CN111196862A - Refining method of sugammadex sodium - Google Patents
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Abstract
The invention discloses a refining method of sugammadex sodium, which comprises the steps of reacting a crude sugammadex sodium product with a sulfur-containing reducing agent in water, and then adding an aprotic polar solvent for crystallization to obtain refined sugammadex sodium. The sulfur-containing reducing agent is preferably selected from sodium sulfide and sodium sulfite. The method can effectively remove stubborn impurities of the sugammadex sodium by adding the sulfur-containing reducing agent, avoids complex operations such as ultrafiltration and column chromatography, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a refining method of sugammadex sodium.
Background
Sugammadex sodium (formula I), chemically known as 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt, is the first and only specific binding neuromuscular blockade antagonist drug developed by the pharmaceutical company msandong worldwide.
Sugammadex sodium injection, marketed under the trade name Bridion (brirestin), administered as a single intravenous injection, was first approved for marketing in the european union in 2008 for 7 months and has so far been registered for marketing in 79 countries including the united states and japan. The approved specifications on the market in China are 2ml:200mg and 5ml:500 mg. Approved indications are antagonism of rocuronium or vecuronium induced neuromuscular blockade in adults; in children and adolescents (2-17 years old), the product is only recommended for conventional antagonism of rocuronium bromide-induced retardation.
The currently reported preparation methods of sugammadex sodium are few, and because stubborn impurities, such as halogenated impurities and 'disulfide' impurities, exist in the sugammadex sodium product and are difficult to remove, the product purity is difficult to improve, so the research on the preparation process at present mainly focuses on improving the quality and purity of the sugammadex sodium product, and the related technical scheme comprises the following steps:
a typical preparation method of sugammadex sodium is disclosed in CN1402737A by akzonobel corporation, comprising: reacting gamma-cyclodextrin with iodine in triphenylphosphine (PPh)3) And DMF to obtain intermediate 6-per-deoxy-6-per-iodo-gamma-cyclodextrin (iodo-gamma-cyclodextrin), and reacting the iodo-gamma-cyclodextrin intermediate with 3-mercaptopropionic acid in the presence of sodium hydride and DMF to obtain 6-per-deoxy-6-per- (3-carboxyethyl) thio-gamma-cyclodextrin sodium salt (sugammadex sodium). The activity of the iodide and the mercapto compound is higher, and the reaction sites reach 8, so that the sugammadex sodium reaction solution has more structural analogs, and the purity is difficult to meet the requirement of the grade of the raw material medicine. In addition, the use of triphenylphosphine results in the formation of triphenylphosphine oxide as a by-product, which is very difficult to remove and requires repeated washing with a solvent, resulting in inconsistent yields of the final product sugammadex sodium. The final sugammadex sodium product must be purified by dialysis or sephadex column, the production scale is limited, the production cost is high, the yield is low, and the method is not suitable for industrial scale-up production.
CN107778383A discloses a refining method of sugammadex sodium, which comprises the steps of adding a protective agent into a crude sugammadex sodium product, and recrystallizing under the protection of inert gas to obtain a pure sugammadex sodium product, wherein the protective agent is selected from mercaptoethanol, thioglycolate ester, mercaptopropionate ester, glutathione, cysteine, cystamine, dithioerythritol, dithiothreitol, a trisubstituted organic phosphorus compound and a trisubstituted organic phosphorus compound. The method can effectively remove stubborn impurities, but the used protective agent can remain in the finished product and influence the product quality.
CN107892727A discloses a purification method of sugammadex sodium, comprising: mixing pre-activated special Egret (TOKUSEISHINIRASAGI) activated carbon or Egret A (SHIRAAGIA) activated carbon with the solution of the crude product of sugammadex sodium, stirring for adsorption, filtering to remove the activated carbon, and crystallizing the filtrate to obtain the sugammadex sodium. The method is simple and convenient to operate, has the defects of needing to use special activated carbon, has high production cost and is not suitable for industrial production.
CN105348412 discloses a purification method of sugammadex sodium, which comprises the following steps: hydrolyzing the crude sugammadex sodium product under an acidic condition to obtain a free acid solid, pulping the free acid solid with water, washing and purifying; reacting free acid with organic amine to prepare the sugammadex ammonium salt, and recrystallizing and purifying the obtained ammonium salt; 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.
