CN102816260A - Preparation method of m-methylbenzeyl substituted 6-amino-beta-cyclodextrin derivative - Google Patents
Preparation method of m-methylbenzeyl substituted 6-amino-beta-cyclodextrin derivative Download PDFInfo
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- CN102816260A CN102816260A CN 201210293774 CN201210293774A CN102816260A CN 102816260 A CN102816260 A CN 102816260A CN 201210293774 CN201210293774 CN 201210293774 CN 201210293774 A CN201210293774 A CN 201210293774A CN 102816260 A CN102816260 A CN 102816260A
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Abstract
The invention provides a preparation method of a m-methylbenzeyl substituted 6-amino-beta-cyclodextrin derivative capable of forming cations and hydrochloride thereof. The method uses beta-cyclodextrin as a starting material and comprises three steps including a 6th site iodine (bromine) substitution and an amino substitution reaction for preparation of Per-6-(3-methylbenzeyl)-amino-6-deoxy-beta-cyclodextrin. The method reaches a final product yield of 65-85%.
Description
Technical field
The present invention relates to a kind of preparation method that can form the substituted beta-cyclodextrin derivative of cationic 6-amido.Present method is for expecting with beta-cyclodextrin; Through three steps such as 6 iodine (bromine) generations, amido substitution reactions, preparation 6-is complete-methyl-benzyl-amido-6-deoxidation-beta-cyclodextrin be Per-6-(3-methylbenzeyl)-amino-6-deoxy-β-cyclodextrin with and hydrochloride.The final product productive rate of this method can reach 65～85%.
Background technology
Schardinger dextrins is one type of natural cyclic oligosaccharides compound, and common have α, β and a γ-Huan Hujing.Wherein beta-cyclodextrin is the most commonly used, and it is by seven alpha-D-glucose unit 1, and 4-glycosidic link ring-type is formed by connecting.The same with other Schardinger dextrins, contain a wetting ability outside surface and a hydrophobicity inside aperture in its molecular structure, this characteristic can form it with chemical compound lot and includes mixture (inclusion compound).Because natural beta-cyclodextrin is water-soluble limited, has therefore limited it and formed the ability of inclusion compound as host compound and guest compound.The main products that is widely used at present is its verivate.Just because of it can with the characteristic of guest compound inclusion compound; In recent years, beta-cyclodextrin derivative is widely used in medicine and field of food comprises increase medicine or the solubleness of guest compound in water, improves bioavailability of medicament; Strengthen stability, the security of medicine or guest compound; Reduce drug toxicity, relax the medicine hemolytic, control drug release speed is covered unpleasant odor or the like.
The constitutional features of beta-cyclodextrin has determined its structural modification to be primarily aimed at 6,3 and 4 in its molecule.With regard to its 6, it is the important seat that is modified into the hydrophobicity and decision " interior hole " degree of depth, can prepare the verivate that 6-ether, thioether, amine etc. have different functions through etherificate, esterification, oxidation, chemical reaction such as crosslinked.Character and the function that beta-cyclodextrin derivative and guest compound form inclusion compound is included in the substituted radical that solubleness in the water depends on beta-cyclodextrin 6 and 3,4.The solubleness of inclusion compound in water that beta-cyclodextrin derivative and ionic target compound form also depends on the ionic type of target compound and beta-cyclodextrin derivative.Need with what stress to be, Schardinger dextrins and guest compound are not to be to form inclusion compound by interatomic covalent linkage in the molecule, but the formation of intermolecular space behavior.Therefore inclusion compound has original all functions of guest compound.
The objective of the invention is constitutional features according to beta-cyclodextrin, invent a kind of can form positively charged ion promptly-N
+H
2-the substituent beta-cyclodextrin derivative of 6-amido, make it comprise that medicine is easy to form the good inclusion compound of solubleness in water with being with cationic guest compound.Following just with beta-cyclodextrin for expecting; Through three steps such as 6 iodine (bromine) generations, amido substitution reactions; Preparation 6-is complete-methyl-benzyl-amido-6-deoxidation-beta-cyclodextrin is Per-6-(3-methylbenzeyl)-amino-6-deoxy-β-cyclodextrin, with and hydrochloride set forth.
Summary of the invention
The present invention is the constitutional features according to beta-cyclodextrin; Aim to provide and a kind ofly can form the substituent b-cyclodextrin derivative of cationic 6-amido, make its can with can with the guest compound of anionic comprise again that with cationic guest compound medicine forms the good inclusion compound of solubleness in water.This beta-cyclodextrin derivative be 6-complete-methyl-benzyl-amido-6-deoxidation-b-Schardinger dextrins is Per-6-(3-methylbenzeyl)-amino-6-deoxy-β-cyclodextrin.Following be its productive rate can reach 65～85% with and the preparation method of hydrochloride.
