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Synthesis method of sugammadex sodium impurities

A technology of sugammadex sodium and synthetic method, which is applied in the field of new synthesis of known compounds, and can solve the problems of no synthetic method, instability to oxygen, low impurity content, etc.

Active Publication Date: 2020-04-17
武汉嘉诺康医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Due to the presence of thioether bonds in the molecular structure of sugammadex sodium, the compound is unstable to oxygen and is easily oxidized to form a series of oxidized impurities and disulfide impurities such as sulfoxide, sulfone, and disulfide during the purification process. During the synthesis of sugammadex sodium, products of different substitutions will also be produced. If the bromines at 8 sites in octa-(6-bromo-6-deoxy)-γ-cyclodextrin are completely substituted, it will be the product sugammadex Sodium glucose, if the bromine at 7 positions in octa-(6-bromo-6-deoxy)-γ-cyclodextrin is the impurity to be studied in this invention, the original research patent mentioned 7 positions Substances where iodine is substituted, but the content of this impurity is extremely low, and there is no synthetic method for this impurity in the open literature

Method used

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  • Synthesis method of sugammadex sodium impurities
  • Synthesis method of sugammadex sodium impurities
  • Synthesis method of sugammadex sodium impurities

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Embodiment 1

[0032] Embodiment 1: a kind of synthetic method of sugammadex sodium impurity, its steps are as follows:

[0033] (1) replace

[0034] At room temperature, under the protection of nitrogen, add 50mL of N,N-dimethylformamide to a 250mL three-necked flask, then add 1.2g of 3-mercaptopropionic acid, then add 0.89g of 60% sodium hydride solid in four batches, add dropwise 5g of octa- The mixture of (6-bromo-6-deoxy)-γ-cyclodextrin and 50mL N,N-dimethylformamide was heated to 40-50°C for 16 hours after dropping, and then cooled to 0-10°C after the reaction was completed. °C suction filtration to obtain 21.3 g of a white solid, which is a crude impurity product.

[0035] (2) refined

[0036] The crude impurity product was beaten with 128 mL of absolute ethanol (volume of absolute ethanol: weight of impurity crude product = 6 mL: 1 g) for 2 h, filtered, and the filter cake was dissolved in purified water (volume: filter cake weight = 3 mL: 1 g), and N was added dropwise. N-dimethy...

Embodiment 2

[0037] Embodiment 2: a kind of synthetic method of sugammadex sodium impurity, its steps are as follows:

[0038] (1) replace

[0039] At room temperature, under nitrogen protection, add 50mL dimethyl sulfoxide to a 250mL three-necked flask, then add 1.2g 3-mercaptopropionic acid, then add 0.89g 60% sodium hydride solid in four batches, add dropwise 5g octa-(6- The mixed solution of bromo-6-deoxy)-γ-cyclodextrin and 50mL dimethyl sulfoxide was heated to 40-50°C for 16 hours after dripping, and then cooled to 0-10°C for suction filtration to obtain white Solid 22.4g.

[0040] (2) refined

[0041] The crude impurity was beaten with 134 mL of absolute ethanol (volume of absolute ethanol: weight of crude impurity = 6 mL: 1 g) for 2 h, filtered, and the filter cake was dissolved in purified water (volume: weight of filter cake = 3 mL: 1 g), and N , N-dimethylformamide (volume: weight of filter cake = 12mL: 1g), crystallize at 20-30°C, filter with suction, dissolve the filter cak...

Embodiment 3

[0042] Embodiment 3: a kind of synthetic method of sugammadex sodium impurity, its steps are as follows:

[0043] (1) replace

[0044] At room temperature, under the protection of nitrogen, add 50mL N,N-dimethylformamide to a 250mL three-necked flask, then add 1.2g of 3-mercaptopropionic acid, then add 4g of 30wt% sodium methoxide solution dropwise, and add dropwise 5g of octa-(6 The mixed solution of -bromo-6-deoxy)-γ-cyclodextrin and 50mL N,N-dimethylformamide was heated to 40-50°C and reacted for 16 hours after the dripping, and then cooled to 0-10°C for pumping Filter to obtain 20.2 g of white solid.

[0045] (2) refined

[0046] The crude impurity product was beaten with 121 mL of absolute ethanol (volume of absolute ethanol: weight of impurity crude product = 6 mL: 1 g) for 2 hours, filtered, and the filter cake was dissolved in purified water (volume: filter cake weight = 3 mL: 1 g), and two Methyl sulfoxide (volume: weight of filter cake = 6mL: 1g), crystallize at 20-...

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Abstract

The invention relates to the technical field of novel synthesis methods of known compounds, and specifically discloses a synthesis method of sugammadex sodium impurities. The method comprises the following steps: reacting octakis-(6-bromo-6-deoxy)-gamma-cyclodextrin, 3-mercaptopropionic acid and alkali in a molar ratio of 1: (3.5-4.5): (7.5-8.5) at 40-50 DEG C for 14-20 hours, and performing refining treatment such as washing and starching, and recrystallization to obtain the sugammadex sodium impurity. The sugammadex sodium impurity prepared by the method has a purity of 99% or above, and thecan be used as a reference substance for quality research.

Description

technical field [0001] The invention relates to the technical field of new synthesis methods of known compounds, in particular to a synthesis method of sugammadex sodium impurities. Background technique [0002] Sugammadex sodium: chemical name: octa-6-perdeoxy-6-full (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, English: Suγdex, trade name: Bridion, sugammadex Sodium was first discovered by Organon Biosciences, which was acquired by Schering-Plough in 2007. Schering-Plough merged with Merck in 2009. Sugammadex sodium is currently owned and sold by Merck. [0003] In 2008, the FDA was concerned that it might cause allergic reactions, so it rejected Schering-Plough’s listing application for sugammadex sodium; at the end of 2009, sugammadex sodium was approved for marketing in Europe; soon Merck began to set up 11 clinical medical centers in China, Initiated the phase III clinical study of sugammadex sodium in China. Sugammadex sodium is used to reverse the effect of r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16
CPCC08B37/0012
Inventor 叶学进范德华张志海魏文国
Owner 武汉嘉诺康医药技术有限公司
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