CN104974275A - Synthetic method of sulfoalkyl ether cyclodextrin derivative - Google Patents
Synthetic method of sulfoalkyl ether cyclodextrin derivative Download PDFInfo
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- CN104974275A CN104974275A CN201510459778.3A CN201510459778A CN104974275A CN 104974275 A CN104974275 A CN 104974275A CN 201510459778 A CN201510459778 A CN 201510459778A CN 104974275 A CN104974275 A CN 104974275A
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Abstract
The invention belongs to the technical field of cyclodextrin derivative preparation and in particular relates to a synthetic method of a sulfoalkyl ether cyclodextrin derivative. The synthetic method of the sulfoalkyl ether cyclodextrin derivative is characterized by firstly adding beta-cyclodextrin to a sodium hydroxide water solution, adding quaternary ammonium salt catalysts, dropwise adding a sulfoalkylation reagent under the ultrasonic condition and then carrying out sulfoalkylation reaction to obtain a sulfoalkyl ether cyclodextrin derivative solution, then removing impurities in the sulfoalkyl ether cyclodextrin derivative solution through membrane separation and finally preparing the sulfoalkyl ether cyclodextrin derivative through spray drying, freeze drying and constant temperature vacuum drying. The synthetic method has the beneficial effects that the reaction time is short; the sulfoalkylation reagent can not be degraded by self in aqueous alkali in a short time, so that impurities can not be generated; as the sulfoalkylation reagent in the process is not subjected to excessive reaction, the excessive alkylation reagent is unnecessary to be degraded by adopting alkali, thus not only saving raw materials but also protecting the environment.
Description
Technical field
The invention belongs to cyclodextrin derivative preparing technical field, be specifically related to a kind of synthetic method of sulfoalkyl ether cyclodextrin derivative.
Background technology
Sulfoalkyl ether cyclodextrin derivative is the polyanionic cyclodextrin derived with sulfoalkyl ether function base.Compare not derivative cyclodextrin, sulfoalkyl cyclodextrin can improve water-soluble and security significantly.
The synthesis of sulfoalkyl ether cyclodextrin derivative take all Betacylcodextrin as starting material at present, then reacts with alkylating reagent in the basic conditions, refines finally by organic deposition method, nanofiltration, ultrafiltration process etc.These methods are all on the books in following patent.US Patent No. 5134127, US5376645, US6153746, US3426011; Chinese patent CN101959508A Sulfoalkyl ether cyclodextrin compositions; The synthesis technique of Chinese patent CN1858071 water soluble sulfoalkyl ether-beta-cyclic dextrine; Chinese patent CN103694376A mono-kind prepares the method for sulfobutyl ether-beta-cyclodextrin; Chinese patent CN102718891A utilizes the method for membrane sepn and solvent deposition purification sulfobutyl ether-beta-cyclodextrin.
The water-fast sultone class alkylating reagent of general employing in current technique, as 1,4-butane sultone, 1,3-propane sultone etc., during reaction, sulfoalkyl reagent can not fully contact with Betacylcodextrin, thus causes the reaction times longer, simultaneously because sulfoalkylation reagent self is degraded for a long time in alkaline solution, easily produce impurity.
In addition, in technique, all adopt excessive alkylating reagent to react, then excessive alkylating reagent is carried out in the basic conditions being decomposed into soluble salt, so that follow-up ultrafiltration, nanofiltration and organic solvent carry out purifies and separates again.There is degradation time long, byproduct molecules amount increases, not easily the shortcoming such as removing.And the mole dosage of the alkylating reagent that technique uses is all at more than 1.1x times of cyclodextrin molar weight, and x is average substitution degree, i.e. the substituent quantity of sulfoalkyl ether of cyclodextrin molecular connection, namely substituent mole number on every mole of cyclodextrin.
Reaction terminates rear excessive alkylating reagent and will be caused waste by alkaline degradation, affects quality product and to environment simultaneously.Therefore, need long reaction time in the current sulfoalkyl cyclodextrin derivative building-up process of a kind of solution badly, alkylating reagent easily self is degraded, is produced impurity, and alkylating reagent adds alkaline degradation further and causes the problems such as waste.
Summary of the invention
The object of this invention is to provide that a kind of reaction times is short, alkylating reagent is not easily degraded, do not produce impurity, save the synthetic method of the sulfoalkyl ether cyclodextrin derivative of alkylating reagent.
