CN101519460A - Synthetic method for hydroxypropyl-beta-cyclodextrin - Google Patents
Synthetic method for hydroxypropyl-beta-cyclodextrin Download PDFInfo
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- CN101519460A CN101519460A CN200910029892A CN200910029892A CN101519460A CN 101519460 A CN101519460 A CN 101519460A CN 200910029892 A CN200910029892 A CN 200910029892A CN 200910029892 A CN200910029892 A CN 200910029892A CN 101519460 A CN101519460 A CN 101519460A
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- cyclodextrin
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Abstract
The invention relates to a synthetic method for hydroxypropyl-beta-cyclodextrin. The synthetic method is characterized by comprising the following steps: (1) charging beta-cyclodextrin, propylene oxide, basic catalyst and deionized water in a molar ratio of 1:2.5-10.5:0.6-3.4:62.9-126 into a closed stainless steel high-pressure autoclave, and carrying out etherification reaction on the materials at a temperature of between 50 and 90 DEG C and a gauge pressure of between 0 and 0.6MPa; (2) neutralizing and filtering the mixture after the reaction; (3) washing the mixture with ethanol; (4) extracting with acetone; and (5) obtaining the hydroxypropyl-beta-cyclodextrin after dialysis and other processes. The synthetic method for the hydroxypropyl-beta-cyclodextrin has higher product yield which can be more than 70 percent (calculated by inventory rating of the beta-cyclodextrin), and the obtained product quality index is in accordance with the 5.0 quality standard of European pharmacopoeia. The synthetic method has the characteristics of simple process, short etherification reaction time, moderate reaction conditions, low impurity content, and the like.
Description
Technical field
The present invention relates to a kind of synthetic method of hydroxypropyl-beta-cyclodextrin, belong to dextrin etherificate art.
Background technology
Cyclodextrin (Cyclodextrin.CD) is the cyclic oligosaccharide natural product that is formed by connecting by 6～15 glucose molecules that starch obtains after the biological enzyme effect, common is α, β, γ-Huan Hujing, wherein the beta-cyclodextrin molecule is cylindric ringwise, one hollow cavity is arranged, but other material that its cavity inclusion is a large amount of, and form nano level inclusion compound.This clathration of beta-cyclodextrin can make guest molecule be protected in its cylindrical cavity, thus have anti-oxidant, fast light photograph, heat-resisting, slowly-releasing, character such as solubilising; In medicine, use, also increased medicine stability, promote to absorb, improved effects such as bioavailability; But the solubleness of beta-cyclodextrin in water is very little, and has certain renal toxicity and hemolytic, has limited its range of application.
Hydroxypropyl-beta-cyclodextrin is the beta-cyclodextrin derivative that attracts most attention at present, its water-soluble height, nontoxic, and having increases the water-soluble of insoluble drug, increases medicine stability and bioavailability, reduces poisonous side effect of medicine, character such as slowly-releasing and controlled release.These characteristics have inspired scientist that it is tested in various fields, particularly in fields such as pharmacy, makeup and equipment protection.
Protected the pharmaceutical composition of the unformed title complex that contains pharmaceutically active agents and hydroxypropyl-beta-cyclodextrin, this title complex can improve the solvability of effective constituent and so improved the absorptivity of medicine by the United States Patent (USP) 4727064 of Pitha application.
Chinese patent 200410071922.8 has related to a kind of Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular diseases, hydroxypropyl-beta-cyclodextrin inclusion and the preparation and the preparation method of borneol more specifically say so, this inclusion compound can be used for preparing injection, oral preparations and external preparation, have and promote medicine to see through hemato encephalic barrier, anti-inflammatory, antibiotic, pain relieving and promote the effect of Transdermal absorption.
The European patent EP 366154 that Shiseido company obtains has been protected the purposes of hydroxypropyl-beta-cyclodextrin in makeup; the title complex of this compound that is slightly soluble in water by ultraviolet sequestering agent, sanitas and perfume compound has good water-solubility; and the makeup that contain them have gratifying stability, and needn't adopt the solubilizing agent of skin irritation.
Recently; 1068303 and the Nihon Noyku of Japanese Patent Sun Oil 63079802 in the purposes that hydroxypropyl-beta-cyclodextrin is used for the equipment protection field has also been described, this illustrated relevant title complex compound toxicity and about the solvability of this title complex and the advantage of stability.
