CN109438591B - Preparation process of sugammadex sodium - Google Patents
Preparation process of sugammadex sodium Download PDFInfo
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Abstract
The invention provides a method for preparing sugammadex sodium with simple process, high purity and high yield, which comprises the following steps: 6-Perdeoxy-6-Periodo- γ -Cyclodextrin was reacted with 3-mercaptopropionic acid in the presence of sodium hydride and BHT to give 6-Perdeoxy-6-per (2-carboxyethyl) thio- γ -Cyclodextrin sodium salt, i.e., sugammadex sodium.
Description
Technical Field
The invention belongs to the field of preparation of medicinal products, and particularly relates to preparation of sugammadex sodium.
Background
Sugammadex sodium (Sugammadex sodium) is a novel selective muscle relaxant antagonist that selectively binds to the amino carrier muscle relaxant and terminates its muscle relaxing effect. The drug is a modified gamma-cyclodextrin, consisting of 8 contiguous glucose molecules in a cyclic molecular structure with a lipophilic inner cavity with an inner diameter optimized to accommodate an amino carrier molecule, such as rocuronium bromide. 8 carboxyl side chains with negative charge and hydrophilicity project outwards from the edge of the cyclodextrin molecule, and acid functional groups (COO-) on the side chains increase the lipophilicity of the inner cavity of the sugammadex sodium and can form an electrostatic bond with a nitrogen atom with positive charge of rocuronium bromide. At the same time, these groups repel each other, thus ensuring the opening of the inner cavity of the cyclodextrin molecule, once the steroid nucleus of rocuronium enters the inner cavity of sugammadex sodium, the negatively charged carboxyl bond is tightly bound to the positively charged quaternary ammonium molecule of rocuronium bromide. Intravenous sugammadex sodium, which, when bound to free rocuronium bromide in plasma, reduces the concentration of free rocuronium bromide in plasma, causing rocuronium bromide at the neuromuscular junction to return to plasma and further bound by sugammadex sodium, causing rocuronium bromide to rapidly transfer from the effector compartment to the central compartment, resulting in rapid reversal of neuromuscular blockade.
The chemical name of sugammadex sodium is: 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt having the following structural formula:
WO0140316 discloses for the first time the structure and preparation of sugammadex sodium. The method takes gamma-cyclodextrin as a raw material, and firstly produces Vilsmeier-Hack reaction with triphenylphosphine, iodine and N, N-dimethylformamide in N, N-dimethylformamide to obtain 6-fully-deoxidized-6-fully-iodo-gamma-cyclodextrin. Reacting 6-per-deoxy-6-per-iodo-gamma-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydride to obtain 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt, namely sugammadex sodium. The route uses inflammable and explosive materials such as sodium hydride and the like, potential safety hazards exist in industrial amplification production, and the content of related impurities of the obtained sugammadex sodium is high.
Adam, Julia m.; bennett, D.et al, Journal of Medicinal Chemistry (2002),45(9),1806-1816, disclose another method for preparing sugammadex sodium, which is to bromize gamma-cyclodextrin to obtain bromo-gamma-cyclodextrin, react bromo-gamma-cyclodextrin with methyl 3-mercaptopropionate to obtain sugammadex methyl ester, and hydrolyze the sugammadex methyl ester in aqueous solution of sodium hydroxide to obtain sugammadex sodium, although the method avoids the use of flammable and explosive substances such as sodium hydride, the purity of the prepared sugammadex sodium is only about 80%, and the whole process is relatively complicated.
Due to the existence of thioether bonds on the sugammadex sodium molecular structure, the compound is unstable to oxygen, and is easy to be oxidized in the purification process to form a series of oxidation impurities and disulfide impurities such as sulfoxide, sulfone, disulfide and the like, and the impurities are mostly generated on the side chain structure of the sugammadex sodium molecule, are similar to the sugammadex sodium structure, have small polarity difference and small molecular weight difference and are difficult to remove.
