CN115109172A - Impurities of sugammadex sodium and preparation method thereof - Google Patents
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Abstract
The application discloses impurity A or impurity A 'and impurity B or impurity B' of sugammadex sodium and a preparation method thereof.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to impurities of sugammadex sodium, a preparation method of the impurities, and application of the impurities as an impurity reference substance.
Background
Sugammadex Sodium was first developed by organic Biosciences (ogangnong), which was purchased by piongpaul corporation (Schering-plus) in 2007, and incorporated piongpaul and Merck (Merck) in 2009. Sugammadex sodium is currently owned and sold by merck. In 2008, sugammadex sodium was first marketed in europe and subsequently in japan, the united states, etc., respectively, and is now marketed in 75 countries. And was approved for marketing in china on 26.4 months in 2017.
Sugammadex sodium, chemical name: 6-Perdeoxy-6-Per (2-carboxyethyl) thio-Gamma-Cyclodextrin sodium salt, England name: sumamadex, trade name: bridion, a modified gamma-cyclodextrin, is the first and only selective muscle relaxation antagonist (SRBA) developed successfully for 20 years, wraps an amino steroid non-depolarizing muscle relaxant through a brand-new and only way to block the relaxation effect, can quickly and predictably reverse the muscle relaxation caused by rocuronium bromide and vecuronium bromide in any strength, has small side effects, can enable the use of a muscle relaxant to be close to an ideal state, and has a quicker and more predictable effect of reversing the neuromuscular blocking effect than the existing drugs. The method is suitable for reversing the neuromuscular blockade caused by rocuronium bromide or vecuronium bromide, reversing (normally reversing and immediately reversing) the neuromuscular blockade caused by adult rocuronium bromide or vecuronium bromide and normally reversing the neuromuscular blockade caused by rocuronium bromide in children and juveniles.
Sugammadex sodium and a preparation method thereof are disclosed in US6670340 for the first time, the prepared sugammadex sodium needs dialysis for 36h for purification, the dialysis time is long, the water consumption is large, a large amount of waste liquid is generated, resources are wasted, the environment is not protected, and the final product obtained after dialysis is in water, and the final product has high solubility in water and is not beneficial to further extraction.
More process impurities and degradation impurities are generated in the preparation and placement processes of the sugammadex sodium, and the impurities need to be removed by adopting a purification process or controlled below 0.1% (w/w) to obtain the high-purity sugammadex sodium, so that the quality requirement of medicinal raw material medicines is met.
At present, the purification method of sugammadex sodium at home and abroad mainly comprises the following steps:
the purification method disclosed in patent WO2012/025937a1 requires column chromatography using silica gel column and sephadex G25, but the product purity is still low; the patent CN104844732A uses a nanofiltration membrane for purification treatment, mainly can remove small molecules, has limited removal of impurities with a structure similar to sugammadex sodium, and cannot ensure high purity.
In the patent WO2017084401, the crude sugammadex sodium is treated by a large amount of adsorbent (20-150% w/w), the adsorbent comprises one or a combination of activated carbon, silica gel, macroporous resin, alumina, a molecular sieve and zeolite, the adsorption loss is large, the yield is low, the amount of single impurity is large, and the industrial amplification is not suitable.
The purification method disclosed in patent CN106565858A adopts ion exchange resin to convert the sugammadex crude product into sugammadex salt, and the sugammadex salt is subjected to thermal pulping and purification, and then is converted into sugammadex salt again through ion exchange resin or sodium hydroxide, so that the purification loss is large, and the production cost is high.
The purification method disclosed in patent CN107892727A screens different activated carbons, and only uses special aigret (TOKUSEI SHIRASAGI) activated carbon and aigret a (SHIRASAGI) activated carbon produced by osaka gas chemical group of japan, and after nitrogen protection and heating pretreatment, the activated carbons are used for small-scale adsorption treatment research of 10g crude sugammadex sodium, and the purity of the sugammadex sodium is greater than 99.5%, and the single impurity is less than 0.1%. The core of the purification process is the activated carbon with specific type requirements, and the purification process is a single foreign manufacturer, so that the production cost is high, and the continuous production is greatly limited.
Patent CN105348412A frees the crude sugammadex sodium under acidic condition to sugammadex acid, recrystallizing and purifying sugammadex acid and organic amine or ammonia substance to obtain ammonium salt, and making the purified sugammadex ammonium salt free under acidic condition and salifying with sodium hydroxide to obtain sugammadex sodium. The method uses strong inorganic acid aqueous solution for many times, easily generates acid degradation impurities, and has great influence on the stability of the purified substrate.
Patent CN107778383A reports that the purity of sugammadex sodium is more than 99.0% by adding glutathione, cysteine, triphenylphosphine and other protective agents into the crude sugammadex sodium under the conventional recrystallization purification condition; the inventor of the application discovers that the purification loss of the method is large by repeating the purification method disclosed by the patent, and dimer impurities which are difficult to remove can be directly enriched in the sugammadex solid phase under the purification condition, are difficult to remove and have higher content.
It can be seen that the purification method of sugammadex sodium at home and abroad at present mainly has the following disadvantages:
1) the purification is carried out by adopting column chromatography or adsorbents such as silica gel column, sephadex G25, macroporous resin, ion exchange resin and the like, the purification cost is high, the process is relatively limited, the universality is not realized, and the industrial amplification production is not facilitated;
2) strong inorganic acid is adopted for dissociation for many times, which affects the stability of cyclodextrin substrate of sugammadex sodium, easily generates acid degradation impurities and affects the medication safety of the sugammadex sodium product;
3) under the conventional recrystallization purification condition, the addition of protective agents such as triphenylphosphine, glutathione, cysteine and the like can inhibit the increase of oxidation impurities and reduce part of easily-removed impurities in sugammadex sodium, but for dimer impurities, the physicochemical properties of the dimer impurities are very similar to those of sugammadex sodium, and the dimer impurities are usually enriched in the sugammadex sodium and are difficult to remove in the conventional recrystallization process.
