CN107325203B - A kind of gamma-cyclodextrin modifier and its preparation method and application - Google Patents
A kind of gamma-cyclodextrin modifier and its preparation method and application Download PDFInfo
- Publication number
- CN107325203B CN107325203B CN201710550900.7A CN201710550900A CN107325203B CN 107325203 B CN107325203 B CN 107325203B CN 201710550900 A CN201710550900 A CN 201710550900A CN 107325203 B CN107325203 B CN 107325203B
- Authority
- CN
- China
- Prior art keywords
- gamma
- cyclodextrin
- preparation
- modifier
- reaction
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Abstract
The invention discloses a kind of gamma-cyclodextrin modifier and its preparation method and application, gamma-cyclodextrin modifier the preparation method comprises the following steps: perhalogeno gamma-cyclodextrin and 3- (chlorosulfonyl) propionic ester replace under alkali effect generates 2- ester group ethyl sulfuryl-gamma-cyclodextrin.Gamma-cyclodextrin modifier can be used for preparing the more glucose sodium that relaxes.Gamma-cyclodextrin modifier preparation method of the present invention is easy to operate, easy control of reaction conditions and yield is higher, has broad application prospects.
Description
Technical field
The present invention relates to the preparation field of polysaccharide, especially a kind of gamma-cyclodextrin modifier and preparation method thereof and use
On the way.
Background technique
Cyclodextrin modified object, which can be used as, reverses conventional use of neuromuscular blocking drug, anti-muscle relaxant.The wherein Portugal Shu Geng
Sugared sodium has rocuronium or Vecuronium Bromide induction when reversing systemic anesthesia in several minutes as a kind of novel anti-muscle relaxant
Moderate and deep intramuscular relexation, the product can make anesthetist operation start it is of flaccid muscles to terminating to control well
Degree, improve surgical quality.
Relax more glucose sodium most disclosed early in patent US6670340, using gamma-cyclodextrin as starting material by with triphenylphosphine
Replace with halogen and generate perhalogeno gamma-cyclodextrin, then generates target product, preparation method under sodium hydride effect with mercaptopropionic acid
It is as follows:
Sulfydryl is reacted with sodium hydride in this route generates sulfydryl sodium, and discharges hydrogen, the sulfydryl sodium and halogenated ring of generation
The row reaction that progresses greatly recklessly generates the more glucose sodium that relaxes, and the reaction route is shorter, but technique is difficult to control, reaction reagent activity ratio
Larger, the impurity of generation is relatively more, and product quality and yield are relatively low.
In the recent period, patent CN104844732 discloses a kind of new method for preparing the more glucose sodium that relaxes, with perhalogeno γ-ring paste
Essence is starting material, generates full sulfydryl gamma-cyclodextrin with thiocarbamide first, then simultaneously basic hydrolysis generates target with methyl acrylate addition
Product, the preparation method is as follows:
This method has made marked progress, but the route main problem is: 1. perhalogeno gamma-cyclodextrin has been difficult with thiocarbamide
It is complete to replace, not exclusively replace impurity extremely difficult removing in final product.In addition, the prolonged pyroreaction of step of replacing easily causes
The degradation of starting material, influences reaction efficiency；2. the method that addition step uses ultraviolet light to irradiate, it is difficult to ensure that reactant is complete
Conversion.
Summary of the invention
The present invention be exactly in order to the low more glucose sodium preparation process yield that solves to relax in the prior art, difficult control of reaction conditions and
The problems such as purifying is more difficult, a kind of gamma-cyclodextrin modifier proposed and its preparation method and application.
The present invention is realized according to following technical scheme.
A kind of gamma-cyclodextrin modifier, structural formula are as follows:
Chain alkane, cycloalkane and the aromatic hydrocarbon for the 1-12 carbon that R refers in formula.
A kind of preparation method of gamma-cyclodextrin modifier, 6- deoxidation -6- perhalogeno gamma-cyclodextrin and 3- (chlorosulfonyl)
Gamma-cyclodextrin modifier is prepared in propionic ester, and preparation route is as follows:
Tetrahydrofuran, N,N-dimethylformamide, N, N- dimethylacetamide is added in the preparation reaction of gamma-cyclodextrin modifier
Amine and dimethyl sulfoxide.
Alkali is added in the preparation reaction of gamma-cyclodextrin modifier.
