CN111518228B - Preparation method of sugammadex sodium - Google Patents
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- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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Abstract
The invention discloses a preparation method of sugammadex sodium. The method takes gamma-cyclodextrin as a raw material, and the gamma-cyclodextrin reacts with 3-mercaptopropionic acid substituted ester under the action of a phosphine reagent and an azo reagent to generate the sugammadex gluconate; the sugamygluconate and an alkaline reagent are hydrolyzed in a solvent at a certain temperature to obtain the target product sugamygluconate. The method for preparing sugammadex sodium has the advantages of mild reaction, saving of the process of gamma-cyclodextrin perhalogenation reaction, simple and time-saving operation, high yield of the obtained target product and suitability for industrial scale-up production.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of sugammadex sodium.
Background
Sugammadex Sodium (Sugammadex Sodium), chemical name octa-6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin Sodium salt, CAS number: 343306-79-6, the specific structural formula is as follows:
the sugammadex sodium is a novel muscle relaxant reversal agent, is firstly developed by Organon corporation in the Netherlands, is used for reversing the blocking effect of a conventionally used neuromuscular blocking drug rocuronium bromide or vecuronium bromide, and can immediately reverse the effect of rocuronium bromide used by adults and the effect of rocuronium bromide used by children and teenagers (2-17 years old). Sugammadex sodium is the first and only Selective Relaxation Binding Agent (SRBA), the first major drug development in the field of narcotics over 20 years, and is known as a milestone muscle relaxation antagonist.
At present, the existing methods for preparing sugammadex sodium are few. The general preparation method is that the gamma-cyclodextrin is halogenated to generate perhalogenated gamma-cyclodextrin, and the target product is obtained by further reacting the perhalogenated gamma-cyclodextrin.
One of the synthetic routes is that under the alkaline condition of sodium hydride, perhalogenated gamma-cyclodextrin and 3-mercaptopropionic acid are subjected to substitution reaction to obtain a target product. The synthesis of sugammadex sodium as disclosed in patent US6670340 is as follows:
the method applies flammable and explosive sodium hydride, has higher risk in industrial scale-up production, and the sodium hydride is in N, N-dimethylformamide and is easy to generate gelation phenomenon, so that the edge of a reaction container can not be stirred and dispersed, and the reaction yield is influenced.
Another synthetic route is that halogenated gamma-cyclodextrin and methyl 3-mercaptopropionate react under the action of inorganic base cesium carbonate to prepare the sugammadecanoate, and the sugammadecanoate is hydrolyzed in sodium hydroxide aqueous solution to generate the sugammadecanoate. Such as Adam, Julia m.; the synthesis of sugammadex sodium, disclosed in Journal of Medicinal Chemistry (2002),45(9), 1806-:
although explosive chemicals such as sodium hydride and the like are avoided in the route, the reaction time is long, expensive cesium carbonate is used, the cost is high, impurities with the content of about 20% are still generated in the thioetherification reaction, the impurities are further hydrolyzed, and the purity of the finally prepared sugammadex sodium is only about 80%.
In addition, patent CN104844732 reports another synthesis method, which uses perhalogenated γ -cyclodextrin as starting material, reacts with thiourea to generate perhydrothio-substituted γ -cyclodextrin, and reacts with acrylic acid under hv condition to prepare sugammadex sodium by click reaction. But the main problems with this route are: the perhalogenated gamma-cyclodextrin and thiourea are difficult to completely replace, and incompletely substituted impurities are extremely difficult to remove in a final product; the acrylic acid used in the substitution reaction has high toxicity, the three wastes generated in the post-treatment process have high pollution, the reactant is not completely converted in the addition reaction under the condition of ultraviolet irradiation, and the prepared target product still needs to be purified by adopting membrane dialysis operation. Therefore, the preparation process has negligible problems in the small-scale synthesis in the laboratory, but the economy of industrial production needs to be evaluated after further scale-up.
Another synthesis method is disclosed in other patents CN107325203 and CN107325204, as shown below. Halogenated gamma-cyclodextrin is used as an initial raw material to prepare a gamma-cyclodextrin modifier with 3- (chlorosulfonyl) propionate, and then the gamma-cyclodextrin modifier is reacted with metal and anhydrous alcohol to reduce sulfonyl groups into thio compounds, and finally the thio compounds are reacted with sodium hydroxide to generate the sugammadex sodium. However, the metal/anhydrous alcohol system is not effective in reducing all sulfone groups, resulting in the appearance of more structurally similar oxidized impurities in the final product.
In summary, the reported technical method for preparing sugammadex sodium mainly has the following problems:
(1) sodium hydride can generate gelation phenomenon in N, N-dimethylformamide, so that the product yield is low; sodium hydride is a high-risk reagent, flammable and explosive substances are generated in the reaction process, and the method has great potential safety hazard in industrial production.
(2) Cesium carbonate is expensive, acts on thioetherification reaction to generate a large amount of impurities, and the purity of the synthesized sugammadex sodium is low.