In sum, at present domestic patent about the hydroxypropyl-beta-cyclodextrin application is more, but report that openly hydroxypropyl-beta-cyclodextrin synthetic patent does not almost have, the synthetic method of reporting in the general document mostly is: NaOH and deionized water are packed in the there-necked flask, stirring and dissolving is warming up to 60 ℃, adds β-CD (beta-cyclodextrin), stir 1h, after β-CD dissolves fully; Under ice bath, lower the temperature, cool the temperature to 6 ℃, slowly drip PO (propylene oxide), after dropwising; Slowly be warming up to 31 ℃, reaction 20h; Reaction neutralizes after finishing again, filters, and washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin.
Above synthetic method etherification reaction is to carry out under uncovered normal pressure, and propylene oxide will slowly drip at low temperatures, complex operation, and the reaction times is longer, generally wants more than the 20h, and exist potential safety hazard.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of hydroxypropyl-beta-cyclodextrin, this method are that etherification reaction is placed airtight stainless steel autoclave, under low pressure carry out, and can shorten the etherification reaction time greatly, thereby simplify synthesis technique.
The scheme of finishing the application's foregoing invention task is, a kind of synthetic method of hydroxypropyl-beta-cyclodextrin is characterized in that, step is as follows:
(1). in airtight stainless steel autoclave, with beta-cyclodextrin, propylene oxide, basic catalyst and deionized water, 1:2.5～10.5:0.6～3.4:62.9～126 feed intake in molar ratio, carry out etherification reaction under 50～90 ℃ of temperature, 0～0.6MPa gauge pressure;
(2). reaction finishes after neutralization is filtered;
(3). washing with alcohol;
(4). acetone extract;
(5). aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin.
Described etherification reaction is in airtight stainless steel autoclave, carries out under the low pressure.
The described etherification reaction time can be 2～4h.
Described basic catalyst can be alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.
Described etherifying reagent is a propylene oxide.
Described etherification reaction temperature can be 50～90 ℃.
Described etherification reaction pressure can be 0～0.6MPa.
That more specifically and more optimizes says that the concrete steps of hydroxypropyl-beta-cyclodextrin synthetic method of the present invention are:
(1). in stainless steel autoclave, add basic catalyst and deionized water, stirring and dissolving adds beta-cyclodextrin again, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 1h down at 50～90 ℃, and beta-cyclodextrin is fully dissolved, the logical in batches propylene oxide of beginning, and after having led to, at 0～0.6MPa pressure, stirring reaction 2～4h under 50～90 ℃ of temperature;
The beta-cyclodextrin that the present invention recommends, propylene oxide, basic catalyst and deionized water be 1:4～8:1.8～2.5:71.5～87.6 in molar ratio.
Is described etherification reaction temperature? 60～80 ℃;
Described etherification reaction pressure is 0.01～0.2Mpa.
(2). after reaction finishes, cooling, discharging neutralizes again, filters;
(3). washing with alcohol;
(4). acetone extract;
(5). aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin.
Hydroxypropyl-beta-cyclodextrin synthetic method product yield of the present invention is higher, can reach (in the beta-cyclodextrin charging capacity) more than 70%, and the products obtained therefrom quality index meets the quality standard of European Pharmacopoeia 5.0.It is simple that the present invention has technology, and the etherificate time is short, reaction conditions gentleness, characteristics such as foreign matter content is low.
Embodiment
Below in conjunction with embodiment the present invention is further described.
Embodiment 1
With sodium hydroxide 15g, deionized water 250ml adds in the 2L stainless steel autoclave, and stirring and dissolving takes by weighing beta-cyclodextrin 200g and adds in the autoclave, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 1h down at 80 ℃, beta-cyclodextrin is fully dissolved, the 64g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0～0.2MPa pressure, stirring reaction 4h under 80 ℃ of temperature is after reaction finishes, cooling, discharging neutralizes again, filter washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 151.4g, yield 75.7%, and product quality indicator sees attached list 1.
Embodiment 2
With sodium hydroxide 15g, deionized water 250ml adds in the 2L stainless steel autoclave, and stirring and dissolving takes by weighing beta-cyclodextrin 200g and adds in the autoclave, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 1h down at 80 ℃, beta-cyclodextrin is fully dissolved, the 64g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0～0.2MPa pressure, stirring reaction 3h under 90 ℃ of temperature is after reaction finishes, cooling, discharging neutralizes again, filter washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 150.2g, yield 75.1%, and product quality indicator sees attached list 1.
