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A kind of preparation method of original research quality cefazolin sodium and its pharmaceutical preparation

A technology of cefazolin sodium and dimethyl carbonate, which is applied in directions such as drug delivery, pharmaceutical formulation, organic chemistry, etc., can solve the problem of cefazolin sodium solvent residue and high water content, high production cost, increased production cost, etc. To avoid the use of freeze-drying technology, control solvent residues, and improve production efficiency

Active Publication Date: 2018-01-16
广东金城金素制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The residual solvent and moisture content of cefazolin sodium obtained by salting and crystallization under the above-mentioned solvent system are all high, and the high drying temperature under reduced pressure leads to an increase in related substances and a decrease in product quality. The use of freeze-drying technology increases production costs and reduces production efficiency. , so the production cost remains high

Method used

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  • A kind of preparation method of original research quality cefazolin sodium and its pharmaceutical preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1 (preparation of cefazolin acid)

[0022] Add 500g boron trifluoride-dimethyl carbonate solution to 500g dimethyl carbonate, add 150g 2-mercapto-5-methyl-1,3,4-thiadiazole, 300g 7-ACA and heat up to 35~ React at 40°C, add 500ml dimethylformamide after the reaction is complete, stir for 10 minutes, then slowly add hydrochloric acid within 20 minutes until the pH is 2-3, adjust the temperature to 25-35°C for 60 minutes, filter, and divide the acetone into two Washing and drying in vacuo to obtain the crude product of TDA;

[0023] Preparation of mixed anhydrides from dichloromethane, tetrazoleacetic acid, triethylamine and pivaloyl chloride;

[0024] Add crude TDA to dichloromethane solvent, lower the temperature to -30°C, add tetramethylguanidine dropwise within 30 minutes, then add dropwise mixed anhydride to control the temperature and react, and obtain cefazolin acid after phase separation, extraction, crystallization and other steps crystals and then pu...

Embodiment 2

[0025] Embodiment 2 (preparation of cefazolin sodium)

[0026] Put 45.5kg of cefazolin acid and 280kg of acetonitrile into a 1000L enamel kettle at room temperature, stir, add 82kg of 5% sodium hydroxide aqueous solution to adjust PH≈7, start to cool down to -5~-10°C, let stand to separate, and acetonitrile Add 15 kg of anhydrous sodium sulfate to the layer and dry for 2 hours, detect that the water content of the acetonitrile mother liquor is 1.4%, filter out the sodium sulfate, then filter the mother liquor with a precision filter, and use a high-vacuum multi-stage Roots pump to distill the mother liquor under reduced pressure at 25-30°C, vacuum The temperature is -0.09MPa~-0.1MPa. When distilling to solid precipitation, stop the distillation, lower the temperature to 0-5°C, stir for 2h, centrifuge, and vacuum-dry the filter cake with a high-vacuum multi-stage Roots pump at a temperature of 30-5°C. 40°C, vacuum degree -0.09MPa~-0.1MPa, after drying, a total of 43.6kg of cefa...

Embodiment 3

[0027] Embodiment 3 (preparation of cefazolin sodium)

[0028] Put 45.5kg of cefazolin acid and 280kg of acetonitrile into a 1000L enamel kettle at room temperature, stir, add 41kg of 10% sodium hydroxide aqueous solution to adjust PH≈7, start to cool down to -5~-10°C, let stand to separate, and acetonitrile Add 15 kg of anhydrous sodium sulfate to the layer and dry for 2 hours, detect that the water content of the acetonitrile mother liquor is 1.6%, filter out the sodium sulfate, and then filter the mother liquor with a precision filter. The temperature is -0.09MPa~-0.1MPa. When distilling to solid precipitation, stop the distillation, lower the temperature to 0-5°C, stir for 2h, centrifuge, and vacuum-dry the filter cake with a high-vacuum multi-stage Roots pump at a temperature of 30-5°C. 40°C, vacuum at -0.09MPa~-0.1MPa, after drying, a total of 43.0kg of cefazolin sodium was obtained, yield: 90.3%, moisture: 0.68%, impurity E was 0.17%, total impurities were 0.89%, aceton...

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Abstract

The invention discloses a preparation method of cefazolin sodium with previous research quality. The preparation method is characterized by comprising the following steps: (1) adding a boron trifluoride-dimethyl carbonate solution into dimethyl carbonate; stirring and adding 2-sulfydryl-5-methyl-1,3,4-thiadiazole and 7-ACA (Acetic Acid) to react; after the reaction is finished, adding dimethyl formamide and dropwise adding hydrochloric acid; adjusting the temperature to 25 to 35 DEG C and reacting for 60 minutes; filtering and washing with acetone; drying in vacuum to obtain a TDA (Toluene Diamine) crude product; (2) preparing mixed anhydride from dichloromethane, tetrazolyl acetic acid, triethylamine and pivaloyl chloride; (3) adding the TDA crude product into a dichloromethane solvent; cooling and dropwise adding tetramethyl guanidine; dropwise adding the mixed anhydride to react, and purifying and refining a crystal through a low-temperature acetonitrile-water extraction process after extraction and crystallization. With the adoption of the preparation method provided by the invention, the moisture content of the product can be reduced and residues of the solvent can be reduced; the increasing of related substances can be effectively reduced, a freeze-drying technology is not used and the production efficiency is improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of original-developed quality cefazolin sodium and a pharmaceutical preparation thereof. Background technique [0002] Cefazolin sodium, chemical name: (6R,7R)-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-[(1H -tetrazol-1-yl)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, molecular formula: C 14 h 13 N 8 NaO 4 S 3 , molecular weight: 476.48, CAS registration number: 27164-46-1, its chemical structural formula: [0003] [0004] Cefazolin sodium is a semi-synthetic cephalosporin antibiotic widely used clinically at present, and it is a broad-spectrum antibiotic. Except for Enterococcus and methicillin-resistant Staphylococcus, this product has good antibacterial activity against other Gram-positive cocci, and Streptococcus pneumoniae and hemolytic streptococcus are highly sensitive to this product. The anti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/04C07D501/12A61K9/14
CPCA61K9/0019A61K9/14C07D501/04C07D501/12C07D501/36
Inventor 傅苗青赵叶青孙滨许蕾朱旭伟马庆双周白水王雷
Owner 广东金城金素制药有限公司
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