(3) Thiourea or metal/anhydrous alcohol reaction systems are very prone to generate by-product impurities which are difficult to remove, and the product purity and yield are affected, so that the refining difficulty and economic cost are increased.
(4) Since the reaction temperature is high, the reaction conditions are severe, oxidation impurities or degradation impurities similar to the structure of the target product are easily generated, and once the series of impurities are generated, the series of impurities are difficult to be refined and removed by conventional operation.
(5) The preparation of the sugammadex sodium firstly needs the perhalogenation of the gamma-cyclodextrin, the perhalogenation of the gamma-cyclodextrin is used for synthesis, and the defects of incomplete halogenation and the like exist in the halogenation reaction process, thus influencing the yield and purity of the product.
In summary of more problems in the prior art, we find that it is still a problem to be solved at present to explore a process route which is low in production cost, high in safety, small in pollution, mild in reaction, easy to operate and control, high in yield and purity and more suitable for industrialization.
Disclosure of Invention
Aiming at the problems of low conversion rate and more generated impurities in the existing process for preparing sugammadex sodium, the invention aims to provide the process for industrially producing the sugammadex sodium, which has the advantages of simple operation, mild reaction conditions, high product yield, low production cost, high safety and low pollution.
The specific technical scheme of the invention is as follows:
wherein R is one of methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl;
a preparation method of sugammadex sodium comprises the following steps:
(1) under the conditions of inert gas protection and shading, adding dried gamma-cyclodextrin, 3-mercaptopropionic acid substituted ester and phosphine reagent into an anhydrous solvent A, after all materials are dissolved, dropwise adding azo reagent at controlled temperature, after the dropwise adding is finished, controlling the temperature until the reaction is finished, filtering, adding a precipitator 1 into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum to obtain an intermediate I;
(2) under the conditions of inert gas protection and shading, slowly adding alkali into the mixed solution of purified water and a solvent B, stirring and uniformly mixing, adding an intermediate I, controlling the temperature until the reaction is finished, concentrating the reaction solution under reduced pressure to obtain a concentrated solution, adding a precipitator 2, performing suction filtration to obtain a crude product, and refining the crude product to obtain the finished sugammadex sodium product.
Preferably, the R is one of methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl, that is, the 3-mercaptopropionic acid substituted ester in the step (1) is one of methyl 3-mercaptopropionate, ethyl 3-mercaptopropionate, n-propyl 3-mercaptopropionate, isopropyl 3-mercaptopropionate, n-butyl 3-mercaptopropionate and tert-butyl 3-mercaptopropionate, wherein ethyl 3-mercaptopropionate is particularly preferred.
Preferably, the phosphine reagent in the step (1) is one of Trimethylphosphine (TMP), tri-n-butylphosphine (TBP), Triphenylphosphine (TPP), 1, 2-bis-Diphenylphosphinoethane (DPPE), diphenyl- (2-pyridyl) phosphine, 4- (dimethylamino) triphenylphosphine, tris [4- (dimethylamino) phenyl ] phosphine, or a combination thereof, wherein triphenylphosphine is particularly preferred.
Preferably, the solvent A in the step (1) is one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide or a combination thereof, wherein dimethyl sulfoxide is particularly preferred.
Preferably, the mass-to-volume ratio of the gamma-cyclodextrin to the solvent A in the step (1) is 1: 8-20 g/mL, wherein the ratio of 1: 15, g/mL.
Preferably, the azo reagent described in step (1) is one of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), di-p-chlorobenzyl azodicarboxylate (DCAD), 1' - (azodicarbonyl) dipiperidine (ADDP), N ' -tetraisopropyl azodicarboxamide (TIPA), N ' -tetramethyl azodicarboxamide (TMAD), 4, 7-dimethyl-3, 4,5,6,7, 8-hexahydro-1, 2,4, 7-tetraazaoctan-3, 8-dione (DHTD), or a combination thereof, wherein diisopropyl azodicarboxylate (DIAD) is particularly preferred.
Preferably, the feeding molar ratio of the gamma-cyclodextrin to the 3-mercaptopropionic acid substituted ester, the phosphine reagent and the azo reagent in the step (1) is 1: 9.6-16.0: 12.0-24.0: 12.0 to 24.0, wherein a ratio of 1: 11.2: 17.6: 17.6.
preferably, the temperature for dripping the azo reagent in the step (1) is-10 to 10 ℃, wherein the particularly preferable temperature is 0 to 5 ℃; the reaction temperature is 20-50 ℃, and particularly preferably 30-35 ℃.
Preferably, the reaction time in the step (1) is 8-12 hours.
Preferably, the precipitant 1 in step (1) is one of mixed solvents of methanol/purified water, ethanol/purified water, isopropanol/purified water, tert-butanol/purified water, acetone/purified water, tetrahydrofuran/purified water, 1, 4-dioxane/purified water, and acetonitrile/purified water, wherein methanol/purified water is particularly preferred.