The alkali is sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, Sodamide, sodium hydride, potassium tert-butoxide, normal-butyl
Lithium, tert-butyl lithium, triethylamine, pyridine, diethylamine, ammonium hydroxide, ethylenediamine, tetramethylethylenediamine and diisopropylamine etc..
The reaction temperature of gamma-cyclodextrin modifier preparation reaction is -30 DEG C to 25 DEG C.
A kind of gamma-cyclodextrin modifier is preparing the application in the more glucose sodium that relaxes.
Present invention obtains following beneficial effects.
Relax in the prior art more glucose sodium preparation process difficult to control, product quality and yield of effective solution of the present invention is low
The problems such as.Preparation method of the present invention relative to the existing more glucose sodium that relaxes, reaction mass significantly improve, and final product content reaches
To 95% or more, product yield can reach 95%；3- (chlorosulfonyl) propionic ester is cheap and easy to get, and property is stablized, substitution reaction item
Part is mild, and reaction efficiency is high, produces easy to control；Metal and absolute alcohol are the method for common reduction sulfone, low in cost, operation letter
Just, reaction efficiency is high, is convenient for industrialized production.
Specific embodiment
Below with reference to embodiment, the invention will be further described.
A kind of gamma-cyclodextrin modifier, structural formula are as follows:
Chain alkane, cycloalkane and the aromatic hydrocarbon for the 1-12 carbon that R refers in formula.
A kind of preparation method of gamma-cyclodextrin modifier, 6- deoxidation -6- perhalogeno gamma-cyclodextrin and 3- (chlorosulfonyl)
Gamma-cyclodextrin modifier is prepared in propionic ester, and preparation route is as follows:
6- deoxidation -6- perhalogeno gamma-cyclodextrin is made by gamma-cyclodextrin and triphenylphosphine and halogen method.
Tetrahydrofuran, N,N-dimethylformamide, N, N- dimethylacetamide is added in the preparation reaction of gamma-cyclodextrin modifier
Amine and dimethyl sulfoxide.
Alkali is added in the preparation reaction of gamma-cyclodextrin modifier.
The alkali is sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, Sodamide, sodium hydride, potassium tert-butoxide, normal-butyl
Lithium, tert-butyl lithium, triethylamine, pyridine, diethylamine, ammonium hydroxide, ethylenediamine, tetramethylethylenediamine and diisopropylamine etc..
The reaction temperature of gamma-cyclodextrin modifier preparation reaction is -30 DEG C to 25 DEG C.
A kind of gamma-cyclodextrin modifier is preparing the application in the more glucose sodium that relaxes.
A kind of preparation method for the more glucose sodium that relaxes, this method use 6- deoxidation -6- perhalogeno gamma-cyclodextrin former for starting
Material successively prepares the more glucose sodium that relaxes through following steps:
1) 6- deoxidation -6- perhalogeno gamma-cyclodextrin and 3- (chlorosulfonyl) propionic ester carry out substitution reaction, obtain γ-ring
Dextrin modifier；
2) it after gamma-cyclodextrin modifier and metal and absolute alcohol reduction sulfuryl become thio object, then reacts with sodium hydroxide,
Obtain the more glucose sodium that relaxes.
The process route of above-mentioned preparation method is as follows:
Chain alkane, cycloalkane and the aromatic hydrocarbon for the 1-12 carbon that R refers in formula.
Metal is alkali and alkaline earth metal ions, such as lithium, sodium, potassium and calcium.Absolute alcohol be anhydrous methanol, ethyl alcohol, isopropanol,
N-butanol, isobutanol and tert-butyl alcohol etc..
The preparation of embodiment 1:2- carbomethoxy ethyl sulfuryl-gamma-cyclodextrin
Dry 50g 6- deoxidation -6- perchloro- gamma-cyclodextrin is dissolved in dry 1L n,N-Dimethylformamide,
- 30 DEG C are cooled to after 22mL triethylamine is added, after 3- (chlorosulfonyl) methyl propionate is slowly added dropwise, temperature control to 0 DEG C of reaction 2h will
The solution is slowly added in reaction solution, and reaction solution is slowly added in 1L Drinking Water, and a large amount of solids are precipitated, and is filtered, 10mL
Cold n,N-Dimethylformamide washs filter cake, obtains off-white powder 55g, yield 110%.
MS (m/z): 2393.35 [M+Na]+。1H-NMR(d6-DMSO): δ 5.90-5.91(16H, m), δ 4.99-5.01
(8H, m), δ 3.55-3.66(32H, m), δ 3.25-3.41(16H, m), δ 3.04-3.11(8H, m), δ 2.74-2.80(24H,
M), δ 2.57-2.60(16H, m).
