Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium

A technology for cefazolin sodium and preparation, which is applied in the field of preparation of the original development quality cefazolin sodium, can solve the problems of cefazolin sodium solvent residue and high water content, high production cost, reduced production efficiency, etc. The effect of using freeze-drying technology to control solvent residues and improve production efficiency

Active Publication Date: 2016-05-04
广东金城金素制药有限公司 +1
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AI-Extracted 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 l...
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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.

Application Domain

Powder deliveryOrganic chemistry

Technology Topic

DiamineDimethyl formamide +22

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  • Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium

Examples

  • Experimental program(6)

Example Embodiment

[0021] Example 1 (Preparation of Cefazolinic Acid)
[0022] Add 500g of boron trifluoride-dimethyl carbonate solution to 500g of dimethyl carbonate, add 150g of 2-mercapto-5-methyl-1,3,4-thiadiazole and 300g of 7-ACA while stirring and increase the temperature to 35~40℃ After the reaction, add 500ml of dimethylformamide, stir for 10 minutes, slowly add hydrochloric acid within 20 minutes to a pH of 2 to 3, adjust the temperature to 25-35 ℃, react for 60 minutes, filter, and wash with acetone twice , Dried in vacuum to obtain crude TDA;
[0023] Dichloromethane, tetrazolium acetic acid, triethylamine, pivaloyl chloride to prepare mixed acid anhydride;
[0024] Add crude TDA to dichloromethane solvent, lower the temperature to -30℃, add tetramethylguanidine dropwise within 30 minutes, and then add dropwise mixed acid anhydride to control the temperature. After phase separation, extraction, crystallization and other steps, cefazolinic acid is prepared The crystals are then purified and refined.

Example Embodiment

[0025] Example 2 (Preparation of Cefazolin Sodium)
[0026] Put 45.5kg of cefazolinic 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 to -5~-10℃, stand for layering, acetonitrile Add 15 kg of anhydrous sodium sulfate to the layer and dry for 2 hours. Check that the moisture content of the mother liquor of acetonitrile is 1.4%. Filter out the sodium sulfate, and then filter the mother liquor with a precision filter. The mother liquor is distilled under reduced pressure at 25~30℃ with a high vacuum multistage Roots pump. When the temperature is between -0.09MPa~-0.1MPa, when the solid is precipitated out, stop the distillation, reduce the temperature to 0~5℃, stir for 2h, centrifuge, the filter cake is vacuum dried with high vacuum multi-stage Roots pump, and the temperature is 30~ 40℃, vacuum degree -0.09MPa~-0.1MPa, after drying, 43.6kg of cefazolin sodium was obtained, yield: 91.5%, moisture: 0.6%, impurity E was 0.15%, total impurity was 0.95%, acetonitrile The residue was 178 ppm.

Example Embodiment

[0027] Example 3 (Preparation of Cefazolin Sodium)
[0028] Put 45.5kg of cefazolinic 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 to -5~-10℃, stand for layering, acetonitrile Add 15 kg of anhydrous sodium sulfate to the layer and dry for 2 hours. Check that the moisture content of the mother liquor of acetonitrile is 1.6%, filter out the sodium sulfate, and then filter the mother liquor with a precision filter. The mother liquor is distilled under reduced pressure at 20~25℃ with a high vacuum multistage Roots pump. When the temperature is between -0.09MPa~-0.1MPa, when the solid is precipitated out, stop the distillation, reduce the temperature to 0~5℃, stir for 2h, centrifuge, the filter cake is vacuum dried with high vacuum multi-stage Roots pump, and the temperature is 30~ 40℃, vacuum degree -0.09MPa~-0.1MPa, after drying, 43.0kg of cefazolin sodium was obtained, yield: 90.3%, moisture: 0.68%, impurity E was 0.17%, total impurity was 0.89%, acetonitrile The residue was 164 ppm.

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