Preferably, the volume ratio of the organic solvent to the purified water in the mixed solvent of the precipitant 1 in the step (1) is 0.5-5: 1, particularly preferably 2: 1.
preferably, the volume ratio of the precipitant 1 to the solvent A in the step (1) is 1-5: 1, particularly preferably 2: 1.
preferably, the base in step (2) is one or a combination of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide and sodium tert-butoxide, and sodium hydroxide is particularly preferred.
Preferably, the solvent B in the step (2) is one of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol or a combination thereof, wherein ethanol is particularly preferred.
Preferably, the mass-to-volume ratio of the intermediate I to the solvent B in the step (2) is 1: 6-12 g/mL, wherein 1: 9, g/mL.
Preferably, the mass-to-volume ratio of the intermediate I to the purified water in the step (2) is 1: 1 to 4 g/mL, and particularly preferably 1: 2, g/mL.
Preferably, the molar ratio of intermediate I to base in step (2) is 1: 9 to 15, particularly preferably 1: 12.
preferably, the reaction temperature in the step (2) is 10-40 ℃, and particularly preferably 20-25 ℃.
Preferably, the reaction time in the step (2) is 2-5 hours.
Preferably, the volume of the concentrated solution in the step (2) is 1/5-1/2 of the volume of the original reaction solution, and particularly 1/3 is preferred.
Preferably, the precipitant 2 in step (2) is one or a combination of methanol, ethanol, isopropanol, tert-butanol, acetone, tetrahydrofuran, 1, 4-dioxane, and acetonitrile, wherein methanol is particularly preferred.
Preferably, the volume ratio of the precipitating agent 2 to the concentrated solution in the step (2) is 3-12: 1, with 6: 1.
the crude product refining step in step (2) can be a refining method in the prior art, and in a preferred embodiment of the invention, the crude product refining step in step (2) is as follows: dissolving the crude product with purified water, adding methanol for crystallization, filtering after crystallization is finished, and drying a filter cake in vacuum to obtain the finished sugammadex sodium product.
In the present invention, the inert gas is generally selected from nitrogen and argon, and argon is particularly preferred.
The dry reagent in the invention is a reagent which is obtained by means of molecular sieve water removal or rectification and the like, and has no influence on reaction due to water or moisture.
The shading condition in the present invention refers to a dark condition where no light is transmitted.
Compared with the prior art, the invention has the following advantages and effects:
(1) the reaction is mild, the reaction system is carried out under a neutral condition, and the use of hazardous reagents such as NaH and the like can be effectively avoided, so that the reaction operation is safer, more economic and more environment-friendly, and the method is more suitable for industrial production;
(2) the synthesis of the key intermediate of the sugammadex sodium by the reaction can be completed within hours, and compared with the prior art in which the reaction is completed within several days, the reaction time is greatly shortened; the reaction is simple and convenient to operate, the process of gamma-cyclodextrin perhalogenation reaction is omitted, the production cost is saved, the content of oxidation impurities or degradation impurities similar to the structure of a target product is reduced, the purity of the obtained target product is higher, and the yield of sugammadex sodium key intermediate sugammadex gluconate is improved to more than 90% from 79% in the prior art.
(3) The key intermediate of the sugammadex sodium synthesized by the reaction, namely the sugammadex sodium, can be used for obtaining the target product sugammadex sodium by simple ester hydrolysis operation, and the yield of the target product is higher while the reaction operation is simplified.
In conclusion, the preparation method of sugammadex sodium provided by the invention has the advantages of high product yield, high purity, low production cost, simplicity and convenience in operation, time saving and high safety, and is particularly suitable for industrial production of sugammadex sodium.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
In the following examples, the procedures and methods not described in detail are conventional methods well known in the art, and reagents used are commercially available, analytically pure or chemically pure, without source or specification.
The purity of the sugammadex sodium is measured by HPLC, and the chromatographic conditions are as follows:
a chromatographic column: phenomenex, Aqua-C18(2.0 mm. times.150 mm,3.0 μm);
mobile phase: mobile phase A: 25.0mmol/L phosphate buffer (pH 3.0) (3.45 g of monobasic sodium phosphate monohydrate taken in a 1000mL volumetric flask, 950mL of water added, pH adjusted to 3.00 ± 0.03 with 1.5mol/L phosphoric acid solution and diluted to the mark with water, shake up) -acetonitrile (83: 20); mobile phase B: acetonitrile;
column temperature: 40 ℃;
detection wavelength: 200 nm;
flow rate: 0.27 mL/min;
sample introduction amount: 2.5 mu L;
the elution gradient is shown in table 1, where the sugammadex sodium (8-substituent) retention time is between about 20.5min and 23.0min, the minor active ingredient 7-substituent is at about 0.65 times the main peak retention time, and the sugammadex sodium purity is calculated as the area and the calculation of 7-substituent and 8-substituent.