Embodiment 3
With sodium hydroxide 15g, deionized water 250ml adds in the 2L stainless steel autoclave, stirring and dissolving, take by weighing beta-cyclodextrin 200g and add in the autoclave,, stir the autoclave good seal, vacuumize, N2 gas displacement twice begins to heat up, stir 1h down at 80 ℃, beta-cyclodextrin is fully dissolved, the 82g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0.2MPa pressure, stirring reaction 4h under 80 ℃ of temperature, after reaction finishes, cooling, discharging neutralizes again, filter, washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 160.2g, yield 80.1%, product quality indicator see attached list 1.
Embodiment 4
With sodium hydroxide 7.5g, deionized water 250ml adds in the 2L stainless steel autoclave, and stirring and dissolving takes by weighing beta-cyclodextrin 200g and adds in the autoclave, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 1h down at 80 ℃, beta-cyclodextrin is fully dissolved, the 64g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0～0.2MPa pressure, stirring reaction 4h under 80 ℃ of temperature is after reaction finishes, cooling, discharging neutralizes again, filter washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 146.5g, yield 73.2%, and product quality indicator sees attached list 1.
Embodiment 5
With sodium hydroxide 15g, deionized water 250ml adds in the 2L stainless steel autoclave, and stirring and dissolving takes by weighing beta-cyclodextrin 200g and adds in the autoclave, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 1h down at 60 ℃, beta-cyclodextrin is fully dissolved, the 78g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0.4MPa pressure, stirring reaction 4h under 60 ℃ of temperature is after reaction finishes, cooling, discharging neutralizes again, filter washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 149.7g, yield 74.8%, and product quality indicator sees attached list 2.
Embodiment 6
With sodium hydroxide 15g, deionized water 250ml adds in the 2L stainless steel autoclave, and stirring and dissolving takes by weighing beta-cyclodextrin 200g and adds in the autoclave, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 2h down at 50 ℃, beta-cyclodextrin is fully dissolved, the 64g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0.4MPa pressure, stirring reaction 4h under 40 ℃ of temperature is after reaction finishes, cooling, discharging neutralizes again, filter washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 139.8g, yield 70%, and product quality indicator sees attached list 2.
Embodiment 7
With sodium hydroxide 15g, deionized water 250ml adds in the 2L stainless steel autoclave, stirring and dissolving, take by weighing beta-cyclodextrin 200g and add in the autoclave,, stir the autoclave good seal, vacuumize, N2 gas displacement twice begins to heat up, stir 1h down at 70 ℃, beta-cyclodextrin is fully dissolved, the 56g propylene oxide is divided in 3 batches of feeding autoclaves, after having led to, at 0.2MPa pressure, stirring reaction 4h under 70 ℃ of temperature, after reaction finishes, cooling, discharging neutralizes again, filter, washing with alcohol, acetone extract, aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin 155.6g, yield 77.8%, product quality indicator see attached list 2.
Product quality indicator among subordinate list 1 embodiment
| Project | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Outward appearance | White powder | White powder | White powder | White powder |
| Substitution value | 5.0 | 5.9 | 7.8 | 4.8 |
| Foreign matter content % | Propylene glycol: 0.4 beta-cyclodextrin: 0.2 | Propylene glycol: 0.3 beta-cyclodextrin: 0.1 | Propylene glycol: 0.7 beta-cyclodextrin: 0.3 | Propylene glycol: 0.9 beta-cyclodextrin: 0.1 |
| Salts contg % | 0.01 | 0.01 | 0.007 | 0.002 |
| Weight loss on drying % | 2.8 | 3.1 | 1.7 | 4.5 |
| Heavy metal % | <0.0005 | <0.0005 | <0.0005 | <0.0005 |
| Solvability (25 ℃) g/100ml water | >60 | >60 | >60 | >60 |
Product quality indicator among subordinate list 2 embodiment
| Project | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| Outward appearance | White powder | White powder | White powder |
| Substitution value | 7.0 | 5.4 | 4.6 |
| Foreign matter content % | Propylene glycol: 0.4 beta-cyclodextrin: 0.1 | Propylene glycol: 0.8 beta-cyclodextrin: 0.2 | Propylene glycol: 0.5 beta-cyclodextrin: 0.3 |
| Salts contg % | 0.01 | 0.009 | 0.006 |
| Weight loss on drying % | 2.7 | 3.6 | 4.3 |
| Heavy metal % | <0.0005 | <0.0005 | <0.0005 |
| Solvability (25 ℃) g/100ml water | >60 | >60 | >60 |
Embodiment 8, and is substantially the same manner as Example 1, but wherein: beta-cyclodextrin, propylene oxide, basic catalyst and deionized water, 1:10.5:3.4:126 feeds intake in molar ratio.Described etherification reaction temperature is 90 ℃; Described etherification reaction pressure is 0.6Mpa.
