CN104558253A - Green synthesis method of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin - Google Patents
Green synthesis method of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin Download PDFInfo
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- CN104558253A CN104558253A CN201410800382.6A CN201410800382A CN104558253A CN 104558253 A CN104558253 A CN 104558253A CN 201410800382 A CN201410800382 A CN 201410800382A CN 104558253 A CN104558253 A CN 104558253A
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Abstract
The invention discloses a green synthesis method of a new compound 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin. The method comprises the following steps: in the presence of anhydrous K2CO3 or anhydrous Na2CO3, reacting beta-cyclodextrin and dimethyl carbonate in a dimethylformamide organic solvent, after the reaction is complete, filtering to remove the anhydrous K2CO3 or anhydrous Na2CO3 and other insoluble substances, distilling under reduced pressure to remove the solvent, and concentrating the solution; precipitating out the product with acetone, and filtering to obtain 2-O-methyl-beta-cyclodextrin; dissolving the obtained 2-O-methyl-beta-cyclodextrin in a 30% sodium hydroxide solution, dropwisely adding quantitative epoxypropane at certain temperature, after the reaction is complete, adding hydrochloric acid to neutralize to neutrality, and distilling to obtain a white solid; and dissolving in dimethylformamide, filtering to remove the salt, pouring the filtrate into acetone to obtain a white precipitate, repeatedly washing with acetone, and finally, immersing in aether to obtain the white powder solid product 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin. The method has the advantages of simple technological conditions, high conversion rate of beta-cyclodextrin and environment friendliness.
Description
Technical field
The present invention relates to a kind of green synthesis method of new compound 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin.
Background technology
Beta-cyclodextrin is the class tubular compound connected into by 7 glucose monomer α-Isosorbide-5-Nitrae glycosidic links.Due to beta-cyclodextrin, there is the molecular structure of cavity and interior hydrophilic outer hydrophobic characteristic makes beta-cyclodextrin be widely used, the aspects such as molecular recognition, separation, medicine, catalysis can be widely used in.But, due to the limitation of lower (solubleness of beta-cyclodextrin is 1.85g/100mL at 25 DEG C of temperature) of the solubleness of beta-cyclodextrin parent and other properties, make it apply and be very limited.In order to improve the character of beta-cyclodextrin, expand its range of application, the character of people to beta-cyclodextrin is improved, beta-cyclodextrin (being again the derivative of beta-cyclodextrin) after improvement all improves a lot in solubleness and other character, makes the range of application of beta-cyclodextrin also more extensive.In order to overcome the little shortcoming of beta-cyclodextrin solubleness, study on the modification being carried out to it both at home and abroad, making it have more excellent character; Improve its effect, open up novelty teabag.Such as, the rising of natural beta-cyclodextrin solubility with temperature and increasing, but the solubility with temperature of methyl beta-cyclodextrin raises and sharply reduces, and has low absorbability, high surface characteristic and stereoselectivity.Those can be replaced skin surfactant formulatory makeup excitatory.Methyl-B-cyclodextrin has larger inclusion characteristic, and the solubleness of inclusion compound in water also enlarges markedly.The characteristic of 2-hydroxypropylβ-cyclodextrin is that security is good, and local irritation is little, has water-soluble and hydrophilic character, not easily causes the hemolytic action in animal body, therefore, can be used for medicine inclusion and solubilising, improves bioavailability.Can forming inclusion complex with various hydrophobic medicine thus increase the water-soluble and medicine stability of medicine, is increase that medicine is water-soluble and medicine stability effect is best at present, application and research cyclodextrin derivative the most widely.
Summary of the invention
The present invention seeks on beta-cyclodextrin, introduce hydrophobic group (methyl) and hydrophilic radical (2-hydroxypropyl) simultaneously, the advantage of comprehensive two kinds of application beta-cyclodextrin derivative widely (methyl-β-cyclodextrin and (2-hydroxypropyl)-beta-cyclodextrin), synthesizing methyl-2-hydroxypropylβ-cyclodextrin has more asymmetric environment, should have 2-O-methyl-6-O-(2-the hydroxypropyl)-beta-cyclodextrin of purposes widely in molecular recognition.
