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High-purity tazobactam sodium compound

A technology for tazobactam sodium and compound, which is applied in the refining field of tazobactam sodium compound, can solve the problems of affecting clinical application, difficult reaction, decreased preparation stability, etc., and is suitable for large-scale industrial production and improves clinical application. The effect of medication, the effect of improving stability

Inactive Publication Date: 2010-04-21
HAINAN MEIDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(1) Take sulbactam as raw material through azidation, protection, cyclization and deprotection to synthesize tazobactam sodium. This route mainly has the following two disadvantages: 1. raw material price is high, and sulbactam is based on 6- APA is used as a raw material, and it is prepared through several steps such as diazotization, oxidation, hydrogenolysis, and debromination, and the yield is only more than 40%. Nitriding reaction is difficult to take place, and productive rate is very low, is the key point that restricts this synthetic route, and the sulfur of ortho position has been fully oxidized and under the situation that there are no other substituents on the methyl group, azidation reaction is very difficult; ( 2) MicetichR.G and MaitiS.N et al reported in 1986 the synthetic route of taking penicillin G potassium salt as raw material to synthesize tazobactam sodium. This synthetic route is except the first four steps of reaction, and all the other steps are the same as that of 6-APA The synthetic route of the raw material is completely consistent with
[0006] The raw material of tazobactam sodium obtained by the method of synthesizing tazobactam sodium in the prior art generally has the problem of low purity, which leads to a sharp decline in the stability of the preparation and affects its clinical application

Method used

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  • High-purity tazobactam sodium compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Purification of Tazobactam Sodium

[0031] (1) Dissolve 100g of tazobactam sodium crude product in 1500ml of water, add 0.01mol / L sulfuric acid solution to adjust the pH value to 2.0, stir to precipitate insoluble matter, filter, and obtain a solid after washing with purified water;

[0032] (2) the solid obtained in step (1) is dissolved in 1000ml of a mixture of dichloromethane and methanol (volume ratio 3: 2), added to a column filled with D101 macroporous resin and passed through, and then mixed with dichloromethane and ethyl acetate (volume Ratio 1: 2) 500ml of the mixture was eluted and purified as the eluent, and the eluate was collected;

[0033] (3) Adjust the pH value of the eluate obtained in step (2) to 5.5 with 5% sodium isooctanoate solution, and precipitate a solid, centrifuge for 10 min, wash with 500 ml of ethyl acetate, and vacuum-dry at 50° C. for 6 hours to obtain a refined product 93.1g, yield 93.1%, HPLC detection purity 99.95%.

Embodiment 2

[0035] Purification of Tazobactam Sodium

[0036] (1) Dissolve 100g of tazobactam sodium crude product in 1500ml of water, add 0.05mol / L hydrochloric acid solution to adjust the pH value to 3.0, stir to precipitate insoluble matter, filter, and obtain a solid after washing with purified water;

[0037] (2) Dissolve the solid obtained in step (1) with 1000ml of a mixture of dichloromethane and methanol (volume ratio 3:2), add to the column filled with AB-8 macroporous adsorption resin and pass through, then dichloromethane and ethyl acetate Esters (volume ratio 1: 2) mixture 500ml are used as eluent for elution and purification, and the eluate is collected;

[0038] (3) The eluent obtained in step (2) was adjusted to a pH value of 6.5 with 5% sodium bicarbonate solution, and a solid was precipitated, centrifuged for 20 min, washed with 500 ml of ethyl acetate, and vacuum-dried at 60° C. for 4 hours to obtain a refined product 92.2g, yield 92.2%, HPLC detection purity 99.92%. ...

Embodiment 3

[0039] The refining of embodiment 3 tazobactam sodium

[0040] (1) Dissolve 100g of tazobactam sodium crude product in 1500ml of water, add 0.1mol / L phosphoric acid solution to adjust the pH value to 4.0, stir to precipitate insoluble matter, filter, and obtain a solid after washing with purified water;

[0041] (2) Dissolve the solid obtained in step (1) with 1000ml of a mixture of dichloromethane and methanol (volume ratio 3:2), add to the column filled with AB-8 macroporous adsorption resin and pass through, then dichloromethane and ethyl acetate Esters (volume ratio 1: 2) mixture 600ml is eluted and purified as an eluent, and the eluate is collected;

[0042] (3) Adjust the pH value of the eluate obtained in step (2) to 8.0 with 0.01mol / L sodium acetate solution, and precipitate a solid, centrifuge for 10 min, wash with 500 ml of ethyl acetate, and vacuum-dry at 55°C for 5 hours to obtain the essence The product is 91.7g, the yield is 91.7%, and the purity detected by HPLC ...

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Abstract

The invention relates to a high-purity tazobactam sodium compound, and particularly provides a method for refining the tazobactam sodium compound. The method comprises the following steps: a, dissolving a tazobactam sodium coarse product into water, regulating the pH value of aqueous solution to less than 7 and collecting solid precipitated from the solution; b, dissolving the solid obtained in the step a into organic solvent to obtain solution to be refined; c, putting the solution to be refined into macroporous absorption resin, performing elution and purification by using eluting agent, and collecting eluent; and d, regulating the pH value of the eluent obtained in the step c to 7 and collecting the precipitated solid to obtain refined tazobactam sodium. The refined tazobactam sodium compound prepared by the method has the purity of over 99.8 percent and the yield of over 90 percent.

Description

field of invention [0001] The invention relates to a method for refining a high-purity tazobactam sodium compound, which belongs to the technical field of medicine. Background technique [0002] Tazobactam sodium (Tazobac tam Sodi um), chemical name: 3a-methyl-7-oxo-3b-(1H-1,2,3,-triazole-1-methylene)-4 -Thia-1-azabicyclo[3.2.0]heptane-2a-sodium carboxylate-4,4-dioxide, molecular formula: C 10 h 11 N 4 NaO 5 S, molecular weight: 322.27, structural formula: [0003] [0004] It is a β-lactamase inhibitor used clinically after clavulanic acid and sulbactam. It was developed by Dapeng Pharmaceutical Company of Japan. Its compound preparation with piperacillin was developed in 1992. The Lederle subsidiary of the American Cyanamid company was first listed in France, and in 1993 it was listed in Britain, Germany, Switzerland and the United States. The inhibitory effect of this product on various enzyme types is stronger than that of sulbactam, which is equivalent to clavu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/87C07D499/18
Inventor 邱民
Owner HAINAN MEIDA PHARMA
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