In order to ensure the safety of subsequent preparation and clinical application, the content of single impurities in the sugammadex sodium is required to be controlled below 0.1%, and the impurities are preferably removed, which cannot be realized by the conventional purification process. Therefore, a new refining method is needed to be developed to reduce the impurity content in sugammadex sodium, especially aiming at dimer impurities, so as to obtain high-purity sugammadex sodium, thereby meeting the requirement of medicine development quality.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a method for refining sugammadex sodium, which can effectively reduce the content of impurities in sugammadex sodium, particularly reduce the content of dimer impurities, and even remove the dimer impurities, thereby improving the purity.
The sugammadex sodium can generate dimer impurities in the preparation or placement process, and the dimer impurities are mainly represented as impurity A or impurity A 'and impurity B or impurity B'; in addition, non-dimer impurities such as lactonization impurity C, impurity D, impurity E, impurity F, impurity G and the like exist, and the structural formula is shown as the following.
In a first aspect, the present application provides a method for refining sugammadex sodium, comprising the steps of:
step (1): under the protection of inert gas, dissolving the sugammadex sodium crude product in water, adding a poor solvent at room temperature, standing for layering, and taking an upper mother solution;
step (2): under the protection of inert gas, the lower organic layer is successively dissolved by adding water, a poor solvent is added, solid is separated out, the filtrate is filtered, and the filtrate is combined with the upper mother liquor;
and (3): and (3) under the protection of inert gas, heating the mother liquor combined in the step (2), adding a poor solvent, cooling, crystallizing, filtering and drying to obtain the sugammadex sodium.
The sugammadex sodium "crude product" in the present application is relative to the refined product, and includes, but is not limited to, a sample with a purity of sugammadex sodium of less than 99.5%, or a sample with a purity of less than 99.0%, or a sample with a purity of less than 98.0%, etc.
The "poor solvent" referred to herein is a solvent having a weak dissolving power for a solute, and an interaction parameter χ with the solute of more than 0.5, with respect to the solute to be dissolved. The "poor solvent" is different for different solutes. The "poor solvent" used in one solute may be the "good solvent" of another solute. For example, "poor solvent" methanol is used in this application for sugamconic acid and "good solvent" for the solute biphenyl.
In the method for refining sugammadex sodium, the poor solvent is used for solute sugammadex sodium. According to a preferred embodiment of the present application, the poor solvent is selected from one or more of DMF, DMSO, NMP, DMAc, acetone, ethyl acetate, n-heptane, acetonitrile, ethanol, methanol, isopropanol, 1, 4-dioxane and tert-butyl methyl ether, preferably DMF or ethanol or a combination thereof.
In the purification method of sugammadex sodium in the present application, the poor solvent may be added in a manner conventional in the art, preferably in a dropwise manner, in the steps (1) to (3).
Preferably, in the method for purifying sugammadex sodium of the present application, a protective agent is not used in the steps (1) to (3); the protective agent is selected from: one or a mixture of more than two of mercaptoethanol, thioglycolate acetate, mercaptopropionate acetate, glutathione, cysteine, cystamine, dithioerythritol and salts of tri-substituent organic phosphine compounds in any proportion.
Further, in the method for purifying sugammadex sodium, the mass-to-volume ratio of sugammadex sodium to water in the step (1) is 1: 0.5-1: 50, preferably 1: 1-1: 10, and more preferably 1: 2-1: 3 in terms of g/ml; the mass-volume ratio of the sugammadex sodium to the poor solvent is 1: 0.5-1: 50, preferably 1: 1-1: 10, and more preferably 1: 2-1: 5 in terms of g/ml.
Or in the step (2), the mass-to-volume ratio of the sugammadex sodium to the added water is 1: 0.25-1: 50, preferably 1: 1-1: 5, and more preferably 1: 1-1: 2 in terms of g/ml; the mass-volume ratio of the sugammadex sodium to the added poor solvent is 1: 0.25-1: 50, preferably 1: 1-1: 10, and more preferably 1: 1.5-1: 4 in terms of g/ml;
or in the step (3), the mass-to-volume ratio of the sugammadex sodium to the added poor solvent is 1: 1-1: 50, preferably 1: 2-1: 20, and more preferably 1: 5-1: 10 in terms of g/ml; the temperature rise range is 40-100 ℃, and preferably 50-70 ℃; the temperature for cooling and crystallizing is-20-30 ℃, and preferably 0-10 ℃.
Optionally, the steps of the refining method of sugammadex sodium described herein are performed under an inert gas environment, and the inert gas described herein includes both group 18 element gas in the well-known definition and nitrogen gas frequently used in the chemical industry, preferably under a nitrogen gas environment.
Preferably, the refining method of the sugammadex sodium is mainly used for reducing the content of the impurity A and/or the impurity B in the sugammadex sodium.
The content refers to the mass percentage (w/w) of the impurity A or the impurity B in the total amount of the sodium sugammadex.
In a second aspect, the application also provides sugammadex sodium prepared by the refining method, wherein the total purity of the sugammadex sodium is not less than 99.5%, and the content of an impurity A or an impurity B in the sugammadex sodium is less than 0.1%.
In a third aspect, the present application provides a method for reducing the content of impurity a and impurity B in sugammadex sodium, comprising the steps of:
step (1): under the protection of inert gas, dissolving the crude sugammadex sodium in water, adding a poor solvent at room temperature, standing for layering, and taking an upper mother solution;
step (2): under the protection of inert gas, the lower organic layer is successively dissolved by adding water, a poor solvent is added, solid is separated out, the filtrate is filtered, and the filtrate is combined with the upper mother liquor;
and (3): and (3) under the protection of inert gas, heating the mother liquor combined in the step (2), adding a poor solvent, cooling, crystallizing, filtering and drying to obtain the sugammadex sodium.