CN106565858A discloses a purification method of sugammadex sodium, comprising: respectively treating cation exchange resin to obtain conversion type ion exchange resin A and B, then converting the sugammadex sodium crude product into sugammadex salt whose solubility in water is less than that of sugammadex sodium under the treatment of conversion type ion exchange resin A, making hot beating and purifying, then converting the sugammadex sodium crude product into sugammadex sodium by conversion type ion exchange resin B, or treating by cation exchange resin, then converting into sugammadex sodium by using sodium hydroxide. The method has the disadvantages of complicated operation, high cost and unsuitability for industrial production, and needs to use ion exchange resin twice.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide the refining method of sugammadex sodium, which has the advantages of simple operation, high product yield, high purity, environmental protection, low cost and suitability for industrial production.
In order to achieve the purpose, the invention provides the following technical scheme:
a refining method of sugammadex sodium comprises the following steps: and (3) reacting the crude sugammadex sodium with a sulfur-containing reducing agent in water, and adding an aprotic polar solvent for crystallization after the reaction is finished to obtain the refined sugammadex sodium.
In one embodiment, the sulfur-containing reducing agent is selected from the group consisting of sodium sulfide, potassium sulfide, ammonium sulfide, magnesium sulfide, calcium sulfide, sodium sulfite, potassium sulfite, ammonium sulfite, magnesium sulfite, calcium sulfite, sodium thiosulfate, potassium thiosulfate, ammonium thiosulfate, magnesium thiosulfate, calcium thiosulfate, sodium dithionite, potassium dithionite, ammonium dithionite, magnesium dithionite, calcium dithionite, and the like, preferably sodium sulfide and sodium sulfite.
In one embodiment, the aprotic polar solvent may be selected from the group consisting of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DME), N-methylpyrrolidone (NMP) and Dimethylsulfoxide (DMSO), preferably N, N-dimethylformamide.
In one embodiment, the ratio of the crude sugammadex sodium to water is 1g (5-15) mL, such as 1g (8-12) mL, such as 1g:10 mL.
In one embodiment, the sulfur-containing reducing agent is present in an amount of 1 to E.C. of crude sugammadex sodium
20 wt%, such as 5 to 15 wt%, for example 10 wt%.
In one embodiment, the volume ratio of the aprotic polar solvent to water is (2-8) to 1, e.g., (3-6): 1; for example (3.5-5): 1.
in one embodiment, the reaction temperature is 50 to 110 ℃, such as 60 to 90 ℃, such as 70 to 80 ℃.
In one embodiment, the reaction time may be 0.3 to 1.5 hours or more, for example 0.5 to 1 hour, as the case may be.
In a specific embodiment, the method comprises the steps of reacting the crude sugammadex sodium with a sulfur-containing reducing agent in water, adding an aprotic polar solvent after the reaction is completed, crystallizing, filtering, washing and drying to obtain the refined sugammadex sodium.
In one embodiment, the washing solvent may be selected from methanol, ethanol, isopropanol, acetone and acetonitrile, preferably methanol and ethanol.
In one embodiment, the drying temperature is 40 to 60 ℃, for example 50 ℃.
According to the invention, halogenated impurities and disulfide impurities can be effectively removed by adding a sulfur-containing reducing agent, the obtained sugammadex sodium can be simply recrystallized once to obtain high-purity sugammadex sodium, and the HPLC purity can reach more than 98%. The production process avoids complicated purification means such as ultrafiltration and column chromatography, and is particularly suitable for industrial large-scale production.
Brief description of the drawings
FIG. 1 is an HPLC chart of the original Bridion5mL injection.
Figure 2 shows an HPLC diagram of crude sugammadex sodium in the preparation.
Figure 3 shows an HPLC plot of refined sugammadex sodium in comparative example 1.
Figure 4 shows an HPLC plot of refined sugammadex sodium in comparative example 2.
FIG. 5 shows an HPLC chart of refined sugammadex sodium in example 1 of the present invention.
Detailed Description
The technical solutions and advantages of the present invention will be further understood by those skilled in the art through the following description and examples, but should not be construed as limiting the present invention in any way. Unless otherwise specified, reagents and materials used in the experiments were all common commercial products.
Through a large number of experiments, the HPLC purity of the crude sugammadex sodium product prepared by the preparation method disclosed by the prior art is basically not higher than 90%, most of refining methods of the crude sugammadex sodium product need to improve the product purity through column chromatography, and the method is inconvenient to operate and is not suitable for industrial production. If the column chromatography is to be avoided, the conventional recrystallization method is adopted for refining, so that stubborn impurities in the crude sugammadex sodium cannot be removed, the HPLC purity can only reach 90-95% basically, the ideal refining effect cannot be achieved, and the product quality is difficult to improve. The inventor obtains the technical scheme of the invention through repeated research and test, and successfully solves the problems for the first time by adding the sulfur-containing reducing agent in the recrystallization process, so that the product purity is obviously improved to more than 98 percent and is superior to the quality of the original product.