The preparation of embodiment 2:2- ethoxycarbonyl ethyl sulfuryl-gamma-cyclodextrin
By dry 25g 6- deoxidation -6- perbromo- gamma-cyclodextrin, it is dissolved in dry 500mL n,N-dimethylacetamide
In, -10 DEG C are cooled to after 10mL pyridine is added, after 3- (chlorosulfonyl) ethyl propionate is slowly added dropwise, temperature control to 10 DEG C of reactions
The solution is slowly added in reaction solution by 1.5h, and reaction solution is slowly added in 500mL Drinking Water, and a large amount of solids are precipitated,
It filters, 10mL cold n,N-dimethylacetamide washs filter cake, obtains off-white powder 28g, yield 112%.
MS (m/z): 2483.57 [M+H]+。1H-NMR(d6-DMSO): δ 5.91-5.93(16H, m), δ 4.99-5.04(8H,
M), δ 3.76-4.03(24H, m), δ 3.24-3.43(16H, m), δ 3.09-3.13(8H, m) and, δ 2.75-2.83(24H, m), δ
2.56-2.60(16H m), δ 1.27-1.33(24H, m).
The preparation of embodiment 3:2- hexamethylene ester group ethyl sulfone base-gamma-cyclodextrin
It is dissolved in dry 25g 6- deoxidation -6- periodo gamma-cyclodextrin in dry 500mL dimethyl sulfoxide, is added
0 DEG C is cooled to after 10mL ethylenediamine, after 3- (chlorosulfonyl) cyclohexyl propionate is slowly added dropwise, temperature control is to 25 DEG C of reaction 1h, by this
Solution is slowly added in reaction solution, and reaction solution is slowly added in 500mL Drinking Water, and a large amount of solids are precipitated, and is filtered, 10mL
Cold dimethyl sulfoxide washs filter cake, obtains off-white powder 32g, yield 128%.
MS (m/z): 2916.23 [M+H]+。1H-NMR(d6-DMSO): δ 5.93-5.95(16H, m), δ 5.01-5.04(8H,
M), δ 3.80-4.02(16H, m), δ 3.23-3.40(16H, m), δ 3.11-3.15(8H, m) and, δ 2.76-2.83(24H, m), δ
2.56-2.64(16H m), δ 1.47-1.55(80H, m).
The preparation of embodiment 4:2- butyl ester base ethyl sulfuryl-gamma-cyclodextrin
By dry 25g6- deoxidation -6- periodo gamma-cyclodextrin, it is dissolved in dry 600mL n,N-Dimethylformamide
In, -20 DEG C are cooled to after 8g sodium hydroxide is added, after 3- (chlorosulfonyl) butyl propionate is slowly added dropwise, temperature control to 5 DEG C of reactions
The solution is slowly added in reaction solution by 2h, and reaction solution is slowly added in 500mL Drinking Water, and a large amount of solids are precipitated, and is taken out
Filter, 10mL cold n,N-Dimethylformamide wash filter cake, obtain off-white powder 29.5g, yield 118%.
MS (m/z): 2452.33 [M+H]+。1H-NMR(d6-DMSO): δ 5.91-5.94(16H, m), δ 4.99-5.06(8H,
M), δ 3.81-4.03(24H, m), δ 3.25-3.43(16H, m), δ 3.12-3.17(8H, m) and, δ 2.76-2.83(24H, m), δ
2.56-2.63(16H m), δ 1.37-1.43(72H, m).
Embodiment 5: the preparation for the more glucose sodium that relaxes
By dry 50g 2- carbomethoxy ethyl sulfuryl-gamma-cyclodextrin, it is dissolved in dry 100mL N, N- dimethyl formyl
In amine, -10 DEG C are cooled to after 20mL dehydrated alcohol is added, after 8g lithium metal is slowly added dropwise, temperature control to 25 DEG C of reaction 1h, in system
After lithium completely consumes, 20mL 2moL/L sodium hydroxide solution is added, 500mL dehydrated alcohol is added in temperature control to 25 DEG C of reaction 2h,
A large amount of off-white powder 42.5g, yield 85% is precipitated.
MS (m/z): 2023.4 [M+Na]+。1H-NMR(d6-DMSO): δ 5.10-5.13(8H, m), δ 4.01-3.98(8H,
M), δ 3.85-3.89(16H, m), δ 3.55-3.65(16H, m), δ 3.04-3.11(8H, m) and, δ 2.94-2.99(8H, m), δ
2.82-2.89(16H m), δ 2.42-2.52(8H, m).