In the above method for reducing the content of the impurity A and the impurity B in sugammadex sodium, the poor solvent is relative to solute sugammadex sodium. According to a preferred embodiment of the present application, the poor solvent is selected from one or more of DMF, DMSO, NMP, DMAc, acetone, ethyl acetate, n-heptane, acetonitrile, ethanol, methanol, isopropanol, 1, 4-dioxane, and tert-butyl methyl ether, preferably DMF or ethanol or a combination thereof.
In the purification method of sugammadex sodium in the present application, the poor solvent may be added in a manner conventional in the art, preferably in a dropwise manner, in the steps (1) to (3).
Preferably, in the method for reducing the content of the impurity A and the impurity B in sugammadex sodium, a protective agent is not used in the steps (1) to (3); the protective agent is selected from: one or a mixture of more than two of mercaptoethanol, thioglycolate acetate, mercaptopropionate acetate, glutathione, cysteine, cystamine, dithioerythritol and salts of tri-substituent organic phosphine compounds in any proportion.
Further, in the method for reducing the content of the impurity A and the impurity B in the sugammadex sodium, the mass-to-volume ratio of the sugammadex sodium to water in the step (1) is 1: 0.5-1: 50, preferably 1: 1-1: 10, and more preferably 1: 2-1: 3 in terms of g/ml; the mass-volume ratio of the sugammadex sodium to the poor solvent is 1: 0.5-1: 50, preferably 1: 1-1: 10, and more preferably 1: 2-1: 5 in terms of g/ml;
or in the step (2), the mass-to-volume ratio of the sugammadex sodium to the added water is 1: 0.25-1: 50, preferably 1: 1-1: 5, and more preferably 1: 1-1: 2 in terms of g/ml; the mass volume ratio of the sugammadex sodium to the added poor solvent is 1: 0.25-1: 50, preferably 1: 1-1: 10, and more preferably 1: 1.5-1: 4 in terms of g/ml;
or in the step (3), the mass-to-volume ratio of the sugammadex sodium to the added poor solvent is 1: 1-1: 50, preferably 1: 2-1: 20, and more preferably 1: 5-1: 10 in terms of g/ml; the temperature rise range is 40-100 ℃, and preferably 50-70 ℃; the cooling crystallization temperature is-20 to 30 ℃, and preferably 0 to 10 ℃.
Optionally, the steps of the method for reducing the content of impurity a and impurity B in sugammadex sodium described herein are carried out under an inert gas environment, the inert gas described herein comprising both a group 18 element gas in the well-known definition and nitrogen gas frequently used in the chemical industry, preferably under a nitrogen atmosphere.
In another aspect of the application, a pharmaceutical preparation is also provided, which contains the sugammadex sodium prepared by the refining method, and pharmaceutically acceptable carriers and auxiliary materials.
Pharmaceutically acceptable carriers or adjuvants are well known in the medical field and are described, for example, in Remington's Pharmaceutical Sciences, Mark Publishing Co (Mack Publishing Co.) (A.R.Gennaro eds., 1985). These substances are non-toxic to recipients at the dosages and concentrations employed.
The pharmaceutical preparation described herein can be administered orally, by injection, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable kit. The preferred mode of administration is intravenous injection.
The pharmaceutical formulations described herein may also be presented in discrete unit form, which may be an aqueous liquid solution or suspension; a solution or suspension in a non-aqueous liquid; or a water-in-oil liquid emulsion; or an oil-in-water liquid emulsion; or encapsulated in liposomes; or pill form, etc.
The medicaments described herein may be in solid dosage forms including, but not limited to, capsules, tablets, lozenges, elixirs, pills, granules, powders or suppositories; the medicaments described above in this application may also be in liquid dosage forms including, but not limited to, solutions, suspensions or emulsions.
In another aspect of the application, the application of the sugammadex sodium prepared by the refining method or a pharmaceutical preparation containing the sugammadex sodium in preparing a medicine for reversing neuromuscular blockade is also provided; preferably the neuromuscular blocking drug is rocuronium bromide or vecuronium bromide.
Specifically, reversing the neuromuscular blockade caused by rocuronium bromide or vecuronium bromide; further, reversing (both conventional and immediate) the neuromuscular blockade caused by rocuronium bromide or vecuronium bromide in humans; alternatively, the neuromuscular blockade caused by rocuronium bromide in children and adolescents was routinely reversed.
The sugammadex sodium prepared by the refining method of the application can be used alone or in combination with one or more other medicines.
The application also provides a method for preparing the sugammadex sodium prepared by the refining method in the application, which is used for preventing or treating and reversing neuromuscular blockade diseases singly or in combination with other medicines.
The term combination includes simultaneous, sequential or alternating use, as well as pharmaceutical dosage forms or pharmaceutical products prepared for the respective combined use in one or more pharmaceutical units.
The reversal of neuromuscular blockade diseases includes reversal of rocuronium-induced muscle relaxation, vecuronium-induced muscle relaxation, pancuronium-induced muscle relaxation, and the like.
The application also provides a preparation method of the sugammadex impurity A or the impurity A', which comprises the following steps:
step 1: preparing impurity G and impurity G', wherein the synthetic route is as follows:
the method specifically comprises the following steps: carrying out substitution reaction on octaiodo gamma-cyclodextrin by using 3-mercaptopropionic acid, and then preparing and separating to obtain an impurity G'; and carrying out acid-base salt forming reaction on the impurity G' and sodium-containing alkali or sodium carbonate to obtain the impurity G, wherein the sodium-containing alkali is preferably one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, amino-containing sodium alkali and sodium hydroxide.
