Purification method of sugammadex sodium

Abstract

The invention belongs to the field of chemistry, and relates to a purification method of sugammadex sodium. The purification method comprises the following steps: mixing a sugammadex sodium crude product with an antioxidant, a complexing agent and water, stirring and dissolving, then adding activated carbon, stirring and filtering to obtain a filtrate, adding an organic solvent into the filtrate, cooling, separating out crystals, filtering to obtain a filter cake, and drying to obtain purified sugammadex sodium. The purification method is beneficial to reducing the content of the purified diphenylphosphine oxide impurity 1, diphenylphosphine oxide impurity 2 and / or triphenylphosphine oxide, is beneficial to avoiding the increase of oxidation impurities, and has unexpected technical effects.

Description

Technical Field

[0001] The invention relates to the field of chemistry, and in particular to a method for purifying sugammadex sodium. Background Art

[0002] Sugammadex Sodium is a chemically synthesized drug, chemical name is 6-deoxy-6-per(2-carboxyethyl)thio-γ-cyclodextrin sodium salt, CAS number: 343306-79-6, molecular formula: C 72 H 104 Na8O 48 S8, molecular weight: 2178.01, is used to quickly reverse neuromuscular blockade caused by anesthetics rocuronium and vecuronium during surgery in adult patients.

[0003] At present, the synthesis process of sodium sugammadex generally uses γ-cyclodextrin as a raw material, reacts with a halogenating agent and triphenylphosphine, and then combines with 3-mercaptopropionic acid to form sodium sugammadex; such as the preparation method of sodium sugammadex disclosed in patent application CN109879986A. However, the inventors found that the triphenylphosphine used in the reaction contains diphenylphosphonic acid impurities and triphenylphosphine oxide impurities, which exist in the prototype or are converted into corresponding derivatives during the synthesis process of sodium sugammadex, resulting in the presence of multiple phosphorus-containing impurities in the product, and these impurities are difficult to remove using conventional purification methods (such as the refining method in patent application CN109879986A), thus seriously affecting the product quality of sodium sugammadex.

[0004] Therefore, there is an urgent need for a purification method for sugammadex sodium with good purification effect. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0006] A method for purifying sugammadex sodium comprises: mixing and dissolving a crude sugammadex sodium with an antioxidant, a complexing agent and water, adding activated carbon, stirring, filtering to obtain a filtrate, adding an organic solvent to the filtrate, cooling, precipitating crystals, filtering, and drying to obtain purified sugammadex sodium; wherein the antioxidant is L-ascorbic acid and the complexing agent is zinc chloride.

[0007] In some embodiments, the organic solvent is selected from at least one of an alcohol organic solvent, dimethyl sulfoxide, N,N-dimethylformamide and tetrahydrofuran.

[0008] In some embodiments, the alcohol organic solvent is selected from at least one of methanol, ethanol, isopropanol and tert-butyl alcohol. In some preferred embodiments, the alcohol organic solvent is selected from at least one of methanol, ethanol and isopropanol.

[0009] In some embodiments, the mixed dissolution is mixed and dissolved at 10° C. to 80° C. In some embodiments, the mixed dissolution is mixed and dissolved at 10° C., 20° C., 30° C., 40° C., 50° C., 60° C., 70° C. or 80° C.

[0010] In some embodiments, the stirring temperature is 10° C. to 80° C. In some embodiments, the stirring temperature is 10° C., 20° C., 30° C., 40° C., 50° C., 60° C., 70° C. or 80° C.

[0011] In some embodiments, the temperature of the filtrate in the operation of adding an organic solvent to the filtrate is 10° C. to 80° C. In some embodiments, the temperature of the filtrate in the operation of adding an organic solvent to the filtrate is 40° C. to 60° C. In some embodiments, the temperature of the filtrate in the operation of adding an organic solvent to the filtrate is 10° C., 20° C., 30° C., 40° C., 50° C., 60° C., 70° C. or 80° C.

[0012] In some embodiments, the cooling is cooling to a temperature 5°C lower than the temperature of the filtrate in the process of adding the organic solvent to the filtrate.

