CN110156917B - 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
- Publication number
- CN110156917B CN110156917B CN201810137748.4A CN201810137748A CN110156917B CN 110156917 B CN110156917 B CN 110156917B CN 201810137748 A CN201810137748 A CN 201810137748A CN 110156917 B CN110156917 B CN 110156917B
- Authority
- CN
- China
- Prior art keywords
- sugammadex sodium
- polymer
- phosphine compound
- sodium
- loaded
- 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
Images
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
- C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Sustainable Development (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
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 the technical field of pharmacy, and relates to a preparation method of sugammadex sodium, in particular to a method for synthesizing and purifying sugammadex sodium by applying a polymer-loaded trivalent phosphine compound.
Background
Sugammadex sodium has the chemical name 6A,6B,6C,6D,6E,7F,6G, 6H-octa-S- (2-carboxyethyl) -6A,6B,6C,6D,6E,7F,6G, 6H-octathio- γ -cyclodextrin, octasodium salt, the molecule of which consists of a lipophilic core and a hydrophilic outer end, the structure of which is as follows:
the sugammadex sodium is a novel muscle relaxant reversal agent developed by Organon corporation in the Netherlands, is clinically used for reversing the nerve and muscle blocking effect of rocuronium bromide or vecuronium bromide, has good curative effect and has excellent safety. Since the european union approved for marketing in 2008, the market has been released in japan, korea, the united states, and the like, and the production market is being declared in our country.
At present, few reports about the preparation process of sugammadex sodium at home and abroad are provided, and the purification process depends on membrane dialysis or column chromatography for purification, so that the difficulty in obtaining high-purity products is high, and the large-scale industrial production is not facilitated.
J.Med.chem.2002,45, 1806-beta 1816 proposes that under the catalysis of triphenylphosphine in an N, N-dimethylformamide system, bromine reacts with gamma-cyclodextrin to obtain 6-deoxy-6-perbromo-gamma-cyclodextrin. The product reacts with 3-mercaptopropionic acid methyl ester under the catalysis of anhydrous cesium carbonate to obtain a product sugammadex methyl ester, and the sugammadex sodium is obtained by hydrolysis through sodium hydroxide. The yield thereof was found to be 60%. The crude sugammadex sodium obtained by the method has low purity and no further purification report.
Chem.asian J.2011,6, 2390-. The reaction intermediate has high purity, less impurities and simple post-treatment and purification of the product. However, the column chromatography process is adopted to prepare the iodo-cyclodextrin, so that the reaction steps are increased, and the time is long. And when the iodo-cyclodextrin prepared by the method is used as a raw material to prepare sugammadex sodium, a qualified product cannot be directly obtained, and the problem of difficult purification of the sugammadex sodium product still exists.
WO0140316PP uses iodine as a halogenating agent to react with gamma-cyclodextrin under the catalysis of triphenylphosphine to generate 6-deoxy-6-full iodo-gamma-cyclodextrin. The intermediate and 3-mercaptopropionic acid are synthesized into thioether, and a target product is obtained after membrane dialysis and purification. The method has simple and reliable route and higher reaction activity, but the product is purified only by membrane dialysis, and the difficulty of obtaining high-purity sugammadex sodium is higher.
CN105348412 discloses a purification method of a sugammadex sodium crude product, which comprises hydrolyzing the sugammadex sodium crude product under an acidic condition to obtain a free acid solid, pulping the free acid solid, washing and purifying the free acid solid; reacting free acid with organic amine to prepare the sugammadex ammonium salt, and recrystallizing and purifying the obtained ammonium salt; and dissociating under an acidic condition to obtain free acid, pulping, washing and purifying the free acid solid water, and reacting the obtained free acid with sodium hydroxide to prepare the sugammadex sodium pure product. The method does not use column chromatography, dialysis and other methods, but has complex steps, needs to convert between free acid and salt for many times and is inconvenient to operate. In addition, due to the instability of the sugammadex structure, the sugammadex structure has the risk of dissociation in the free process under the acidic condition, acidic damage impurities are formed, and the difficulty in purifying the product is increased.