In some embodiments of the invention, the substitution reaction is carried out with octaiodo-gamma-cyclodextrin in an organic solvent containing a sodium base, 3-mercaptopropionic acid. Preferably, the sodium-containing base is selected from one or more of NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, an amino-containing sodium base and sodium hydroxide, more preferably NaH. Preferably, the organic solvent is selected from one or more of DMF, DMAC, NMP, DMI; more preferably, the organic solvent is DMF.
In some embodiments of the present invention, the reaction temperature for the substitution reaction is about 20 to about 30 deg.C, preferably about 25 deg.C. In the substitution reaction, the molar ratio of octaiodo gamma-cyclodextrin to 3-mercaptopropionic acid to sodium-containing alkali is 1: 7: 14.
in some embodiments of the invention, the substitution reaction is followed by purification and preparative isolation. Preferably, the purification is pulping purification; more preferably, the solvent for pulping and purifying is one or more of alcohols, organic acids, inorganic solvents (such as water), ethers, ketones and nitriles. Such alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol, and tert-butanol. The ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole, and dimethoxyethane. Nitriles include, but are not limited to, acetonitrile and propionitrile. Ketones include, but are not limited to, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone. Organic acids include, but are not limited to, formic acid, acetic acid.
In some preferred embodiments of the invention, the solvent for pulping and purifying is a mixed solution of alcohols, inorganic solvents and organic acids; more preferably a mixed solution of ethanol, water and acetic acid; more preferably, the volume ratio is 4-10: 1-2: 1-2 of a mixed solution of ethanol, water and acetic acid, for example, the volume ratio of 5: 1:1. 4: 1:1. 5: 1: 1.2, 5: 1.2: 1.2, 5: 1.2: 1, ethanol, water and acetic acid.
In some embodiments of the invention, the temperature of the beating purification is 0-10 ℃, e.g., 0 ℃, 2 ℃, 5 ℃, 6 ℃, 8 ℃,9 ℃, 10 ℃.
And 2, step: preparing impurity F and impurity F', wherein the synthetic route is as follows:
the method specifically comprises the following steps: the impurity G and thiourea generate an isothiourea intermediate, and the impurity F' is obtained through hydrolysis, preparation and separation; and carrying out acid-base salt forming reaction on the impurity F' and sodium-containing alkali or sodium carbonate to obtain the impurity F, wherein the sodium-containing alkali is preferably one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, amino-containing sodium alkali and sodium hydroxide.
In some embodiments of the invention, impurity G reacts with thiourea at a reaction temperature of 70-90 ℃ to form an isothiourea intermediate, preferably at a reaction temperature of 80 ℃.
In some embodiments of the invention, the isothiourea intermediate is hydrolyzed in a basic solution (e.g., sodium hydroxide solution), preferably at a temperature of 80-95 deg.C, e.g., 80 deg.C, 82 deg.C, 85 deg.C, 88 deg.C, 90 deg.C, 92 deg.C, 95 deg.C.
In some embodiments of the invention, the isothiourea intermediate is hydrolyzed, purified, and then preparative separated to yield impurity F'.
And step 3: preparing impurity A and impurity A', wherein the synthetic route is as follows:
the method comprises the following specific steps: carrying out substitution reaction on the impurity G ' and the impurity F ', and then preparing and separating to obtain an impurity A '; the impurity A' and sodium-containing alkali or sodium carbonate are subjected to acid-base salt forming reaction to obtain the impurity A, and preferably, the sodium-containing alkali is one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, amino-containing sodium alkali and sodium hydroxide.
In some embodiments of the invention, impurity G 'undergoes a substitution reaction with impurity F' in a base and an organic solvent. Preferably, the organic solvent is selected from one or more of DMF, DMAC, NMP and DMI; more preferably DMF. Preferably, the base is potassium tert-butoxide.
In some embodiments of the present invention, the reaction temperature of the substitution reaction is 60 to 80 ℃, preferably 65 to 70 ℃, such as 65 ℃, 68 ℃, 70 ℃.
The technical scheme provided by the application has the following advantages:
in a poor solvent/water system, by controlling the dosage ratio of the crude sugammadex sodium product to water or the poor solvent within a certain range, preferentially separating out and enriching dimer impurities A and B until solids are removed, separating (separating and filtering) to obtain a high-purity mother liquor, and further adding the poor solvent for crystallization separation to obtain the high-yield and high-purity sugammadex sodium; overcomes the defect that the impurity A and the impurity B are enriched in sugammadex sodium and are difficult to remove under the conventional purification condition. The total purity of the sugammadex sodium obtained by the refining method provided by the application can reach more than 99.5%, the impurity A is not detected, the impurity B is less than 0.1%, the other single impurities are less than 0.1%, and the total impurity content is less than 0.5%. The refining system is simple, the condition is mild, the cost is low, and the method is very suitable for social mass production.
The impurity A or the impurity A 'and the impurity B or the impurity B' of the sugammadex sodium provided by the application can be used as impurity reference substances and applied to quality control of corresponding impurities in the sugammadex sodium.
Drawings
FIG. 1: HPLC profile of sugammadex sodium refined in example 1.
FIG. 2: HPLC profile of sodium protopanaxarate injection.
Detailed Description
The present disclosure is further illustrated by the following specific examples, but it should not be construed that the scope of the present disclosure is limited to the following examples, and it is apparent to those skilled in the art that the following examples may be appropriately combined, replaced, adjusted, modified and the like according to the inventive concept and the entire content of the present disclosure, and the raw materials, solvents, reagents, operation steps, reaction conditions and the like in the following examples are still within the scope of the present disclosure.
In the following examples, as well as in the context of the present specification and claims, the following abbreviations have the following meanings, which have generally accepted meanings for undefined abbreviations.