The synthetic method of sulfoalkyl ether cyclodextrin derivative of the present invention, first cyclodextrin is joined in aqueous sodium hydroxide solution, add quaternary ammonium salt catalyzer, sulfoalkylation reaction is carried out again drip sulfoalkylation reagent under Ultrasonic Conditions after, obtain sulfoalkyl ether cyclodextrin derivative solution, then impurity is wherein removed by membrane sepn, finally by spraying dry, lyophilize, the obtained sulfoalkyl ether cyclodextrin derivative of constant-temperature vacuum drying.
The quality of described sodium hydroxide is 0.2 ~ 0.7 times of cyclodextrin quality, and the mass percent concentration of aqueous sodium hydroxide solution is 12 ~ 40%.
Described cyclodextrin is alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin.
Described quaternary ammonium salt catalyzer is one or more in benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride.
The quality of described quaternary ammonium salt catalyzer is 0.5 ~ 1% of cyclodextrin quality.
Described hyperacoustic frequency 15 ~ 60kHz, the time dripping sulfoalkylation reagent is 0.5 ~ 3h.
Described sulfoalkylation reagent is Isosorbide-5-Nitrae-butane sultone or PS.
The mol ratio of described cyclodextrin and sulfoalkyl reagent is 1:1.0 ~ 1.02x, x is cyclodextrin average substitution degree.
3 ~ 6 hours described sulfoalkylation reaction times, temperature of reaction 40 ~ 85 DEG C.
Described film is ultra-filtration membrane, nanofiltration membrane, can be mineral membrane or organic membrane, and profile is rolled film, plate film or hollow-fibre membrane.
The impurity and quaternary ammonium salt catalyzer etc. such as impurity of the present invention comprises sodium-chlor, 4-hydroxybutane-1-sulfonic acid, two (4-sulphur butyl) ether disodium.
The present invention has following beneficial effect:
Reaction times of the present invention is short, and the sulfoalkylation reagent short period of time auto-degradation can not occur in alkaline solution, thus produces impurity.Because the sulfoalkylation reagent in technique is not excessive response, without the need to adopting alkali to degrade excessive alkylating reagent again, both economizing in raw materials, protecting environment again.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
11.35g (0.01mol) beta-cyclodextrin is joined in 9.08g 25wt.% aqueous sodium hydroxide solution, add 0.079g benzyltriethylammoinium chloride, 9.53g (0.07mol) 1 is dripped with 0.5h under 15kHz Ultrasonic Conditions, 4-butane sultone is in 60 DEG C of reaction 5h, obtain sulfobutyl ether Betacylcodextrin solution, then removing impurity wherein by Ultra filtration membrane, is the sulfobutyl ether Betacylcodextrin of 7 finally by spraying dry, lyophilize, the obtained substitution value of constant-temperature vacuum drying.
Embodiment 2
11.35g (0.01mol) beta-cyclodextrin is joined in 31.78g 15wt.% aqueous sodium hydroxide solution, add 0.057g tetrabutylammonium chloride, 4.89g (0.04mol) 1 is dripped with 1h under 60kHz Ultrasonic Conditions, 3-propane sultone is in 40 DEG C of reaction 6h, obtain sulfopropyl ether Betacylcodextrin solution, then removing impurity wherein by nanofiltration membrane separation, is the sulfopropyl ether Betacylcodextrin of 4 finally by spraying dry, lyophilize, the obtained substitution value of constant-temperature vacuum drying.
Embodiment 3
11.35g (0.01mol) beta-cyclodextrin is joined in 20.43g 35wt.% aqueous sodium hydroxide solution, add 0.1135g Dodecyl trimethyl ammonium chloride, 13.89g (0.102mol) 1 is dripped with 2.5h under 40kHz Ultrasonic Conditions, 4-butane sultone is in 85 DEG C of reaction 6h, obtain sulfobutyl ether Betacylcodextrin solution, then removing impurity wherein by Ultra filtration membrane, is the sulfobutyl ether Betacylcodextrin of 10 finally by spraying dry, lyophilize, the obtained average substitution degree of constant-temperature vacuum drying.
Embodiment 4
Adopt the beta-cyclodextrin in alpha-cylodextrin replacement embodiment 1, all the other processes are as embodiment 1.