CN106565858 discloses a purification method of sugammadex sodium, wherein a crude sugammadex sodium is converted into sugammadex salt under the treatment of ion exchange resin, and the sugammadex salt is recrystallized and purified and then is converted into the sugammadex sodium by ion resin. The product obtained by the method has good purity and mild conditions. However, the treatment process is complicated, and the ionic resin needs to be treated, which increases the difficulty of industrial application.
The polymer supported trivalent phosphine compound is a novel reagent for supporting trivalent organic phosphine groups on a macromolecular framework through chemical bonding, and is increasingly drawing the attention of researchers as a substitute of a traditional organic phosphorus reagent.
R1＝Ph；(CH2)n；(CH2)nCO-；etc.
R2,R3＝R1＝H；Ph；(CH2)n；(CH2)nCO-；etc.
The polymer supporting the skeleton is mainly polyethylene, polystyrene, urea-formaldehyde resin, dextran, or the like. The trivalent phosphine groups which can be loaded are mainly-PPh 3, -TEP, -DCEP, -TCEP, -TFP, -TPPTS and the like. The polymer loaded trivalent phosphine compound has stable skeleton and is usually pelletized into spherical resin with certain mesh number, so that the polymer loaded trivalent phosphine compound has the advantages of convenient use, convenient recovery, recyclability and the like.
Corresponding literature for applying polymer-supported trivalent phosphine compounds to synthesis and purification of sugammadex sodium is not available at present.
Disclosure of Invention
The invention provides a method for synthesizing sugammadex sodium by using a polymer-supported trivalent phosphine compound and purifying the sugammadex sodium, and the method has the advantages of environmental friendliness and high purity of the obtained product.
In order to solve the technical problems, the invention provides a method for synthesizing sugammadex sodium by using a polymer-supported trivalent phosphine compound, wherein the sugammadex sodium has a structural formula shown in a formula I,
the method comprises the following steps:
1) general formula II
Under the catalysis of crosslinked polystyrene supported triphenylphosphine, halogen reacts with a formula II to obtain 6-deoxy-6-perhalogenated-gamma-cyclodextrin shown in a formula III, and the reaction formula is as follows:
2) and synthesizing thioether from the compound shown in the formula III and 3-mercaptopropionic acid to obtain a crude sugammadex sodium product shown in the formula I, wherein the reaction formula is as follows:
3) and purifying the crude sugammadex sodium obtained in the step 2) by using a polymer loaded trivalent phosphine compound.
Further, the halogen in the step 1) is chlorine, bromine or iodine.
The supported skeleton of the polymer supported trivalent phosphine compound is selected from but not limited to polyethylene, polystyrene, polypropylene, urea-formaldehyde resin and glucan; the trivalent phosphine compound which can be loaded is selected from but not limited to the group selected from but not limited to-PPh 3, -TEP, -DCEP, -TCEP, -TFP, -TPPTS and the like; the polymer supported trivalent phosphine compound in the step 1 is a polymer supported triphenylphosphine compound, and is selected from but not limited to crosslinked polystyrene supported triphenylphosphine resin, crosslinked polypropylene supported triphenylphosphine resin and the like; the polymer supported trivalent phosphine compound in the step 3 is preferably but not limited to one or a combination of more than one of crosslinked polystyrene supported triphenylphosphine resin, crosslinked polypropylene supported tris (2-furyl) phosphine resin, crosslinked polystyrene supported tris (2-carboxyethyl) phosphine resin and crosslinked polystyrene supported triphenylphosphine tri-m-sulfonate.
The purification process of the crude sugammadex sodium product in the step 3) is as follows:
dissolving the crude sugammadex sodium in water or a mixed solvent consisting of water and a poor solvent of the sugammadex sodium, adding a polymer-loaded trivalent phosphine compound, replacing with nitrogen, stirring, and crystallizing to obtain the pure sugammadex sodium.