Sample HPLC analytical methods:
gradient elution was performed using a reversed phase chromatography system [ test by high performance liquid chromatography (national pharmacopoeia 2015, four ministry of general rules 0512) ], using octadecylsilane chemically bonded silica as a filler, 25mM sodium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid) -acetonitrile (83:20, V/V) as a mobile phase a, and acetonitrile as a mobile phase B, according to the following table. The detection wavelength is 200nm, the flow rate is 0.5mL/min, and the column temperature is 40 ℃. The gradient elution table is as follows:
| T(min) | 0 | 5 | 15 | 22 | 27 | 32 | 37 | 42 | 42.01 | 52 |
| B(％) | 0 | 0 | 2 | 8 | 25 | 50 | 70 | 70 | 0 | 0 |
| A(％) | 100 | 100 | 98 | 92 | 75 | 50 | 30 | 30 | 100 | 100 |
the related substance analysis spectrum of Bridion injection (specification: 500mg/5mL) of the original product on the market shows that the HPLC purity is 96.129%, as shown in figure 1.
Preparation of crude Exsugammadex sodium
Reference is made to the method of patent CN 1188428C: A20L round bottom reactor was charged with dry DMF (4.5L), 3-mercaptopropionic acid (122mL, 1.4mol) was dissolved in DMF at room temperature, and to this solution was added sodium hydride (123g, 3.08mmol, 60%) in three portions. The mixture was stirred for an additional 30 minutes and a solution of 6-fully deoxy-6-fully iodo-gamma-cyclodextrin (312g, 140mmol) in 4.5L of dry DMF was added dropwise to the mixture. After the addition, the reaction mixture was heated to 70 ℃ and held for 12 hours. After cooling, water (1L) was added to the mixture and the volume was concentrated in vacuo to 4L, to which ethanol (25L) was added to cause precipitation. The solid precipitate was collected by filtration and dialyzed for 36 hours. The volume was concentrated in vacuo to 2L, ethanol was added to this, and the precipitate was collected by filtration and dried to give crude sugammadex sodium compound as a white solid (130g, yield 43%, HPLC purity 87.9%, fig. 2).
Wherein, the stubborn impurities are impurities with relative retention time of 1.74, and the content is 1.37 percent; 0.783% of impurities with a relative retention time of 1.93, corresponding to peak numbers 13 and 15, respectively, of fig. 2).
Comparative example 1 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (10mL) and methanol (50mL) was added dropwise. Stirring was continued for 30 minutes after the addition was complete. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave a white solid (1.65g, yield: 55.0%, purity: 89.4%, FIG. 3).
Wherein, the stubborn impurities are impurities with relative retention time of 1.74, and the content is 1.502%; 0.161% relative to 1.93 impurities, corresponding to peak numbers 18 and 20 of fig. 3, respectively).
COMPARATIVE EXAMPLE 2 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL) and DMF (105mL) was added dropwise. Stirring was continued for 30 minutes after the addition was complete. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave a white solid (2.2g, yield: 73.3%, purity: 94.4%, FIG. 4).
Wherein, the stubborn impurities are impurities with relative retention time of 1.74, and the content is 0.936 percent; the impurity content, 0.804% with respect to retention time 1.93, corresponds to peak numbers 13 and 15 of fig. 4, respectively.
From the results of comparative examples 1 and 2, it can be seen that the stubborn impurities in the crude sugammadex sodium product could not be removed by the conventional recrystallization method, and the purity of the refined sugammadex sodium product was low, not reaching 95%. Further, the present inventors have tried various other recrystallization methods, which cannot remove the above impurities and achieve a desired purification effect, and thus these methods cannot solve the problems of the prior art.
EXAMPLE 1 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.3g, yield: 76.7%, purity: 98.1%, FIG. 5).
As shown in fig. 5, both of the recalcitrant impurities having a relative retention time of 1.74 and the recalcitrant impurities having a relative retention time of 1.93 were not detected, and the purity of the purified product was significantly improved.
EXAMPLE 2 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 105 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.2g, yield: 73.3%, purity: 98.0%).
EXAMPLE 3 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.15g) was added, the temperature was raised to 70 ℃, stirred for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.1g, yield: 70%, purity: 97.9%).