DMF ═ N, N-dimethylformamide
DMSO ═ dimethyl sulfoxide
NMP ═ N-methylpyrrolidone
DMAc ═ N, N-dimethylacetamide
HPLC ═ high performance liquid chromatography
The main components are as follows: sugammadex sodium, octamercapto-substituted product
Auxiliary components: mono-hydroxysugammadex sodium, heptamercapto-substituted monohydroxy product
According to the pharmacological/toxicological Review and Evaluation description of FDA sugammadex sodium (Pharmacology/Toxicology Review and Evaluation), mono-hydroxysugammadex sodium is pharmaceutically equivalent to the main component of sugammadex sodium and can be considered as an API component. Therefore, the total purity described in the following examples is the mass percentage of the sum of the amounts of the principal component of sugammadex sodium (octamercapto-substituted product) and mono-hydroxysugammadex sodium (heptamercapto-substituted monohydroxy product) in the product.
The experimental conditions are as follows:
the purity of the product is measured by an HPLC method, and the calculation method comprises the following steps: area normalization method.
The chromatographic column is C 18 A chromatographic column; the detection wavelength is 200 nm; the flow rate is 0.8 ml/min;
mobile phase A: 20mmol/L potassium dihydrogen phosphate buffer solution (pH value of 2.0-2.5)
Mobile phase B: acetonitrile;
a gradient elution procedure was used.
The structures of impurity a and impurity B were determined by nmr spectroscopy: BRUKER AVANCE III HD400MHz type superconductive nuclear magnetic resonance spectrometer, test condition: solvent D 2 O, temperature 294.7K.
High resolution mass spectrometry: the instrument model is as follows: ABSciex TripleTOF 5600+
And (3) testing conditions are as follows: an ionization mode: EI +; scanning range: 600-5000 Da;
preparation of crude sugammadex sodium:
Iodogamma-Cyclodextrins can be prepared from gamma-cyclodextrin iodophores by Methods for Selective Modifications of Cyclodextrins, chem.Rev.1998,98, 197-7 1996.
Step (1): sodium hydride (7.16kg, 60%) was added to dry DMF (317L) under a nitrogen atmosphere and an ice bath. Slowly dropwise adding a mixed solution of tri-p-tolylphosphine (1.74kg) -3-mercaptopropionic acid (9.52kg) -DMF (12.2L) at the temperature of 0-10 ℃, heating to 65-75 ℃ after adding, reacting under stirring, slowly dropwise adding a mixed solution of mono-iodo gamma-cyclodextrin (12.16kg) -tri-p-tolylphosphine (0.46kg) -DMF (63.4L), and reacting for about 4 hours under continuous stirring. And (3) cooling the reaction liquid to 0-10 ℃, adding water (60.9L), heating to 55-70 ℃, and reacting for about 2 hours under stirring. The reaction mixture was cooled to room temperature, filtered, the filter cake was dissolved in water (97.4L), filtered over celite, and ethanol (244L) was added to the filtrate, which was filtered to give sugammadex sodium (10.96kg, yield 90%, total purity 92.53%).
Step (2): under the protection of nitrogen, 10.96kg of sugammadex sodium prepared above was added to a mixed solvent of DMF (21.9L) and water (21.9L). At room temperature, tri-p-tolyl phosphine (411g), acrylic acid (1.5kg) and 10% sodium hydroxide aqueous solution (7.26L) were sequentially added, the temperature was raised to 50 to 60 ℃ after the addition, the reaction was stirred for 2 to 8 hours, DMF (41L) was added dropwise, the reaction solution was cooled to room temperature, and suction filtration was performed to obtain sugammadex sodium (10.74kg, yield 98%, total purity 94.60%).
And (3): under the protection of nitrogen, 10.74kg of the sugammadex sodium prepared above is added into a mixed solvent of DMF (21.5L) and water (21.5L), tri-p-methylphenyl phosphine (184.5g) is added, after the addition, the temperature is raised to 60-70 ℃, the reaction is stirred for 2-5 h, DMF (21.5L) is dropwise added, the reaction liquid is cooled to room temperature, and the mixture is subjected to suction filtration and drying to obtain the sugammadex sodium (10.2kg, yield 95%, total yield of three steps: 84%, and total purity 98.44%).
HPLC detection is carried out on the sugammadex sodium prepared in the step (3), and the detection result shows that the total purity of the sugammadex sodium is 98.44%, the content of the impurity A is 0.12%, the content of the impurity B is 0.091%, the total impurities are 1.56%, the total number of the impurities is 28, and 5 impurities with the single impurity content of more than 0.1% are obtained. The sugammadex sodium obtained in step (3) was used as a crude sugammadex sodium in the following examples.
Example 1: refining of sugammadex sodium
Step (1): under the protection of nitrogen, dissolving 0.2kg of crude sugammadex sodium in 0.4L of water, dropwise adding 0.6LDMF at room temperature, making the system turbid, standing for layering, separating, and temporarily storing the upper mother solution;
step (2): under the protection of nitrogen, continuously adding 0.2L of water into the lower-layer viscous organic phase for dissolving, dropwise adding 0.3L of DMF, separating out a solid, filtering, and combining the filtrate with the upper-layer mother liquor;
and (3): and (3) under the protection of nitrogen, heating the mother liquor combined in the step (2) to 50-70 ℃, dropwise adding 1.6L of DMF, cooling to 0-10 ℃, crystallizing, filtering, and drying to obtain purified sugammadex sodium (0.188Kg, with the total yield of 94%).
The refined sugammadex product obtained in this example was subjected to HPLC detection, as shown in fig. 1, and the experimental data are shown in table 1. As can be seen from fig. 1 and table 1, the total purity was 99.68%, impurity a was not detected, the content of impurity B was 0.046%, and the content of other individual impurities was less than 0.1%.