Embodiment 5
Adopt the beta-cyclodextrin in γ-cyclodextrin replacement embodiment 1, all the other processes are as embodiment 1.
Claims (10)
1. the synthetic method of a sulfoalkyl ether cyclodextrin derivative, it is characterized in that: first cyclodextrin is joined in aqueous sodium hydroxide solution, add quaternary ammonium salt catalyzer, sulfoalkylation reaction is carried out again drip sulfoalkylation reagent under Ultrasonic Conditions after, obtain sulfoalkyl ether cyclodextrin derivative solution, then impurity is wherein removed by membrane sepn, finally by spraying dry, lyophilize, the obtained sulfoalkyl ether cyclodextrin derivative of constant-temperature vacuum drying.
2. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: the quality of sodium hydroxide is 0.2 ~ 0.7 times of cyclodextrin quality, and the mass percent concentration of aqueous sodium hydroxide solution is 12 ~ 40%.
3. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: cyclodextrin is alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin.
4. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: quaternary ammonium salt catalyzer is one or more in benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride.
5. the synthetic method of the sulfoalkyl ether cyclodextrin derivative according to claim 1 or 4, is characterized in that: the quality of quaternary ammonium salt catalyzer is 0.5 ~ 1% of cyclodextrin quality.
6. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: hyperacoustic frequency 15 ~ 60kHz, and the time dripping sulfoalkylation reagent is 0.5 ~ 3h.
7. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: sulfoalkylation reagent is Isosorbide-5-Nitrae-butane sultone or PS.
8. the synthetic method of the sulfoalkyl ether cyclodextrin derivative according to claim 1 or 7, is characterized in that: the mol ratio of cyclodextrin and sulfoalkyl reagent is 1:1.0 ~ 1.02x, x is cyclodextrin average substitution degree.
9. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: 3 ~ 6 hours sulfoalkylation reaction times, temperature of reaction 40 ~ 85 DEG C.
10. the synthetic method of sulfoalkyl ether cyclodextrin derivative according to claim 1, is characterized in that: film is ultra-filtration membrane or nanofiltration membrane; Or film is mineral membrane or organic membrane.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565860A (en) * | 2016-10-20 | 2017-04-19 | 石家庄学院 | Method for preparing sulfobutyl ether-beta-cyclodextrin |
| CN107129546A (en) * | 2017-06-27 | 2017-09-05 | 淄博千汇生物科技有限公司 | The green synthesis method of sulfoalkyl betadex |
| US10040872B2 (en) | 2012-10-22 | 2018-08-07 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| US10117951B2 (en) | 2008-04-28 | 2018-11-06 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
| US10323103B2 (en) | 2012-02-28 | 2019-06-18 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| US10633462B2 (en) | 2012-02-15 | 2020-04-28 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
| US10851184B2 (en) | 2014-08-22 | 2020-12-01 | Cydex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
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| US20130184357A1 (en) * | 2008-04-28 | 2013-07-18 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10117951B2 (en) | 2008-04-28 | 2018-11-06 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
| US11806402B2 (en) | 2008-04-28 | 2023-11-07 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
| US10780177B2 (en) | 2008-04-28 | 2020-09-22 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
| US10633462B2 (en) | 2012-02-15 | 2020-04-28 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
| US11208500B2 (en) | 2012-02-15 | 2021-12-28 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
| US10323103B2 (en) | 2012-02-28 | 2019-06-18 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| US10040872B2 (en) | 2012-10-22 | 2018-08-07 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| US10800861B2 (en) | 2012-10-22 | 2020-10-13 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| US10851184B2 (en) | 2014-08-22 | 2020-12-01 | Cydex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
| US11795241B2 (en) | 2014-08-22 | 2023-10-24 | Cydex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
| CN106565860A (en) * | 2016-10-20 | 2017-04-19 | 石家庄学院 | Method for preparing sulfobutyl ether-beta-cyclodextrin |
| CN107129546B (en) * | 2017-06-27 | 2019-05-21 | 淄博千汇生物科技有限公司 | The green synthesis method of sulfoalkyl betadex |
| CN107129546A (en) * | 2017-06-27 | 2017-09-05 | 淄博千汇生物科技有限公司 | The green synthesis method of sulfoalkyl betadex |
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