[0013] -100°C. In some embodiments, the cooling is cooling to 10°C-40°C lower than the temperature of the filtrate in the operation of adding an organic solvent to the filtrate. In some embodiments, the cooling is cooling to 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80, 85°C, 90°C, 95°C or 100°C lower than the temperature of the filtrate in the operation of adding an organic solvent to the filtrate.

[0014] In some embodiments, the stirring time is 1 h to 5 h. In some embodiments, the stirring time is 1 h, 2 h, 3 h, 4 h or 5 h.

[0015] In some embodiments, each 1g of the crude sodium sugammadex is dissolved in 0.5ml-5.0ml of the water. In some embodiments, each 1g of the crude sodium sugammadex is dissolved in 0.5ml, 1.0ml, 1.5ml, 2.0ml, 2.5ml, 3.0ml, 3.5ml, 4.0ml, 4.5ml or 5.0ml of the water.

[0016] In some embodiments, the mass ratio of the L-ascorbic acid to the crude sodium sugammadex is 0.05:100 to 0.20:100. In some embodiments, the mass ratio of the L-ascorbic acid to the crude sodium sugammadex is 0.05:100, 0.10:100, 0.15:100 or 0.20:100.

[0017] In some embodiments, the mass ratio of the zinc chloride to the crude sodium sugammadex is 0.05:100 to 0.50:100. In some embodiments, the mass ratio of the zinc chloride to the crude sodium sugammadex is 0.05:100, 0.10:100, 0.15:100, 0.20:100, 0.25:100, 0.30:100, 0.35:100, 0.40:100, 0.45:100 or 0.50:100.

[0018] In some embodiments, the mass ratio of the activated carbon to the crude sodium gluconate is 0.10:100-10:100. In some embodiments, the mass ratio of the activated carbon to the crude sodium gluconate is 0.10:100, 0.50:100, 1:100, 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100, 9:100 or 10:100.

[0019] In some embodiments, the crude sugammadex sodium contains diphenylphosphine oxide impurities and / or triphenylphosphine oxide impurities; and the purification method is used to remove diphenylphosphine oxide impurities and / or triphenylphosphine oxide impurities in the crude sugammadex sodium.

[0020] In some embodiments, the purification method is used to remove diphenylphosphine oxide impurities and / or triphenylphosphine oxide impurities in the crude sugammadex sodium, and avoid the increase of oxidative impurities during the purification process.

[0021] In some embodiments, the diphenylphosphine oxide impurities include diphenylphosphine oxide impurity 1 and / or diphenylphosphine oxide impurity 2; the structures of the diphenylphosphine oxide impurity 1 and diphenylphosphine oxide impurity 2 are respectively:

[0022] (diphenylphosphine oxide impurity 1), (Diphenylphosphine oxide impurity 2).

[0023] In some embodiments, the structure of the triphenylphosphine oxide impurity is:

[0024] In some embodiments, the oxidized impurities are those having a molecular structure of The two diastereoisomers of The S atom in (the two dots under the S atom indicate that the atom is a chiral center).

[0025] In some embodiments, the method for preparing the crude sugammadex sodium comprises:

[0026] (1) γ-cyclodextrin reacts with a halogenating agent and triphenylphosphine in a solvent at a certain temperature A, and undergoes a first post-treatment to obtain 6-perdeoxy-6-perhalogenated-γ-cyclodextrin;

[0027] (2) In an organic solvent, the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin obtained in step (1) is reacted with 3-mercaptopropionic acid at a certain temperature B in the presence of a base, and subjected to a second post-treatment to obtain the crude sodium sugammadex.

[0028] In some embodiments, in the step (1), during the mixing of the halogenating agent with γ-cyclodextrin, triphenylphosphine and solvent, the system temperature is less than 60°C.

[0029] In some embodiments, the system temperature is less than 25°C during the mixing process of the base with the organic solvent, 6-perdeoxy-6-perhalogenated-γ-cyclodextrin and 3-mercaptopropionic acid in step (2). In some embodiments, the system temperature is 5°C-20°C during the mixing process of the base with the organic solvent, 6-perdeoxy-6-perhalogenated-γ-cyclodextrin and 3-mercaptopropionic acid in step (2). In some embodiments, the system temperature is 10°C-20°C during the mixing process of the base with the organic solvent, 6-perdeoxy-6-perhalogenated-γ-cyclodextrin and 3-mercaptopropionic acid in step (2).

