Preparation method of ceftezole acid

A technology of ceftezole acid and tetrazole acetic acid, which is applied in the field of preparation of ceftezole acid, can solve the problems of complex process flow, high production cost, cumbersome steps, etc., and achieve simple process flow, low cost and high yield Effect

Pending Publication Date: 2019-05-31
GUANGXI KELUN PHARMA
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  • Description
  • Claims
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Problems solved by technology

[0007] The preparation method of ceftezole acid in the prior art is a three-step method, and the existing problems are: complex process flow, cumbersome steps and high production cost, specifically including the following steps: Step 1: the production of intermediate MTZ-1, including the reaction , crystallization, centrifu...

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  • Preparation method of ceftezole acid
  • Preparation method of ceftezole acid
  • Preparation method of ceftezole acid

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Experimental program
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Effect test

Embodiment 1

[0048] The preparation method of the ceftezole acid of the present embodiment, comprises the steps:

[0049] Step 1: Production of intermediate MTZ-1

[0050] Add 33.0kg of dimethyl carbonate, 5.0kg of anhydrous formic acid, 11.0kg of 7-ACA and 5.5kg of 2-mercapto-1,3,4-thiadiazole into the reaction kettle, cool down to 0°C while stirring; then add 33.0 kg of boron trifluoride dimethyl carbonate was controlled at a temperature of 10° C., and reacted for 50 minutes to obtain the MTZ-1 reaction solution.

[0051] Transfer the MTZ-1 reaction solution into water with 2.0 times the weight of the reaction solution, adjust the pH value to 1.0 with sodium carbonate solid, centrifuge at 600 rpm for 6 hours, and dry at 45°C for 7 hours with a boiling drying bed , to obtain 11.9kg intermediate MTZ-1.

[0052] Step 2: Production of MTZ

[0053] Add 100kg of dichloromethane and 5.5kg of tetrazoleacetic acid into the reaction kettle, cool to -10°C, add triethylamine dropwise under stirri...

Embodiment 2

[0057] The preparation method of the ceftezole acid of the present embodiment, comprises the steps:

[0058] Step 1: Production of intermediate MTZ-1

[0059] Add 44.0kg of dimethyl carbonate, 5.5kg of anhydrous formic acid, 11.0kg of 7-ACA and 4.9kg of 2-mercapto-1,3,4-thiadiazole into the reaction kettle, and cool down to 10°C while stirring; 37.5 kg of boron trifluoride acetonitrile, the temperature is controlled at 20°C, and after 60 minutes of reaction, the MTZ-1 reaction solution is obtained.

[0060] Transfer the MTZ-1 reaction solution into water with 2.5 times the weight of the reaction solution, adjust the pH value to 2.0 with ammonia water, centrifuge at 800 rpm for 5.5 hours, and dry at 50°C for 6.5 hours in a blast drying oven. 12.2 kg of intermediate MTZ-1 were obtained.

[0061] Step 2: Production of MTZ

[0062] Add 100kg of dichloromethane and 4.90kg of tetrazoleacetic acid into the reaction kettle, cool to -10°C, add triethylamine dropwise under stirring u...

Embodiment 3

[0066] The preparation method of the ceftezole acid of the present embodiment, comprises the steps:

[0067] Step 1: Production of intermediate MTZ-1

[0068] Add 50.0kg of dimethyl carbonate, 5.5kg of anhydrous formic acid, 11.0kg of 7-ACA and 7.0kg of 2-mercapto-1,3,4-thiadiazole into the reaction kettle, and cool down to 20°C while stirring; 50.0 kg of boron trifluoride diethyl ether was controlled at a temperature of 30° C., and reacted for 75 minutes to obtain a MTZ-1 reaction solution.

[0069] Transfer the MTZ-1 reaction solution into water with 3.0 times the weight of the reaction solution, adjust the pH value to 3.0 with triethylamine, centrifuge at 1000 rpm for 5 hours, and dry at 55°C for 6 Hours, 12.0kg intermediate MTZ-1 was obtained.

[0070] Step 2: Production of MTZ

[0071] Add 100kg of dichloromethane and 4.5kg of tetrazoleacetic acid into the reaction kettle, cool to -10°C, add triethylamine dropwise under stirring until the tetrazoleacetic acid is comple...

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Abstract

The invention discloses a preparation method of ceftezole acid and belongs to the field of pharmaceutical technology. The preparation method of the ceftezole acid comprises the following steps of producing an intermediate of MTZ-1, specifically, adding in dimethyl carbonate, anhydrous formic acid, 7-ACA (7-aminocephalosporanic acid) and 2-mercapto-1, 3, 4-thiadiazol, then adding in Lewis acid as the catalyst for reaction, and then performing centrifugation and drying to obtain the intermediate of MTA-1; producing MTZ, specifically, adding in dichloromethane and tetrazole-1-acetic acid, coolingdown, dropwise adding in triethylamine, cooling down, adding in 4-methylpyridine and pivaloyl chloride for reaction, cooling down to obtain a mixed anhydride, adding in the TMZ-2, dropwise adding thetriethylamine for reaction, in a stirring state, adding in water for extraction, mixing for layering, decoloring the extracted aqueous phase, regulating the pH of and crystalizing the decolored solution, then performing centrifugation, washing and drying to obtain refined MTZ, namely, the ceftezole acid. The preparation method of the ceftezole acid changes a three-step method in the prior art into a two-step method, thereby effectively improving the yield, saving the cost and reducing sewage emission.

Description

technical field [0001] The invention relates to a preparation method of ceftezole acid, which belongs to the technical field of pharmacy. Background technique [0002] Ceftezole sodium, alias Yi Tixin, English name: Ceftezole Sodium, chemical name: (6R, 7R)-3-[[(1,3,4-thiazol-2-yl)sulfur]methyl]-7- [(1H-tetrazol-1-yl)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt. The structural formula is: [0003] [0004] Ceftezole sodium is a semi-synthetic cephalosporin derivative, and its mechanism of action is to exert antibacterial activity by inhibiting the synthesis of bacterial cell walls. Indications are respiratory system infection, urinary system infection, sepsis, peritonitis. It was produced successively in Japan, the United States, and Italy in the 1970s. It belongs to the first generation of cephalosporins. It is widely used clinically because of its cheap price and good performance. [0005] Ceftezole acid is the main raw material...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/04C07D501/06
Inventor 杨庆江欧世强夏志科杨晋超王清明周倩霞闫显森侯金春谭清钟蒋文明
Owner GUANGXI KELUN PHARMA
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