TABLE 1 elution gradiometer
Example 1
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (75.15g, 0.56mol) and triphenylphosphine (230.82g, 0.88mol) into anhydrous dimethyl sulfoxide (1000mL), after all materials are dissolved, dropwise adding diisopropyl azodicarboxylate (DIAD, 177.94g, 0.88mol) at the temperature of 0-5 ℃, reacting at the temperature of 30-35 ℃ for 8 hours after the dropwise adding is finished, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: 2: 1, 2000mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at the temperature of 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 96%, and the purity is 98.52%.
Example 2
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (64.41g, 0.48mol) and triphenylphosphine (230.82g, 0.88mol) into anhydrous dimethyl sulfoxide (1000mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding diethyl azodicarboxylate (DEAD, 153.14g, 0.88mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 8 hours, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V ═ 2: 1, 2000mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 91%, and the purity is 96.34%.
Example 3
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (60.38g, 0.45mol) and triphenylphosphine (230.82g, 0.88mol) into anhydrous dimethyl sulfoxide (1000mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding diethyl azodicarboxylate (DEAD, 153.12g, 0.88mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 8 hours, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V ═ 2: 1, 2000mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 85%, and the purity is 91.80%.
Example 4
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (107.35g, 0.80mol) and triphenylphosphine (230.82g, 0.88mol) into anhydrous dimethyl sulfoxide (1000mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding diethyl azodicarboxylate (DEAD, 153.14g, 0.88mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 8 hours, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V ═ 2: 1, 2000mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 93%, and the purity is 94.65%.
Example 5
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (110.71g, 0.825mol) and triphenylphosphine (230.82g, 0.88mol) into anhydrous dimethyl sulfoxide (1000mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding diethyl azodicarboxylate (DEAD, 153.14g, 0.88mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 8 hours, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V ═ 2: 1, 2000mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 90%, and the purity is 91.26%.
Example 6
Synthesis of methyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), methyl 3-mercaptopropionate (67.29g, 0.56mol) and trimethylphosphine (66.86g, 0.88mol) into anhydrous N-methylpyrrolidone (1200mL), after all materials are dissolved, dropwise adding di-tert-butyl azodicarboxylate (DBAD, 202.51g, 0.88mol) at the temperature of-10 to-5 ℃, after the dropwise adding is finished, reacting at the temperature of 20 to 25 ℃ for 10 hours, detecting the reaction is finished, finishing the reaction, filtering, adding ethanol/purified water (V: V is 1: 1, 2500mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at the temperature of 35 to 40 ℃ to obtain the methyl sugamate (intermediate I), wherein the yield is 94%, and the purity is 96.84%.
Example 7
Synthesis of isopropyl sugammadate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), 3-mercaptopropionic acid isopropyl ester (83.00g, 0.56mol) and diphenyl- (2-pyridyl) phosphine (231.68g, 0.88mol) into anhydrous dimethyl sulfoxide (1000mL), after all materials are dissolved, dropwise adding 1,1' - (azodicarbonyl) dipiperidine (ADDP, 221.74g and 0.88mol) at the temperature of 5-10 ℃, after dropwise adding, reacting for 9 hours at the temperature of 45-50 ℃, finishing the reaction after detecting the reaction, filtering, adding acetonitrile/purified water (V: 3: 1, 2500mL) into filtrate for crystallization, filtering after crystallization, and drying a filter cake in vacuum at the temperature of 35-40 ℃ to obtain the sumotero isopropyl gluconate (intermediate I), wherein the yield is 93%, and the purity is 95.78%.
Example 8
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (75.14g, 0.56mol) and triphenylphosphine (157.37g, 0.60mol) into anhydrous dimethyl sulfoxide (600mL), after all materials are dissolved, dropwise adding diisopropyl azodicarboxylate (DIAD, 121.33g, 0.60mol) at the temperature of 0-5 ℃, reacting at the temperature of 30-35 ℃ for 10 hours after the dropwise adding is finished, detecting the reaction is finished, filtering, adding methanol/purified water (V: 2: 1, 1200mL) into the filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at the temperature of 35-40 ℃ to obtain the ethyl sugamonate (intermediate I), wherein the yield is 92% and the purity is 94.90%.
Example 9
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (75.12g, 0.56mol) and triphenylphosphine (144.26g, 0.55mol) into anhydrous dimethyl sulfoxide (800mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding diisopropyl azodicarboxylate (DIAD, 111.22g, 0.55mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 11.5 hours, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V is 2: 1, 1600mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 87%, and the purity is 90.86%.
Example 10
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (75.15g, 0.56mol) and triphenylphosphine (314.75g, 1.20mol) into anhydrous dimethyl sulfoxide (1200mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding diisopropyl azodicarboxylate (DIAD, 242.65g, 1.20mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 8.5 hours, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V is 4: 1, 3500mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 93%, and the purity is 95.63%.
