CN110156917A - Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound - Google Patents
Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound Download PDFInfo
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- 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 a method for synthesizing and purifying sugammadex sodium by applying a polymer-loaded trivalent phosphine compound. The polymer-supported trivalent phosphine compound is adopted to replace triphenylphosphine to synthesize a crude sugammadex sodium product, and the polymer-supported trivalent phosphine compound is applied to the purification process of the crude sugammadex sodium product, so that the purity of the obtained finished sugammadex sodium product reaches 100.0% (containing monohydroxy sugammadex sodium), and the single impurity is less than 0.1%. The invention meets the requirement of green chemistry and has very high environmental protection significance and economic value.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to the preparation method of easypro more glucose sodium, and in particular to negative using polymer
The method for carrying the synthesis of trivalent phosphine compound and purifying the more glucose sodium that relaxes.
Background technique
Relax the more entitled 6A of glucose Sodium chemistry, 6B, 6C, 6D, 6E, 7F, 6G, eight-S- of 6H- (2- carboxyethyl) -6A, 6B, 6C,
Eight thio-y-cvclodextrin of 6D, 6E, 7F, 6G, 6H-, eight sodium salts, molecule are made of lipophilic core and hydrophilic outer end, the chemical combination
The structure of object is as follows:
The more glucose sodium that relaxes is a kind of novel muscle relaxant reversal agent researched and developed by Dutch Organon company, clinically conduct
Rocuronium or the effect of vecuronium neuromuscular blockade are reversed, there is good curative effect, and have fabulous safety.From 2008
Year July European Union ratify its listing since, listed in states such as Japan, South Korea, the U.S., and just declare production in China and list.
Currently, both at home and abroad about relax more glucose sodium preparation process report it is less, and purification process be dependent on film dialysis or
Column chromatography is purified, and is obtained that high purity product difficulty is big, is unfavorable for the progress of large-scale industrial production.
J.Med.Chem.2002,45,1806-1816 propose in n,N-Dimethylformamide system, triphenyl phosphorus catalysis
Under, bromine reacts to obtain 6- deoxidation -6- perbromo--gamma-cyclodextrin with gamma-cyclodextrin.The product and 3- mercapto-propionate exist
Under the catalysis of Carbon Dioxide caesium, reaction obtains the easypro more glucose methyl esters of product, then through sodium hydroxide hydrolysis, obtains the more glucose sodium that relaxes.
Yield 60%.Method obtains the more glucose sodium crude product that relaxes according to this, and purity is lower, does not there is the report being further purified.
J.2011,6,2390, gamma-cyclodextrin iodo -2399 is first obtained 6- deoxidation -6- periodo-γ-by Chem.Asian
Cyclodextrin crude product, the crude product and acetic anhydride are purified by silica gel column chromatography at ester, then sodium methoxide hydrolysis, and it is higher to obtain purity
6- deoxidation -6- periodo-gamma-cyclodextrin highly finished product, finally obtain target product at ether in 3- mercaptopropionic acid.Among the reaction
Body purity is high, impurity is few, and the post-processing purifying of product is relatively simple.But iodo cyclodextrin is prepared using column chromatography technique, is increased
Reaction step, takes a long time.And when preparing easypro more glucose sodium as raw material using iodo cyclodextrin made from this method, not
Qualified product can be directly obtained, the purification difficult problem for the more glucose sodium product that relaxes can be still faced.
WO0140316PP uses iodine to react under triphenyl phosphorus catalysis with gamma-cyclodextrin as halide reagent, and it is de- to generate 6-
Oxygen -6- periodo-gamma-cyclodextrin.The intermediate obtains target production again with 3- mercaptopropionic acid at thioether after film dialysis purification
Object.This method route is simple and reliable, and reactivity is higher, but the purifying of product obtains high-purity and relax only with film dialysis purification
The difficulty of more glucose sodium is higher.
CN105348412 discloses a kind of purification process of more glucose sodium crude product that relaxes, by easypro more glucose sodium crude product in acidity
Under the conditions of hydrolyze, obtain free acid solid, the mashing washing purifying of free acid solid water；Free acid is reacted with organic amine again, is made
Standby easypro more glucammonium salts, obtained ammonium salt recrystallization purifying；It is free that free acid, free acid solid water are beaten under acid condition
Plasm scouring purifying, obtained free acid are reacted with sodium hydroxide, prepare the more glucose sodium pure product that relaxes.Column chromatography is not used in this method,
The methods of dialysis, but complex steps, need the multiple conversions between free acid and salt, inconvenient.In addition, due to the more glucose that relaxes
The unstability of self structure, during in acid condition free, self structure has the risk of dissociation, is formed acid broken
Bad impurity increases the difficulty of refined product.
