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Preparation method for sugammadex and intermediates thereof

A technique for sugammadex sodium and intermediates, which is applied in the field of preparation of sugammadex sodium and its intermediates, can solve the problems of low yield, difficulty in post-processing and purification, and unsuitability for industrialized large-scale production. High yield, high yield and high purity, high purity effect

Inactive Publication Date: 2016-01-27
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, triphenylphosphine oxide is produced in this route reaction, and post-treatment purification is very difficult. It needs to be washed repeatedly with N,N-dimethylformamide under nitrogen atmosphere, and the yield is very low, which is not suitable for large-scale industrial production. , it is necessary to optimize the process

Method used

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  • Preparation method for sugammadex and intermediates thereof
  • Preparation method for sugammadex and intermediates thereof
  • Preparation method for sugammadex and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 6-perdeoxy-6-per(2-carboxyethyl)sulfide-γ-cyclodextrin (sugammadex sodium)

[0057]

[0058]

[0059] Step 1: Perchlorinated γ-cyclodextrin (compound 2)

[0060] Add dry N,N-dimethylformamide (20 L) into a 50 L dry reaction kettle, replace the air with nitrogen, and cool in an ice bath. Oxalyl chloride (3.916Kg) was added dropwise at 0-5°C. During the dropwise addition, gas and solids were produced, and the reaction was violent. The dropwise addition was completed in 105 minutes, and stirring was continued for 0.5 hours. Dry γ-cyclodextrin (compound 1) (2Kg) was dissolved in dry N,N-dimethylformamide (15L), and added dropwise to the above reaction system at 5-10°C. The temperature was raised to 65-70°C, the reaction was continued for 85 hours, and the reaction was stopped. Cool the reaction solution to room temperature, add it to ice water (90L), adjust the pH value of the mixture to 8-9 with 5mol / L sodium hydroxide solution, a large amount of solids precipitat...

Embodiment 2

[0067] 6-perdeoxy-6-per(2-carboxyethyl)sulfide-γ-cyclodextrin (sugammadex sodium)

[0068]

[0069] Step 1: Perchlorinated γ-cyclodextrin (compound 2)

[0070] Add dry N,N-dimethylformamide (75 mL) into a 250 mL dry three-necked flask, replace with nitrogen, and cool in an ice bath. Thionyl chloride (29.4 g) was added dropwise at 0-5°C, and the dropwise addition was completed in 30 minutes, then the temperature was raised to room temperature and the reaction was continued with stirring for 1 hour. Add dry γ-cyclodextrin (Compound 1) (10g) into the reaction system at 5-10°C, raise the temperature to 70-75°C for 24 hours, cool the reaction solution to room temperature, and concentrate under reduced pressure to half the volume of the reaction solution , add the remaining solution to ice water (1.5 L), adjust the pH value of the mixed solution to 8-9 with sodium hydroxide, a large amount of solids are precipitated, raise the temperature of the reaction system to room temperatu...

Embodiment 3

[0074] Preparation of perchlorinated γ-cyclodextrin (compound 2)

[0075] Add dry N,N-dimethylformamide (15 L) into a 50 L dry reaction kettle, replace the air with nitrogen, and cool with an ice bath. Oxalyl chloride (3.35Kg) was added dropwise at a temperature of 0-5°C, and the addition was completed in 110 minutes, and the stirring was continued for 0.5 hour. Dry γ-cyclodextrin (compound 1) (2Kg) was dissolved in dry N,N-dimethylformamide (10L), and added dropwise to the above reaction system at 5-10°C. The temperature was raised to 65-70° C., and the reaction was continued for 20 hours. Cool the reaction solution to room temperature, add it to ice water (90L), adjust the pH value of the mixture to 8-9 with sodium hydroxide, a large amount of solids precipitate, raise the reaction temperature to room temperature and continue stirring for 1 hour, suction filtration, filter cake It was washed with water (15 L) and dried to obtain perchlorinated γ-cyclodextrin (compound 2) (...

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Abstract

The invention provides a preparation method for sugammadex and intermediates thereof. The method comprises a step that a compound in the formula (I) and a chloride agent are subjected to a chlorination reaction, wherein the chloride agent is selected from thionyl chloride and oxalyl chloride. The formula (I) is shown in the specification. The method is advantaged by simple technology process, high yield, high purity and no pollution, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of sugammadex sodium and an intermediate thereof. Background technique [0002] Sugammadex is a neuromuscular anesthesia reversal agent developed by Merck for the induction of neuromuscular anesthetics (NMBA, also known as muscle relaxants) such as rocuronium bromide or vecuronium bromide. [0003] Inversion agents of neuromuscular anesthetics are often given to patients at the end of surgery or a period of intensive therapy to help restore muscle function. Commonly used reversal agents for neuromuscular anesthetics are acetylcholinesterase inhibitors (AChE) such as efenonium chloride, neostigmine, and pyridostigmine bromide, which are not suitable for depolarizing neuromuscular anesthetics such as succinylcholine. reverse. AKZONOBELN.V. has reported that chemical chelating agents (complexes formed by neuromuscular anesthetics and inversion agents) are used as inversion agents and are effective for both n...

Claims

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Application Information

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IPC IPC(8): C08B37/00
Inventor 杨家亮赵富强肖至阳隆元强赵紫微
Owner SICHUAN HAISCO PHARMA CO LTD
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