TABLE 1 HPLC TEST OF SUBINGUGAMENTANG refined product prepared in EXAMPLE 1
| Serial number | Retention time (min) | Peak area (mAU s) | Peak area (%) | Number of impurities |
| 1 | 13.746 | 26.60832 | 0.0657 | / |
| 2 | 18.090 | 27.01808 | 0.0667 | / |
| 3 | 20.376 | 625.67218 | 1.5441 | Mono-hydroxysugammadex sodium |
| 4 | 29.639 | 3.97662e4 | 98.1376 | Shugeng glucose sodium salt |
| 5 | 42.138 | 27.69884 | 0.0684 | Impurity E |
| 6 | 44.314 | 7.48801 | 0.0185 | / |
| 7 | 45.579 | 10.11244 | 0.0250 | / |
| 8 | 49.710 | 11.41474 | 0.0282 | / |
| 9 | 54.551 | 18.66687 | 0.0461 | Impurity B |
Example 2: refining of sugammadex sodium
Step (1): under the protection of nitrogen, dissolving 0.2kg of crude sugammadex sodium in 0.4L of water, dropwise adding 0.8L of DMAc at room temperature, keeping the system turbid, standing for layering, separating liquid, and temporarily storing the upper mother liquid;
step (2): under the protection of nitrogen, continuously adding 0.2L of water into the lower-layer viscous organic phase for dissolving, dropwise adding 0.4L of DMAc, separating out a solid, filtering, and combining the filtrate with the upper-layer mother liquor;
and (3): under the protection of nitrogen, heating the mother liquor combined in the step (2) to 50-70 ℃, dropwise adding 1.2L DMAc, cooling to 0-10 ℃ for crystallization, and performing suction filtration and drying to obtain purified sugammadex sodium (0.182Kg, the total yield is 91%, the total purity is 99.54%, the impurity A is not detected, and the content of the impurity B is 0.065%).
Example 3: refining of sugammadex sodium
Step (1): under the protection of nitrogen, dissolving 0.2kg of crude sugammadex sodium in 0.6L of water, dropwise adding 1.0L of ethanol at room temperature to obtain turbid system, standing for layering, separating liquid, and temporarily storing the upper mother liquid;
step (2): under the protection of nitrogen, continuously adding 0.4L of water into the lower-layer viscous organic phase for dissolving, dropwise adding 0.8L of ethanol, separating out a solid, filtering, and combining the filtrate with the upper-layer mother liquor;
and (3): under the protection of nitrogen, heating the mother liquor combined in the step (2) to 50-70 ℃, dropwise adding 1.0L of ethanol, cooling to 0-10 ℃ for crystallization, and performing suction filtration and drying to obtain purified sugammadex sodium (0.184Kg, the total yield is 92%, the total purity is 99.58%, the impurity A is not detected, and the content of the impurity B is 0.074%).
Example 4: refining of sugammadex sodium
Step (1): under the protection of nitrogen, dissolving 0.2kg of crude sugammadex sodium in 0.4L of water, dripping 0.6L of acetonitrile at room temperature to obtain a turbid system, standing for layering, separating liquid, and temporarily storing an upper mother liquid;
step (2): under the protection of nitrogen, continuously adding 0.2L of water into the lower-layer viscous organic phase for dissolving, dropwise adding 0.3L of acetonitrile, separating out a solid, filtering, and combining the filtrate with the upper-layer mother liquor;
and (3): under the protection of nitrogen, heating the mother liquor combined in the step (2) to 50-70 ℃, dropwise adding 2.0L acetonitrile, cooling to 0-10 ℃ for crystallization, and performing suction filtration and drying to obtain purified sugammadex sodium (0.185Kg, the total yield is 92.5%, the total purity is 99.52%, the impurity A is not detected, and the content of the impurity B is 0.071%).
Example 5: refining of sugammadex sodium
Step (1): under the protection of nitrogen, dissolving 5.6kg of crude sugammadex sodium in 11.2L of water, dropwise adding 16.8LDMF at room temperature, making the system turbid, standing for layering, separating, and temporarily storing the upper mother solution;
step (2): under the protection of nitrogen, continuously adding 5.6L of water into the lower-layer viscous organic phase for dissolving, dropwise adding 8.4L of DMF, separating out solids, filtering, and combining the filtrate and the upper-layer mother liquor;
and (3): and (3) under the protection of nitrogen, heating the mother liquor combined in the step (2) to 50-70 ℃, dropwise adding 45L of DMF, cooling to 0-10 ℃, crystallizing, filtering, and drying to obtain purified sugammadex sodium (5.2Kg, total yield 93%).
HPLC detection is carried out on the refined sugammadex product obtained in the embodiment, and the detection result shows that the total purity of the sugammadex is 99.66%, the impurity A is not detected, the content of the impurity B is 0.069%, and other single impurities are less than 0.1%.
Example 6: separating and purifying impurity A and impurity B by medium-pressure liquid phase
Recovering the solid separated in the step (2) in the embodiment 5, separating by medium-pressure liquid phase, collecting the fraction with the retention time of 20min to obtain impurity A', 65mg and the purity of 93.86%; the fraction with retention time of 30min was collected to yield impurity B' as white powder, 150mg, purity 91.40%. And respectively carrying out acid-base salt forming reaction on the impurity A 'or the impurity B' and sodium hydroxide to obtain the corresponding impurity A or impurity B.