CN106565858 discloses a kind of purification process of more glucose sodium that relaxes, and the more glucose sodium crude product that relaxes is in amberlite
Under the processing of rouge, it is converted to the more glucose salt that relaxes, is converted to the more glucose sodium that relaxes through recrystallization purifying, then by ion exchange resin.This method
Obtained product purity is preferable, mild condition.But treatment process is relatively complicated, needs to handle ion exchange resin, increase
The difficulty of industrial applications.
And Polymer-supported trivalent phosphine compound is that a kind of pass through in macromolecular scaffold is chemically bonded load trivalent organic phosphine
The novel agent of group increasingly causes the attention of researcher as a kind of substitute of traditional organophosphorus reagent.
R1=Ph；(CH2)n；(CH2)nCO-；etc.
R2, R3=R1=H；Ph；(CH2)n；(CH2)nCO-；etc.
Polymer as Polymer-supported skeleton mainly has polyethylene, polystyrene, polystyrene, pollopas, Portugal
Glycan etc..The trivalent phosphine groups that can be supported mainly have-PPh3 ,-TEP ,-DCEP ,-TCEP ,-TFP ,-TPPTS etc..Polymer
The skeleton for loading trivalent phosphine compound is stablized, and the spherical resin of certain mesh number is usually granulated into, therefore has easy to use, recycling
It is convenient, the advantages that can be recycled.
The corresponding text that Polymer-supported trivalent phosphine compound is applied to easypro more glucose sodium synthesis and purifying is had not seen at present
It offers.
Summary of the invention
The present invention provides a kind of using the easypro more glucose sodium of Polymer-supported trivalent phosphine compound synthesis and the side purified
Method, this method have the advantages that product purity that is environmentally protective and obtaining is high.
In order to solve the above technical problems, a kind of application Polymer-supported trivalent phosphine compound of the present invention synthesizes the more glucose sodium that relaxes
Method, it is described relax more glucose sodium structural formula such as formula I,
Include the following steps:
1), by Formula II
Under the catalysis of crosslinked polystyrene load triphenylphosphine, halogen reacts to obtain 6- shown in formula III with Formula II and takes off
Oxygen -6- perhalogeno-gamma-cyclodextrin, reaction equation are as follows:
2), by formula III compound represented and 3- mercaptopropionic acid sulfide synthesis to get to the more glucose sodium that relaxes shown in Formulas I
Crude product, reaction equation are as follows:
3), the easypro more glucose sodium crude product for obtaining step 2), is purified using Polymer-supported trivalent phosphine compound.
Further, halogen described in step 1) is chlorine, bromine or iodine.
The load skeleton of above-mentioned Polymer-supported trivalent phosphine compound is selected from but not limited to polyethylene, polystyrene, poly- third
Ethylene, pollopas, glucan；The trivalent phosphine compound that can be supported selected from but not limited to group selected from but not limited to-
PPh3 ,-TEP ,-DCEP ,-TCEP ,-TFP ,-TPPTS etc.；The phosphine compound of Polymer-supported trivalent described in step 1 is polymer
Triphenylphosphine compound is loaded, selected from but not limited to crosslinked polystyrene load triphenylphosphine resin, crosslinked polypropylene load three
Phenylphosphine resin etc.；The phosphine compound of Polymer-supported trivalent described in step 3 is preferably but not limited to crosslinked polystyrene load three
Phenylphosphine resin, crosslinked polypropylene load three (2- furyl) phosphorus resins and crosslinked polystyrene loads three (2- carboxyethyl) phosphine trees
One or several kinds of combinations of rouge, crosslinked polystyrene load three sulfonate of triphenylphosphine.
Easypro more glucose sodium purifying crude process described in step 3) is specific as follows:
The more glucose sodium crude product that relaxes is dissolved in the in the mixed solvent of water or water and the more glucose sodium poor solvent composition that relaxes, is added
Polymer-supported trivalent phosphine compound, nitrogen displacement after be stirred, crystallization to get to relax more glucose sodium pure product.