Example 11
Synthesis of ethyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), ethyl 3-mercaptopropionate (75.12g, 0.56mol) and triphenylphosphine (327.86g, 1.25mol) into anhydrous dimethyl sulfoxide (1300mL), after all materials are dissolved, dropwise adding diisopropyl azodicarboxylate (DIAD, 252.76g, 1.25mol) at the temperature of 0-5 ℃, reacting at the temperature of 30-35 ℃ for 8 hours after the dropwise adding is finished, detecting the reaction is finished, finishing the reaction, filtering, adding methanol/purified water (V: V is 5: 1, 4000mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at the temperature of 35-40 ℃ to obtain the ethyl sugamate (intermediate I), wherein the yield is 88%, and the purity is 90.44%.
Example 12
Synthesis of n-butyl sugamonate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), N-butyl 3-mercaptopropionate (90.72g, 0.56mol) and 4- (dimethylamino) triphenylphosphine (268.72g, 0.88mol) into anhydrous N, N-dimethylformamide (1200mL), after all the materials are dissolved, dropwise adding di-p-chlorobenzyl azodicarboxylate (DCAD, 323.12g, 0.88mol) at the temperature of 0-5 ℃, reacting for 12 hours at the temperature of 30-35 ℃, detecting the completion of the reaction, finishing the reaction, filtering, adding acetone/purified water (V: V is 4: 1, 2500mL) into the filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at the temperature of 35-40 ℃ to obtain the N-butyl sudornate (intermediate I), wherein the yield is 95%, and the purity is 96.68%.
Example 13
Synthesis of tert-butyl sugammadate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), tert-butyl 3-mercaptopropionate (90.75g, 0.56mol) and 1, 2-bis-diphenylphosphinoethane (350.61g, 0.88mol) into anhydrous N, N-dimethylacetamide (600mL), after all materials are dissolved, dropwise adding N, N, N ', N' -tetramethyl azodicarboxamide (TMAD, 151.53g, 0.88mol) at the temperature of 0-5 ℃, after the dropwise adding is finished, reacting for 11 hours at the temperature of 30-35 ℃, detecting the reaction is finished, finishing the reaction, filtering, adding isopropanol/purified water (V: V3: 1, 3000mL) into the filtrate for crystallization, filtering after the crystallization is finished, and vacuum drying the filter cake at the temperature of 35-40 ℃ to obtain the tert-butyl suger gluconate (intermediate I), wherein the yield is 93%, and the purity is 96.26%.
Example 14
Synthesis of n-propyl sugamonate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), N-propyl 3-mercaptopropionate (73.95g, 0.56mol) and tri-N-butylphosphine (177.76g, 0.88mol) into anhydrous N, N-dimethylacetamide (1200mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding 4, 7-dimethyl-3, 4,5,6,7, 8-hexahydro-1, 2,4, 7-tetraazaoctacin-3, 8-diketone (DHTD, 149.63g, 0.88mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 10.5 hours, detecting the reaction is finished, finishing the reaction, filtering, adding 1, 4-dioxane/purified water (V: V is 0.5: 1, 3000mL) into the filtrate, crystallizing, filtering after the crystallization is finished, and drying the filter cake in vacuum at 35-40 ℃ to obtain the N-propyl sugammadex (intermediate I), the yield was 92% and the purity was 95.76%.
Example 15
Synthesis of methyl sugamogluconate (intermediate I)
Under the protection of argon and under the condition of shading, adding dried gamma-cyclodextrin (64.86g, 0.05mol), methyl 3-mercaptopropionate (67.22g, 0.56mol) and tris [4- (dimethylamino) phenyl ] phosphine (330.86g, 0.88mol) into anhydrous dimethyl sulfoxide (1300mL), controlling the temperature to be 0-5 ℃ after all materials are dissolved, dropwise adding N, N, N ', N' -tetraisopropyl azodicarboxamide (TIPA, 249.92g, 0.88mol), controlling the temperature to be 30-35 ℃ after the dropwise adding is finished, reacting for 11.5 hours, detecting the reaction is finished, finishing the reaction, filtering, adding tetrahydrofuran/purified water (V: V1: 1, 1300mL) into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum at 35-40 ℃ to obtain the sunmore gluconic acid methyl ester (intermediate I), wherein the yield is 93%, and the purity is 96.71%.
Example 16
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium hydroxide (24.00g, 0.6mol) into a mixed solution of purified water (220mL) and ethanol (1000mL), stirring uniformly, adding sugammaduoate (intermediate I, 111.33g, 0.05mol), controlling the temperature to 20-25 ℃ to react for 3 hours, after the reaction is finished, concentrating the reaction liquid under reduced pressure to about 1/3 amount, adding methanol (2400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (500mL), using methanol (3000mL) as a precipitator to crystallize, filtering after crystallization is finished, and performing vacuum drying on a filter cake to obtain a sugammadex finished product with the yield of 94%, wherein t is detected by HPLC (high performance liquid chromatography), wherein t is t R 21.403min is sugammadex sodium with purity 99.62%.
