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Method for preparing sugammadex sodium and sugammadex sodium intermediate

A technology of sugammadex sodium and intermediates, which is applied in the field of preparation of pharmaceutical compounds, can solve problems such as high cost, difficult operation, and large pollution, and achieve the effects of environmentally friendly synthesis methods, reduced production costs, and convenient production operations

Inactive Publication Date: 2019-06-14
陈文辉
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The inventor has conducted research on the methods disclosed above, and found that the main disadvantages of these patents are: low yield, high pollution, high cost, and difficult operation in large-scale production

Method used

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  • Method for preparing sugammadex sodium and sugammadex sodium intermediate
  • Method for preparing sugammadex sodium and sugammadex sodium intermediate
  • Method for preparing sugammadex sodium and sugammadex sodium intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0056] Preparation of Sugammadex Sodium

[0057] The first step: the key intermediate 6-perdeoxy-6-perbromo-γ-cyclodextrin

[0058] Under the protection of nitrogen, 4 kg of dimethylformamide, 1.5 kg of γ-cyclodextrin (dried at 105° C.) and 5.0 kg of triphenylphosphine solution were sequentially added into a 50 L reactor. Cool the reaction system to 0-5°C, add 3.5kg of dibromohydantoin in DMF dropwise, and control the temperature during the dropwise addition to ≤60°C. After the dropwise addition, raise the temperature of the reaction system to 75-90°C, and stir for 4 hours.

[0059] After the reaction is complete, cool the system down to room temperature, transfer it to a 100L enamel reaction kettle, add 2.0kg of methanol, cool the reaction system down to room temperature, add a pre-configured sodium hydroxide aqueous solution dropwise to adjust the pH to 8-10; then add water dropwise 30kg, after the dropwise addition was completed, the temperature was controlled and stirred ...

Embodiment 2

[0069] Preparation of key intermediate 6-perdeoxy-6-perbromo-γ-cyclodextrin (formula II)

[0070] Under the protection of nitrogen, 400 ml of dimethylformamide, 150 g of γ-cyclodextrin (not dried) and 550 g of triphenylphosphine solution were sequentially added into a 5 L reaction flask. Cool the reaction system to 0-5°C, add 400g of dibromohydantoin in DMF dropwise, and control the temperature during the dropwise addition to ≤60°C. After the dropwise addition, raise the temperature of the reaction system to 75-90°C, and stir for 4 hours.

[0071] After the reaction is complete, cool the system down to room temperature, transfer it to a 5L glass reactor, add 200g of methanol, cool the reaction system down to room temperature, add dropwise a preconfigured aqueous sodium hydroxide solution to adjust the pH to 10; then add dropwise 3.0kg of water, After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours. Suction filtration, the filter ca...

Embodiment 3

[0073] Preparation of key intermediate 6-perdeoxy-6-perbromo-γ-cyclodextrin (formula II)

[0074] Under the protection of nitrogen, 50 ml of dimethylformamide, 15 g of γ-cyclodextrin (not dried) and 500 g of triphenylphosphine solution were sequentially added into a 500 ml reaction flask. Cool the reaction system to 0-5°C, add dropwise a solution of 350g of dibromohydantoin in dimethylformamide, and control the temperature during the dropwise addition to ≤60°C. After the dropwise addition, raise the temperature of the reaction system to 75-90°C, and stir Reaction 4h.

[0075] After the reaction is complete, cool the system to room temperature, transfer it to a 1L reaction bottle, add 30ml of methanol, cool the reaction system to room temperature, add dropwise a pre-configured aqueous sodium hydroxide solution to adjust the pH to 10; then add 300g of water dropwise, and add Complete temperature control and stir at room temperature for 5 h. Suction filtration, the filter cake ...

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Abstract

The invention relates to a method for preparing sugammadex sodium and a sugammadex sodium intermediate. The method comprises the following steps that a, gamma-cyclodextrin, a halogenating agent and triphenylphosphine react in N,N-dimethylformamide; after the reaction is completed, alkali is added into reaction liquid for regulating the pH value of the reaction liquid to reach a neutral state and then reach an alkaline state; then, water is added for separating out solid; filtering is performed; through pulping and washing, an intermediate of 6-deoxy-6-perhalogeno-gamma-cyclodextrin (2) is obtained; b, in an organic solvent, the formula (2) and 3-mercaptopropionic acid react under the alkaline condition to generate sugammadex sodium; c, the sugammadex sodium crude product is refined to obtain the sugammadex sodium.

Description

Technical field: [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a method of high-purity sugammadex sodium and its intermediate. Background technique: [0002] Sugammadex Sodium (Sugammadex Sodium) chemical name, 6-full deoxy-6-full (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, CAS number: 343306-79-6, molecular formula: C72H104Na8O48S8 , Molecular weight: 2178.01, is a chemically synthesized drug for rapid reversal of neuromuscular blockade caused by anesthetics rocuronium bromide and vecuronium bromide during surgery in adult patients. Sugammadex is a synthetic modified γ-cyclodextrin consisting of a lipophilic core and a hydrophilic outer end. Sugammadex, administered through intravenous injection, can significantly improve the recovery of muscle relaxation after surgery, and quickly reverse the neuromuscular blockade of steroidal muscle relaxants in a short period of time. The drug was launched in Europe in 2008 an...

Claims

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Application Information

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IPC IPC(8): C08B37/16
Inventor 陈文辉
Owner 陈文辉
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