Technical scheme provided by the invention is: a kind of green synthesis method of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin, comprises the following steps:
Step 1) at 10-60 DEG C of temperature, in anhydrous K
2cO
3or anhydrous Na
2cO
3under existence, beta-cyclodextrin and methylcarbonate react 0.5-56 hour in solvent dimethylformamide, with TLC monitoring reaction in reaction process;
Step 2) react completely after, cross filter anhydrous K
2cO
3or anhydrous Na
2cO
3and other insolubles, underpressure distillation goes out solvent dimethylformamide, and solution concentrates;
Step 3) add acetone, stir, be settled out product, elimination acetone, obtaining powder solid is 2-O-methyl-B-cyclodextrin;
Step 4) gained 2-O-methyl-B-cyclodextrin is dissolved in the aqueous sodium hydroxide solution of 30%, drip the mixing solutions of propylene oxide and acetonitrile, 0-70 DEG C of temperature, under normal pressure, reaction 0.5-48 hour;
Step 5) with extremely neutral with sodium hydroxide solution in the hydrochloric acid soln of 10 mol/L, distillation obtains white solid;
Step 6) dissolve the product in white solid with dimethyl formamide, the sodium-chlor filtered is crossed after dissolving, the solution of removing sodium-chlor is poured in 50-200 milliliter acetone, obtain white depositions, continue to use acetone repetitive scrubbing, finally soak with ether and obtain white powder solid phase prod 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin.
Described step 1) in, the mol ratio of methylcarbonate and beta-cyclodextrin: 1:1-1:9.
Described step 1) in, beta-cyclodextrin and anhydrous K
2cO
3or anhydrous Na
2cO
3mass ratio is: 1:5-86:1.
Described step 1) in, the mol ratio of beta-cyclodextrin and solvent dimethylformamide is: 1:1500-1:200.
Described step 4) in, the volume ratio of propylene oxide and acetonitrile is 1:15.
Described step 4) in, the mol ratio of propylene oxide and beta-cyclodextrin is: 0.1:1-7:1.
The invention has the beneficial effects as follows:
The present invention utilizes the hydrogen atom synthesis 2-O-methyl-B-cyclodextrin on green methylating reagent methylcarbonate Chagerdβcyclodextrins on 2 hydroxyls; Utilizing the hydroxyl reaction of propylene oxide in the basic conditions on open loop and 2-O-methyl-B-cyclodextrin on 6 to synthesize 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin, is the green synthesis method that one prepares new compound 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin.The present invention has synthesized a kind of new compound, and synthetic route is green, simple, and reaction conditions is gentle, and processing condition are simple, and the transformation efficiency of beta-cyclodextrin is high, and after reaction, the total conversion rate of beta-cyclodextrin is 72-99%, environmentally friendly; This compound has larger application potential at Yao thing Fu Liao ﹑ Shi product Tian Jia Ji ﹑ chemical etc.
Accompanying drawing explanation
When considered in conjunction with the accompanying drawings, by referring to detailed description below, more completely can understand the present invention better and easily learn wherein many adjoint advantages, but accompanying drawing described herein is used to provide a further understanding of the present invention, form a part of the present invention, schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention, wherein:
Fig. 1 is 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin mass spectrum that embodiment 1 obtains;
Fig. 2 is 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin mass spectrum that embodiment 2 obtains.