Example 17
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium hydroxide (18.00g, 0.45mol) into a mixed solution of purified water (220mL) and ethanol (1000mL), stirring uniformly, adding sugammaduonic acid ethyl ester (intermediate I, 111.33g, 0.05mol), controlling the temperature to be 20-25 ℃ for reaction for 3 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/3 amount, adding methanol (2400mL), filtering to obtain a crude product, and using pure water to prepare the crude productDissolving in water (400mL), crystallizing with methanol (2400mL) as precipitant, filtering after crystallization, vacuum drying filter cake to obtain sugammadex sodium product with yield of 90%, and detecting by HPLC, wherein t is R 20.673min is sugammadex sodium with purity of 99.40%.
Example 18
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium hydroxide (17.20g, 0.43mol) into a mixed solution of purified water (220mL) and ethanol (1000mL), stirring uniformly, adding sugammaduoate (intermediate I, 111.33g, 0.05mol), controlling the temperature to 20-25 ℃ to react for 3 hours, after the reaction is finished, concentrating the reaction liquid under reduced pressure to about 1/3 amount, adding methanol (2400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (350mL), using methanol (2000mL) as a precipitator to crystallize, filtering after crystallization is finished, and performing vacuum drying on a filter cake to obtain a sugammadex finished product, wherein the yield is 87%, and the product is detected by HPLC, wherein t is t R 21.668min is sugammadex sodium with purity 98.82%.
Example 19
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium hydroxide (30.00g, 0.75mol) into a mixed solution of purified water (220mL) and ethanol (1000mL), stirring uniformly, adding sugammadecanoate (intermediate I, 111.33g, 0.05mol), controlling the temperature to 20-25 ℃ for reaction for 3 hours, after the reaction is finished, concentrating the reaction liquid under reduced pressure to about 1/3 amount, adding methanol (2400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (400mL), using methanol (2400mL) as a precipitator for crystallization, filtering after the crystallization is finished, performing vacuum drying on a filter cake to obtain a sugammadex finished product, wherein the yield is 92%, and the product is detected by HPLC (high performance liquid chromatography), wherein t is t R 21.450min is sugammadex sodium with purity of 99.14%.
Example 20
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, sodium hydroxide (32.00g, 0.80mol) is slowly added into a mixed solution of purified water (220mL) and ethanol (1000mL), after uniform stirring, ethyl sugamonate (intermediate) is added111.33g, 0.05mol), controlling the temperature to be 20-25 ℃ until the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/3 volume, adding methanol (2400mL), carrying out suction filtration to obtain a crude product, dissolving the crude product with purified water (400mL), using methanol (2400mL) as a precipitator for crystallization, filtering after crystallization is finished, drying a filter cake in vacuum to obtain a finished product of sugammadex sodium, wherein t is detected by HPLC, the yield is 92%, and t is R 21.643min is sugammadex sodium with purity of 98.64%.
Example 21
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium ethoxide (40.83g, 0.6mol) into a mixed solution of purified water (220mL) and n-propanol (700mL), stirring uniformly, adding n-propyl sugamonate (intermediate I, 116.93g, 0.05mol), controlling the temperature to 35-40 ℃ for reaction for 2 hours, after the reaction is finished, concentrating the reaction liquid under reduced pressure to about 1/2 volume, adding 1, 4-dioxane (1400mL), carrying out suction filtration to obtain a crude product, dissolving the crude product with purified water (450mL), using ethanol (2700mL) as a precipitator for crystallization, filtering after the crystallization is finished, carrying out vacuum drying on a filter cake to obtain a finished sugamonate sodium product, wherein the yield is 91%, and the detection is carried out by HPLC, wherein t is t R 22.465min is sugammadex sodium with purity of 99.32%.
Example 22
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium methoxide (32.41g, 0.6mol) into a mixed solution of purified water (220mL) and methanol (1200mL), stirring uniformly, adding n-butyl sugamonate (intermediate I, 122.53g, 0.05mol), controlling the temperature to 10-15 ℃ for reaction for 5 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/5 volume, adding acetonitrile (3400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (400mL), using ethanol (2400mL) as a precipitator for crystallization, filtering after crystallization is finished, performing vacuum drying on a filter cake to obtain a finished sugammadex sodium product, wherein the yield is 90%, and the t is detected by HPLC (high performance liquid chromatography), wherein t is t R 22.272min is sugammadex sodium with purity of 99.26%.
Example 23
Synthesis of sugammadex sodium
Argon protection and shieldingSlowly adding sodium tert-butoxide (57.61g, 0.6mol) into a mixed solution of purified water (220mL) and tert-butanol (1000mL) under the condition of light, stirring uniformly, adding tert-butyl sugammadecanoate (intermediate I, 122.52g, 0.05mol), controlling the temperature to 20-25 ℃ for reaction for 3 hours, after the reaction is finished, concentrating the reaction liquid under reduced pressure to about 1/3 volume, adding tert-butanol (2400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (450mL), using methanol (2700mL) as a precipitator for crystallization, filtering after the crystallization is finished, and performing vacuum drying on a filter cake to obtain a finished sugammadecangosate sodium product with the yield of 92%, wherein t is detected by HPLC (high performance liquid chromatography), wherein t is t R 20.760min is sugammadex sodium with purity of 99.38%.