[0030] In some embodiments, the halogenating agent in step (1) comprises N-bromosuccinimide or dibromohydantoin; and the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin is 6-perdeoxy-6-perbromo-γ-cyclodextrin.

[0031] In some embodiments, the reaction of step (1) is carried out under the protection of nitrogen or an inert gas.

[0032] In some embodiments, the reaction of step (2) is carried out under the protection of nitrogen or an inert gas.

[0033] In some embodiments, the solvent in step (1) comprises at least one of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

[0034] In some embodiments, the organic solvent in step (2) comprises at least one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, dichloromethane, ethyl acetate and tert-butyl methyl ether.

[0035] In some embodiments, the base in step (2) is sodium hydroxide.

[0036] In some embodiments, the certain temperature A is 75° C.-90° C. In some embodiments, the certain temperature A is 75° C., 80° C., 85° C. or 90° C.

[0037] In some embodiments, the certain temperature B is 80° C.-100° C. In some embodiments, the certain temperature B is 75° C., 80° C., 85° C. or 90° C.

[0038] In some embodiments, the first post-treatment includes: cooling to room temperature, adding methanol, stirring, then adding sodium hydroxide aqueous solution to adjust the pH to 8-10 (for example, 8, 9 or 10), then adding water, stirring for 3-5 hours (for example, 3 hours, 4 hours or 5 hours), filtering to obtain a first filter cake, washing the first filter cake with methanol, filtering to obtain a second filter cake, and drying the second filter cake to obtain the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin.

[0039] In some embodiments, the mass ratio of the methanol in the first post-treatment to the solvent in step (1) is 1:1-1:3. In some embodiments, the mass ratio of the methanol in the first post-treatment to the solvent in step (1) is 1:2.

[0040] In some embodiments, the mass ratio of the methanol to the water in the first post-treatment is 1:10-1:50. In some embodiments, the mass ratio of the methanol to the water in the first post-treatment is 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45 or 1:50. In some embodiments, the mass ratio of the methanol to the water in the first post-treatment is 1:15.

[0041] In some embodiments, the second post-treatment comprises: (S1) cooling to 40°C-60°C (e.g., 40°C, 45°C, 50°C, 55°C or 60°C), adding water, stirring at 50°C-60°C (e.g., 40°C, 45°C, 50°C, 55°C or 60°C) for 1h-2h, cooling to 15°C-30°C (e.g., 15°C, 20°C, 25°C or 30°C) for crystallization, filtering to obtain a third filter cake, wherein the third filter cake is washed with methanol, Filter to obtain a fourth filter cake; (S2) add water to the fourth filter cake, raise the temperature to 50°C-60°C (e.g., 50°C, 55°C or 60°C) under nitrogen protection, then add dimethyl sulfoxide, cool to 15°C-30°C (e.g., 15°C, 20°C, 25°C or 30°C), stir to crystallize, and filter to obtain a fifth filter cake; (S3) slurry the fifth filter cake with ethanol, filter to obtain a sixth filter cake, and dry to obtain the crude sodium sugammadex.

[0042] In some embodiments, the mass ratio of the water in step (S1) in the second post-treatment to the organic solvent in step (2) is 1.0:1.0-1.0:2.0. In some embodiments, the mass ratio of the water in step (S1) in the second post-treatment to the organic solvent in step (2) is 1.0:1.5;

[0043] In some embodiments, the mass ratio of water to dimethyl sulfoxide in the second post-treatment step (S2) is 1:1-1:10. In some embodiments, the mass ratio of water to dimethyl sulfoxide in the second post-treatment step (S2) is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0044] In some embodiments, the mass ratio of the water in step (S2) in the second post-treatment to the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin in step (2) is 1:1-1:5. In some embodiments, the mass ratio of the water in step (S2) in the second post-treatment to the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin in step (2) is 1:1, 1:2, 1:3, 1:4 or 1:5.

