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Sulbactam sodium compound containing one-twentieth water and pharmaceutical composition thereof

A technology of sulbactam sodium and compound, which is applied in the field of chemical engineering and pharmaceutical crystallization, can solve the problems of low thermal decomposition temperature, unstable product quality, poor fluidity, etc., and achieves wide application prospect, stable product quality and good thermal stability. Effect

Inactive Publication Date: 2019-01-04
梁怡
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The concentration of 2 μg / ml has a strong inhibitory effect on Richmond-Syks Ⅱ, Ⅲ, Ⅳ and Ⅴ type β-lactamases, but has no effect on Ⅰ type β-lactamases
[0003] The synthesis of sulbactam sodium is reported in the literature. Using 6-APA as the starting material, the sulbactam sodium compound is prepared through diazotization, oxidation, reduction, and salt formation. This method has achieved industrial production, but there are problems in actual operation. Problems such as incomplete oxidation, high cost of hydrogen reduction using palladium carbon as a catalyst, difficult process control, and unstable quality of finished products; in addition, the sulbactam sodium compound prepared by this method is anhydrous, and has poor storage stability and thermal decomposition. Low temperature, poor fluidity, easy to absorb moisture and other serious problems
Thereby influence product quality, cause preparation product unclear, turbidity unqualified, and reduced the stability of preparation, in order to obtain a kind of performance more excellent sulbactam sodium compound, propose the present invention

Method used

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  • Sulbactam sodium compound containing one-twentieth water and pharmaceutical composition thereof
  • Sulbactam sodium compound containing one-twentieth water and pharmaceutical composition thereof
  • Sulbactam sodium compound containing one-twentieth water and pharmaceutical composition thereof

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Embodiment 1

[0030] The preparation of embodiment 1 1 / 20 water sulbactam sodium compound

[0031] (1) Add 813g bromine to 3.9L ethyl acetate, cool to 5°C, slowly add 150ml 3mol / L sulfuric acid solution, keep the temperature, slowly add 429g 6-APA, then slowly add 279g sodium nitrite, react 1h, slowly add 4mol / L sodium bisulfite solution until the solution is colorless, let it stand for 15min, separate layers, extract the aqueous layer with ethyl acetate 3 times, combine the organic layers, wash 2 times with saturated brine to obtain 6, 6-dibromopenicillium ammonia solution;

[0032] (2) Add 2.6L of purified water to the above organic phase, stir, cool to 0°C, keep the temperature, adjust the pH value to 5.7 with 4mol / L sodium hydroxide solution, slowly add 390g of potassium permanganate and 240g of phosphoric acid The mixture was kept warm for 30 minutes, and the pH value was adjusted to 1.5 with 3mol / L sulfuric acid solution. Keeping the temperature and pH value unchanged, slowly added 4...

Embodiment 2

[0038] The preparation of embodiment 2 1 / 20 water sulbactam sodium compound

[0039] (1) Add 190g bromine to 1L ethyl acetate, cool to 0°C, slowly add 35ml 3mol / L sulfuric acid solution, keep the temperature, slowly add 100g 6-APA, then slowly add 65g sodium nitrite, react for 1h , slowly add 4mol / L sodium bisulfite solution until the solution is colorless, let it stand for 30min, separate layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers, and wash twice with saturated brine to obtain 6,6 - dibromopenicillium ammonia solution;

[0040] (2) Add 1L of purified water to the above organic phase, stir, cool to 1°C, keep the temperature, adjust the pH value to 6.0 with 4mol / L sodium hydroxide solution, slowly add a mixture of 93g potassium permanganate and 56g phosphoric acid , keep warm for 40min, adjust the pH value to 2.0 with 3mol / L sulfuric acid solution, keep the temperature and pH value constant, slowly add 4mol / L sodium bisulfite solutio...

Embodiment 3

[0046] The preparation of embodiment 3 1 / 20 water sulbactam sodium compound

[0047] (1) Add 285g bromine to 1.4L ethyl acetate, cool to 2°C, slowly add 52ml 3mol / L sulfuric acid solution, keep the temperature, slowly add 150g 6-APA, then slowly add 100g sodium nitrite, react 1h, slowly add 4mol / L sodium bisulfite solution until the solution is colorless, let it stand for 15min, separate layers, extract the aqueous layer with ethyl acetate 3 times, combine the organic layers, wash 2 times with saturated brine to obtain 6, 6-dibromopenicillium ammonia solution;

[0048] (2) Add 1.2L of purified water to the above organic phase, stir, cool to 2°C, keep the temperature, adjust the pH value to 6.0 with 4mol / L sodium hydroxide solution, slowly add 275g of potassium permanganate and 165g of phosphoric acid The mixture was kept warm for 30 minutes, and the pH value was adjusted to 2.0 with 3mol / L sulfuric acid solution. Keeping the temperature and pH value unchanged, slowly added 4m...

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Abstract

The invention discloses a sulbactam sodium compound containing one-twentieth water. The sulbactam sodium compound is white crystalline powder, and each mole of sulbactam sodium contains one-twentiethmole of water. The sulbactam sodium compound has main diffraction peaks at the positions with the corresponding main X-ray characteristic diffraction peak 2 theta angle of 14.23+ / -0.2 degrees, 17.76+ / -0.2 degrees, 19.22+ / -0.2 degrees, 23.09+ / -0.2 degrees, 24.60+ / -0.2 degrees and 27.86+ / -0.2 degrees. The sulbactam sodium compound prepared by means of a method has high stability and meets the requirements for being used a raw material of a preparation.

Description

technical field [0001] The invention belongs to the technical field of chemical engineering pharmaceutical crystallization, and in particular relates to a 1 / 20 water sulbactam sodium compound and a pharmaceutical composition thereof. Background technique [0002] Sulbactam sodium is a penicillane sulfone developed by Pfizer Research Laboratory of the United States in 1978 and proved to have an enzyme-inhibiting effect. The chemical name is 2S-2(2α,5α)3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate sodium 4,4-diox. Sulbactam sodium is an irreversible competitive β-lactamase inhibitor, which can inhibit the β-lactamase produced by Gram-positive and negative bacteria (except Pseudomonas aeruginosa), and has an irreversible interaction with the enzyme. After the reaction, the enzyme is inactivated, and the activity of the enzyme cannot be restored after the inhibitor is removed. Sulbactam sodium has a strong and irreversible inhibitory effect on β-lactamases...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/86C07D499/18C07D499/04A61K31/43A61P31/04
CPCC07B2200/13C07D499/04C07D499/18C07D499/86
Inventor 梁怡
Owner 梁怡