Example 24
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium isopropoxide (49.24g, 0.6mol) into a mixed solution of purified water (110mL) and isopropanol (1000mL), stirring uniformly, adding ethyl sugamonate (intermediate I, 111.33g, 0.05mol), controlling the temperature to be 20-25 ℃ for reacting for 3 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/4 amount, adding acetone (1600mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (400mL), performing crystallization by using methanol (2400mL) as a precipitator, filtering after the crystallization is finished, performing vacuum drying on a filter cake to obtain a finished sugammadex sodium product with the yield of 91%, and performing HPLC (high performance liquid chromatography) detection, wherein t is detected R 21.095min is sugammadex sodium with purity of 99.36%.
Example 25
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium isopropoxide (49.25g, 0.6mol) into a mixed solution of purified water (440mL) and isopropanol (1000mL), stirring uniformly, adding ethyl sugamonate (intermediate I, 111.33g, 0.05mol), controlling the temperature to be 20-25 ℃ for reacting for 3 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/3 amount, adding isopropanol (2400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (450mL), performing crystallization by using methanol (2700mL) as a precipitator, filtering after the crystallization is finished, drying a filter cake in vacuum to obtain a finished sugammadex sodium product with the yield of 92%, and detecting by HPLC, wherein t is detected R SHUGENGGLUCO (22.255 min)Sodium, purity 99.26%.
Example 26
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium n-butoxide (57.62g, 0.6mol) into a mixed solution of purified water (210mL) and n-butanol (950mL), stirring uniformly, adding sugammadecanoate (intermediate I, 105.71g, 0.05mol), controlling the temperature to 20-25 ℃ for reaction for 3 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/3 amount, adding methanol (2400mL), carrying out suction filtration to obtain a crude product, dissolving the crude product with purified water (400mL), using methanol (2400mL) as a precipitator for crystallization, filtering after the crystallization is finished, drying a filter cake in vacuum to obtain the sugammadeca sodium finished product with the yield of 91%, and detecting by HPLC, wherein t is t R 20.870min is sugammadex sodium with purity of 99.40%.
Example 27
Synthesis of sugammadex sodium
Under the protection of argon and under the condition of shading, slowly adding sodium n-propoxide (49.25g, 0.6mol) into a mixed solution of purified water (230mL) and ethanol (1050mL), stirring uniformly, adding isopropyl sugamonate (intermediate I, 116.94g, 0.05mol), controlling the temperature to be 20-25 ℃ for reaction for 3 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure to about 1/3 amount, adding tetrahydrofuran (2400mL), performing suction filtration to obtain a crude product, dissolving the crude product with purified water (400mL), performing crystallization by using acetone (2400mL) as a precipitator, filtering after the crystallization is finished, performing vacuum drying on a filter cake to obtain a sugammadex finished product, wherein t is detected by HPLC (high performance liquid chromatography), wherein the yield is 91%, and t is detected by HPLC (detection), wherein t is t R 21.150min is sugammadex sodium with purity of 99.38%.
Comparative example 1
Taking phosphorus triiodide (658.75g, 1.6mol), controlling the temperature to be 0-5 ℃, adding the phosphorus triiodide into DMF (400mL), controlling the temperature to be 20-25 ℃, stirring for 1 hour, controlling the temperature to be 5-10 ℃ under the protection of nitrogen, dropwise adding a DMF (500mL) solution of gamma-cyclodextrin (64.86g, 0.05mol), controlling the temperature to be 65-70 ℃, stirring for reaction for 14 hours, controlling the temperature to be 65-70 ℃, after the reaction is finished, cooling the reaction liquid to be 20-25 ℃, decompressing and steaming out the DMF, adding purified water (200mL) into the concentrated solution for dilution, controlling the temperature to be 5-10 ℃, dropwise adding a sodium hydroxide solution to adjust the PH to be 8, controlling the temperature to be 20-25 ℃, stirring for 1 hour, performing suction filtration, leaching the purified water of a filter cake, and obtaining the crude product of the filter cake, namely 6-fully-deoxy-6-full iodo-gamma-cyclodextrin; diluting the crude 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin product with purified water (300mL), controlling the temperature to be 20-25 ℃, stirring for 1 hour, filtering the suspension, and drying the filter cake at 55-60 ℃ for 12 hours to obtain the finished 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin product, wherein the yield is 90% and the purity is 95.54%.
Adding 3-mercapto methyl propionate (38.42g, 0.32mol), triphenylphosphine (0.84g, 3.2mmol) into N, N-dimethylformamide (250mL), adding the prepared 6-total deoxy-6-total iodo-gamma-cyclodextrin (87.05g, 0.04mol) and cesium carbonate (39.14g, 0.12mol) under nitrogen protection, controlling the temperature at 50 ℃ to react for 3 days, pouring the reaction turbid liquid into 1.2L of purified water stirred at room temperature after the reaction is finished, performing suction filtration, and washing a filter cake with acetone. The wet product was recrystallized from N, N-dimethylformamide and acetone and dried to yield sugammadex methyl ester in 88% yield and 96.24% purity with a total yield of 79.2%.