EXAMPLE 4 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (40mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (140mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.0g, yield: 67.7%, purity: 97.8%).
EXAMPLE 5 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.6g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.1g, yield: 70%, purity: 97.8%).
EXAMPLE 6 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 60 ℃, stirred for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.2g, yield 73.3%, purity: 97.8%).
EXAMPLE 7 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfite (0.3g) was added, the temperature was raised to 70 ℃, stirred for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.1g, yield 70%, purity: 97.6%).
EXAMPLE 8 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 ℃ and stirred for 30 minutes, and DME (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.1g, yield 70%, purity: 97.5%).
EXAMPLE 9 purification of sodium sugammadex
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 ℃, stirred for 30 minutes, and DMSO (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.0g, yield 67%, purity: 97.7%).
EXAMPLE 10 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 ℃, stirred for 30 minutes, and NMP (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with methanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.2g, yield 73.3%, purity: 97.8%).
EXAMPLE 11 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with ethanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.2g, yield 73.3%, purity: 98.0%).
EXAMPLE 12 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with acetone (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.1g, yield: 70%, purity: 97.7%).
EXAMPLE 13 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with acetonitrile (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.0g, yield: 67%, purity: 97.9%).
EXAMPLE 14 purification of sugammadex sodium
Crude sugammadex sodium (3g) was dissolved in purified water (30mL), sodium sulfide (0.3g) was added, the temperature was raised to 70 deg.C, stirring was carried out for 30 minutes, and DMF (105mL) was added dropwise. After the dropwise addition, the temperature was slowly decreased to room temperature, and the stirring was continued for 30 minutes. Filtration and washing of the solid with isopropanol (20mL) followed by vacuum drying at 50 ℃ for 8h gave sugammadex sodium as a white solid (2.1g, yield: 70%, purity: 97.6%).
It can be seen from the above embodiments of the present invention that, in the recrystallization refining process of the crude product, the technical problem in the art is successfully solved by adding the sulfur-containing reducing agent, two stubborn impurities are effectively removed, and the purity of the sugammadex sodium crude product is significantly improved from 87.9% to more than 97%, even more than 98%, which is superior to the purity quality of the conventional refining method and the original product in the prior art, and a significant effect is obtained. In addition, the method does not need complicated processes such as column chromatography, ultrafiltration and the like, is simple and convenient to operate, and is very suitable for industrial production and application.
In addition, a person skilled in the art can make partial modifications or improvements based on the technical scheme of the present invention, such as replacing solvents and reagents with similar properties, increasing the number of recrystallization times to further improve purity, etc., without departing from the spirit of the present invention, and all that falls within the protection scope of the present invention.
Claims (10)
1. A refining method of sugammadex sodium comprises the following steps: and (3) reacting the crude sugammadex sodium with a sulfur-containing reducing agent in water, and adding an aprotic polar solvent for crystallization after the reaction is finished to obtain the refined sugammadex sodium.
2. The process according to claim 1, wherein the sulfur-containing reducing agent is selected from the group consisting of sodium sulfide, potassium sulfide, ammonium sulfide, magnesium sulfide, calcium sulfide, sodium sulfite, potassium sulfite, ammonium sulfite, magnesium sulfite, calcium sulfite, sodium thiosulfate, potassium thiosulfate, ammonium thiosulfate, magnesium thiosulfate, calcium thiosulfate, sodium dithionite, potassium dithionite, ammonium dithionite, magnesium dithionite, calcium dithionite, preferably sodium sulfide and sodium sulfite.
3. The process of claim 1, wherein the aprotic polar solvent is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
4. The method according to claim 1, wherein the ratio of the crude sugammadex sodium to water is 1g (5-15) mL.
5. A process according to claim 1, wherein the sulphur-containing reducing agent is used in an amount of 1 to 20 wt%, preferably 5 to 15 wt% of the crude sugammadex sodium.
6. The method according to claim 1, wherein the volume ratio of the aprotic polar solvent to water is (2-8): 1.
7. The process of claim 1, wherein the reaction temperature is 50 to 110 ℃.
8. The method of claim 1, comprising: and (3) reacting the crude sugammadex sodium with a sulfur-containing reducing agent in water, adding an aprotic polar solvent after the reaction is finished, crystallizing, filtering, washing and drying to obtain the refined sugammadex sodium.
9. The method of claim 8, wherein the washed solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, and acetonitrile.
10. The method of claim 8, wherein the drying temperature is 40-60 ℃.
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