The solvent that the poor solvent of easypro more glucose sodium and the crystallization use described in step 3) be respectively methanol, ethyl alcohol,
One of isopropanol, DMF, DMSO, acetonitrile, acetone or Several combinations.
The dosage of Polymer-supported triphenylphosphine compound described in step 1) is 1~50 times of gamma-cyclodextrin equivalent；Step
It is rapid 2) described in the dosage of 3- mercaptopropionic acid be 7~15 times of gamma-cyclodextrin equivalent；Step 3) the Polymer-supported trivalent phosphine
The dosage of compound is 0.1%~200% (W/W) of easypro more glucose sodium crude product.
Further, the synthesis process of the easypro more glucose sodium of the present invention is specific as follows:
The synthesis process of the step 1) 6- deoxidation -6- perhalogeno-gamma-cyclodextrin is as follows: under stirring condition, in flask
Crosslinked polystyrene load triphenylphosphine resin and anhydrous DMF is added, halogen simple substance, system heat release is added；After drying is added
Gamma-cyclodextrin is warming up to 70 DEG C and reacts 24 hours；Reaction terminates, cooling system, filters and removes crosslinked polystyrene load triphen
Base phosphine resin, be added in filtrate sodium methoxide methanol solution filter after, by filtration cakes torrefaction；Water is added into residue again to filter,
Filter cake is washed respectively and acetone is washed, and is finally dried in vacuo, is obtained the full deoxidation -6- perhalogeno-gamma-cyclodextrin solid of 6- of yellow；
The synthesis process of step 2) the more glucose sodium crude product that relaxes is as follows: adding in batches into the DMF solution of 3- mercaptopropionic acid
Enter 60% sodium hydride；Full deoxidation -6- perhalogeno-the gamma-cyclodextrin of 6- that step 1) obtains is added in cooling；Stir temperature reaction
Cool down again afterwards, water quenching reaction is added, is concentrated in vacuo solvent；Residue is added in acetone again, is filtered, filter cake vacuum drying
After obtain it is flaxen relax more glucose sodium crude product.
The easypro more glucose sodium purifying crude process of step 3) is as follows: easypro more glucose sodium crude product is dissolved in water or water and the more glucose that relaxes
The in the mixed solvent of sodium poor solvent composition adds Polymer-supported trivalent phosphine compound, carries out crystallization after nitrogen displacement, i.e.,
Obtain the more glucose sodium pure product that relaxes.Wherein, the solvent that the more poor solvent of glucose sodium and the crystallization use that relaxes is respectively methanol, second
One of alcohol, isopropanol, DMF, DMSO, acetonitrile, acetone or Several combinations；Relax more glucose sodium crude product solution concentration be preferably
0.1~90%, further preferably 10~20%；The dosage of Polymer-supported trivalent phosphine compound is preferably 1~200%, into
One step preferably 0.5~10%.
Compared with prior art, the invention has the following advantages that
The present invention substitutes triphenylphosphine, halogenating agent collective effect, by γ-using Polymer-supported triphenylphosphine compound
Cyclodextrin is halogenated, preparation 6- deoxidation -6- it is halogenated-gamma-cyclodextrin；It is reacted again with 3- mercaptopropionic acid, synthesizes the more glucose sodium crude product that relaxes.
The present invention applies Polymer-supported trivalent phosphine compound reagent during relaxing more glucose sodium purifying crude, benefit
With the reproducibility of the resin, inhibit the generation of oxidation impurities, finally obtains the easypro more glucose sodium finished product that purity reaches 100.0%.
The method that the present invention was synthesized and purified easypro more glucose sodium using Polymer-supported trivalent phosphine compound avoids free
Organic phosphine compound residual in the product, it is easier to relax more glucose sodium crude product purifying.Polymer-supported trivalent phosphine compound
Also recycling can be activated by processing, improve the economy of reaction, meet the requirement of Green Chemistry, there is very high ring
Protect meaning and economic value.
Detailed description of the invention
The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.
Fig. 1: original grinds the commercially available more glucose sodium injection HPLC figure that relaxes；
Fig. 2: relax more glucose sodium crude product HPLC figure；
Fig. 3: relax more glucose sodium highly finished product HPLC figure；
Fig. 4: relax more glucose sodium crude product HPLC figure；
Fig. 5: relax more glucose sodium highly finished product HPLC figure；
Fig. 6: relax more glucose sodium crude product HPLC figure；
Fig. 7: relax more glucose sodium highly finished product HPLC figure.
