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Preparation method of high-purity sugammadex sodium

A sugammadex sodium, high-purity technology, which is applied in the chemical and pharmaceutical field, can solve problems such as complex by-products and degradation impurities, difficult purification of sugammadex sodium, and high-purity products, so as to improve the total purity and process Easy handling, no effects of highly toxic reagents

Active Publication Date: 2021-10-22
吉林省博大伟业制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Sugammadex sodium is a structurally modified γ-cyclodextrin with a complex structure, and the preparation reaction process is prone to produce a large number of complex by-products and degradation impurities
Moreover, there are thioether bonds in the molecular structure of sugammadex sodium, which makes the compound unstable to oxygen, and is easily oxidized to form a series of impurities such as sulfoxide, sulfone, and disulfide during the purification process. Most of the impurities are produced in sugammadex On the side chain structure of the sodium glucose molecule, the impurities are similar to sugammadex sodium in structure, with small polarity difference and molecular weight difference, which are difficult to remove by conventional means. This characteristic makes the purification of sugammadex sodium very difficult
At present, there are few reports on the preparation process of sugammadex sodium at home and abroad, and the purification process relies on membrane dialysis or column chromatography for purification. It is difficult to obtain high-purity products, which is not conducive to large-scale industrial production.

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0060] Embodiment 1: the preparation of Vilsmeier Haack reagent

[0061] In the four-neck flask, nitrogen protection was passed through, and 756.8g of triphenylphosphine and 2356ml of dry DMF were successively added at room temperature (20-25°C), and stirred to dissolve. Under nitrogen protection at room temperature (20-25°C) and stirring, 465.85g of bromine was slowly added dropwise, and the temperature was kept below 40°C during the dropwise addition. After the dropwise addition, stir and react at room temperature (20-25°C) for 1 hour, then cool down to 0°C, and under nitrogen protection, filter the reactants in the four-necked bottle, and rinse the filter cake with 0°C DMF 1200ml×2 Twice, then rinse the filter cake twice with 1200ml x 2 of dry methyl tert-butyl ether, and vacuum-dry at room temperature for 5h to obtain 440g of dry Vilsmeier Haack reagent for use.

[0062]

Embodiment 2

[0063] Example 2: Preparation of 6-perdeoxy-6-perbromo-γ-cyclodextrin

[0064] In a four-neck flask, under nitrogen protection, add 100 g of dry γ-cyclodextrin and 1200 ml of DMF in sequence at room temperature, and stir to dissolve. Cool down to 0°C, under nitrogen protection and stirring, add the Vilsmeier Haack reagent of Example 1 in five batches, add 73g each time for the first four times, stir and react for 5min after adding, then add the next time, add 76.73g for the fifth time, and always Keep the temperature when adding the Vilsmeier Haack reagent should not exceed 25°C. After the addition was completed and stirred for 5 min, the temperature of the system was raised to 73° C., and stirred for 6 h under the protection of nitrogen. After the reaction was completed, the temperature was lowered to 40° C., and 140 ml of water was slowly added dropwise to quench the reaction (30 min), and stirring was continued at this temperature for 3.5 h. 1200ml of water was added drop...

Embodiment 3

[0067] Embodiment 3: preparation sugammadex sodium crude product

[0068] In a 500ml four-neck bottle, pass through nitrogen protection, add 50g of perbrominated intermediate at room temperature, then add 1000ml of dimethyl sulfoxide, and stir until it dissolves. 29.5 g of 3-mercaptopropionic acid were added with stirring. Add 166.7ml of 20% sodium hydroxide aqueous solution dropwise to the reaction solution under stirring (the dropping time is not less than 15 minutes, and the dropping temperature is lower than 30°C), and after stirring at room temperature for 5 minutes, the reaction system is heated to 50°C, and the temperature is kept for reaction 6 hours. After the reaction, the system was cooled to room temperature, and 2500 ml of ethanol was added dropwise with stirring. Solids were precipitated, and the stirring was continued for 10 minutes, filtered, and the filter cake was washed twice with a small amount of ethanol. At room temperature, transfer the solid obtained ...

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Abstract

The present application relates to the preparation of the desired intermediate Haack reagent, the reaction of the intermediate 3-mercaptopropionic acid with 6-per-deoxy-6-per-bromo-gamma-cyclodextrin, and a purification method which improves the total purity of sugammadex. The invention provides an improved industrially feasible method, the method is effective, time-consuming and reproducible, and less toxic reagents are involved.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and provides a preparation method of high-purity sugammadex sodium and a preparation method of crude sugammadex sodium. Background technique [0002] Sugammadex sodium (sugammadexsodium), chemical name 6-full deoxy-6-full (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, is a chemically modified γ-cyclodextrin, through the The neuromuscular blocking drugs rocuronium or vecuronium form complexes in plasma that reduce the amount of neuromuscular blocking drugs bound to nicotinic receptors at the neuromuscular junction, thereby reversing the effects of rocuronium. Bromide- or vecuronium-induced neuromuscular blockade. Sugammadex sodium was first launched in Europe in September 2013 under the brand name Bridion, launched in the United States in 2015, and launched in China in 2017. The approved indications include: 1) Antagonizing neuromuscular blockade induced by rocuronium bromide or ...

Claims

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Application Information

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IPC IPC(8): C08B37/16
CPCC08B37/0012C08B37/0003
Inventor 谢文博韩智旭孙雪姜新王进政王雪钱博李晓璇黄晓光王恩思
Owner 吉林省博大伟业制药有限公司
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