Disclosure of Invention
The invention provides a method for preparing sugammadex sodium, which has the advantages of simple process, high purity and high yield. The method is to add BHT (namely 2, 6-di-tert-butyl-4-methylphenol) in the process of preparing the sugammadex sodium. BHT is stable in structure, is not easy to participate in reaction, but is easier to oxidize, and when the BHT is subjected to an oxidation environment, BHT is preferentially oxidized, so that the generation of oxidation impurities and disulfide bond impurities is reduced.
The method comprises the following steps: 6-Perdeoxy-6-Periodo- γ -Cyclodextrin was reacted with 3-mercaptopropionic acid in the presence of sodium hydride and BHT to give 6-Perdeoxy-6-per (2-carboxyethyl) thio- γ -Cyclodextrin sodium salt, i.e., sugammadex sodium.
The 6-per-deoxy-6-per-iodo-gamma-cyclodextrin of the present invention can be prepared by the method disclosed in WO 0140316.
The reaction route for completely preparing sugammadex sodium is as follows:
(1) iodinating gamma-cyclodextrin (gamma-CD) with iodine in the presence of triphenylphosphine to obtain 6-fully-deoxy-6-fully iodo-gamma-cyclodextrin (gamma-ICD);
(2) reacting gamma-ICD with sodium hydride and 3-mercaptopropionic acid in the presence of BHT to obtain sugammadex sodium.
Wherein, sodium hydride is commercially available sodium hydride, and the content thereof is 60%.
The molar ratio of the 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to the sodium hydride is 1:10 to 50, preferably 1:20 to 25. The molar ratio of 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to BHT is 1: 0.05-1, preferably 1: 0.1. The molar ratio of the 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to the 3-mercaptopropionic acid is 1: 5-20, preferably 1: 10-15.
According to the method, BHT is added, so that the generation of oxidation impurities 1, oxidation impurities 2 and disulfide bond impurities in the product is effectively inhibited, wherein the content of the oxidation impurities 1 is reduced to be below 0.04% from 0.3%, the content of the oxidation impurities 2 is reduced to be below 0.04% from 0.31%, and the content of the disulfide bond impurities is reduced to be below 0.05%, so that the purity of the obtained crude sugammadex sodium product is high and can reach 99.13%, and the high-purity sugammadex sodium can be obtained directly through simple adsorption and crystallization.
The structure of oxidized impurity 1 is as follows:
the structure of the oxidized impurity 2 is as follows:
the disulfide bond impurities have the following structure:
drawings
FIG. 1 HPLC spectrum of example 2
FIG. 2 HPLC spectrum of example 3
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be described in detail below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, which are provided for the purpose of making the disclosure more complete and complete. The reagents and starting materials used were all commercially available except for the preparation provided. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
Example 1
Preparation of gamma-ICD
A2000 mL three-necked flask was charged with 160mL of DMF and triphenylphosphine (30.1g, 15eq) under nitrogen, and iodine (30.5g, 15.6eq) was added to produce a vigorous exotherm with 25. + -. 5 ℃ and stirred for 10 min. Dried gamma-cyclodextrin (10g, 7.7mmol) was added and the reaction was stirred for 24 hours at 70 ℃ after the addition. The reaction solution was cooled to 10 ℃, and a sodium methoxide solution (3.1g sodium was added to 50ml methanol) was added thereto, followed by stirring and reaction for 30min, followed by addition of 800ml methanol, addition of 500ml purified water, and filtration of the solid. 18.5g of crude γ -ICD was washed with water (3X 100ml) and then acetone (3X 100 ml).
Adding 18.5g of gamma-ICD into a 500ml three-mouth bottle under the protection of nitrogen, adding 185g of DMF, heating to 70 ℃, dropwise adding 125g of purified water, finishing dropwise adding, washing out a large amount of solid, naturally and slowly cooling, stirring for 4 hours at 25 ℃, and filtering to obtain 17.6g of wet gamma-ICD.