Specific embodiment
The present invention, the range of but do not limit the invention in any way are further described below by way of example.
The Polymer-supported three including crosslinked polystyrene load triphenylphosphine resin that following embodiments uses
Valence phosphine compound is commercial product, and other chemical reagent are also commercial product.
Embodiment 1
1,6- deoxidation -6- periodo-gamma-cyclodextrin synthesis
Under stirring, crosslinked polystyrene load triphenylphosphine resin (60.2g), anhydrous DMF are added into flask
(160ml) is added elemental iodine (30.5g, 15.6 equivalents), system heat release.Be added it is dry after gamma-cyclodextrin (10g,
7.7mmol), 70 DEG C are warming up to react 24 hours.Reaction terminates, cooling system, filters and removes crosslinked polystyrene load triphen
The methanol solution (3.1g sodium is dissolved in 50ml methanol) of sodium methoxide is added in filtrate for base phosphine resin, stirs 30 minutes, adds it to
In 800ml methanol, filter, filtration cakes torrefaction.500ml water is added into residue, filters, filter cake washes (3*100ml), then again
It is washed (3*100ml) with acetone, 70 DEG C of vacuum drying obtain the full deoxidation -6- periodo-gamma-cyclodextrin solid of 6- of yellow
(16.2g).The crosslinked polystyrene of recycling loads triphenylphosphine resin, washs through DMF, dries after water washing, uses trichlorosilane
It is recycled after reduction treatment；
2, the synthesis of easypro more glucose sodium
60% hydrogenation is added into the DMF solution (1.0g 3- mercaptopropionic acid, be dissolved in 30mlDMF) of 3- mercaptopropionic acid
Sodium (476mg, 22 equivalents), is added portionwise.The DMF solution of the full deoxidation -6- periodo-gamma-cyclodextrin of 6- is added in cooling
(1.4g6- is complete, and deoxidation -6- periodo-gamma-cyclodextrin is dissolved in 30ml DMF), stirring are warming up to 70 DEG C and react 24 hours.Reaction
Finish, be down to room temperature, 20ml water quenching reaction is added, then vacuum concentration falls most of solvent.Residue is added to 500ml third
It in ketone, filters, 70 DEG C of filter cake vacuum drying obtain faint yellow solid (2.25g relax more glucose sodium crude product), purity 98.3%
(see Fig. 2).
3, the purifying of easypro more glucose sodium
Under nitrogen protection, the more glucose sodium crude product 2g that relaxes is taken, is dissolved in 10ml water, crosslinked polystyrene is added into solution
It loads triphenylphosphine resin (0.2g), stirring is warming up to 70 DEG C, under nitrogen protection, and the DMF of 25ml is added dropwise into solution, and solution is micro-
It is mixed.It is slowly down to room temperature, there is white solid precipitation, filters, obtains white solid 1.8g.Above-mentioned recrystallization process is repeated, is obtained white
Solid 1.2g.The solid is through HPLC detection purity 100.0% (containing the easypro more glucose sodium of monohydroxy).(see Fig. 3).
Embodiment 2
1,6- deoxidation -6- perbromo--gamma-cyclodextrin synthesis
Under stirring, crosslinked polystyrene load triphenylphosphine resin (60.2g), anhydrous DMF are added into flask
(160ml) is added dropwise bromine (19.2g, 15.6 equivalents), system heat release.Gamma-cyclodextrin (10g, 7.7mmol) after drying is added,
70 DEG C are warming up to react 24 hours.Reaction terminates, cooling system, filters and removes crosslinked polystyrene load triphenylphosphine resin,
The methanol solution (3.1g sodium is dissolved in 50ml methanol) of sodium methoxide is added in filtrate, stirs 30 minutes, adds it to 800ml methanol
In, it filters, filtration cakes torrefaction.500ml water is added into residue, filters, filter cake washes (3*100ml), is then washed again with acetone
(3*100ml), 70 DEG C of vacuum drying, obtains the full deoxidation -6- perbromo- of 6--gamma-cyclodextrin solid (13.2g) of yellow.Recycling
Crosslinked polystyrene load triphenylphosphine resin, wash through DMF, dried after water washing, with being followed after trichlorosilane reduction treatment
Ring uses；
2, the synthesis of easypro more glucose sodium
60% hydrogenation is added into the DMF solution (1.0g 3- mercaptopropionic acid, be dissolved in 30mlDMF) of 3- mercaptopropionic acid
Sodium (476mg, 22 equivalents), is added portionwise.The DMF solution of the full deoxidation -6- perbromo--gamma-cyclodextrin of 6- is added in cooling
(1.2g6- is complete, and deoxidation -6- perbromo--gamma-cyclodextrin is dissolved in 30ml DMF), stirring are warming up to 70 DEG C and react 24 hours.Reaction
It finishes, is down to room temperature, 20ml water quenching reaction is added, then vacuum concentration falls most of solvent.Residue is added to 500ml
It in acetone, filters, 70 DEG C of filter cake vacuum drying obtain faint yellow solid (2.11g), and purity is 97.5% (see Fig. 4).