The poor solvent of the sugammadex sodium in the step 3) and the solvent used for crystallization are respectively one or a combination of a plurality of methanol, ethanol, isopropanol, DMF, DMSO, acetonitrile and acetone.
The dosage of the polymer supported triphenylphosphine compound in the step 1) is 1-50 times of the equivalent of gamma-cyclodextrin; the using amount of the 3-mercaptopropionic acid in the step 2) is 7-15 times of the equivalent of the gamma-cyclodextrin; the dosage of the polymer loaded with the trivalent phosphine compound in the step 3) is 0.1-200% (W/W) of the crude sugammadex sodium.
Further, the synthesis process of the sugammadex sodium of the invention is as follows:
the synthesis process of the 6-deoxy-6-perhalogenated-gamma-cyclodextrin in the step 1) is as follows: under the condition of stirring, adding crosslinked polystyrene supported triphenylphosphine resin and anhydrous DMF into a flask, adding a halogen simple substance, and releasing heat of the system; adding dried gamma-cyclodextrin, heating to 70 ℃ and reacting for 24 hours; after the reaction is finished, cooling the system, removing the crosslinked polystyrene supported triphenylphosphine resin by suction filtration, adding a methanol solution of sodium methoxide into the filtrate, and drying a filter cake; adding water into the residue, performing suction filtration, washing the filter cake with water and acetone respectively, and finally performing vacuum drying to obtain yellow 6-fully-deoxy-6-fully-halogenated-gamma-cyclodextrin solid;
step 2) the synthesis process of the crude sugammadex sodium product is as follows: adding 60% sodium hydride in batches into a DMF solution of 3-mercaptopropionic acid; cooling, and adding the 6-fully-deoxy-6-fully-halogenated-gamma-cyclodextrin obtained in the step 1); stirring, heating, reacting, cooling, adding water, quenching, and vacuum concentrating the solvent; and adding the residue into acetone, performing suction filtration, and performing vacuum drying on a filter cake to obtain a light yellow crude sugammadex sodium product.
Step 3) the purification process of the crude sugammadex sodium product is as follows: dissolving the crude sugammadex sodium in water or a mixed solvent consisting of water and a poor solvent of the sugammadex sodium, adding a polymer-supported trivalent phosphine compound, replacing with nitrogen, and crystallizing to obtain the pure sugammadex sodium. Wherein, the poor solvent of the sugammadex sodium and the solvent used for crystallization are respectively one or a combination of a plurality of methanol, ethanol, isopropanol, DMF, DMSO, acetonitrile and acetone; the concentration of the sugammadex sodium crude product solution is preferably 0.1-90%, and the further preferably 10-20%; the amount of the polymer-supported trivalent phosphine compound is preferably 1 to 200%, more preferably 0.5 to 10%.
Compared with the prior art, the invention has the following advantages:
according to the invention, a polymer-loaded triphenylphosphine compound is adopted to replace triphenylphosphine, and a halogenating reagent is used for halogenating the gamma-cyclodextrin to prepare 6-deoxy-6-halogeno-gamma-cyclodextrin; then reacts with 3-mercaptopropionic acid to synthesize the crude product of the sugammadex sodium.
According to the invention, the polymer loaded trivalent phosphine compound reagent is applied to the purification process of the crude sugammadex sodium product, and the reducibility of the resin is utilized to inhibit the generation of oxidation impurities, so that the finished sugammadex sodium product with the purity of 100.0% is finally obtained.