Beta-cyclodextrin (
1) press Baer, H H, Berenguel, A V etc. (
Carbohydr. Res.1992,
228, 307) method pass through PPh
3Carry out 6 periodo obtain 6-iodine (bromine)-6-deoxidation-beta-cyclodextrin (
2).Compound
2Again through the amido substitution reaction generate 6-complete-methyl-benzyl-amido-6-deoxidation-beta-cyclodextrin (
3).Compound
3Process the compound that it is prone to dissolve water with HCl
3Hydrochloride, see Fig. 1.The productive rate of present method final product can reach 65～85%.
Description of drawings
Fig. 1: compound
3The preparation route.
Embodiment
Below in conjunction with embodiment implementation of the present invention is described.
Embodiment 1:
6-iodo-6-deoxidation-beta-cyclodextrin (
2
) preparation
With beta-cyclodextrin (
1) for expecting, according to the method synthetic compound of (Carbohydr. Res. 228:307-314) such as Baer HH
2The experiment productive rate is 92%.
6-is complete-methyl-benzyl-6-deoxidation-beta-cyclodextrin (
3
) preparation
Add 3-anisole methylamine (155 mmole) in the compound 2 (0.45 mmole), stir and be heated to 75
oC reacted 48 hours.Reaction solution is cooled to room temperature afterwards, adds 5 milliliters of MTBEs, and also with 10 * 10 milliliters washing with acetone, vacuum-drying promptly gets faint yellow solid compound 3 to filtering precipitate, yield 92%.[R]
D?+12°(
c?=?1.0?in?DMF?at?25?°C);?LC-ESIMS?
m/z?[M?+?2]
2+/2,?[M?+?3/3]
3+/3；
1H?NMRδppm?(400?MHz,?CD
3SOCD
3)?7.20～7.04?(m,?35H),?6.68?(bd,?
J?=?1.5Hz),?4.86?(bd,?7H,?H-1),?3.73?(m,?7H,?H-5),?3.71?(m?,?7H,?H-3),?3.69?(m,?7H,?H-2),?2.63?(d,
?J?=?12.5Hz,?7H,?H-α),?2.56?(d,
?J?=?12.5Hz,?7H?,H-β),?2.03?(s,?21H,?CH
3)。
6-is complete-methyl-benzyl-6-deoxidation-beta-cyclodextrin (
3
) preparation of hydrochloride
Compound
3In (450 milligrams) water-soluble (4 milliliters), stir, add 1 N NaOH (2.1 milliliters, 2.1 mmoles), filter, throw out difference water (3 * 5 milliliters) and acetone (3 * 5 milliliters) respectively wash the final vacuum drying three times.Dry thing adds entry (1 milliliter); Stir, slowly add 1 N HCl (2.2 milliliters, 2.2 mmoles) and become clear liquor up to mixed solution; Add remaining N HCl solution again; Stirred 18 hours under the room temperature, leach throw out and, promptly get compound after the vacuum-drying with acetone (3 * 5 milliliters) washing three times
3Hydrochloride.The residue of filtrating after vacuum-drying filters with ethanol (4 milliliters) dissolving, and filtrating was at room temperature placed three days, leach throw out and with washing with acetone after vacuum-drying obtains extra compound
3Hydrochloride.This compound is the water recrystallization again, and its purity can reach 98～99%.
Claims (2)
1. preparation method that can form cationic substituted 6-amido-beta-cyclodextrin derivative of methyl-benzyl and hydrochloride thereof.
2. present method is for expecting with beta-cyclodextrin; Through three steps such as 6 iodine (bromine) generations, amido substitution reactions; Preparation 6-is complete-and methyl-benzyl-amido-6-deoxidation-beta-cyclodextrin is Per-6-(3-methylbenzeyl)-amino-6-deoxy-β-cyclodextrin, and the productive rate of final product is 65～85%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210293774 CN102816260A (en) | 2012-08-17 | 2012-08-17 | Preparation method of m-methylbenzeyl substituted 6-amino-beta-cyclodextrin derivative |
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|---|---|---|---|
| CN 201210293774 CN102816260A (en) | 2012-08-17 | 2012-08-17 | Preparation method of m-methylbenzeyl substituted 6-amino-beta-cyclodextrin derivative |
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|---|---|
| CN102816260A true CN102816260A (en) | 2012-12-12 |
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|---|---|---|---|
| CN 201210293774 Pending CN102816260A (en) | 2012-08-17 | 2012-08-17 | Preparation method of m-methylbenzeyl substituted 6-amino-beta-cyclodextrin derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387426A (en) * | 2014-10-11 | 2015-03-04 | 浙江大学 | Method for regioselective synthesis of 6-O-acryloylsaccharide derivatives |
| 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 |
-
2012
- 2012-08-17 CN CN 201210293774 patent/CN102816260A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387426A (en) * | 2014-10-11 | 2015-03-04 | 浙江大学 | Method for regioselective synthesis of 6-O-acryloylsaccharide derivatives |
| 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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Application publication date: 20121212 |