And adding the gamma-ICD wet product obtained in the previous step into a 500ml three-neck flask under the protection of nitrogen, adding 40g of DMF, heating to 70 ℃, adding 210g of acetone solution, cooling to 25 ℃, stirring for 4 hours, performing suction filtration to obtain a wet product, performing vacuum drying with the water temperature set to 70 ℃, and drying for 8 hours to obtain the pure gamma-ICD product.
Example 2
Comparative example
1900g of DMF was added under the protection of nitrogen, 60% sodium hydrogen (36.7g, 0.92mol) was added, the temperature was reduced to-5 ℃, a DMF solution of 3-mercaptopropionic acid (46.3g, 0.44mol) was added dropwise, the temperature was controlled at-5. + -. 5 ℃, the dropwise addition was completed, the temperature was increased to room temperature and the reaction was stirred for 2 hours, a DMF solution of 6-fully-deoxy-6-fully iodo- γ -cyclodextrin (95.0g, 0.04mol) obtained in example 1 was added, the temperature was increased to 45 ℃ and the reaction was carried out for 12 hours. After the reaction, the reaction mixture was cooled to 5 ℃ and 558g of purified water was added dropwise and filtered to obtain a crude product.
Dissolving the crude product obtained in the previous step by using 400g of water, adding 150g of diatomite and 1.0g of activated carbon, stirring at room temperature for 30min, filtering, transferring the filtrate into a 2000ml three-necked bottle, replacing the filtrate with nitrogen for three times, dropwise adding 1200g of DMF solution, stirring at room temperature for 3 hours, and filtering to obtain the wet sugammadex sodium product.
And dissolving the wet sugammadex sodium product obtained in the previous step by using 200g of purified water, adding the dissolved solution into 800g of absolute ethyl alcohol, stirring the solution at room temperature for 3 hours, filtering the solution, drying the obtained solid by using vacuum at the water temperature of 90 ℃ for 4 hours to obtain the pure sugammadex sodium product, wherein the yield is 79.5 percent, the purity is 98.3 percent, the content of the oxidized impurity 1 is 0.30 percent, the content of the oxidized impurity 2 is 0.31 percent, and the content of the disulfide impurity is 0.42 percent.
Example 3
1900g of DMF is added under the protection of nitrogen, 60% of sodium hydrogen (36.7g, 0.92mol) is added, BHT (0.88g, 0.004 mol) is added, the temperature is reduced to-5 ℃, DMF solution of 3-mercaptopropionic acid (46.3g, 0.44mol) is added dropwise, the temperature is controlled to be minus or plus 5 ℃, dropwise addition is completed, the temperature is increased to room temperature, stirring reaction is carried out for 2 hours, DMF solution of 6-fully-deoxy-6-fully iodo-gamma-cyclodextrin (95.0g, 0.04mol) obtained in example 1 is added, the temperature is increased to 45 ℃, the reaction is carried out for 12 hours, the reaction is finished, the temperature is reduced to 5 ℃, 558g of purified water is added dropwise, and a crude product is obtained by filtration.
Dissolving the crude product obtained in the previous step by using 400g of water, adding 150g of diatomite and 1.0g of activated carbon, stirring at room temperature for 30min, filtering, transferring the filtrate into a 2000ml three-necked bottle, replacing the filtrate with nitrogen for three times, dropwise adding 1200g of DMF solution, stirring at room temperature for 3 hours, and filtering to obtain the wet sugammadex sodium product.
And dissolving the wet sugammadex sodium product obtained in the previous step by using 200g of purified water, adding the dissolved solution into 800g of absolute ethyl alcohol, stirring the solution at room temperature for 3 hours, filtering the solution, drying the obtained solid by using vacuum at the water temperature of 90 ℃ for 4 hours to obtain the pure sugammadex sodium product, wherein the yield is 82.3%, the purity is 99.13%, the content of the oxidized impurity 1 is 0.03%, the content of the oxidized impurity 2 is 0.02%, and the content of the disulfide impurity is 0.03%.