The medium-pressure liquid-phase preparation and separation method comprises the following steps:
the instrument comprises: biotage lsolera One;
detection wavelength: 200 nm;
preparing a column: flash ball AQ C18(20-35um, 330 g);
mobile phase: a phase of 0.1% formic acid solution and B phase of acetonitrile;
flow rate: 25ml/min
Elution gradient:
| time (min) | 0 | 35 | 36 | 42 | 43 |
| A(％) | 82 | 72 | 20 | 20 | 82 |
| B(％) | 18 | 28 | 80 | 80 | 18 |
The structure of the impurity A' is confirmed:
1 H-NMR(400MHz,D 2 O)：5.11-5.03(8H，m)，4.08-4.02(9H，m)，3.95-3.87(9H，m)，3.61-3.48(16H，m)，3.23-3.15(7H，m)，3.03-2.99(7H，m)，2.93-2.86(14H，m)，2.57-2.52(14H，m)。
ESI + ：m/z 1934.3756[M+2Na] 2+
the structure of the impurity B' is confirmed:
1 H-NMR(400MHz，D 2 O)：5.14-4.92(16H，m)，3.99(16H，m)，3.90-3.79(16H，m)，3.68-3.44(32H，m)，3.12-3.09(16H，m)，2.94-2.91(16H，m)，2.83-2.80(32H，m)，2.47-2.43(32H，m)。
ESI + ：m/z 2019.4045[M+H+Na] 2+
example 7: preparation of impurity A of sugammadex sodium
1. Preparation of impurity G'
Step 1: octaiodo-gamma-cyclodextrin (10.13g, 1.0eq) and DMF (30ml) were added to a reaction flask, stirring was started, and the temperature was controlled at 0-5 ℃.
And 2, step: DMF (300ml) and 3-mercaptopropionic acid (3.45g, 7.0eq) were added to another reaction flask, stirring was started, the temperature was controlled at 5-15 ℃, NaH (2.98g, 74.4mmol, 14.0eq) was added in portions, and stirring was carried out for 15 minutes after the addition was completed.
And step 3: and (3) controlling the temperature to be 0-5 ℃, slowly dripping the reaction liquid in the step (2) into the solution in the step (1), slowly heating the reaction temperature to room temperature after dripping, continuously stirring for 2 hours, and performing suction filtration. Adding the filter cake into a mixed solution of ethanol (250 ml)/water (50 ml)/acetic acid (50ml) in batches at the temperature of 0-10 ℃, stirring for 1 hour, carrying out suction filtration, leaching the filter cake with ethanol (100ml), carrying out suction drying, and carrying out forced air drying on the filter cake at the temperature of 35 ℃ to obtain a crude product (6.14g, white-like powder). The crude product was isolated by medium pressure liquid phase preparative separation, the corresponding fractions were collected and lyophilized to yield sugammadex impurity G' (322mg, white powder).
1 H-NMR(400MHz,D 2 O)：5.08-5.04(8H，m)，4.02-3.98(8H，m)，3.89-3.81(8H，m)，3.55-3.47(16H，m)，3.36-3.31(1H，m)，3.18-3.11(7H，m)，3.05-3.00(1H，m)，2.97-2.92(7H，m)，2.86-2.82(14H，m)，2.49-2.45(14H，m)。
High resolution mass spectrometry (ESI +): m/z 2023.3167[ M + H ]] +
2. Preparation of impurity F'
Adding DMF (30ml), sodium sugammadex impurity G (2.18G) and thiourea (0.8G) into a reaction bottle, starting stirring, slowly raising the reaction temperature to 80 ℃ after dripping, continuing stirring for 3 hours, and reducing the reaction temperature to room temperature; ethanol (100ml) was then added dropwise, stirred for 1 hour, filtered off with suction, and the wet weight of the filter cake, 6.21g, was used directly in the next step.
Adding NaOH aqueous solution (50ml, 1g NaOH dissolved in 50ml purified water) and filter cake (6.21g) in the previous step into a reaction bottle, starting stirring, slowly raising the reaction temperature to 90 ℃, continuing stirring for 7 hours, and reducing the reaction temperature to room temperature. Then, celite was added and the filtrate was dropped into ethanol (150ml), stirred for 1 hour, filtered, and the filter cake was dried at 35 ℃ by forced air to obtain a crude product (2.94g, pale yellow solid). The crude product was isolated by preparative medium pressure liquid chromatography and the corresponding fractions were collected to yield sugammadex impurity F' (478mg, white powder).
1 H-NMR(400MHz,D 2 O)：5.04-5.00(8H，m)，4.02(8H，m)，3.88-3.79(8H，m)，3.54-3.43(16H，m)，3.15-3.11(8H，m)，2.95-2.92(8H，m)，2.84-2.81(14H，m)，2.43-2.44(14H，m)。
High resolution mass spectrometry (ESI +): m/z 1929.3953[ M + H ]] +
3. Preparation of impurity A and impurity A'
DMF (5ml), potassium tert-butoxide (0.52g) and sodium sugammadex impurity F' (1.14g) were added to the tube, the stirring was turned on and the reaction temperature rose to 80 ℃. Then, a DMF (3ml) solution of sugammadex sodium impurity G' (0.54G) is dropped into the sealed tube, and the reaction is carried out for 20 hours at the temperature of 65-70 ℃. After the reaction was complete, the crude product (1.32g, white solid) was obtained by suction filtration. The crude product was isolated by medium pressure liquid phase preparative separation and the corresponding fractions were collected to yield sugammadex impurity a' (90mg, purity 91.10%, white powder). And carrying out acid-base salt forming reaction on the impurity A' and sodium hydroxide to obtain the impurity A.
The obtained impurity A 'was measured by NMR, and the data was the same as those of the impurity A' in example 6.
Comparative example 1: purification of sugammadex sodium by the method of patent CN107778383A
Preparing crude sugammadex sodium according to the method disclosed in patent CN107778383A, taking 100g of the crude sugammadex sodium, adding 3L of water for dissolving, adding 5g of dithiothreitol, heating to reflux under the protection of nitrogen, adding 8L of acetonitrile, stirring to room temperature after the addition is finished, crystallizing, and filtering to obtain 30g of sugammadex sodium, wherein the yield is 30%.
