Method for refining sugammadex sodium

A technology of sugammadex sodium and a purification method, applied in the field of drug synthesis, can solve the problems of easy generation of acid degradation impurities, high purification cost, influence on the stability of cyclodextrin substrates and the like

Active Publication Date: 2019-12-31
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015]1) Column chromatography or adsorbent purification such as silica gel column, Sephadex G25, macroporous resin, ion exchange resin, etc., the purification cost is high, and the process Relatively limited, not universal, not conducive to industrial scale-up production;
[0016]2) Repeated use of strong inorganic acid for dissociation will have an impact on the stability of the cyclodextrin substrate of sugammadex sodium, and it is easy to produce acid-degraded impurities , affecting the drug safety of sugammadex sodium products;
[0017]3) Under conventional recrystallization purification conditions, adding protective agents such as triphenylpho

Method used

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  • Method for refining sugammadex sodium
  • Method for refining sugammadex sodium
  • Method for refining sugammadex sodium

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0105] Preparation of crude sugammadex sodium:

[0106] Iodo γ-cyclodextrin can be prepared by iodination of γ-cyclodextrin. For the preparation method, refer to the literature Methods for Selective Modifications of Cyclodextrins, Chem. Rev. 1998, 98, 1977-1996.

[0107] Step (1): Add sodium hydride (7.16 kg, 60%) to dry DMF (317 L) under nitrogen atmosphere and ice bath. Slowly add the mixed solution of tri-p-tolylphosphine (1.74kg)-3-mercaptopropionic acid (9.52kg)-DMF (12.2L) dropwise at 0-10°C, heat up to 65-75°C and react under stirring after the addition, and then Slowly add the mixed solution of all-iodo γ-cyclodextrin (12.16kg)-tri-p-tolylphosphine (0.46kg)-DMF (63.4L) dropwise, and continue stirring for about 4 hours. The reaction solution was lowered to 0-10°C, water (60.9 L) was added, and the temperature was raised to 55-70°C with stirring for about 2 hours. The reaction solution was cooled to room temperature, suction filtered, the filter cake was dissolved in w...

Embodiment 1

[0111] Embodiment 1: Refining of sugammadex sodium

[0112] Step (1): Under the protection of nitrogen, dissolve 0.2 kg of sugammadex sodium crude product in 0.4 L of water, add 0.6 LDMF dropwise at room temperature, the system becomes turbid, stand to separate layers, separate liquid, and temporarily store the upper mother liquid;

[0113] Step (2): Under the protection of nitrogen, continue to add 0.2L water to dissolve the viscous organic phase in the lower layer, add 0.3L DMF dropwise, precipitate solid, filter, and combine the filtrate with the upper mother liquor;

[0114] Step (3): Under the protection of nitrogen, raise the temperature of the combined mother liquor in step (2) to 50-70°C, add 1.6L DMF dropwise, cool down to 0-10°C to crystallize, filter and dry to obtain purified sugammadex Sodium sugar (0.188Kg, total yield 94%).

[0115] The sugammadex sodium refined product that the present embodiment obtains carries out HPLC detection, as figure 1 The experimenta...

Embodiment 2

[0118] Embodiment 2: Refining of sugammadex sodium

[0119] Step (1): under the protection of nitrogen, dissolve 0.2 kg of sugammadex sodium crude product in 0.4 L of water, add 0.8 LDMAc dropwise at room temperature, the system is turbid, stand to separate layers, separate liquid, and temporarily store the upper mother liquid;

[0120] Step (2): Under the protection of nitrogen, continue to add 0.2L water to dissolve the viscous organic phase in the lower layer, add 0.4L DMAc dropwise, precipitate solid, filter, and combine the filtrate with the upper mother liquor;

[0121] Step (3): Under the protection of nitrogen, raise the temperature of the combined mother liquor in step (2) to 50-70°C, add 1.2L DMAc dropwise, cool down to 0-10°C to crystallize, filter and dry to obtain purified sugammadex Sodium sugar (0.182Kg, total yield 91%, total purity 99.54%, impurity A was not detected, impurity B content was 0.065%).

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Abstract

The invention discloses a method for refining sugammadex sodium. The method comprises the following steps: liquid separating and refining a crude sugammadex sodium product in a poor solvent/water system, preferentially separating out and enriching dimer impurities which are difficult to remove into solids to remove, separating (liquid separating and filtering) to obtain a mother liquor, further adding a poor solvent for crystallizing to obtain high-purity sugammadex sodium. According to the refining method provided by the invention, the contents of dimer impurities A and B can be effectively reduced; the total purity of the refined sugammadex sodium is greater than 99.5%, the impurity A is not detected in the finished product, the content of impurity B is less than 0.1%, the content of other single impurity is less than 0.1%, the adopted reagents are all conventional and easy to obtain, the operation is simple and safe, and the method is very suitable for industrial amplification underconventional production conditions.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for refining sugammadex sodium, in particular to a method for reducing the content of impurity A or impurity B in sugammadex sodium. Background technique [0002] Sugammadex Sodium was first developed by Organon Biosciences (Organon Corporation), which was acquired by Schering-Plough in 2007, and Schering-Plough merged with Merck in 2009. Sugammadex sodium is currently owned and sold by Merck. In 2008, Sugammadex Sodium was launched in Europe for the first time, and then in Japan, the United States and other countries, and is now on the market in 75 countries. It was approved for listing in China on April 26, 2017. [0003] Sugammadex sodium, chemical name: 6-full deoxy-6-full (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, English name: sugammadex, trade name: Bridion, is a modified γ-cyclodextrin, the first and only selective muscle relaxant...

Claims

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Application Information

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IPC IPC(8): C08B37/16A61K31/724A61P21/00
CPCC08B37/0012C08B37/0003A61K31/724A61P21/00
Inventor 李发光高宏祁浩飞侯云泽刘群肖宇胡佰艳霍翔宏王琦王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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