3, the purifying of easypro more glucose sodium
Under nitrogen protection, the more glucose sodium crude product 2g that relaxes is taken, is dissolved in 10ml water, crosslinked polystyrene is added into solution
Three (2- carboxyethyl) phosphine resins (0.15g) are loaded, stirring is warming up to 70 DEG C, under nitrogen protection, is added dropwise 25ml's into solution
DMF, solution are micro- mixed.It is slowly down to room temperature, there is white solid precipitation, filters, obtains white solid 1.7g.Repeat above-mentioned recrystallized
Journey obtains white solid 1.1g.The solid is dissolved in 10ml water, and crosslinked polystyrene is added and loads three (2- carboxyethyl) phosphine resins
(0.1g), active carbon 0.1g, suction filtration, concentration stir the solid through HPLC detection purity 100.0% (containing the easypro more glucose of monohydroxy
Sodium).(see Fig. 5).
Embodiment 3
1,6- deoxidation -6- perchloro--gamma-cyclodextrin synthesis
Under stirring, crosslinked polystyrene load triphenylphosphine resin (60.2g), anhydrous DMF are added into flask
(160ml) is added carbon tetrachloride (18.5g, 15.6 equivalents), system heat release.Be added it is dry after gamma-cyclodextrin (10g,
7.7mmol), 60 DEG C are warming up to react 40 hours.Reaction terminates, cooling system, filters and removes crosslinked polystyrene load triphen
The methanol solution (3.1g sodium is dissolved in 50ml methanol) of sodium methoxide is added in filtrate for base phosphine resin, stirs 30 minutes, adds it to
In 800ml methanol, filter, filtration cakes torrefaction.500ml water is added into residue, filters, filter cake washes (3*100ml), then again
It is washed (3*100ml) with acetone, 70 DEG C of vacuum drying obtain the full deoxidation -6- perchloro--gamma-cyclodextrin solid of 6- of yellow
(16.2g).The crosslinked polystyrene of recycling loads triphenylphosphine resin, washs through DMF, dries after water washing, uses trichlorosilane
It is recycled after reduction treatment；
2, the synthesis of easypro more glucose sodium
60% hydrogenation is added into the DMF solution (1.0g 3- mercaptopropionic acid, be dissolved in 30mlDMF) of 3- mercaptopropionic acid
Sodium (476mg, 22 equivalents), is added portionwise.The DMF solution of the full deoxidation -6- perchloro--gamma-cyclodextrin of 6- is added in cooling
(1.4g6- is complete, and deoxidation -6- periodo-gamma-cyclodextrin is dissolved in 30ml DMF), stirring are warming up to 70 DEG C and react 24 hours.Reaction
Finish, be down to room temperature, 20ml water quenching reaction is added, then vacuum concentration falls most of solvent.Residue is added to 500ml third
It in ketone, filters, 70 DEG C of filter cake vacuum drying obtain faint yellow solid (2.25g), and purity is 98.0% (see Fig. 6).
3, the purifying of easypro more glucose sodium
Under nitrogen protection, the more glucose sodium crude product 2g that relaxes is taken, is dissolved in 10ml water, crosslinked polystyrene is added into solution
Three sulfonate (0.2g) of triphenylphosphine are loaded, stirring is warming up to 70 DEG C, under nitrogen protection, the DMF of 25ml is added dropwise into solution,
Solution is micro- mixed.It is slowly down to room temperature, there is white solid precipitation, filters, obtains white solid 1.8g.Above-mentioned recrystallization process is repeated,
Obtain white solid 1.2g.The solid is through HPLC detection purity 100.0% (containing the easypro more glucose sodium of monohydroxy).(see Fig. 7).