Claims (10)
1. The preparation method of sugammadex sodium is characterized by comprising the following steps:
wherein R is one of methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl;
(1) under the conditions of inert gas protection and shading, adding dried gamma-cyclodextrin, 3-mercaptopropionic acid substituted ester and phosphine reagent into an anhydrous solvent A, after all materials are dissolved, dropwise adding azo reagent at controlled temperature, after the dropwise adding is finished, controlling the temperature until the reaction is finished, filtering, adding a precipitator 1 into filtrate for crystallization, filtering after the crystallization is finished, and drying a filter cake in vacuum to obtain an intermediate I;
(2) under the conditions of inert gas protection and shading, slowly adding alkali into the mixed solution of purified water and a solvent B, uniformly stirring, adding an intermediate I, controlling the temperature until the reaction is finished, concentrating the reaction solution under reduced pressure to obtain a concentrated solution, adding a precipitator 2, performing suction filtration to obtain a crude product, and refining the crude product to obtain the finished sugammadex sodium product.
2. The process for the preparation of sugammadex sodium according to claim 1, wherein the phosphine reagent in step (1) is one of trimethylphosphine, tri-n-butylphosphine, triphenylphosphine, 1, 2-bisdiphenylphosphinoethane, diphenyl- (2-pyridyl) phosphine, 4- (dimethylamino) triphenylphosphine, tris [4- (dimethylamino) phenyl ] phosphine, or a combination thereof.
3. The process for preparing sugammadex sodium according to claim 1, wherein the solvent a in step (1) is one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or a combination thereof.
4. The process for preparing sugammadex sodium according to claim 1, wherein the azo reagent in step (1) is one of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate), di-p-chlorobenzyl azodicarboxylate, 1' - (azodicarbonyl) dipiperidine, N, N, N ', N ' -tetraisopropyl azodicarboxamide, N, N, N ', N ' -tetramethyl azodicarboxamide, 4, 7-dimethyl-3, 4,5,6,7, 8-hexahydro-1, 2,4, 7-tetraazaoctacin-3, 8-dione, or a combination thereof.
5. The process for preparing sugammadex sodium according to claim 1, wherein the molar ratio of the gamma-cyclodextrin to the substituted 3-mercaptopropionate, the phosphine reagent and the azo reagent in step (1) is 1: 9.6-16.0: 12.0-24.0: 12.0 to 24.0.
6. The preparation method of sugammadex sodium according to claim 1, wherein the temperature of the azo reagent added in step (1) is-10 to 10 ℃; the reaction temperature is 20-50 ℃.
7. The method for preparing sugammadex sodium according to claim 1, wherein the precipitant 1 in step (1) is one of mixed solvents of methanol/purified water, ethanol/purified water, isopropanol/purified water, tert-butanol/purified water, acetone/purified water, tetrahydrofuran/purified water, 1, 4-dioxane/purified water, and acetonitrile/purified water.
8. The method for preparing sugammadex sodium according to claim 1, wherein the base in step (2) is one or a combination of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide and sodium t-butoxide.
9. The process for preparing sugammadex sodium according to claim 1, wherein the solvent B in step (2) is one or a combination of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.
10. The process for preparing sugammadex sodium according to claim 1, wherein the precipitant 2 in step (2) is one or a combination of methanol, ethanol, isopropanol, tert-butanol, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile.
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| CN104844732A (en) * | 2015-03-27 | 2015-08-19 | 山东滨州智源生物科技有限公司 | Preparation method for sugammadex sodium |
| CN107325204A (en) * | 2017-07-07 | 2017-11-07 | 中国大冢制药有限公司 | A kind of preparation method for the more glucose sodium that relaxes |
| CN107686530A (en) * | 2017-10-16 | 2018-02-13 | 河北坤安药业有限公司 | A kind of synthetic method for the more glucose sodium that relaxes |
| CN108047354A (en) * | 2017-11-07 | 2018-05-18 | 山东达冠医药科技有限公司 | A kind of high-purity is relaxed the more preparation of glucose sodium and its intermediate and purification process |
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| EP3421503A1 (en) * | 2016-06-29 | 2019-01-02 | Beijing Creatron Institute Of Pharmaceutical Research Co., Ltd. | Sugammadex preparation and purification method |
| CN107325204A (en) * | 2017-07-07 | 2017-11-07 | 中国大冢制药有限公司 | A kind of preparation method for the more glucose sodium that relaxes |
| CN107686530A (en) * | 2017-10-16 | 2018-02-13 | 河北坤安药业有限公司 | A kind of synthetic method for the more glucose sodium that relaxes |
| CN108047354A (en) * | 2017-11-07 | 2018-05-18 | 山东达冠医药科技有限公司 | A kind of high-purity is relaxed the more preparation of glucose sodium and its intermediate and purification process |
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