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Method for purifying sugammadex sodium

A technology of sugammadex sodium and purification method, which is applied in the field of drug synthesis, and can solve problems such as the influence of cyclodextrin substrate stability, easy generation of oxidation or other decomposed impurities, and influence on the drug safety of sugammadex sodium products , to achieve a significant effect of purification

Active Publication Date: 2018-12-18
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] 3) Repeated use of strong inorganic acid dissociation will affect the stability of the cyclodextrin substrate of sugammadex sodium, and it is easy to produce oxidation or other decomposed impurities, which will affect the drug safety of sugammadex sodium products. and theoretically cannot be repeated

Method used

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  • Method for purifying sugammadex sodium
  • Method for purifying sugammadex sodium
  • Method for purifying sugammadex sodium

Examples

Experimental program
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Effect test

preparation example

[0086] Preparation example: Preparation of crude sugammadex sodium:

[0087] 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.

[0088] Sodium hydride (58.8 g, 60%) was added to dry DMF (2.6 L) under nitrogen protection and ice bath. Slowly add the mixed solution of triphenylphosphine (12.3g)-3-mercaptopropionic acid (78.2g)-DMF (0.5L) dropwise at 0-10°C, heat up to 65-75°C and react under stirring, then slowly Add the mixed solution of periodo γ-cyclodextrin (100g)-triphenylphosphine (3.9g)-DMF (0.7L) dropwise, and continue stirring for about 6h. The reaction solution was lowered to 0-10°C, water (0.6 L) was added, and the temperature was raised to 55-70°C for about 3 hours under stirring. Cool the reaction solution to room temperature, filter with suction, dissolve the filter cake with water (1.0L), filter with diatoma...

Embodiment 1

[0089] Embodiment 1: Purification of sugammadex sodium

[0090] Step (1): Under nitrogen atmosphere, add triethylamine (0.8L) to acetic acid (4L), stir to cool down to room temperature, continue to add tri-p-methylphenylphosphine (8.4g, 0.1eq), sugammadex Sodium sugar crude product (0.6Kg, 1eq), stirred until completely dissolved, controlled temperature at 20-40°C, continued to stir for 1-5h, added dropwise acetone (2.4L) to force crystallization, stirred for 1-2h, and dried by suction to obtain More gluconic acid (0.49Kg, HPLC total purity 98.60%).

[0091] Step (2): Under nitrogen atmosphere, add tri-p-methylphenylphosphine (7.4g, 0.1eq) to DMF (0.98L), and continue to add sugammadex (0.49Kg, 1eq ), heated to 35-50°C, stirred until completely dissolved, added dropwise acetonitrile (1.96L) at 35-50°C under temperature control, lowered to room temperature, stirred for 1-2 hours, and dried by suction to obtain purified sugammadex (0.44Kg, HPLC total purity 99.42%).

[0092] ...

Embodiment 2

[0093] Embodiment 2: Purification of sugammadex sodium

[0094] Step (1): Add triethylamine (0.5L) to acetic acid (5.5L), stir down to room temperature, continue to add tri-p-methylphenylphosphine (84g, 1eq), crude sugammadex sodium (0.6 Kg, 1eq), stirred until completely dissolved, controlled the temperature at 20-40°C, continued to stir for 1-5h, added dropwise acetone (2.4L) to force crystallization, stirred for 1-2h, and dried by suction to obtain sugammadex ( 0.4Kg).

[0095] Step (2): Add tri-p-methylphenylphosphine (7.1g, 0.1eq) to DMF (0.98L), continue to add sugammadex (0.4Kg, 1eq) obtained in step (1), and heat up to Stir at 35-50°C until completely dissolved, add acetonitrile (1.96L) dropwise, lower to room temperature, stir for 1-2 hours, then filter and dry to obtain purified sugammadex (0.4Kg).

[0096] Step (3): Add the sugammadex (0.4Kg, 1eq) obtained in step (2) to the sodium hydroxide (0.09Kg, 10eq)-water (1.76L) solution under ice bath, warm up to room tem...

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Abstract

The invention discloses a method for purifying sugammadex sodium. The method is characterized in that a sugammadex sodium crude product is subjected to dissociation in an organic acid-organic alkali-reducing agent mixture system into sugammadex acid, the free condition is mild, the product stability is high, and the purification effect of the sugammadex acid is better, and after further recrystallization purification and salt formation, the high-purity sugammadex sodium can be obtained. Both the dissociation and recrystallization steps of the purification method introduce a reducing agent so that the reaction system has oxidation resistance, and effectively controls the formation of oxidized impurities, the reagent is easy to obtain, and the operation is simple and safe, compared with theprior art, a large amount of activated carbon, multitime long-time dialysis and preparation of HPLC are employed, the sugammadex sodium is purified, the method is more suitable for industrial amplification, and provides bulk drugs of sugammadex sodium which can meet the purity requirements and impurity limitation for preparation production. The invention further discloses high-purity sugammadex sodium with content being more than 99.5% and single impurity of less than 0.1%, and a preparation and use thereof.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for purifying 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. In 2016, Merck proposed to go public in China. [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 antagonist (SRBA) successfully developed in 20 years, blocks The relaxation effect can quickly and predicta...

Claims

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Application Information

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IPC IPC(8): C08B37/16A61K31/724A61P21/00
CPCC08B37/0012
Inventor 李发光高宏侯云泽刘群肖宇白俊鹏孟秋月霍翔宏王琦王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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