[0045] In some embodiments, the method for preparing the crude sugammadex sodium comprises:

[0046] (i) γ-cyclodextrin and triphenylphosphine are mixed in a solvent to obtain a mixed solution 1, and then a halogenating agent solution is added dropwise, and then reacted at a certain temperature C, and subjected to a third post-treatment to obtain 6-perdeoxy-6-perhalogenated-γ-cyclodextrin, wherein the halogenating agent solution is prepared by dissolving the halogenating agent in the solvent;

[0047] (ii) mixing the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin obtained in step (i) with an organic solvent and 3-mercaptopropionic acid to obtain a mixed solution 2, adding a base, reacting at a certain temperature D, and performing a fourth post-treatment to obtain the crude sodium sugammadex.

[0048] In some embodiments, during the mixing process of the halogenating agent solution and the mixed solution 1 in step (i), the system temperature is less than 60°C.

[0049] In some embodiments, during the mixing process of the alkali and the mixed solution 2 in step (ii), the system temperature is less than 25°C. In some embodiments, during the mixing process of the alkali and the mixed solution 2 in step (ii), the system temperature is 5°C-20°C. In some embodiments, during the mixing process of the alkali and the mixed solution 2 in step (ii), the system temperature is 10°C-20°C. In some embodiments, during the mixing process of the alkali and the mixed solution 2 in step (ii), the system temperature is 10°C, 15°C or 20°C.

[0050] In some embodiments, the halogenating agent in step (i) comprises N-bromosuccinimide or dibromohydantoin; and the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin is 6-perdeoxy-6-perbromo-γ-cyclodextrin.

[0051] In some embodiments, the reaction of step (i) is carried out under the protection of nitrogen or an inert gas.

[0052] In some embodiments, the reaction of step (ii) is carried out under the protection of nitrogen or an inert gas.

[0053] In some embodiments, the solvent in step (i) comprises at least one of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

[0054] In some embodiments, the organic solvent in step (ii) comprises at least one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, dichloromethane, ethyl acetate and tert-butyl methyl ether.

[0055] In some embodiments, the base in step (ii) is sodium hydroxide.

[0056] In some embodiments, the certain temperature C is 75°C-90°C. In some embodiments, the certain temperature C is 75°C, 80°C, 85°C or 90°C.

[0057] In some embodiments, the certain temperature D is 80° C.-100° C. In some embodiments, the certain temperature D is 75° C., 80° C., 85° C. or 90° C.

[0058] In some embodiments, the third post-treatment includes: cooling to room temperature, adding methanol, stirring, then adding sodium hydroxide aqueous solution to adjust the pH to 8-10, then adding water, stirring for 3-5 hours, filtering to obtain a seventh filter cake, washing the seventh filter cake with methanol, filtering to obtain an eighth filter cake, drying the eighth filter cake to obtain the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin.

[0059] In some embodiments, the mass ratio of the methanol in the third post-treatment to the solvent in step (i) is 1:1-1:3. In some embodiments, the mass ratio of the methanol in the third post-treatment to the solvent in step (i) is 1:2.

[0060] In some embodiments, the mass ratio of the methanol to the water in the third post-treatment is 1:10-1:50. In some embodiments, the mass ratio of the methanol to the water in the third post-treatment is 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45 or 1:50. In some embodiments, the mass ratio of the methanol to the water in the third post-treatment is 1:15.

[0061] In some embodiments, the fourth post-treatment includes: (P1) cooling to 40°C-60°C, adding water, stirring at 50°C-60°C for 1h-2h, cooling to 15°C-30°C for crystallization, filtering to obtain a ninth filter cake, washing the ninth filter cake with methanol, filtering to obtain a tenth filter cake; (P2) adding water to the tenth filter cake, heating to 50°C-60°C under nitrogen protection, then adding dimethyl sulfoxide, cooling to 15°C-30°C, stirring for crystallization, filtering to obtain an eleventh filter cake; (P3) slurrying the eleventh filter cake with ethanol, filtering to obtain a twelfth filter cake, and drying to obtain the crude sodium sugammadex.