HPLC detection is carried out on the refined sugammadex product in the comparative example 1, and the detection result shows that the total purity of the sugammadex is 96.70%, the impurity A is 0.22%, the impurity B is 0.071%, the total number of the impurities is 26, and the content of a single impurity is 8, wherein the content of the single impurity is more than 0.1%.
Comparative example 2: detection of impurity A and impurity B in commercially available primary grinding Shubiglucose sodium injection
A sample of the commercially available sodium protopanaxarate injection (available from Mushadong, Germany, under batch No. M034113) was analyzed by HPLC, and the spectrum of the commercially available product is shown in FIG. 2, and the experimental data are shown in Table 2. Total purity 98.14%, impurity A0.24%, impurity B0.069%, number of impurities 17, single impurity content > 0.1% impurity 5.
TABLE 2 HPLC test results for sodium sugammadex injection available on the market
| Serial number | Retention time (min) | Peak area (mAU. s) | Peak area (%) | Impurity numbering |
| 1 | 10.287 | 13.99252 | 0.0499 | / |
| 2 | 11.568 | 7.04455 | 0.0251 | / |
| 3 | 14.175 | 99.11649 | 0.3534 | / |
| 4 | 15.144 | 7.83262 | 0.0279 | / |
| 5 | 18.637 | 111.28273 | 0.3967 | / |
| 6 | 20.809 | 457.26880 | 1.6302 | Mono-hydroxysugammadex sodium |
| 7 | 28.787 | 68.09583 | 0.2428 | |
| 8 | 30.242 | 27070.44845 | 96.5087 | Shugeng glucose sodium salt |
| 9 | 38.069 | 5.35789 | 0.0191 | / |
| 10 | 43.067 | 64.92190 | 0.2315 | / |
| 11 | 45.947 | 38.32251 | 0.1366 | / |
| 12 | 49.444 | 8.97157 | 0.0320 | / |
| 13 | 50.538 | 5.08289 | 0.0181 | / |
| 14 | 50.892 | 14.82101 | 0.0528 | / |
| 15 | 53.761 | 19.31502 | 0.0689 | Impurity B |
| 16 | 55.201 | 22.60620 | 0.0806 | / |
| 17 | 55.895 | 12.09314 | 0.0431 | / |
| 18 | 56.908 | 11.60212 | 0.0414 | / |
| 19 | 57.666 | 11.56036 | 0.0412 | / |
The HPLC detection results of the crude sugammadex sodium, the samples of the examples and the samples of the comparative example 1 and the samples of the commercially available original sugammadex sodium injection are summarized in Table 3.
TABLE 3HPLC DETERMINATION OF EXAMPLES AND COMPARATIVE EXAMPLES
As can be seen from table 3, the technical scheme provided by the application can effectively reduce the content of impurity a and impurity B in sugammadex sodium, and especially can remove impurity a, so that the product purity is further improved, and a guarantee is provided for the safety of subsequent preparations and clinical medication. And the refining system is simple, the defect that part of impurities which are difficult to purify are enriched in separated solids under the conventional purification conditions is overcome, and the method for obtaining high-purity sugammadex sodium by using a special adsorbent in the field is replaced. Mild conditions and low cost, and is very suitable for social mass production.
Claims (4)
1. Sugammadex sodium impurity a or impurity a' has the structural formula shown below:
2. sugammadex sodium impurity B or impurity B' has the structural formula shown below:
3. a process for the preparation of impurity a or impurity a' of sugammadex sodium according to claim 1, comprising the steps of:
step 1: preparing impurity G and impurity G', wherein the synthetic route is as follows:
carrying out substitution reaction on octaiodo gamma-cyclodextrin by using 3-mercaptopropionic acid, and then preparing and separating to obtain an impurity G'; performing acid-base salt forming reaction on the impurity G' and sodium-containing alkali or sodium carbonate to obtain an impurity G, wherein the sodium-containing alkali is preferably one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, amino-containing sodium alkali and sodium hydroxide;
step 2: preparing impurity F and impurity F', wherein the synthetic route is as follows:
the impurity G and thiourea generate an isothiourea intermediate, and then the isothiourea intermediate is hydrolyzed, prepared and separated to obtain an impurity F'; performing acid-base salt forming reaction on the impurity F' and sodium-containing alkali or sodium carbonate to obtain an impurity F, wherein the sodium-containing alkali is preferably selected from one or more of NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, amino-containing sodium alkali and sodium hydroxide;
and step 3: preparing impurity A and impurity A', wherein the synthetic route is as follows:
carrying out substitution reaction on the impurity G ' and the impurity F ', and then preparing and separating to obtain an impurity A '; the impurity A' and sodium-containing alkali or sodium carbonate are subjected to acid-base salt forming reaction to obtain the impurity A, and preferably, the sodium-containing alkali is one or more selected from NaH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium amino-containing alkali and sodium hydroxide.
4. Use of the impurity a or impurity a 'of claim 1 or the impurity B or impurity B' of claim 2 as an impurity control.
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| CN111320712B (en) * | 2020-04-09 | 2022-03-04 | 江苏海悦康医药科技有限公司 | Synthesis method of sugammadex sodium intramolecular thioether impurity |
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| CN111607019B (en) * | 2020-06-23 | 2021-03-02 | 常州制药厂有限公司 | Purification method of sugamonic acid |
| CN111607020B (en) * | 2020-06-23 | 2021-03-09 | 湖南如虹制药有限公司 | Method for removing turbidity and visible foreign matters of sugammadex sodium |
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| Publication number | Publication date |
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| CN115505051B (en) | 2023-07-07 |
| CN110627925A (en) | 2019-12-31 |
| CN110627925B (en) | 2022-09-06 |
| CN115505051A (en) | 2022-12-23 |
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