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1/10 water sulbactam sodium compound and pharmaceutical composition preparation

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: 2019-01-08
HAINAN MEILAN SMITH KLINE PHARMA
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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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  • 1/10 water sulbactam sodium compound and pharmaceutical composition preparation
  • 1/10 water sulbactam sodium compound and pharmaceutical composition preparation
  • 1/10 water sulbactam sodium compound and pharmaceutical composition preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of embodiment 1 1 / 10 water sulbactam sodium compound

[0031] (1) Add 380g bromine to 1.8L ethyl acetate, cool to 0°C, slowly add 70ml 3mol / L sulfuric acid solution, keep the temperature, slowly add 200g 6-APA, then slowly add 130g 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 1.2L of purified water to the above organic phase, stir, cool to 0°C, keep the temperature, adjust the pH value to 5.5 with 4mol / L sodium hydroxide solution, slowly add 184g of potassium permanganate and 110g 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 4m...

Embodiment 2

[0038] The preparation of embodiment 2 1 / 10 water sulbactam sodium compound

[0039] (1) Add 382g bromine to 2L ethyl acetate, cool to 5°C, slowly add 70ml 3mol / L sulfuric acid solution, keep the temperature, slowly add 201g 6-APA, then slowly add 129g sodium nitrite, react for 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 three times, combine the organic layers, and wash twice with saturated brine to obtain 6,6 - dibromopenicillium ammonia solution;

[0040] (2) Add 1.5L of purified water to the above organic phase, stir, cool to 5°C, keep the temperature, adjust the pH value to 6.5 with 4mol / L sodium hydroxide solution, slowly add 185g of potassium permanganate and 111g of phosphoric acid The mixture was kept warm for 30 minutes, and the pH value was adjusted to 2.5 with 3mol / L sulfuric acid solution. Keeping the temperature and pH value unchanged, slowl...

Embodiment 3

[0046] The preparation of embodiment 3 1 / 10 water sulbactam sodium compound

[0047] (1) Add 1.14kg bromine into 5.4L ethyl acetate, cool to 2°C, slowly add 210ml 3mol / L sulfuric acid solution, keep the temperature, slowly add 600g 6-APA, then slowly add 400g sodium nitrite, React for 1 h, slowly add 4 mol / L sodium bisulfite solution until the solution is colorless, let stand for 15 min, separate layers, extract the aqueous layer with ethyl acetate 3 times, combine the organic layers, and wash with saturated brine twice to obtain 6 , 6-dibromopenicillamine solution;

[0048] (2) Add 4.6L 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 550g of potassium permanganate and 330g 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 ad...

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Abstract

The invention discloses a 1 / 10 water sulbactam sodium compound, each molar of sulbactam sodium contains 1 / 10 molar of water, and the 1 / 10 water sulbactam sodium compound is white crystalline powder. When the angle 2theta of the corresponding main X-ray characteristic diffraction peak is 14.24 plus or minus 0.2 degrees, 19.22 plus or minus 0.2 degrees, 20.40 plus or minus 0.2 degrees, 23.09 plus orminus 0.2 degrees, and 27.88 plus or minus 0.2 degrees, the 1 / 10 water sulbactam sodium compound has a characteristic diffraction peak. The 1 / 10 water sulbactam sodium compound prepared through a method is excellent in stability and meets the requirement on the raw material of a preparation.

Description

technical field [0001] The invention belongs to the technical field of chemical engineering medicine crystallization, and in particular relates to a 1 / 10 sulbactam sodium compound and a pharmaceutical composition preparation 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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IPC IPC(8): C07D499/86C07D499/16A61K31/43A61P31/04
CPCC07D499/16C07D499/86
Inventor 陈晓滨
Owner HAINAN MEILAN SMITH KLINE PHARMA