[0062] In some embodiments, the mass ratio of the water in step (P1) in the fourth post-treatment to the organic solvent in step (ii) is 1.0:1.0-1.0:2.0. In some embodiments, the mass ratio of the water in step (P1) in the fourth post-treatment to the organic solvent in step (ii) is 1.0:1.5.

[0063] In some embodiments, the mass ratio of water to dimethyl sulfoxide in step (P2) of the fourth post-treatment is 1:1-1:10. In some embodiments, the mass ratio of water to dimethyl sulfoxide in step (P2) of the fourth post-treatment is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0064] In some embodiments, the mass ratio of the water in step (P2) in the fourth post-treatment to the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin in step (ii) is 1:1-1:5. In some embodiments, the mass ratio of the water in step (P2) in the fourth post-treatment to the 6-perdeoxy-6-perhalogenated-γ-cyclodextrin in step (ii) is 1:1, 1:2, 1:3, 1:4 or 1:5.

[0065] Beneficial Effects

[0066] Compared with the prior art, the present invention has at least one of the following beneficial effects:

[0067] (1) The addition of L-ascorbic acid during the purification process of the present invention is beneficial to avoiding the growth of oxidative impurities 1 and oxidative impurities 2 during the purification process of sugammadex sodium. In particular, compared with other antioxidants, the L-ascorbic acid of the present invention is more conducive to reducing the generation of the oxidative impurities, which has unexpected technical effects.

[0068] (2) The present invention adds zinc chloride as a complexing agent during the purification process, which is beneficial to reducing the content of diphenylphosphine oxide impurity 1, diphenylphosphine oxide impurity 2 and / or triphenylphosphine oxide after purification, and is beneficial to avoiding the growth of oxidized impurities 1 and oxidized impurities 2. In particular, compared with other complexing agents, the complexing agent of the present invention has a better effect in reducing the impurity content, thereby having an unexpected technical effect.

[0069] Terminology

[0070] The term "room temperature" means ambient temperature, which refers to a temperature between about 10°C and about 35°C, or between about 20°C and 30°C, or about 25°C.

[0071] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0072] In the following, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number with a value of N is disclosed, any number with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% will be explicitly disclosed, where "+ / -" means plus or minus. DETAILED DESCRIPTION

[0073] Those skilled in the art can refer to the content of this article and appropriately improve the chromatographic condition parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method of the present invention has been described by preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0074] 1. Chromatographic conditions for detection of phosphorus-containing impurities and oxidized impurities

[0075] Chromatographic columns: two Phenomenex, Aqua C18, 3μm, 150mm x 2.0mm columns connected in series;

[0076] Mobile phase and elution method: 0.025mol / L phosphate buffer (pH 3.0) (take 3.45g of sodium dihydrogen phosphate monohydrate, put it in a 1000ml volumetric flask, add 950ml of water, adjust the pH value to 3.00±0.03 with 1.5mol / L phosphoric acid solution, and dilute with water to the scale, shake well)-acetonitrile (83:20) as mobile phase A; acetonitrile as mobile phase B; perform gradient elution according to the table below,

[0077]

[0078]

[0079] Detection wavelength: 200nm;

[0080] Column temperature: 40°C;

[0081] Flow rate: 0.27ml / min.

[0082] 2. Impurity structure and its location in the chromatogram under the chromatographic conditions described:

[0083] Diphenylphosphine oxide impurity 1 structure: RRT (relative retention time) is about 2.64;

[0084] Diphenylphosphine oxide impurity 2 structure: RRT (relative retention time) is about 2.49;

[0085] Triphenylphosphine structure: RRT (relative retention time) is about 3.72;

[0086] The oxidized impurities of the present invention include oxidized impurities 1 and oxidized impurities 2, wherein, through mass spectrometry detection and mechanism inference, the oxidized impurities 1 and oxidized impurities 2 are non-corresponding isomers of each other, and they have a molecular structure The chiral center is S atom in; in the present invention, under the chromatographic conditions, the RRT (relative retention time) of the oxidized impurity 1 is about 0.45; the RRT (relative retention time) of the oxidized impurity 2 is about 0.59.