Example 4
1900g of DMF is added under the protection of nitrogen, 60% of sodium hydrogen (36.7g, 0.92mol) is added, BHT (0.44g, 0.002 mol) is added, the temperature is reduced to-5 ℃, a DMF solution of 3-mercaptopropionic acid (46.3g, 0.44mol) is added dropwise, the temperature is controlled to be minus or plus 5 ℃, the dropwise addition is completed, the temperature is increased to room temperature, the reaction is stirred for 2 hours, a DMF solution of 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (95.0g, 0.04mol) obtained in example 1 is added, the temperature is increased to 45 ℃, the reaction is 12 hours, the reaction is completed, the temperature is reduced to 5 ℃, 558g of purified water is added dropwise, and a crude product is obtained by filtration.
Dissolving the crude product obtained in the previous step by using 400g of water, adding 150g of diatomite and 1.0g of activated carbon, stirring at room temperature for 30min, filtering, transferring the filtrate into a 2000ml three-necked bottle, replacing the filtrate with nitrogen for three times, dropwise adding 1200g of DMF solution, stirring at room temperature for 3 hours, and filtering to obtain the wet sugammadex sodium product.
And dissolving the wet sugammadex sodium product obtained in the previous step by using 200g of purified water, adding the dissolved solution into 800g of absolute ethyl alcohol, stirring the solution at room temperature for 3 hours, filtering the solution, drying the obtained solid by using vacuum at the water temperature of 90 ℃ for 4 hours to obtain the pure sugammadex sodium product, wherein the yield is 81.0 percent, the purity is 99.02 percent, the content of the oxidized impurity 1 is 0.04 percent, the content of the oxidized impurity 2 is 0.04 percent, and the content of the disulfide impurity is 0.05 percent.
Example 5
1900g of DMF was added under the protection of nitrogen, 60% of sodium hydrogen (36.7g, 0.92mol) was added, BHT (8.8g, 0.04mol) was added, the temperature was reduced to-5 ℃, a DMF solution of 3-mercaptopropionic acid (46.3g, 0.44mol) was added dropwise, the temperature was controlled at-5. + -. 5 ℃, the dropwise addition was completed, the temperature was increased to room temperature and stirred for reaction for 2 hours, a DMF solution of 6-fully deoxy-6-fully iodo-gamma-cyclodextrin (95.0g, 0.04mol) obtained in example 1 was added, the temperature was increased to 45 ℃ and the reaction was carried out for 12 hours. After the reaction, the reaction mixture was cooled to 5 ℃ and 558g of purified water was added dropwise and filtered to obtain a crude product.
Dissolving the crude product obtained in the previous step by using 400g of water, adding 150g of diatomite and 1.0g of activated carbon, stirring at room temperature for 30min, filtering, transferring the filtrate into a 2000ml three-necked bottle, replacing the filtrate with nitrogen for three times, dropwise adding 1200g of DMF solution, stirring at room temperature for 3 hours, and filtering to obtain the wet sugammadex sodium product.
And dissolving the wet sugammadex sodium product obtained in the previous step by using 200g of purified water, adding the dissolved solution into 800g of absolute ethyl alcohol, stirring the solution at room temperature for 3 hours, filtering the solution, drying the obtained solid by using vacuum at the water temperature of 90 ℃ for 4 hours to obtain the pure sugammadex sodium product, wherein the yield is 81.8 percent, the purity is 99.08 percent, the content of the oxidized impurity 1 is 0.03 percent, the content of the oxidized impurity 2 is 0.03 percent, and the content of the disulfide impurity is 0.03 percent.