Embodiment
The present invention is described in detail as follows in conjunction with the embodiments:
Embodiment 1:
With in three mouthfuls of burning round-bottomed bottles of reflux condensing tube and stirring, add in 4g beta-cyclodextrin (3.6mmol) and 150mL dimethylformamide (DMF) and stir to clarify, then add anhydrous 1.0g K
2cO
3, stir after 10 minutes and add 1.0mL (16mmol) carbonic diester methyl esters again, continue to stir, control temperature 25 DEG C, react 8 hours, reaction process thin-layer chromatography (TLC) monitors response situation.After reaction terminates, centrifugation removing anhydrous K
2cO
3and suspended substance, decompression, liquidus temperature is 60-90 DEG C, and underpressure distillation goes out solvent DMF and unreacted methylcarbonate, obtains 2-O-methyl-B-cyclodextrin 3.4g; Obtained 3.4g 2-O-methyl-B-cyclodextrin is dissolved in the aqueous sodium hydroxide solution of 150mL 30%, drips the solution 16mL of propylene oxide and acetonitrile (volume ratio is 1:15), 0 DEG C of temperature, under normal pressure, react 8 hours; With extremely neutral with sodium hydroxide solution in the hydrochloric acid soln of 10 mol/L, distillation obtains white solid; The product in white solid is dissolved with dimethyl formamide, the sodium-chlor filtered is crossed after dissolving, the solution of removing sodium-chlor is poured in 150 milliliters of acetone, obtain white precipitate, repeatedly wash at continuation acetone, finally soak 16h with 200mL ether, obtain white powder solid phase prod 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin 3.1g.The yield 77.5% of beta-cyclodextrin, average substitution degree is 2.5.2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin mass spectrum that embodiment 1 obtains is as shown in Fig. 1.
Embodiment 2:
Burning in round-bottomed bottles with reflux condensing tube and stirring three mouthfuls, add in 4g beta-cyclodextrin (3.6mmol) and 150mL DMF and stir to clarify, then 1.5g anhydrous K 2CO3 is added, stir after 10 minutes and add 2.0mL (32mmol) carbonic diester methyl esters again, continue to stir, control temperature 40 DEG C, react 24 hours, reaction process thin-layer chromatography (TLC) monitors response situation.After reaction terminates, centrifugation removing anhydrous K 2CO3 and suspended substance, decompression, liquidus temperature is 60-90 DEG C, and underpressure distillation goes out solvent DMF and unreacted methylcarbonate, obtains 2-O-methyl-B-cyclodextrin 3.5g; Obtained 3.5g 2-O-methyl-B-cyclodextrin is dissolved in the aqueous sodium hydroxide solution of 150mL 30%, drips the solution 32mL of propylene oxide and acetonitrile (volume ratio is 1:15), 5 DEG C of temperature, under normal pressure, react 16 hours; With extremely neutral with sodium hydroxide solution in the hydrochloric acid soln of 10 mol/L, distillation obtains white solid; The product in white solid is dissolved with dimethyl formamide, the sodium-chlor filtered is crossed after dissolving, the solution of removing sodium-chlor is poured in 150 milliliters of acetone, obtain white precipitate, repeatedly wash at continuation acetone, finally soak 16h with 200mL ether, obtain white powder solid phase prod 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin 3.3g.The yield 82.5% of beta-cyclodextrin, average substitution degree is 3.6.2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin mass spectrum that embodiment 2 obtains is as shown in Fig. 2.
The explanation of above example just understands core concept of the present invention for helping; Meanwhile, for one of ordinary skill in the art, according to thought of the present invention, all will change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention.
Claims (6)
1. a green synthesis method for 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin, is characterized in that, comprise the following steps:
Step 1) at 10-60 DEG C of temperature, in anhydrous K
2cO
3or anhydrous Na
2cO
3under existence, beta-cyclodextrin and methylcarbonate react 0.5-56 hour in solvent dimethylformamide, with TLC monitoring reaction in reaction process;
Step 2) react completely after, cross filter anhydrous K
2cO
3or anhydrous Na
2cO
3and other insolubles, underpressure distillation goes out solvent dimethylformamide, and solution concentrates;
Step 3) add acetone, stir, be settled out product, elimination acetone, obtaining powder solid is 2-O-methyl-B-cyclodextrin;
Step 4) gained 2-O-methyl-B-cyclodextrin is dissolved in the aqueous sodium hydroxide solution of 30%, drip the mixing solutions of propylene oxide and acetonitrile, 0-70 DEG C of temperature, under normal pressure, reaction 0.5-48 hour;
Step 5) with extremely neutral with sodium hydroxide solution in the hydrochloric acid soln of 10 mol/L, distillation obtains white solid;
Step 6) dissolve the product in white solid with dimethyl formamide, the sodium-chlor filtered is crossed after dissolving, the solution of removing sodium-chlor is poured in 50-200 milliliter acetone, obtain white depositions, continue to use acetone repetitive scrubbing, finally soak with ether and obtain white powder solid phase prod 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin.
