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Synthesis method of sugammadex sodium dimer impurity

A technology of sugammadex sodium and a synthesis method, which is applied in the field of chemical substance synthesis and preparation, can solve problems such as poor qualitative and quantitative accuracy, and achieve the effects of improving quality, improving accuracy and reducing risks.

Inactive Publication Date: 2020-07-31
江苏海悦康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The dimer impurity formula 1 is a reaction by-product, there is no reference substance supply at home and abroad, and there is no report on the synthesis method of this impurity in domestic and foreign literature and patents, the self-control method is currently used, and its qualitative and quantitative accuracy is not good enough. In order to improve the comfort To improve the quality of raw materials and preparations of sugammadex sodium and reduce the risk of clinical medication, it is necessary to carry out more detailed research and monitoring on the impurities in raw materials and preparations of sugammadex sodium. The synthesis method of the reference substance has become a top priority

Method used

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  • Synthesis method of sugammadex sodium dimer impurity
  • Synthesis method of sugammadex sodium dimer impurity
  • Synthesis method of sugammadex sodium dimer impurity

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Embodiment 1

[0039] The examples are used to illustrate the present invention, but should not be construed as limiting the present invention.

[0040] Preparation of Intermediate 3:

[0041] Add octa-(6-bromo-6-deoxy)-γ-cyclodextrin (40g, 22.2mmol) and 140mL DMF to a 250mL reaction flask, stir to dissolve. Add sodium sulfide nonahydrate (2.67g, 11.1mmol) and react at 20°C for 24 hours. Filter to remove undissolved sodium sulfide nine water. Add 140 mL of DMF to the filtrate to dilute, add 450 mL of methyl isobutyl ketone dropwise, stir for half an hour after dropping, and filter to obtain a crude product. The crude product was repeatedly purified by DMF / methyl isobutyl ketone 3 to 5 times to remove the raw material octa-(6-bromo-6-deoxy)-γ-cyclodextrin. The crude product was purified by DMF / MeOH / water repeatedly 5 times to remove intramolecular thioether by-products. After vacuum drying at 45°C, 2.2 g of Intermediate 3 was finally obtained as a light gray solid.

Embodiment 2

[0043] The examples are used to illustrate the present invention, but should not be construed as limiting the present invention.

[0044] Preparation of compound 1:

[0045] Add sodium hydroxide (1.47g, 36.6mmol) and 6.4mL of purified water to a 100mL three-necked flask, stir and dissolve, then fully replace with nitrogen for protection, cool down to 0-10°C and add 3-mercaptopropionic acid (1.95g, 18.3mmol) dropwise ). After the drop, the temperature was raised to 40°C, and 2.12g (0.63mmol) of intermediate 3 in 16mL of DMSO was slowly added, and the reaction was carried out at 45-50°C for four hours after the addition. After adding 11.2 mL of water, the reaction solution became clear. After maintaining the temperature for half an hour, add 4.2 mL of DMSO, cool down to 0-5°C for crystallization and filtration, rinse the filter cake with absolute ethanol, and dry it in vacuum at 40°C to obtain 2.2 g of crude product. The crude product was recrystallized from water / methanol an...

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Abstract

The invention discloses a synthesis method of a sugammadex sodium dimer impurity, and relates to the technical field of chemical substance synthesis and preparation. The method comprises the followingsteps: by taking 8-(6-bromo-6-deoxy)-gamma-cyclodextrin as a raw material, adding a sulfide to react to obtain an intermediate product, namely intermolecular thioether; and reacting the intermediateproduct with 3-mercaptopropionic acid in a sodium hydroxide aqueous solution to obtain the final product sugammadex sodium dimer impurity. The method has the beneficial effects that the quality of thesugammadex sodium raw material is improved, the qualitative and quantitative accuracy is improved, the risk of clinical medication is reduced, and the research and monitoring on impurities in the sugammadex sodium raw material and the preparation are facilitated.

Description

technical field [0001] The invention belongs to the technical field of synthesis and preparation of chemical substances, in particular to a synthesis method of sugammadex sodium dimer impurities. Background technique [0002] Sugammadex sodium (sugammadex sodium), chemical name: octa-6-perdeoxy-6-perfect (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, the chemical structure is as follows: [0003] [0004] Sugammadex sodium was approved by the European Union in 2008, and its trade name is Bridion (Bridion). It was launched in Japan and the United States in 2010 and 2015 respectively, and is currently on the market in many countries around the world. Sugammadex sodium is produced by Organon in the Netherlands and was owned by Merck through an acquisition transaction in 2009. Brettim is the first selective relaxation antagonist indicated for the reversal of neuromuscular blocking agents and is the first and only selective relaxation antagonist. [0005] WO2017144734A2 p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16
CPCC08B37/0012
Inventor 方从坤裴欣宇姜春阳谢军李惠
Owner 江苏海悦康医药科技有限公司
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