[0087] ND: means not detected, that is, the detected content is less than 0.01%.

[0088] Example 1: Preparation of crude sodium gluconate

[0089] The preparation was carried out according to the method of Example 1 of patent application CN109879986A, as follows:

[0090] Step 1: Preparation of 6-perdeoxy-6-perbromo-γ-cyclodextrin

[0091] Under nitrogen protection, 400g of N,N-dimethylformamide, 150g of γ-cyclodextrin (dried at 105°C) and 500g of triphenylphosphine (purchased commercially) were added in sequence to dissolve. The reaction system was cooled to 5°C, and a solution of 350g of dibromohydantoin in DMF was added dropwise, and the temperature was controlled at <60°C during the addition process. After the addition was completed, the reaction system was heated to 90°C and stirred for 4h. After the reaction was completed, the temperature was cooled to room temperature, 200g of methanol was added, 30wt% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 8, and then 3kg of water was added dropwise, and then stirred at room temperature for 4h, and filtered to obtain a first filter cake, the first filter cake was washed with 500g of methanol, filtered to obtain a second filter cake, and the second filter cake was vacuum dried at 70°C to obtain 6-full deoxy-6-perbromo-γ-cyclodextrin.

[0092] Step 2: Preparation of crude sugammadex sodium (i.e., sugammadex sodium refined by the method of Example 1 of CN109879986A, defined as crude sugammadex sodium in the present invention)

[0093] Under nitrogen protection, 1.36 kg of dimethylformamide, 120 g of 6-deoxy-6-perbromo-γ-cyclodextrin obtained in step 1, and 92 g of 3-mercaptopropionic acid were added in sequence. The reaction system was cooled to 5°C, and a pre-prepared methanol solution containing 70 g of sodium hydroxide was slowly added dropwise, with the temperature being controlled at <25°C during the addition process. After the addition was completed, the temperature was controlled at 80°C for 4 hours.

[0094] After the reaction was completed, the reaction system was cooled to 50°C, 960 g of water was added dropwise, and the temperature was controlled at 50°C for stirring and reaction for 1 hour. The reaction system was then cooled to 25°C and kept warm for crystallization for 5 hours. The third filter cake was obtained by suction filtration, and the third filter cake was slurried with 180 g of methanol for 2 hours and filtered to obtain a fourth filter cake.

[0095] 360 g of water and the fourth filter cake were added in sequence, and then the reaction system was heated to 50°C under nitrogen protection, and 1.72 kg of dimethyl sulfoxide was added dropwise; after the addition was completed, the temperature was cooled to room temperature and stirred for crystallization for 5 hours. Filtered with suction to obtain the fifth filter cake, the fifth filter cake was slurried with ethanol, filtered to obtain the sixth filter cake, the sixth filter cake was collected, and vacuum dried at 75°C for 20 hours to obtain crude sodium gluconate. Phosphorus impurities and oxidative impurities in the crude sodium gluconate obtained were detected by HPLC, and the results were:

[0096] Diphenylphosphine impurity 1 content: 0.22%;

[0097] Diphenylphosphine impurity 2 content: 0.21%;

[0098] Triphenylphosphine content: 0.31%;

[0099] Oxidation impurity 1 content: 0.05%;

[0100] Oxidation impurity 2 content: 0.05%;

[0101] Total amount of other impurities: 0.04%.

[0102] Example 2: Purification using methanol as solvent

[0103] The crude sodium dextrose (2.00 g) obtained in Example 1 was mixed with L-ascorbic acid (2 mg), zinc chloride (2 mg) and water at 50°C, stirred to dissolve, and activated carbon (10 mg) was added. The mixture was stirred at 50°C for 1 h, filtered, and 20 ml of methanol was added dropwise to the filtrate at 50°C. After the addition was completed, the mixture was cooled to 20°C, crystals were precipitated, filtered, and a filter cake was obtained. The purified sodium dextrose (1.96 g, yield 98%) was obtained.