Embodiment 6: the preparation for the more glucose sodium that relaxes
By dry 50g 2- ethoxycarbonyl ethyl sulfuryl-gamma-cyclodextrin, it is dissolved in dry 100mL N, N- dimethyl formyl
In amine, -10 DEG C are cooled to after 15mL anhydrous methanol is added, after 6g metallic sodium is slowly added dropwise, temperature control to 5 DEG C of reaction 2h, in system
After sodium completely consumes, 20mL 2moL/L sodium hydroxide solution is added, 500mL dehydrated alcohol is added in temperature control to 25 DEG C of reaction 2h,
A large amount of off-white powder 41.5g, yield 83% is precipitated.
MS (m/z): 2023.5 [M+Na]+。1H-NMR(d6-DMSO): δ 5.09-5.12(8H, m), δ 3.98-4.01(8H,
M), δ 3.85-3.88(16H, m), δ 3.53-3.64(16H, m), δ 3.06-3.15(8H, m) and, δ 2.93-2.99(8H, m), δ
2.82-2.89(16H m), δ 2.43-2.51(8H, m).
Embodiment 7: the preparation for the more glucose sodium that relaxes
By dry 50g 2- hexamethylene ester group ethyl sulfone base-gamma-cyclodextrin, it is dissolved in dry 120mL N, N- dimethyl methyl
In amide, -20 DEG C are cooled to after 15g anhydrous tertiary butanol is added, after 6g metallic potassium is slowly added dropwise, temperature control to -5 DEG C of reaction 4h, body
After potassium completely consumes in system, 20mL 2moL/L sodium hydroxide solution is added, the anhydrous second of 600mL is added in temperature control to 25 DEG C of reaction 2h
A large amount of off-white powder 35g, yield 70% is precipitated in alcohol.
MS (m/z): 2023.4 [M+Na]+。1H-NMR(d6-DMSO): δ 5.09-5.11(8H, m), δ 3.98-4.02(8H,
M), δ 3.86-3.89(16H, m), δ 3.53-3.65(16H, m), δ 3.06-3.16(8H, m) and, δ 2.93-3.01(8H, m), δ
2.82-2.89(16H m), δ 2.43-2.50(8H, m).
Embodiment 8: the preparation for the more glucose sodium that relaxes
By dry 50g 2- hexamethylene ester group ethyl sulfone base-gamma-cyclodextrin, it is dissolved in dry 110mL N, N- dimethyl methyl
In amide, it is cooled to 0 DEG C after 16mL anhydrous isopropyl alcohol is added, after 7.5g calcium metal is slowly added dropwise, temperature control to 10 DEG C of reaction 4h, body
After calcium completely consumes in system, 20mL 2moL/L sodium hydroxide solution is added, the anhydrous second of 650mL is added in temperature control to 25 DEG C of reaction 2h
A large amount of off-white powder 37.5g, yield 75% is precipitated in alcohol.
MS (m/z): 2023.4 [M+Na]+。1H-NMR(d6-DMSO): δ 5.10-5.12(8H, m), δ 3.98-4.02(8H,
M), δ 3.85-3.88(16H, m), δ 3.53-3.65(16H, m), δ 3.06-3.16(8H, m) and, δ 2.92-3.02(8H, m), δ
2.82-2.87(16H m), δ 2.43-2.51(8H, m).
Claims (2)
1. a kind of preparation method of gamma-cyclodextrin modifier, it is characterised in that: 6- deoxidation -6- perhalogeno gamma-cyclodextrin and 3-
Gamma-cyclodextrin modifier is prepared in (chlorosulfonyl) propionic ester, and preparation route is as follows:
Chain alkane, cycloalkane or the aromatic hydrocarbon for the 1-12 carbon that R refers in formula；
By dry 6- deoxidation -6- perhalogeno gamma-cyclodextrin, it is dissolved in dry n,N-Dimethylformamide or N, N- dimethyl
In acetamide or dimethyl sulfoxide or tetrahydrofuran, be cooled to reaction temperature after alkali is added, the reaction temperature be -30 DEG C extremely
25 DEG C, after 3- (chlorosulfonyl) propionic ester is slowly added dropwise, which is slowly added in reaction solution by temperature control, and reaction solution is slow
It is added in Drinking Water, a large amount of solids is precipitated, filter, and wash filter cake.
