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Preparation method of ceftezole acid and sodium salt thereof

A technology of ceftezole acid and tetrazolium acetic acid, which is applied in the field of medicine, can solve the problems of easy production of by-products, high equipment requirements, and increased costs, and achieve the effects of low cost, shortened reaction time, and improved yield

Inactive Publication Date: 2021-01-05
湖北凌晟药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is easy to cause pollution to the environment, high cost, and low yield, and the 7-position acylation reaction needs to be carried out under low temperature conditions, which increases the cost and requires high equipment.
In addition, 7-ACA was used as the starting material to react with tetrazoleacetic acid under the catalysis of DCC to produce 7-tetrazolium acetamidocephalosporanic acid, which was then combined with 2-mercapto-1,3,4-thiadi Azole reacts to generate ceftezole acid, the route is simple, but the yield is low, and it is easy to produce by-products

Method used

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  • Preparation method of ceftezole acid and sodium salt thereof
  • Preparation method of ceftezole acid and sodium salt thereof
  • Preparation method of ceftezole acid and sodium salt thereof

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preparation example Construction

[0024] The embodiment of the present invention provides a kind of preparation method of ceftezole, comprising the following steps:

[0025] S1: 2-mercapto-1,3,4-thiadiazole and 7-ACA were used as raw materials, and boron trifluoride dimethyl carbonate complex was used as a catalyst to synthesize the intermediate 7-ACT. The involved reaction formula is as follows;

[0026]

[0027] S2: Tetrazolium acetic acid is reacted with terephthaloyl dichloride to form a mixed anhydride, and then reacted with the intermediate 7-ACT to synthesize ceftezole acid. The involved reaction formula is as follows.

[0028]

Embodiment 1

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

[0036] S1: Add 300L of dimethyl carbonate to the reaction kettle, under the protection of nitrogen, add 337.5kg of boron trifluoride dimethyl carbonate complex and 50kg of formic acid, stir and cool down to 4°C, under the protection of nitrogen and the temperature <10 Add 48kg of MTD and 100kg of 7-ACA under the condition of ℃, rinse the pipeline of the container with 30L dimethyl carbonate, the system starts to be turbid, and quickly becomes clear to a light yellow clear solution, and the temperature is raised to 18℃ for 35min to obtain 7-ACT The reaction solution, sampling HPLC test 7-ACA content <3%,

[0037]Add 800L of deionized water to the crystallization tank, add 0.5kg of sodium metabisulfite and 0.5kg of disodium ethylenediaminetetraacetate, stir and adjust the temperature to 4°C, add the resulting reaction solution, at 4°C Adjust the pH to 0.8 with sodium hydroxide within 70 minutes, slowly stir an...

Embodiment 2

[0044] A preparation method of ceftezole, comprising the steps of:

[0045] S1: Add 300L of dimethyl carbonate to the reaction kettle, under nitrogen protection, add 335kg of boron trifluoride dimethyl carbonate complex and 40kg of formic acid, stir and cool down to 5°C, under nitrogen protection and the temperature <10°C Adding 45kg of MTD and 100kg of 7-ACA under the same conditions, the system started to become turbid, and quickly became clear to obtain a light yellow clear solution. The temperature was raised to 20°C and reacted for 30 minutes to obtain a reaction solution containing 7-ACT. Sample HPLC was used to test the content of 7-ACA < 3%,

[0046] Add 800L of deionized water to the crystallization tank, add 0.5kg of sodium metabisulfite and 0.5kg of disodium ethylenediaminetetraacetate, stir and adjust the temperature to 5°C, add the resulting reaction solution, at 5°C Adjust the pH to 0.5 with sodium hydroxide within 60 minutes, slowly stir and grow the crystals f...

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Abstract

The invention relates to the technical field of medicines, and particularly discloses a preparation method of ceftezole acid and sodium salt thereof. The preparation method comprises the following steps: adding MTD and 7-ACA into a dimethyl carbonate, boron trifluoride dimethyl carbonate complex and formic acid system, and reacting at 18-22 DEG C to obtain an intermediate 7-ACT; and reacting the 7-ACT with a mixed anhydride solution prepared from TAA and TCL at 11-14 DEG C, and carrying out decolorizing, crystallizing, centrifuging and drying operations to obtain the ceftezole acid. The methodcomprises the following steps: adding ceftezole acid into water, regulating the pH value to 4.9-5.5 by using sodium bicarbonate, primarily growing crystals in a methanol-ethanol mixed solvent, and supplementing ethanol to further grow crystals, thereby obtaining ceftezole sodium. The preparation method provided by the invention has the advantages of simple process, mild reaction conditions and small pollution, the cost can be reduced, the yield of the ceftezole acid can be effectively improved, the yield of the ceftezole sodium prepared from the ceftezole acid is more than or equal to 98 percent, and the purity of the obtained ceftezole sodium is more than 99.8 percent.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of ceftezole acid and its sodium salt. Background technique [0002] Ceftezole acid, the chemical name is (6R)-8-oxo-7-[(1H-1-tetrazolylacetyl)amino]-3-[[2-(1,3,4-thia Diazolyl)thio]methyl]-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid, synthesized and developed by Japan Fujisawa Pharmaceutical Co. Semisynthetic cephalosporin antibiotic. Ceftezole acid is the main raw material for preparing ceftezole sodium, and its quality directly affects the quality of ceftezole sodium. [0003] At present, there are few documents about the synthesis process of ceftezole acid, mainly using tetrazolium acetic acid as the starting material, firstly preparing the acid chloride, and then reacting with 7-ACA to obtain the intermediate 7-tetrazolium acetamido cephalosporin acid, and then synthesize ceftezole acid with 2-mercapto-1,3,4-thiadiazole. This method is eas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/04C07D501/12C07D501/36
CPCC07D501/04C07D501/12C07D501/36
Inventor 何健金联明金大俊门万辉邹菁
Owner 湖北凌晟药业股份有限公司
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