It should be noted that above-described embodiment is only presently preferred embodiments of the present invention, there is no for the purpose of limiting the invention
Protection scope, the equivalent substitution or substitution made on the basis of the above all belong to the scope of protection of the present invention.
Claims (6)
1. a kind of method for synthesizing the more glucose sodium that relaxes using Polymer-supported trivalent phosphine compound, the structure of the more glucose sodium that relaxes
Formula such as formula I,
It is characterized by comprising the following steps:
1), by Formula II
Under the catalysis of crosslinked polystyrene load triphenylphosphine, halogen reacts to obtain with Formula II 6- deoxidation -6- shown in formula III
Perhalogeno-gamma-cyclodextrin, reaction equation are as follows:
2), by formula III compound represented and 3- mercaptopropionic acid sulfide synthesis to get to the more glucose sodium crude product that relaxes shown in Formulas I,
Reaction equation is as follows:
3), the easypro more glucose sodium crude product for obtaining step 2), is purified using Polymer-supported trivalent phosphine compound.
2. a kind of method that the more glucose sodium that relaxes is synthesized using Polymer-supported trivalent phosphine compound as described in claim 1,
Be characterized in that: halogen described in step 1) is chlorine, bromine or iodine.
3. a kind of method that the more glucose sodium that relaxes is synthesized using Polymer-supported trivalent phosphine compound as described in claim 1,
Be characterized in that: the load skeleton of the Polymer-supported trivalent phosphine compound is selected from but not limited to polyethylene, polystyrene, poly- third
Ethylene, pollopas, glucan；The trivalent phosphine compound that can be supported selected from but not limited to group selected from but not limited to-
PPh3,-TEP,-DCEP,-TCEP,-TFP,-TPPTS；The phosphine compound of Polymer-supported trivalent described in step 1) is polymer
Triphenylphosphine compound is loaded, selected from but not limited to crosslinked polystyrene load triphenylphosphine resin, crosslinked polypropylene load three
Phenylphosphine resin；The phosphine compound of Polymer-supported trivalent described in step 3) is preferably but not limited to crosslinked polystyrene load triphen
Base phosphine resin, crosslinked polypropylene load three (2- furyl) phosphorus resins and crosslinked polystyrene loads three (2- carboxyethyl) phosphine trees
One or several kinds of combinations of rouge, crosslinked polystyrene load three sulfonate of triphenylphosphine.
4. a kind of method that the more glucose sodium that relaxes is synthesized using Polymer-supported trivalent phosphine compound as described in claim 1,
It is characterized in that, easypro more glucose sodium purifying crude process described in step 3) is as follows:
The more glucose sodium crude product that relaxes is dissolved in the in the mixed solvent of water or water and the more glucose sodium poor solvent composition that relaxes, adds polymerization
Object load trivalent phosphine compound, nitrogen displacement after be stirred, crystallization to get to relax more glucose sodium pure product.
5. a kind of method that the more glucose sodium that relaxes is synthesized using Polymer-supported trivalent phosphine compound as claimed in claim 4,
Be characterized in that, the solvent that the poor solvent of easypro more glucose sodium and the crystallization use described in step 3) be respectively methanol, ethyl alcohol,
One of isopropanol, DMF, DMSO, acetonitrile, acetone or Several combinations.
6. a kind of method that the more glucose sodium that relaxes is synthesized using Polymer-supported trivalent phosphine compound as described in claim 1,
Be characterized in that: the dosage of Polymer-supported triphenylphosphine compound described in step 1) is 1~50 times of gamma-cyclodextrin equivalent；
The dosage of 3- mercaptopropionic acid described in step 2) is 7~15 times of gamma-cyclodextrin equivalent；Step 3) the Polymer-supported trivalent
The dosage of phosphine compound is 0.1%~200% (W/W) of easypro more glucose sodium crude product.
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| CN104628891A (en) * | 2015-01-20 | 2015-05-20 | 中国大冢制药有限公司 | Method for preparing 6-deoxy-6-haloalkyl cyclodextrin |
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| CN106565858A (en) * | 2016-10-13 | 2017-04-19 | 王炳永 | Purification method for sugammadex sodium |
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