According to the method for synthesizing and purifying the sugammadex sodium by using the polymer-supported trivalent phosphine compound, the free organic phosphine compound is prevented from remaining in the product, and the crude sugammadex sodium is easier to purify. The polymer loaded trivalent phosphine compound can be recycled through treatment and activation, so that the reaction economy is improved, the requirements of green chemistry are met, and the method has high environmental protection significance and economic value.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1: original research HPLC chart of sodium sugammadex injection;
FIG. 2: HPLC profile of crude sugammadex sodium;
FIG. 3: HPLC profile of sugammadex refined product;
FIG. 4: HPLC profile of crude sugammadex sodium;
FIG. 5: HPLC profile of sugammadex refined product;
FIG. 6: HPLC profile of crude sugammadex sodium;
FIG. 7: HPLC profile of sugammadex refined product.
Detailed Description
The invention is further described below by way of examples, without limiting the scope of the invention in any way.
The polymer-supported trivalent phosphine compound including the crosslinked polystyrene-supported triphenylphosphine resin used in each of the following examples was a commercially available product, and other chemical agents were also commercially available products.
Example 1
1. Synthesis of 6-deoxy-6-wholly iodo-gamma-cyclodextrin
To a flask was added crosslinked polystyrene supported triphenylphosphine resin (60.2g), anhydrous DMF (160ml) with stirring, and elemental iodine (30.5g,15.6 equivalents) was added and the system exothermed. Dried gamma-cyclodextrin (10g, 7.7mmol) was added and the reaction was allowed to warm to 70 ℃ for 24 hours. After the reaction, the system was cooled, the crosslinked polystyrene supported triphenylphosphine resin was removed by suction filtration, the filtrate was added with a methanol solution of sodium methoxide (3.1g sodium in 50ml methanol), stirred for 30 minutes, added to 800ml methanol, suction filtered, and the filter cake was dried. To the residue was added 500ml of water, filtered, the filter cake washed with water (3 x 100ml) and then with acetone (3 x 100ml), and dried under vacuum at 70 ℃ to give a yellow solid of 6-fully deoxy-6-fully iodo- γ -cyclodextrin (16.2 g). Washing the recovered crosslinked polystyrene loaded triphenylphosphine resin with DMF (dimethyl formamide), washing with water, drying, and reducing with trichlorosilane for recycling;
2. synthesis of sugammadex sodium
To a DMF solution of 3-mercaptopropionic acid (1.0g of 3-mercaptopropionic acid dissolved in 30ml of DMF) was added 60% sodium hydride (476mg, 22 equivalents) in portions. Cooling, adding DMF solution of 6-fully deoxy-6-fully iodo-gamma-cyclodextrin (1.4g 6-fully deoxy-6-fully iodo-gamma-cyclodextrin dissolved in 30ml DMF), stirring, and heating to 70 deg.C for reaction for 24 hr. After the reaction, the temperature was lowered to room temperature, and 20ml of water was added to quench the reaction, followed by vacuum concentration to remove most of the solvent. The residue was added to 500ml of acetone, filtered off with suction and the filter cake was dried under vacuum at 70 ℃ to give a pale yellow solid (2.25g of crude sugammadex sodium) with a purity of 98.3% (see FIG. 2).
3. Purification of sugammadex sodium
Under the protection of nitrogen, 2g of the crude sugammadex sodium is dissolved in 10ml of water, crosslinked polystyrene supported triphenylphosphine resin (0.2g) is added into the solution, the temperature is raised to 70 ℃ under stirring, 25ml of DMF is added into the solution dropwise under the protection of nitrogen, and the solution is slightly mixed. Slowly cooling to room temperature, precipitating white solid, and vacuum filtering to obtain white solid 1.8 g. The above recrystallization procedure was repeated to obtain 1.2g of a white solid. The solid was 100.0% pure by HPLC (containing monohydroxy sugammadex sodium). (see FIG. 3).