Embodiment 9, and is substantially the same manner as Example 1, but wherein: beta-cyclodextrin, propylene oxide, basic catalyst and deionized water, 1:2.5:0.6:62.9 feeds intake in molar ratio.Described etherification reaction temperature is 50 ℃; Described etherification reaction pressure is 0.1Mpa.
Embodiment 10, and is substantially the same manner as Example 1, but wherein: beta-cyclodextrin, propylene oxide, basic catalyst and deionized water be 1:8:2.5:87.6 in molar ratio.Described etherification reaction temperature is 80 ℃; Described etherification reaction pressure is 0.2Mpa.
Embodiment 11, and is substantially the same manner as Example 1, but wherein: beta-cyclodextrin, propylene oxide, basic catalyst and deionized water be 1:4:1.8:71.5 in molar ratio.Described etherification reaction temperature is 60 ℃; Described etherification reaction pressure is 0.01Mpa.
Claims (5)
1, a kind of synthetic method of hydroxypropyl-beta-cyclodextrin is characterized in that, step is as follows:
(1). in airtight stainless steel autoclave, with beta-cyclodextrin, propylene oxide, basic catalyst and deionized water, 1:2.5～10.5:0.6～3.4:62.9～126 feed intake in molar ratio, carry out etherification reaction under 50～90 ℃ of temperature, 0～0.6MPa gauge pressure;
(2). reaction finishes after neutralization is filtered;
(3). washing with alcohol;
(4). acetone extract;
(5). aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin.
2, the synthetic method of hydroxypropyl-beta-cyclodextrin according to claim 1 is characterized in that,
The described etherification reaction time is 2～4h;
Described basic catalyst is sodium hydroxide or potassium hydroxide;
Described etherifying reagent is a propylene oxide;
Described etherification reaction temperature is 50～90 ℃;
Described etherification reaction pressure is 0～0.6Mpa.
3, the synthetic method of hydroxypropyl-beta-cyclodextrin according to claim 2 is characterized in that, the concrete steps of described synthetic method are:
(1). in stainless steel autoclave, add basic catalyst and deionized water, stirring and dissolving adds beta-cyclodextrin again, with the autoclave good seal, stirs, and vacuumizes N
2Gas displacement twice begins to heat up, and stirs 1h down at 50～90 ℃, and beta-cyclodextrin is fully dissolved, the logical in batches propylene oxide of beginning, and after having led to, at 0～0.6MPa pressure, stirring reaction 2～4h under 50～90 ℃ of temperature;
(2). after reaction finishes, cooling, discharging neutralizes again, filters;
(3). washing with alcohol;
(4). acetone extract;
(5). aftertreatments such as dialysis make hydroxypropyl-beta-cyclodextrin.
4, the synthetic method of hydroxypropyl-beta-cyclodextrin according to claim 3 is characterized in that, described beta-cyclodextrin, propylene oxide, basic catalyst and deionized water be 1:4～8:1.8～2.5:71.5～87.6 in molar ratio.
5, according to the synthetic method of the described hydroxypropyl-beta-cyclodextrin of one of claim 1～4, it is characterized in that,
Described etherification reaction temperature is 60～80 ℃;
Described etherification reaction pressure is 0.01～0.2Mpa.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276762A (en) * | 2011-07-19 | 2011-12-14 | 浙江大学 | Effective and spatial-region selective synthesis method of monohydroxy and dihydroxy cyclodextrin derivatives |
| CN103694376A (en) * | 2014-01-10 | 2014-04-02 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing sulfobutyl ether-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 |
| 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 |
-
2009
- 2009-03-20 CN CN200910029892A patent/CN101519460A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276762A (en) * | 2011-07-19 | 2011-12-14 | 浙江大学 | Effective and spatial-region selective synthesis method of monohydroxy and dihydroxy cyclodextrin derivatives |
| CN103694376A (en) * | 2014-01-10 | 2014-04-02 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing sulfobutyl ether-beta-cyclodextrin |
| CN103694376B (en) * | 2014-01-10 | 2016-04-13 | 凯莱英医药集团（天津）股份有限公司 | A kind of method preparing sulfobutyl ether-beta-cyclodextrin |
| US10246524B2 (en) | 2014-01-10 | 2019-04-02 | Asymchem Laboratories (Tianjin) Co., Ltd. | Method for preparing sulfobutyl ether-β-cyclodextrin |
| CN110317283A (en) * | 2019-06-06 | 2019-10-11 | 荆楚理工学院 | A kind of synthesis technology of beta-cyclodextrin derivative |
| 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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