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Preparation method of cefotetan disodium

A technology of cefotetan disodium and cefotetan acid, which is applied in the field of cefotetan disodium, can solve the problems of high impurity content, unstable quality, and poor fluidity, and achieve low impurity content, good fluidity, and high quality The effect of stability

Active Publication Date: 2019-05-31
NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved in the present invention is to provide a preparation method of cefotetan disodium, avoiding the occurrence of problems such as high impurity content, poor fluidity, unstable quality, and high energy consumption in traditional freeze-dried products

Method used

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  • Preparation method of cefotetan disodium
  • Preparation method of cefotetan disodium
  • Preparation method of cefotetan disodium

Examples

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preparation example Construction

[0029] A preparation method of Cefotetan Disodium, comprising the steps of:

[0030] A. Add methanol to the reactor, stir and control the temperature at 0-5°C, then add cefotetan acid, then add the salt-forming agent, stir until dissolved, and obtain a mixed solution; the volumetric dosage of methanol is the same as that of cefotetan acid The weight ratio of the feed is 13-17:1mL / g; the salt-forming agent is sodium isooctanoate or anhydrous sodium acetate, and the molar ratio of the salt-forming agent to cefotetan acid is 2-2.08:1.

[0031] B. Control the temperature at 3-7°C, first add a small amount of organic solvent to the mixed solution until the system is slightly muddy, and then perform a crystal growth, the crystal growth time is 60-90 minutes; the organic solvent is absolute ethanol or isobutanol, The adding method of the organic solvent is dropwise, and the dropping rate of the organic solvent per 30 g of cefotetan acid is 4-8 mL / min.

[0032] C. Add an organic solv...

Embodiment 1

[0035] A preparation method of Cefotetan Disodium, comprising the steps of:

[0036] A. Add 390mL of methanol to the reaction bottle, start stirring and control the temperature at 5°C, add 30g of cefotetan acid, add 9.3g of anhydrous sodium acetate, stir to dissolve completely, and obtain a mixed solution.

[0037] B. Control the temperature of the reaction system at 7°C, add ethanol dropwise to the mixed solution at a flow rate of 4 mL / min until slightly turbid, stop feeding, and grow crystals for 60 min.

[0038] C. Add ethanol at 12mL / min after the crystal growth in step B, add 900mL of ethanol in steps B and C, stop feeding, control the temperature at 3°C ​​for crystal growth for 30 minutes, and filter to obtain cefotetan disodium solid crystals.

[0039] D. Wash the cefotetan disodium solid crystal once with 30mL absolute ethanol, wash once with the mixture of 30mL ethanol and 60mL acetone, atomize 3mL methanol through a methanol atomization device, and use sterile nitrog...

Embodiment 2

[0041] A preparation method of Cefotetan Disodium, comprising the steps of:

[0042] A. Add 510mL of methanol to the reaction bottle, start stirring and control the temperature at 0°C, add 30g of cefotetan acid, add 19.5g of sodium isooctanoate, stir to dissolve completely, and obtain a mixed solution.

[0043] B. Control the temperature of the reactor at 3°C, add ethanol dropwise to the mixed solution at a flow rate of 8 mL / min until slightly turbid, stop feeding, and grow crystals for 90 min.

[0044]C. Add ethanol at 16mL / min after the crystal growth in step B, add 1200mL ethanol in steps B and C, stop feeding, control the temperature at 3°C ​​for crystal growth for 60min, and filter to obtain cefotetan disodium solid crystals.

[0045] D. Wash the cefotetan disodium solid crystal once with 30mL of absolute ethanol, wash once with 45mL of ethanol and 60mL of acetone mixture, atomize 9mL of methanol through a methanol atomization device, and use sterile nitrogen to drive the...

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Abstract

The invention discloses a preparation method of cefotetan disodium and belongs to the technical field of medicine. The preparation method includes the steps of A, adding methanol to a reactor by stirring and controlling the temperature, and then adding cefotetan disodium and salt-forming agent by stirring until dissolved clarification is achieved to obtain a mixed solution; B, controlling the temperature of the reactor and adding a small amount of organic solvent to the reactor till the system is a bit muddy for primary crystallization; C, after the completion of primary crystallization, adding an organic solvent for secondary crystallization, and performing filtration to obtain cefotetan disodium solid crystal; D, washing the cefotetan disodium solid crystal prior to atomizing drying andvacuum drying to obtain a cefotetan disodium product. The cefotetan disodium is low in the content of purities, good in fluidity, uniform in size distribution, stable in quality, convenient for subsequent sub-packaging of powder and needle preparation products and high in safety of drug use. The preparation method has the advantages of simpleness in operation and energy conservation and environment protection.

Description

technical field [0001] The invention relates to cephalosporins, in particular to cefotetan disodium, and belongs to the technical field of medicine. Background technique [0002] Cefotetan disodium is a second-generation cephalosporin antibiotic, which was first developed by Fujisawa Company in Japan in 1979 and first launched in Japan in the late 1980s. FDA Approved as New Drug on December 27, 1985 (Cefotetan Disodium Sterile Powder Injection) is listed in the United States. The chemical name of cefotetan disodium is [6R-(6α,7α)]-7-[[[4-(2-amino-1-carboxy-2-oxoethylene)-1,3-disulfide Heterocyclobutan-2-yl]carbonyl]amino]-7-methoxy-3-[[(1-methyl-1H--tetrazol-5-yl)thio]methyl]-8-oxo Dai-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid disodium salt, the chemical structure is as follows: [0003] [0004] Cefotetan disodium is mainly obtained by the process of aseptic freeze-drying in the existing patented technology, and the production of cefotetan disodium by th...

Claims

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Application Information

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IPC IPC(8): C07D501/57C07D501/04C07D501/12
Inventor 贾全田洪年胡利敏张锁庆魏宝军张立斌马亚松贺娇任峰刘树斌
Owner NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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