Example 2
1. Synthesis of 6-deoxy-6-perbromo-gamma-cyclodextrin
To the flask was added, with stirring, crosslinked polystyrene supported triphenylphosphine resin (60.2g), anhydrous DMF (160ml), and bromine (19.2g,15.6 equivalents) was added dropwise, whereupon the system exothermed. Dried gamma-cyclodextrin (10g, 7.7mmol) was added and the reaction was allowed to warm to 70 ℃ for 24 hours. After the reaction, the system was cooled, the crosslinked polystyrene supported triphenylphosphine resin was removed by suction filtration, the filtrate was added with a methanol solution of sodium methoxide (3.1g sodium in 50ml methanol), stirred for 30 minutes, added to 800ml methanol, suction filtered, and the filter cake was dried. To the residue was added 500ml of water, filtered, the filter cake washed with water (3 x 100ml), then with acetone (3 x 100ml), and dried under vacuum at 70 ℃ to give a yellow solid of 6-fully deoxy-6-fully bromo- γ -cyclodextrin (13.2 g). Washing the recovered crosslinked polystyrene loaded triphenylphosphine resin with DMF (dimethyl formamide), washing with water, drying, and reducing with trichlorosilane for recycling;
2. synthesis of sugammadex sodium
To a DMF solution of 3-mercaptopropionic acid (1.0g of 3-mercaptopropionic acid dissolved in 30ml of DMF) was added 60% sodium hydride (476mg, 22 equivalents) in portions. Cooling, adding DMF solution of 6-fully-deoxy-6-fully bromo-gamma-cyclodextrin (1.2g of 6-fully-deoxy-6-fully bromo-gamma-cyclodextrin dissolved in 30ml of DMF), stirring, heating to 70 ℃, and reacting for 24 hours. After the reaction, the temperature was lowered to room temperature, 20ml of water was added to quench the reaction, and most of the solvent was concentrated in vacuo. The residue was added to 500ml of acetone, filtered with suction and the filter cake was dried under vacuum at 70 ℃ to give a pale yellow solid (2.11g) with a purity of 97.5% (see FIG. 4).
3. Purification of sugammadex sodium
Under the protection of nitrogen, 2g of crude sugammadex sodium is dissolved in 10ml of water, crosslinked polystyrene loaded tris (2-carboxyethyl) phosphine resin (0.15g) is added into the solution, the solution is stirred and heated to 70 ℃, 25ml of DMF is dripped into the solution under the protection of nitrogen, and the solution is mixed slightly. Slowly cooling to room temperature, precipitating white solid, and vacuum filtering to obtain white solid 1.7 g. The above recrystallization procedure was repeated to obtain 1.1g of a white solid. The solid was dissolved in 10ml of water, and crosslinked polystyrene-supported tris (2-carboxyethyl) phosphine resin (0.1g) and 0.1g of activated carbon were added thereto, followed by suction filtration, concentration and stirring, to thereby obtain a solid having a purity of 100.0% by HPLC (purity by HPLC) (containing monohydroxystilucon sodium). (see FIG. 5).
Example 3
1. Synthesis of 6-deoxy-6-perchloro-gamma-cyclodextrin
To the flask was added crosslinked polystyrene supported triphenylphosphine resin (60.2g), anhydrous DMF (160ml) with stirring, carbon tetrachloride (18.5g,15.6 equivalents) was added and the system exothermed. Dried gamma-cyclodextrin (10g, 7.7mmol) was added and the reaction was allowed to warm to 60 ℃ for 40 hours. After the reaction, the system was cooled, the crosslinked polystyrene supported triphenylphosphine resin was removed by suction filtration, the filtrate was added with a methanol solution of sodium methoxide (3.1g sodium in 50ml methanol), stirred for 30 minutes, added to 800ml methanol, suction filtered, and the filter cake was dried. To the residue was added 500ml of water, filtered, the filter cake washed with water (3 x 100ml) and then with acetone (3 x 100ml), and dried under vacuum at 70 ℃ to give a yellow solid of 6-per-deoxy-6-per-chloro-y-cyclodextrin (16.2 g). Washing the recovered crosslinked polystyrene loaded triphenylphosphine resin with DMF (dimethyl formamide), washing with water, drying, and reducing with trichlorosilane for recycling;
2. synthesis of sugammadex sodium
To a DMF solution of 3-mercaptopropionic acid (1.0g of 3-mercaptopropionic acid dissolved in 30ml of DMF) was added 60% sodium hydride (476mg, 22 equivalents) in portions. Cooling, adding DMF solution of 6-per-deoxy-6-per-chloro-gamma-cyclodextrin (1.4g of 6-per-deoxy-6-per-iodo-gamma-cyclodextrin dissolved in 30ml of DMF), stirring, and heating to 70 ℃ for reaction for 24 hours. After the reaction, the temperature was lowered to room temperature, and 20ml of water was added to quench the reaction, followed by vacuum concentration to remove most of the solvent. The residue was added to 500ml of acetone, filtered with suction and the filter cake was dried under vacuum at 70 ℃ to give a pale yellow solid (2.25g) with a purity of 98.0% (see FIG. 6).
