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Method for preparing sugammadex sodium

A technology of sugammadex sodium and sodium base, applied in the field of drug synthesis, can solve the problems of low yield, difficult to purify, not much, easy to be oxidized, etc., and achieve the effect of improving the total yield and purity

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

AI Technical Summary

Problems solved by technology

[0008] The above-mentioned 3 kinds of preparation processes all optimize the base of mercaptopropionation on the basis of patent US6670340, so that the yield and purity are improved, but these methods either require a large amount of activated carbon, or require expensive preparation liquid phase instruments, or After many times of tedious dialysis, it is not suitable for industrial production
[0009] Although the synthesis route of sugammadex sodium is short, the technical requirements are high, especially the step of mercaptopropionic acid substitution. During the synthesis process, it is easy to generate a large number of other substitution by-products, such as 1-6 substitution by-products, and multiple sulfur Ether groups and hydroxyl groups are easily oxidized during the reaction and post-treatment, degrading by-products and target products, resulting in low yields and difficult purification
[0010] There are not many preparation methods of sugammadex sodium reported in the literature, and as mentioned above, they cannot meet the requirements of industrial scale-up production while overcoming the problem of low yield / purity, resulting in the quantitative production of sugammadex sodium bulk drug It is very difficult, so a more optimized preparation process is urgently needed to solve this technical problem

Method used

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  • Method for preparing sugammadex sodium
  • Method for preparing sugammadex sodium
  • Method for preparing sugammadex sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0072] Example 1: Sodium hydride (706 g, 60%) was added to dry DMF (31.2 L) under nitrogen and ice bath. Slowly add the mixed solution of tri-p-tolylphosphine (172g)-3-mercaptopropionic acid (938g)-DMF (1.2L) dropwise at 0~10°C. Add all-iodide γ-cyclodextrin (1.2kg)-tri-p-tolylphosphine (45g)-DMF (6.25L) mixed solution, and continue stirring for about 4 hours. The reaction solution was lowered to 0-10°C, water (6 L) was added, and the temperature was raised to 55-70°C with stirring for about 2 hours. Cool the reaction solution to room temperature, filter with suction, dissolve the filter cake with water (9.6L), filter with diatomaceous earth, add ethanol (24L) to the filtrate, and filter with suction to obtain the crude product of sugammadex sodium (1.1kg, harvested Yield 92%, purity 91.35%).

Embodiment 2

[0073]Example 2: 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 (1.0 L), filter with diatomaceous earth, add ethanol (2.0 L) to the filtrate, and filter with suction to obtain the crude sugammadex sodium (90 g, harvested Yield 90%, purity 90.97%).

Embodiment 3

[0074] Example 3: Sodium methoxide (79.6 g) was added to dry DMI (2.6 L) under nitrogen protection and ice bath. Slowly add the mixed solution of tricyclohexylphosphine (29.0g)-3-mercaptopropionic acid (78.2g)-DMI (0.5L) dropwise at 0-10°C, heat up to 65-75°C and react under stirring, then slowly Add the mixed solution of all-iodide γ-cyclodextrin (100g)-tricyclohexylphosphine (9.0g)-DMI (0.7L) dropwise, and continue stirring for about 8 hours. 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 4 hours under stirring. Cool the reaction solution to room temperature, filter with suction, dissolve the filter cake with water (1.0 L), filter with diatomaceous earth, add ethanol (2.0 L) to the filtrate, and filter with suction to obtain the crude sugammadex sodium (90 g, harvested 90% yield, 89.35% purity)

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Abstract

The invention discloses a method for preparing sugammadex sodium. The method is characterized in that perhalogeno gamma-cyclodextrin and 3-mercaptopropionic acid or / and a sodium salt thereof are subjected to a replacement reaction in a sodium base-reducing agent-organic solvent system for preparing sugammadex sodium, the method effectively controls the formation of process impurities with similarstructure of sugammadex sodium from a reaction process, and obtains high-yield and high-purity product after simple post-treatment. The invention further provides a method for purifying of a crude product of the sugammadex sodium and conversion of impurities to the target product in a one-step reaction, which is simple, efficient and wasteful, the method improves the yield and purity from variousaspects, and solves the problems of complex operation, high requirements on instruments and low yield in the prior art method, and is suitable for industrial mass production of the sugammadex sodium.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing 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 predictably ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16
CPCC08B37/0003C08B37/0012
Inventor 李发光高宏刘群侯云泽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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