Sugammadex sodium intermediate diphenylphosphinic acid derivative impurity and preparation method thereof

A technology of sugammadex sodium and diphenyl phosphate, which is applied in the field of drug impurity synthesis, can solve the problem that the impurity of sugammadex sodium diphenyl phosphate has not been reported, and the research on impurities of diphenyl phosphate derivatives has not been mentioned, etc. question

Inactive Publication Date: 2020-11-20
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

[0009] Currently Tianjin Kelun Pharmaceuticals patent application CN110627926A provides 21 sugammadex sodium API related substances and their preparation methods and applications, but the

Method used

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  • Sugammadex sodium intermediate diphenylphosphinic acid derivative impurity and preparation method thereof
  • Sugammadex sodium intermediate diphenylphosphinic acid derivative impurity and preparation method thereof
  • Sugammadex sodium intermediate diphenylphosphinic acid derivative impurity and preparation method thereof

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Embodiment 1

[0037] Embodiment 1 A sugammadex sodium intermediate diphenyl phosphate derivative impurity, its preparation method is as follows:

[0038] Under nitrogen protection, add N,N-dimethylformamide (10.5ml) and diphenylphosphoric acid (2.87g, 13.16mmol) into a 100ml three-necked flask, control the internal temperature to ≤10°C, and then add cesium carbonate (4.29 g, 13.16mmol), stirring and reacting for 0.5 hours, while stirring and reacting, add N,N-dimethylformamide (18ml) in a 100ml beaker, then add 6-full deoxy-6-full iodo-γ-ring Dextrin (3.58g, 1.65mmol), stirred until the solids were completely dissolved and set aside, after the stirring reaction was completed for 0.5 hours, add the above-mentioned 6-perdeoxy-6-periodo-γ-cyclodextrin dropwise into a 100ml three-necked flask. Solution, after the dropwise addition, heat up to 60-65°C for 18 hours, then cool down to 20-30°C, add 100ml of purified water to the reaction system, stir at room temperature for 1h, filter, and filter c...

Embodiment 2

[0047] Embodiment 2 A sugammadex sodium intermediate diphenyl phosphate derivative impurity, its preparation method is as follows:

[0048]At room temperature, under the protection of nitrogen, add dimethylsulfoxide (5.3ml) and diphenylphosphoric acid (0.91g, 4.15mmol) into a 100ml three-necked flask, control the internal temperature to ≤10°C, and then add sodium hydroxide (0.17g, 4.15mmol), stirred and reacted for 0.5 hour, while stirring and reacted, dimethyl sulfoxide (9ml) was added in a 100ml beaker, and then 6-full deoxy-6-full iodo-γ-cyclodextrin (1.79g, 0.83mmol), stir until the solids are all dissolved and set aside, after the stirring reaction is completed for 0.5 hours, add the above-mentioned 6-perdeoxy-6-periodo-γ-cyclodextrin solution dropwise into a 100ml three-necked bottle, after the dropwise addition , heat up to 60-65°C and react for 18 hours, then cool down to 20-30°C, add 50ml of purified water to the reaction system, stir at room temperature for 1 hour, f...

Embodiment 3

[0049] Embodiment 3 A sugammadex sodium intermediate diphenyl phosphate derivative impurity, its preparation method is as follows:

[0050] At room temperature, under argon protection, add dimethyl sulfoxide (10.5ml) and diphenylphosphoric acid (4.31g, 19.74mmol) to a 100ml three-necked flask, control the internal temperature to ≤10°C, and then add 60% sodium hydride (0.79 g, 19.74mmol), stirring and reacting for 0.5 hour, while stirring and reacting, add dimethyl sulfoxide (18ml) in a 100ml beaker, then add 6-full deoxy-6-full iodo-γ-cyclodextrin (3.58 g, 1.65mmol), stir until the solids are all dissolved and set aside, after the stirring reaction is completed for 0.5 hours, add the solution of the above-mentioned 6-perdeoxy-6-periodo-γ-cyclodextrin dropwise to a 100ml three-necked bottle, and add dropwise After completion, raise the temperature to 60-65°C for 18 hours, then lower the temperature to 20-30°C, add 100ml of purified water to the reaction system, stir at room tem...

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Abstract

The invention relates to the technical field of medicine impurity synthesis. The invention discloses a diphenylphosphinic acid derivative impurity in a sugammadex sodium intermediate gamma-ICD and a preparation method of the diphenylphosphinic acid derivative impurity. The preparation method of the impurity comprises the following steps: (1) dissolving diphenylphosphinic acid in an organic solvent, adding a certain amount of alkali under the protection of inert gas, carrying out stirring and reacting for a period of time at a certain temperature, then adding 6-total deoxy-6-total iodo-gamma-cyclodextrin, reacting for a period of time at a certain temperature, and carrying out aftertreatment to obtain a compound crude product shown as a formula I; and (2) separating and purifying the crudeproduct to obtain the single compound shown in the formula I. The invention provides a standard reference substance for quality control of the sugammadex sodium intermediate gamma-ICD, and is particularly important for impurity research and quality control of the sugammadex sodium intermediate gamma-ICD; and the preparation method disclosed by the invention has the beneficial effects that the operation is convenient, the reaction conditions are mild and controllable, the reaction stability is high, and the reaction product is high in yield and purity.

Description

technical field [0001] The invention relates to the field of drug impurity synthesis, in particular to a sugammadex sodium intermediate diphenyl phosphate derivative impurity and a preparation method thereof. Background technique [0002] Sugammadex Sodium, chemical name 6-perdeoxy-6-perfect (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, trade name Bridion, CAS: 343306-71- 8. The structural formula is as follows: [0003] [0004] Sugammadex sodium is a selective relaxation agent used to reverse the effect of muscle relaxants rocuronium bromide or vecuronium bromide, which was first discovered by the Dutch company Organon Biosciences. On July 25, 2008, the European Medicines Agency approved sugammadex sodium for marketing in Europe. On October 20, 2010, sugammadex sodium was approved for marketing in Japan. In November 2015, the FDA approved the drug for marketing in the United States. At present, CFDA has approved the listing of sugammadex sodium in China on April ...

Claims

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Application Information

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IPC IPC(8): C08B37/16
CPCC08B37/0012
Inventor 魏文国童勇古双喜陈炯叶学进张波
Owner 武汉嘉诺康医药技术有限公司
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