[0104] The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected by HPLC, and the results were:

[0105] Diphenylphosphine impurity 1 content: 0.01%;

[0106] Diphenylphosphine impurity 2 content: 0.02%;

[0107] Triphenylphosphine content: ND;

[0108] Oxidation impurity 1 content: 0.05%;

[0109] Oxidation impurity 2 content: 0.05%;

[0110] Total amount of other impurities: 0.04%.

[0111] Example 3: Purification using ethanol as solvent

[0112] Referring to the method of Example 2, 20 ml of methanol was replaced with 20 ml of ethanol, and the remaining operations were the same as in Example 2 to obtain purified sugammadex sodium (19.5 g, yield 98%). The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected, and the results were:

[0113] Diphenylphosphine impurity 1 content: 0.01%;

[0114] Diphenylphosphine impurity 2 content: 0.01%;

[0115] Triphenylphosphine content: ND;

[0116] Oxidation impurity 1 content: 0.05%;

[0117] Oxidation impurity 2 content: 0.05%;

[0118] Total amount of other impurities: 0.04%.

[0119] Example 4: Purification using isopropanol as solvent

[0120] Referring to the method of Example 2, 20 ml of methanol was replaced with 20 ml of isopropanol, and the remaining operations were the same as in Example 2 to obtain purified sugammadex sodium (1.97 g, yield 99%). The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected, and the results were:

[0121] Diphenylphosphine impurity 1 content: 0.02%;

[0122] Diphenylphosphine impurity 2 content: ND;

[0123] Triphenylphosphine content: ND;

[0124] Oxidation impurity 1 content: 0.05%;

[0125] Oxidation impurity 2 content: 0.05%;

[0126] Total amount of other impurities: 0.04%.

[0127] Comparative Example 1: No addition of L-ascorbic acid

[0128] Referring to the method of Example 2, L-ascorbic acid was not added, and the remaining operations were the same as in Example 2 to obtain purified sodium sugammadex (1.98 g, yield 99%). The phosphorus impurities and oxidative impurities in the purified sodium sugammadex were detected, and the results were:

[0129] Diphenylphosphine impurity 1 content: 0.02%;

[0130] Diphenylphosphine impurity 2 content: ND;

[0131] Triphenylphosphine content: ND;

[0132] Oxidation impurity 1 content: 0.15%;

[0133] Oxidation impurity 2 content: 0.18%;

[0134] Total amount of other impurities: 0.04%.

[0135] Comparative Example 2: No zinc chloride added

[0136] The method of reference example 2 was used, but zinc chloride was not added. The remaining operations were the same as those of example 2 to obtain purified sugammadex sodium (1.95 g, yield 98%). The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected, and the results were as follows:

[0137] Diphenylphosphine impurity 1 content: 0.15%;

[0138] Diphenylphosphine impurity 2 content: 0.18%;

[0139] Triphenylphosphine content: 0.16%;

[0140] Oxidation impurity 1 content: 0.05%;

[0141] Oxidation impurity 2 content: 0.05%;

[0142] Total amount of other impurities: 0.04%.

[0143] Comparative Example 3: No addition of L-ascorbic acid and zinc chloride

[0144] Referring to the method of Example 2, L-ascorbic acid and zinc chloride were not added, and the remaining operations were the same as in Example 2 to obtain purified sugammadex sodium (1.96 g, yield 98%). The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected, and the results were:

[0145] Diphenylphosphine impurity 1 content: 0.15%;

[0146] Diphenylphosphine impurity 2 content: 0.18%;

[0147] Triphenylphosphine content: 0.16%;

[0148] Oxidation impurity 1 content: 0.15%;

[0149] Oxidation impurity 2 content: 0.18%;

[0150] Total amount of other impurities: 0.04%.

[0151] Comparative Examples 4-6: Screening of Antioxidants

[0152] Referring to the method of Example 2, 2 mg of L-ascorbic acid was replaced by 2 mg of the antioxidants described in Table 1, and the remaining operations were the same as in Example 2 to obtain purified sugammadex sodium. The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected, and the results are shown in Table 1.

