphosphine acid esters base – β – cyclodextrin and application |
| GB2568550B (en) * | 2017-11-21 | 2021-06-30 | Univ Cape Town | Method of synthesising 6-deoxy-6-amino-ß-d-glucopyranoside-containing polymers |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2011
- 2011-01-13 CN CN 201110006332 patent/CN102174125B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 周婕等.全苯异氰酸酯化环糊精固定相对手性药物的拆分.《应用化学》.2009,第26卷(第3期),全文. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288983A (en) * | 2013-06-17 | 2013-09-11 | 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102174125A (en) | 2011-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2668436C (en) | Process for preparing nebivolol | |
| CN102174125B (en) | Preparation and application of novel CH2-N=C-Ar group-modified cyclodextrin derivatives | |
| CN110938077A (en) | Method for synthesizing Avapritinib | |
| CN114394923B (en) | Preparation method of N-acyl-2-alkyl indoline compound | |
| JP2009522210A (en) | 2,2 ', 6,6'-tetraoxazoline biphenyl ligand and method for preparing the same | |
| CN104804006A (en) | Method for synthesizing chiral Tr*ger's base derivatives | |
| CN112851556B (en) | Novel aggregation-induced emission Golgi fluorescence probe and preparation method and application thereof | |
| CN101560191B (en) | Alpha-menaphthyl substituted spiro bis(oxazoline) ligands, synthetic method and application thereof in synthesizing pyrazolidine derivatives | |
| CN102718768A (en) | Chiral five-membered bicyclic guanidine compound, preparation method and application thereof | |
| JP4961568B2 (en) | Ligand, production method thereof, and catalyst using the ligand | |
| JP6676146B2 (en) | Novel production method of chromanol derivative | |
| JP2012082155A (en) | Triazolium salt and method for producing the same, and method for producing alkylated oxindol using azide alcohol and asymmetric reaction | |
| CN109251227B (en) | Chiral compound containing ferrocene skeleton and rigid spiro structure, synthesis and application | |
| CN114853608A (en) | Synthetic method of [60] fullerene hydrogen derivative catalyzed by N-heterocyclic carbene | |
| WO2014126008A1 (en) | Catalyst and method for producing optically active anti-1,2-nitroalkanol compound | |
| JPH1095759A (en) | Dendritic nitrogen-containing organic compound bearing planar chiral or axial chiral terminal group, its preparation and use | |
| JP4004976B2 (en) | Fullerene derivatives | |
| WO2006004093A1 (en) | Process for producing optically active phenylpropylamine derivative | |
| CN103288983B (en) | Cyclodextrin derivative modified by oxazoline group as well as preparation method and application thereof | |
| CN110684043B (en) | C-N axis chiral arylamine compound and preparation method thereof | |
| CN116396196B (en) | Method for preparing amido isothiocyanate/amido thiourea compound in one pot | |
| CN114160206B (en) | Catalyst for catalytic synthesis of optically active indole compound, application and synthesis method thereof, and optically active indole compound | |
| Ou et al. | Synthesis and characterization of macrocyclic compounds with a hydroxyl functional group | |
| Sapre et al. | Synthesis of enantiomerically enriched benzimidazole-triazoles: Application as organocatalyst for asymmertric Diels-Alder reaction | |
| JP2004262790A (en) | Rotaxane compound having salen metal complex in cyclic compound, method for producing the same and its intermediate and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130102 Termination date: 20140113 |