3. Purification of sugammadex sodium
Under the protection of nitrogen, 2g of the crude sugammadex sodium is dissolved in 10ml of water, crosslinked polystyrene supported triphenylphosphine tri-m-sulfonate (0.2g) is added into the solution, the temperature is raised to 70 ℃ under stirring, 25ml of DMF is dripped into the solution under the protection of nitrogen, and the solution is mixed slightly. Slowly cooling to room temperature, precipitating white solid, and vacuum filtering to obtain white solid 1.8 g. The above recrystallization procedure was repeated to obtain 1.2g of a white solid. The solid was 100.0% pure by HPLC (containing monohydroxy sugammadex sodium). (see FIG. 7).
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and all equivalent substitutions or substitutions made on the above-mentioned embodiments are included in the scope of the present invention.
Claims (3)
1. A method for synthesizing sugammadex sodium by using a polymer-supported trivalent phosphine compound is disclosed, wherein the sugammadex sodium has a structural formula shown in a formula I,
the method is characterized by comprising the following steps:
1) general formula II
Under the catalysis of crosslinked polystyrene supported triphenylphosphine, halogen reacts with a formula II to obtain 6-deoxy-6-perhalogenated-gamma-cyclodextrin shown in a formula III, and the reaction formula is as follows:
2) and synthesizing thioether from the compound shown in the formula III and 3-mercaptopropionic acid to obtain a crude sugammadex sodium product shown in the formula I, wherein the reaction formula is as follows:
3) purifying the crude sugammadex sodium obtained in the step 2) by using a polymer loaded trivalent phosphine compound, wherein the specific purification process comprises the following steps: under the protection of nitrogen, dissolving the crude sugammadex sodium in water, adding crosslinked polystyrene loaded tris (2-carboxyethyl) phosphine resin into the solution, stirring and heating to 70 ℃, dropwise adding DMF into the solution under the protection of nitrogen, and slightly mixing the solution; slowly cooling to room temperature, separating out white solid, and performing suction filtration to obtain white solid; repeating the recrystallization process to obtain a white solid; dissolving the solid in water, adding crosslinked polystyrene loaded tris (2-carboxyethyl) phosphine resin and activated carbon, performing suction filtration, concentrating and stirring the solid, and detecting the purity of the solid by HPLC (high performance liquid chromatography) to be 100.0%, wherein the solid contains monohydroxystilbene sodium gluconate.
2. The method for synthesizing sugammadex sodium by using the polymer-supported trivalent phosphine compound as claimed in claim 1, wherein: the halogen in the step 1) is chlorine, bromine or iodine.