[0153] Table 1: Screening of antioxidants

[0154]

[0155]

[0156] Conclusion: Compared with other antioxidants, L-ascorbic acid is more conducive to reducing the growth of oxidative impurities 1 and 2 during the purification process of sugammadex sodium.

[0157] Comparative Examples 7-9: Screening of Complexing Agents

[0158] Referring to the method of Example 2, 2 mg of zinc chloride was replaced by 2 mg of the complexing agent described in Table 2, and the remaining operations were the same as in Example 2 to obtain purified sugammadex sodium. The phosphorus impurities and oxidative impurities in the purified sugammadex sodium were detected, and the results are shown in Table 2.

[0159] Table 2: Screening of complexing agents

[0160]

[0161] Conclusion: Compared with other complexing agents, the present invention adopts zinc chloride as a complexing agent, which is more conducive to reducing the content of diphenylphosphine oxide impurity 1, diphenylphosphine oxide impurity 2, and triphenylphosphine oxide after purification, and is more conducive to avoiding the growth of oxidized impurities 1 and oxidized impurities 2, and has unexpected technical effects.

[0162] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the parameters for implementation. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for purifying sugammadex sodium, characterized in that: include: The crude sugammadex sodium is mixed and dissolved with an antioxidant, a chelating agent and water, and then activated carbon is added, stirred, filtered to obtain a filtrate, an organic solvent is added to the filtrate, cooled, crystals are precipitated, filtered, and dried to obtain purified sugammadex sodium; wherein the antioxidant is L-ascorbic acid and the chelating agent is zinc chloride.

2. The purification method according to claim 1, wherein the organic solvent is selected from at least one of an alcohol organic solvent, dimethyl sulfoxide, N,N-dimethylformamide and tetrahydrofuran; wherein the alcohol organic solvent is selected from at least one of methanol, ethanol, isopropanol and tert-butanol; preferably, the alcohol organic solvent is selected from at least one of methanol, ethanol and isopropanol.

3. The purification method according to any one of claims 1 to 2, wherein the mixed dissolution is mixed dissolution at 10°C to 80°C or 50°C; and / or The stirring temperature is 10°C to 80°C or 40°C to 60°C or 50°C; and / or The temperature of the filtrate in the operation of adding the organic solvent to the filtrate is 10°C to 80°C or 40°C to 60°C or 50°C; and / or The cooling is to cool the filtrate to a temperature 5°C-100°C or 10°C-40°C lower than the temperature of the filtrate in the operation of adding the organic solvent to the filtrate.

4. The purification method according to any one of claims 1 to 3, wherein the stirring time is 1 h to 5 h.

5. The purification method according to any one of claims 1 to 4, wherein 1 g of the crude sodium sugammadex is dissolved in 0.5 ml to 5.0 ml of the water; and / or The mass ratio of the antioxidant to the crude sugammadex sodium is 0.05:100 to 0.20:100 or 0.10:100; and / or The mass ratio of the complexing agent to the crude sodium sugammadex is 0.05:100 to 0.50:100 or 0.10:100; and / or The mass ratio of the activated carbon to the crude sugammadex sodium is 0.10:100-10:100 or 0.50:

100.

6. The purification method according to any one of claims 1 to 5, wherein the crude sugammadex sodium contains diphenylphosphine oxide impurities and / or triphenylphosphine oxide impurities; the purification method is used to remove diphenylphosphine oxide impurities and / or triphenylphosphine oxide impurities in the crude sugammadex sodium; and / or The purification method is used to remove diphenylphosphine oxide impurities and / or triphenylphosphine oxide impurities in the crude sodium sugammadex and avoid the increase of oxidative impurities during the purification process.

7. The purification method according to claim 6, wherein the diphenylphosphine oxide impurities include diphenylphosphine oxide impurity 1 and / or diphenylphosphine oxide impurity 2; the structures of the diphenylphosphine oxide impurity 1 and diphenylphosphine oxide impurity 2 are respectively: (diphenylphosphine oxide impurity 1), (diphenylphosphine oxide impurity 2); and / or The structure of the triphenylphosphine oxide impurity is: and / or The oxidative impurities are those with a molecular structure of The two diastereoisomers of The S atom in .

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