2. the green synthesis method of a kind of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin according to claim 1, is characterized in that, described step 1) in, the mol ratio of methylcarbonate and beta-cyclodextrin: 1:1-1:9.
3. the green synthesis method of a kind of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin according to claim 1, is characterized in that, described step 1) in, beta-cyclodextrin and anhydrous K
2cO
3or anhydrous Na
2cO
3mass ratio is: 1:5-86:1.
4. the green synthesis method of a kind of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin according to claim 1, it is characterized in that, described step 1) in, the mol ratio of beta-cyclodextrin and solvent dimethylformamide is: 1:1500-1:200.
5. the green synthesis method of a kind of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin according to claim 1, is characterized in that, described step 4) in, the volume ratio of propylene oxide and acetonitrile is 1:15.
6. the green synthesis method of a kind of 2-O-methyl-6-O-(2-hydroxypropyl)-beta-cyclodextrin according to claim 1, is characterized in that, described step 4) in, the mol ratio of propylene oxide and beta-cyclodextrin is: 0.1:1-7:1.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796544A (en) * | 2019-02-01 | 2019-05-24 | 廊坊兴龙生物技术有限公司 | 2,6- bis--O- methyl-cycloheptaamylose industrial production process and its method of inspection |
| CN110317283A (en) * | 2019-06-06 | 2019-10-11 | 荆楚理工学院 | A kind of synthesis technology of beta-cyclodextrin derivative |
| CN111234050A (en) * | 2020-03-20 | 2020-06-05 | 淄博千汇生物科技有限公司 | Green preparation process of methyl betacyclodextrin |
| CN112661874A (en) * | 2020-12-30 | 2021-04-16 | 曲阜市天利药用辅料有限公司 | 6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant and preparation method thereof |
| US11279774B2 (en) | 2019-01-03 | 2022-03-22 | Underdog Pharmaceuticals, Inc. | Cyclodextrin dimers, compositions thereof, and uses thereof |
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| CN101508741A (en) * | 2009-03-16 | 2009-08-19 | 濮阳职业技术学院 | Process for synthesis of methylation-beta-cyclodextrin with dimethyl carbonate and beta-cyclodextrin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11279774B2 (en) | 2019-01-03 | 2022-03-22 | Underdog Pharmaceuticals, Inc. | Cyclodextrin dimers, compositions thereof, and uses thereof |
| CN109796544A (en) * | 2019-02-01 | 2019-05-24 | 廊坊兴龙生物技术有限公司 | 2,6- bis--O- methyl-cycloheptaamylose industrial production process and its method of inspection |
| CN109796544B (en) * | 2019-02-01 | 2021-06-01 | 廊坊兴龙生物技术有限公司 | Industrial preparation method and inspection method of 2, 6-di-O-methyl-beta-cyclodextrin |
| CN110317283A (en) * | 2019-06-06 | 2019-10-11 | 荆楚理工学院 | A kind of synthesis technology of beta-cyclodextrin derivative |
| CN111234050A (en) * | 2020-03-20 | 2020-06-05 | 淄博千汇生物科技有限公司 | Green preparation process of methyl betacyclodextrin |
| CN112661874A (en) * | 2020-12-30 | 2021-04-16 | 曲阜市天利药用辅料有限公司 | 6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant and preparation method thereof |
| CN112661874B (en) * | 2020-12-30 | 2022-01-07 | 曲阜市天利药用辅料有限公司 | 6-hydroxypropyl substituted beta-cyclodextrin functional medicine adjuvant and preparation method thereof |
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