Claims (8)
1. A method for preparing sugammadex sodium, which comprises the following steps: reacting 6-per-deoxy-6-per-iodo-gamma-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydride and BHT to obtain 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt.
2. The method according to claim 1, wherein the molar ratio of 6-per-deoxy-6-per-iodo- γ -cyclodextrin to sodium hydride is 1:10 to 50.
3. The method of claim 2, wherein the molar ratio of 6-per-deoxy-6-per-iodo- γ -cyclodextrin to sodium hydride is 1:20 to 25.
4. The process of claim 1, wherein the molar ratio of 6-per-deoxy-6-per-iodo- γ -cyclodextrin to BHT is 1: 0.05 to 1.
5. The process of claim 2, wherein the molar ratio of 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to BHT is 1: 0.1.
6. The method of claim 1, wherein the molar ratio of 6-per-deoxy-6-per-iodo- γ -cyclodextrin to 3-mercaptopropionic acid is 1:5 to 20.
7. The method of claim 2, wherein the molar ratio of 6-per-deoxy-6-per-iodo- γ -cyclodextrin to 3-mercaptopropionic acid is 1:10 to 15.
8. The method of any one of claims 1-7, which is: adding DMF under the protection of nitrogen, adding 60% sodium hydrogen, adding BHT, cooling to-5 ℃, dropwise adding a DMF solution of 3-mercaptopropionic acid, controlling the temperature to be-5 +/-5 ℃, completing dropwise adding, heating to room temperature, stirring for reaction, adding a DMF solution of 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin, heating to 45 ℃, reacting, cooling to 5 ℃ after the reaction is finished, dropwise adding purified water, and filtering to obtain a crude product; dissolving the crude product obtained in the previous step with water, adding diatomite and active carbon, stirring at room temperature for 30min, filtering, transferring the filtrate into a three-necked bottle, replacing with nitrogen, dropwise adding a DMF solution, stirring at room temperature for 3 hours, and filtering to obtain a wet sugammadex product; and (3) dissolving the wet sugammadex sodium product obtained in the previous step by using purified water, adding the solution into absolute ethyl alcohol, stirring for 3 hours at room temperature, filtering, and drying the obtained solid in vacuum to obtain the pure sugammadex sodium product.
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| CN112830981A (en) * | 2019-11-22 | 2021-05-25 | 北京泰德制药股份有限公司 | Intermediate of sugammadex sodium and preparation method thereof |
| CN113121724B (en) * | 2019-12-31 | 2023-11-07 | 上海汇伦医药股份有限公司 | Purification method of sodium sugammadex |
| CN111574642B (en) * | 2020-06-23 | 2021-03-19 | 湖南如虹制药有限公司 | Purification method of sugammadex sodium |
| CN113637097A (en) * | 2021-08-10 | 2021-11-12 | 北京恒创星远医药科技有限公司 | 6-full-deoxidation-6-full-iodo-gamma-cyclodextrin crystal and preparation method and application thereof |
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| WO2017144734A2 (en) * | 2016-06-23 | 2017-08-31 | Synthon B.V. | Process for making sugammadex |
| 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 |
| CN109021147A (en) * | 2017-06-08 | 2018-12-18 | 天津科伦药物研究有限公司 | A kind of purification process for the more glucose sodium that relaxes |
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| WO2001040316A1 (en) * | 1999-11-29 | 2001-06-07 | Akzo Nobel N.V. | 6-mercapto-cyclodextrin derivatives: reversal agents for drug-induced neuromuscular block |
| WO2012025937A1 (en) * | 2010-08-25 | 2012-03-01 | Ramamohan Rao Davuluri | Improved process for preparation of sugammadex |
| CN105777944A (en) * | 2016-03-28 | 2016-07-20 | 广西大学 | Method for preparing dehydroabietic acid-beta-cyclodextrin ester |
| WO2017144734A2 (en) * | 2016-06-23 | 2017-08-31 | Synthon B.V. | Process for making sugammadex |
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