3. The method for synthesizing sugammadex sodium by using the polymer-supported trivalent phosphine compound as claimed in claim 1, wherein: the dosage of the polymer supported triphenylphosphine compound in the step 1) is 1-50 times of the equivalent of gamma-cyclodextrin;
the using amount of the 3-mercaptopropionic acid in the step 2) is 7-15 times of the equivalent of the gamma-cyclodextrin; the dosage of the polymer loaded with the trivalent phosphine compound in the step 3) is 0.1-200% W/W of the crude sugammadex sodium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810137748.4A CN110156917B (en) | 2018-02-10 | 2018-02-10 | Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810137748.4A CN110156917B (en) | 2018-02-10 | 2018-02-10 | Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110156917A CN110156917A (en) | 2019-08-23 |
| CN110156917B true CN110156917B (en) | 2021-07-16 |
Family
ID=67641445
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810137748.4A Active CN110156917B (en) | 2018-02-10 | 2018-02-10 | Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110156917B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN106565858A (en) * | 2016-10-13 | 2017-04-19 | 王炳永 | Purification method for sugammadex sodium |
| WO2017084401A1 (en) * | 2016-06-29 | 2017-05-26 | 北京睿创康泰医药研究院有限公司 | Sugammadex preparation and purification method |
-
2018
- 2018-02-10 CN CN201810137748.4A patent/CN110156917B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| WO2017084401A1 (en) * | 2016-06-29 | 2017-05-26 | 北京睿创康泰医药研究院有限公司 | Sugammadex preparation and purification method |
| CN106565858A (en) * | 2016-10-13 | 2017-04-19 | 王炳永 | Purification method for sugammadex sodium |
Non-Patent Citations (1)
| Title |
|---|
| 负载有机膦的合成及其在有机催化领域的应用;刘海灵;《化学进展》;20130324;第25卷(第2/3期);第322-329页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110156917A (en) | 2019-08-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109867673B (en) | Method for synthesizing palbociclib | |
| CN114276220B (en) | Preparation method of o-phenyl phenoxyethanol | |
| CN1679586A (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| JP5246516B2 (en) | Method for isolating methyl-4-formylbenzoate and dimethyl terephthalate | |
| CN110156917B (en) | Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound | |
| CN109593143B (en) | Purification method for preparing intermediate from sugammadex sodium | |
| CN101891653A (en) | Clean production method of symmetric N,N'-disubstituted urea | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| CN103113254B (en) | Technology for directly synthesizing acetaminophen from nitrobenzene | |
| CN113444004B (en) | 3, 5-dibromo-o-amino benzaldehyde production process | |
| CN111253272B (en) | Method for preparing benzamide compound | |
| CN109824687B (en) | Novel synthetic method of xylofuranose derivative | |
| CN108203385B (en) | Method for preparing 3- (4-fluoro-2-nitrophenyl) acetone | |
| CN113773235B (en) | Synthesis method of clorsulon | |
| CN113024484B (en) | Method for purifying and preparing high-purity promoter CZ and application thereof | |
| CN113336636B (en) | Synthesis process of DL-mandelic acid with high yield | |
| CN109704940B (en) | Synthetic method of alpha-bromo-cinnamaldehyde | |
| CN115322239B (en) | Method for recovering diketone from mandipropamid carbon loss ester mother liquor | |
| CN102030684A (en) | Clean production method for symmetrical N,N'-dialkylurea | |
| CN1410417A (en) | Preparation method of glycine | |
| CN117903069A (en) | Synthesis method of fampicin intermediate 2-bromo-5-chloropyrazine | |
| CN107043374B (en) | Method for preparing 1,2, 3-thiadiazole-5-formamide compound | |
| CN114292229A (en) | Preparation method of 3-bromo-4-methoxypyridine | |
| CN113929587A (en) | Preparation method of 2-amino-5-chlorophenol | |
| CN114890942A (en) | 3-bromo-6-chloropyridine-2-formic acid and preparation method thereof |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220523 Address after: 230000 room 603, building 1, Lianhua garden, Hong Kong Macao garden, 820 Furong Road, Shushan District, Hefei City, Anhui Province Patentee after: Guo Hui Address before: 230000 4th floor, unit C, building 1, Shenzhen Hong Kong digital industrial base, 1689 Xiyou Road, high tech Zone, Hefei City, Anhui Province Patentee before: HEFEI BOSIKECHUANG PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right |