2. a kind of preparation method of gamma-cyclodextrin modifier according to claim 1, it is characterised in that: the alkali is hydrogen
Sodium oxide molybdena, potassium hydroxide, sodium methoxide, potassium methoxide, Sodamide, sodium hydride, potassium tert-butoxide, n-BuLi, tert-butyl lithium, three second
Amine, pyridine, diethylamine, ammonium hydroxide, ethylenediamine, tetramethylethylenediamine or diisopropylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710550900.7A CN107325203B (en) | 2017-07-07 | 2017-07-07 | A kind of gamma-cyclodextrin modifier and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710550900.7A CN107325203B (en) | 2017-07-07 | 2017-07-07 | A kind of gamma-cyclodextrin modifier and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107325203A CN107325203A (en) | 2017-11-07 |
| CN107325203B true CN107325203B (en) | 2019-09-24 |
Family
ID=60196438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710550900.7A Active CN107325203B (en) | 2017-07-07 | 2017-07-07 | A kind of gamma-cyclodextrin modifier and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107325203B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591402A (en) * | 2009-05-05 | 2009-12-02 | 杭州奥默医药技术有限公司 | 6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof |
| CN104844732A (en) * | 2015-03-27 | 2015-08-19 | 山东滨州智源生物科技有限公司 | Preparation method for sugammadex sodium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4026875B2 (en) * | 1996-09-04 | 2007-12-26 | 日本食品化工株式会社 | Method for producing cyclodextrin derivative |
-
2017
- 2017-07-07 CN CN201710550900.7A patent/CN107325203B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591402A (en) * | 2009-05-05 | 2009-12-02 | 杭州奥默医药技术有限公司 | 6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof |
| CN104844732A (en) * | 2015-03-27 | 2015-08-19 | 山东滨州智源生物科技有限公司 | Preparation method for sugammadex sodium |
Non-Patent Citations (1)
| Title |
|---|
| β-环糊精6-位伯羟基的选择性磺酰化;郭生金 等;《晋中师范高等专科学校学报》;20010331;第18卷(第01期);第19-20页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107325203A (en) | 2017-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3474865B1 (en) | Process for making sugammadex | |
| CN107325204B (en) | A kind of preparation method for the more glucose sodium that relaxes | |
| US20160009827A1 (en) | An Improved Process for Preparation of Sugammadex Sodium | |
| JP6012872B2 (en) | High capacity polymer hydrogen storage material and synthesis method thereof | |
| EP2609120A1 (en) | Improved process for preparation of sugammadex | |
| CN107021984B (en) | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates | |
| CN109336091B (en) | Graphene in-situ growth silver nanowire hybrid conductive material and preparation method and application thereof | |
| CN107325203B (en) | A kind of gamma-cyclodextrin modifier and its preparation method and application | |
| US20120264929A1 (en) | Method for producing n-acetyl-d-glucosamine | |
| RU2017142725A (en) | METHOD OF OBTAINING NITROGENIUM YPRITIS DERIVATIVES | |
| CN105273026B (en) | A kind of pharmaceutical intermediate and its preparation method and application | |
| CN103803658A (en) | Method for preparing porous magnetic nanoclusters through etching | |
| BRPI0706719A2 (en) | process to produce high purity monopentaerythritol and monopentaerythritol produced by | |
| CN107162944B (en) | The preparation method of 2,3- dimethyl benzene methyl sulfide | |
| JP6093947B2 (en) | β-1,3-glucan nanofiber and method for producing the same | |
| CN104892476B (en) | Synthesis method of Tiamulin | |
| CN110615859B (en) | Preparation method of sodium gluconate | |
| CN108715875B (en) | Method for synthesizing heparin sulfate oligosaccharide with definite structure by enzyme chemistry method | |
| CN111153821A (en) | Preparation method of D-p-hydroxyphenylglycine methyl ester | |
| JP2012232971A5 (en) | ||
| WO2008096763A1 (en) | Phase transfer catalyst and process for producing poly(fullerene hydroxide) | |
| CN108912328A (en) | A kind of preparation method of heavy metal ion chelating agent | |
| CN103709030A (en) | Environmentally-friendly preparation method of ciprofibrate | |
| WO2014027873A4 (en) | Preparation of novel modified chitosan/clay bio-composites | |
| CN109942426B (en) | Treatment method for recycling S- (-) -lipoic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |