CN107325203A - A kind of cyclodextrin modified things of γ and its production and use - Google Patents
A kind of cyclodextrin modified things of γ and its production and use Download PDFInfo
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- CN107325203A CN107325203A CN201710550900.7A CN201710550900A CN107325203A CN 107325203 A CN107325203 A CN 107325203A CN 201710550900 A CN201710550900 A CN 201710550900A CN 107325203 A CN107325203 A CN 107325203A
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- cyclodextrin
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- 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
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Abstract
The invention discloses cyclodextrin modified things of a kind of γ and its production and use, the preparation method of the cyclodextrin modified things of γ is：Perhalogeno γ cyclodextrin and 3 (chlorosulfonyl) the propionic esters 2 ester group ethyl sulfuryl γ cyclodextrin of substitution generation under alkali effect.The cyclodextrin modified things of γ can be used for preparing the more glucose sodium that relaxes.The cyclodextrin modified thing preparation methods of γ of the present invention are easy to operate, easy control of reaction conditions and yield is higher, have broad application prospects.
Description
Technical field
The present invention relates to the preparation field of polysaccharide, particularly a kind of gamma-cyclodextrin trim and preparation method thereof and use
On the way.
Background technology
Cyclodextrin modified thing can be used as the conventional use of neuromuscular blocking drug of reverse, anti-muscle relaxant.Wherein Shu Geng Portugals
Sugared sodium is reversed as a kind of new anti-muscle relaxant in several minutes has rocuronium or Vecuronium Bromide to induce during systemic anesthesia
Moderate and deep intramuscular relexation, it is of flaccid muscles to terminating to control well that the product can be such that anesthetist starts in operation
Degree, improve surgical quality.
Relax more glucose sodium most disclosed early in patent US6670340, by starting material of gamma-cyclodextrin by with triphenylphosphine
Perhalogeno gamma-cyclodextrin is generated with halogen substitution, then target product, preparation method are generated under sodium hydride effect with mercaptopropionic acid
It is as follows：
Sulfydryl produces sulfydryl sodium with sodium hydride reaction in this route, and discharges hydrogen, sulfydryl sodium and the halo ring Hu essence of generation
Carry out reaction and produce the more glucose sodium that relaxes, the reaction scheme is shorter, but technique is difficult control, its reaction reagent expression activitiy
Greatly, the impurity of generation is relatively more, and product quality and yield are than relatively low.
In the recent period, patent CN104844732 discloses a kind of new method for preparing the more glucose sodium that relaxes, and is pasted with perhalogeno γ-ring
Essence is starting material, generates full sulfydryl gamma-cyclodextrin with thiocarbamide first, then simultaneously basic hydrolysis generates target with methyl acrylate addition
Product, preparation method is as follows：
This method has made marked progress, but the route subject matter is：1. perhalogeno gamma-cyclodextrin is difficult to take completely with thiocarbamide
The extremely difficult removing in end-product of generation, not exclusively substitution impurity.In addition, the prolonged pyroreaction of step of replacing easily causes starting
The degraded of material, influences reaction efficiency；2. addition step uses the method that ultraviolet irradiates, it is difficult to ensure that reactant turns completely
Change.
The content of the invention
The present invention be exactly in order to the low more glucose sodium preparation technology 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 trim proposed and its production and use.
The present invention is realized according to following technical scheme.
A kind of gamma-cyclodextrin trim, its structural formula is 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 trim, 6- deoxidations -6- perhalogenos gamma-cyclodextrin and 3- (chlorosulfonyl)
Propionic ester prepares gamma-cyclodextrin trim, and syntheti c route is as follows：
Gamma-cyclodextrin trim prepare reaction in add tetrahydrofuran, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide and
Dimethyl sulfoxide (DMSO).
Gamma-cyclodextrin trim prepares in reaction and adds alkali.
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, ammoniacal liquor, ethylenediamine, tetramethylethylenediamine and diisopropylamine etc..
The reaction temperature that gamma-cyclodextrin trim prepares reaction is -30 DEG C to 25 DEG C.
A kind of application of gamma-cyclodextrin trim in the more glucose sodium that relaxes is prepared.
Present invention obtains following beneficial effect.
It is low that the present invention effectively solves relax the in the prior art control of more glucose sodium preparation technology hardly possible, product quality and yield
The problems such as.Preparation method of the invention relative to the existing more glucose sodium that relaxes, reaction mass is significantly improved, and final product content reaches
To more than 95%, product yield can reach 95%；3- (chlorosulfonyl) propionic ester is cheap and easy to get, and property is stable, substitution reaction bar
Part is gentle, and reaction efficiency is high, produces easy to control；Metal and absolute alcohol are the method for common reduction sulfone, with low cost, operation letter
Just, reaction efficiency is high, is easy to industrialized production.
Embodiment
With reference to embodiment, the invention will be further described.
A kind of gamma-cyclodextrin trim, its structural formula is 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 trim, 6- deoxidations -6- perhalogenos gamma-cyclodextrin and 3- (chlorosulfonyl)
Propionic ester prepares gamma-cyclodextrin trim, and syntheti c route is as follows：
6- deoxidation -6- perhalogenos gamma-cyclodextrins are made by gamma-cyclodextrin with triphenylphosphine and halogen method.
Prepared by gamma-cyclodextrin trim adds tetrahydrofuran, N,N-dimethylformamide, N, N- dimethylacetamides in reaction
Amine and dimethyl sulfoxide (DMSO).
Gamma-cyclodextrin trim prepares in reaction and adds alkali.
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, ammoniacal liquor, ethylenediamine, tetramethylethylenediamine and diisopropylamine etc..
The reaction temperature that gamma-cyclodextrin trim prepares reaction is -30 DEG C to 25 DEG C.
A kind of application of gamma-cyclodextrin trim in the more glucose sodium that relaxes is prepared.
A kind of preparation method for the more glucose sodium that relaxes, this method uses 6- deoxidations -6- perhalogenos gamma-cyclodextrin former for starting
Material, prepares the more glucose sodium that relaxes through following steps successively：
1）6- deoxidations -6- perhalogenos gamma-cyclodextrin carries out substitution reaction with 3- (chlorosulfonyl) propionic ester, obtains gamma-cyclodextrin
Trim；
2）Gamma-cyclodextrin trim turns into after thio thing with metal and absolute alcohol reduction sulfuryl, then is reacted with sodium hydroxide, obtains
Relax more glucose sodium.
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 absolute methanol, ethanol, isopropanol,
N-butanol, isobutanol and tert-butyl alcohol etc..
Embodiment 1：The preparation of 2- carbomethoxies ethyl sulfuryl-gamma-cyclodextrin
Dry 50g 6- deoxidation -6- perchloro- gamma-cyclodextrins are dissolved in dry 1L DMFs, added
Be cooled to -30 DEG C after 22mL triethylamines, be slowly added dropwise after 3- (chlorosulfonyl) methyl propionate, temperature control to 0 DEG C reaction 2h, this is molten
Liquid is slowly added in reaction solution, and reaction solution is slowly added in 1L Drinking Waters, separates out a large amount of solids, and suction filtration, 10mL is cold
DMF washs filter cake, obtains off-white powder 55g, yield 110%.
MS(m/z)：2393.35[M+Na]+。1H-NMR（d6-DMSO）：δ5.90-5.91（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）.
Embodiment 2：The preparation of 2- ethoxycarbonyies ethyl sulfuryl-gamma-cyclodextrin
Dry 25g 6- deoxidation -6- perbromo- gamma-cyclodextrins are dissolved in dry 500mL DMAs,
Add 10mL pyridines after be cooled to -10 DEG C, be slowly added dropwise after 3- (chlorosulfonyl) ethyl propionate, temperature control to 10 DEG C reaction 1.5h,
The solution is slowly added in reaction solution, reaction solution is slowly added in 500mL Drinking Waters, a large amount of solids of precipitation, suction filtration,
DMA washing filter cake cold 10mL, obtains off-white powder 28g, yield 112%.
MS(m/z)：2483.57[M+H]+。1H-NMR（d6-DMSO）：δ5.91-5.93（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）, δ 2.75-2.83（24H, m）, δ
2.56-2.60（16H, m）, δ 1.27-1.33（24H, m）.
Embodiment 3：The preparation of 2- hexamethylene ester group ethyl sulfones base-gamma-cyclodextrin
Dry 25g 6- deoxidation -6- periodo gamma-cyclodextrins are dissolved in dry 500mL dimethyl sulfoxide (DMSO)s, add 10mL
0 DEG C is cooled to after ethylenediamine, is slowly added dropwise after 3- (chlorosulfonyl) cyclohexyl propionate, temperature control is to 25 DEG C of reaction 1h, by the solution
It is slowly added in reaction solution, reaction solution is slowly added in 500mL Drinking Waters, separate out a large amount of solids, suction filtration, 10mL is cold
Dimethyl sulfoxide (DMSO) washs filter cake, obtains off-white powder 32g, yield 128%.
MS(m/z)：2916.23[M+H]+。1H-NMR（d6-DMSO）：δ5.93-5.95（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）, δ 2.76-2.83（24H, m）, δ
2.56-2.64（16H, m）, δ 1.47-1.55（80H, m）.
Embodiment 4：The preparation of 2- butyl ester base ethyls sulfuryl-gamma-cyclodextrin
Dry 25g6- deoxidation -6- periodo gamma-cyclodextrins are dissolved in dry 600mL DMFs, plus
- 20 DEG C are cooled to after entering 8g sodium hydroxides, is slowly added dropwise after 3- (chlorosulfonyl) butyl propionate, temperature control is to 5 DEG C of reaction 2h, by this
Solution is slowly added in reaction solution, and reaction solution is slowly added in 500mL Drinking Waters, separates out a large amount of solids, suction filtration, 10mL
Cold DMF washing filter cake, obtains off-white powder 29.5g, yield 118%.
MS(m/z)：2452.33[M+H]+。1H-NMR（d6-DMSO）：δ5.91-5.94（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）, 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 of easypro more glucose sodium
By dry 50g 2- carbomethoxies ethyls sulfuryl-gamma-cyclodextrin, dry 100mL DMFs are dissolved in
In, -10 DEG C are cooled to after adding 20mL absolute ethyl alcohols, is slowly added dropwise after 8g lithium metals, temperature control is to 25 DEG C of reaction 1h, lithium in system
Completely after consumption, 20mL 2moL/L sodium hydroxide solutions are added, temperature control adds 500mL absolute ethyl alcohols, analysis to 25 DEG C of reaction 2h
Go out a large amount of off-white powder 42.5g, yield 85%.
MS(m/z)：2023.4 [M+Na]+。1H-NMR（d6-DMSO）：δ5.10-5.13（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）, 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 of easypro more glucose sodium
By dry 50g 2- ethoxycarbonyies ethyls sulfuryl-gamma-cyclodextrin, dry 100mL DMFs are dissolved in
In, -10 DEG C are cooled to after adding 15mL absolute methanols, is slowly added dropwise after 6g metallic sodiums, temperature control is to 5 DEG C of reaction 2h, sodium in system
Completely after consumption, 20mL 2moL/L sodium hydroxide solutions are added, temperature control adds 500mL absolute ethyl alcohols, analysis to 25 DEG C of reaction 2h
Go out a large amount of off-white powder 41.5g, yield 83%.
MS(m/z)：2023.5[M+Na]+。1H-NMR（d6-DMSO）：δ5.09-5.12（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）, 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 of easypro more glucose sodium
By dry 50g 2- hexamethylene ester group ethyl sulfones base-gamma-cyclodextrin, dry 120mL DMFs are dissolved in
In, -20 DEG C are cooled to after adding 15g anhydrous tertiary butanols, is slowly added dropwise after 6g metallic potassiums, extremely -5 DEG C of temperature control is reacted in 4h, system
After potassium consumption completely, 20mL 2moL/L sodium hydroxide solutions are added, temperature control adds 600mL absolute ethyl alcohols to 25 DEG C of reaction 2h,
Separate out a large amount of off-white powder 35g, yield 70%.
MS(m/z)：2023.4[M+Na]+。1H-NMR（d6-DMSO）：δ5.09-5.11（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）, 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 of easypro more glucose sodium
By dry 50g 2- hexamethylene ester group ethyl sulfones base-gamma-cyclodextrin, dry 110mL DMFs are dissolved in
In, 0 DEG C is cooled to after adding 16mL anhydrous isopropyl alcohols, is slowly added dropwise after 7.5g calcium metals, temperature control is to 10 DEG C of reaction 4h, in system
After calcium consumption completely, 20mL 2moL/L sodium hydroxide solutions are added, temperature control adds 650mL absolute ethyl alcohols to 25 DEG C of reaction 2h,
Separate out a large amount of off-white powder 37.5g, yield 75%.
MS(m/z)：2023.4[M+Na]+。1H-NMR（d6-DMSO）：δ5.10-5.12（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）, δ 2.92-3.02（8H, m）, δ
2.82-2.87（16H, m）, δ 2.43-2.51（8H, m）.
Claims (7)
1. a kind of gamma-cyclodextrin trim, its structural formula is as follows：
Chain alkane, cycloalkane and the aromatic hydrocarbon for the 1-12 carbon that R refers in formula.
2. the preparation method of gamma-cyclodextrin trim described in a kind of claim 1, it is characterised in that：6- deoxidation -6- perhalogenos
Gamma-cyclodextrin prepares gamma-cyclodextrin trim with 3- (chlorosulfonyl) propionic ester, and syntheti c route is as follows：
。
3. a kind of preparation method of gamma-cyclodextrin trim according to claim 2, it is characterised in that：Gamma-cyclodextrin is repaiied
Prepared by jewelry adds tetrahydrofuran, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide and dimethyl sulfoxide (DMSO) in reaction.
4. a kind of preparation method of gamma-cyclodextrin trim according to claim 2, it is characterised in that：Gamma-cyclodextrin is repaiied
Jewelry prepares in reaction and adds alkali.
5. a kind of preparation method of gamma-cyclodextrin trim according to claim 4, 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, ammoniacal liquor, ethylenediamine, tetramethylethylenediamine and diisopropylamine.
6. a kind of preparation method of gamma-cyclodextrin trim according to claim 2, it is characterised in that：Gamma-cyclodextrin is repaiied
The reaction temperature that jewelry prepares reaction is -30 DEG C to 25 DEG C.
7. application of the gamma-cyclodextrin trim in the more glucose sodium that relaxes is prepared described in a kind of claim 1-6.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1077303A (en) * | 1996-09-04 | 1998-03-24 | Nippon Shokuhin Kako Co Ltd | Production of cyclodextrin derivative |
| 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 |
-
2017
- 2017-07-07 CN CN201710550900.7A patent/CN107325203B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1077303A (en) * | 1996-09-04 | 1998-03-24 | Nippon Shokuhin Kako Co Ltd | Production of cyclodextrin derivative |
| 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 |
|---|
| 郭生金 等: "β-环糊精6-位伯羟基的选择性磺酰化", 《晋中师范高等专科学校学报》 * |
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