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HCL ceftizoxime alapivoxil synthesizing process

A technique for the synthesis of ceftizoxime hydrochloride and a synthetic process, which is applied in the field of synthetic process of ceftizoxime propivoxil hydrochloride, can solve the problems of many by-products and high cost, and achieve the effects of reliable purity, mild reaction conditions, and cost reduction

Active Publication Date: 2009-12-30
ZHEJIANG YATAI PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] This route has the disadvantages of more by-products and higher cost

Method used

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  • HCL ceftizoxime alapivoxil synthesizing process

Examples

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Embodiment 1

[0034] A kind of synthesis technique of cefazolin hydrochloride propiproxil, (1) first prepare solid cefazoxime: weigh 0.04mol 7-ANCA 8g and 0.04mol AE active ester 12.21g, add 7-ANCA to 40ml acetone solvent 25ml of water and 25ml of ethyl acetate were used for washing, and the aqueous layer was adjusted to pH 5-6 with 6N hydrochloric acid. Acidic, stirred, filtered, and dried at 60° C. to obtain 13 g of cefizoxime as a light yellow powdery solid; the yield was 162.5%.

[0035] (2) Weigh 3.83 g (0.01 mol) of cefizoxime obtained in step (1), add 20 ml of DMF solvent, cool to 0° C., and carry out stirring reaction with 3 g of methyl iodide (0.012 mol) to become clear after 3 hours; Then 150 ml of ethyl acetate was added for extraction, and the organic layer was washed successively with sodium bicarbonate with a concentration of 1% by mass and sodium hydrogen sulfite solution with a concentration of 1% by mass, and each washing was repeated three times. Then, it was dried at 60°...

Embodiment 2

[0039] A kind of synthesis technique of cefazolin hydrochloride propiproxil, (1) first prepare solid cefazoxime: weigh 0.04mol 7-ANCA 8g and 0.04mol AE active ester 12.72g, add 7-ANCA to 40ml acetonitrile solvent , at room temperature, carry out stirring reaction with AE active ester for 5 hours, concentrate and remove acetone, and then carry out suction washing through 25ml water and 25ml ethyl acetate as the washing solution, and the aqueous layer is adjusted with 6N hydrochloric acid. The pH value is slightly acidic at 5-6. , stirred, filtered, and dried at 60° C. to obtain 11.81 g of cefizoxime as a light yellow powdery solid; the yield was 147.6%.

[0040] (2) Weigh 3.83 g (0.01 mol) of cefizoxime obtained in step (1), add 20 ml of tetrahydrofuran solvent, cool to 0°C, and carry out stirring reaction with methyl iodide 1.94 g (0.008 mol) for 3 hours, and then it becomes clear Then add 150ml ethyl acetate to extract, the organic layer is washed successively with the sodium...

Embodiment 3

[0044] A kind of synthesis technique of cefizoxime hydrochloride propiproxil, (1) first prepare solid cefizoxime: weigh 0.04mol 7-ANCA 8g and 0.1mol AE active ester 30.52g, add 7-ANCA to 40ml methanol solvent , at room temperature, carry out stirring reaction with AE active ester for 7.5 hours, concentrate and remove acetone, then carry out suction washing through 25ml water and 50ml ethyl acetate as washing liquid, and the aqueous layer is adjusted with 9N hydrochloric acid to pH value at 5-6 slightly acidic , stirred, filtered, and dried at 60° C. to obtain 12.64 g of ceftizoxime as a light yellow powdery solid; the yield was 157.9%.

[0045] (2) Weigh 3.83 g (0.01 mol) of cefizoxime obtained in step (1), add 20 ml of dimethyl sulfoxide solvent, cool to 0°C, and carry out stirring reaction with 3.39 g (0.014 mol) of methyl iodide for 4.5 hours Then it became clear; then 150 ml of ethyl acetate was added for extraction, and the organic layer was washed successively with 1% so...

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Abstract

The invention discloses a HCL ceftizoxime alapivoxil synthesizing process comprising the following four steps: (1) taking 7-amino-hydrogen cephalosporanic acid and AE active ester as raw materials, dissolving the 7-amino-hydrogen cephalosporanic acid with organic solvent and then causing the dissolved 7-amino-hydrogen cephalosporanic acid to react with the AE active ester; and carrying out stirring reaction at the room temperature; (2) dissolving ceftizoxime obtained from the step (1) with the organic solvent and then causing the dissolved ceftizoxime to react with iodine methyl ester; (3) dissolving ceftizoxime alapivoxil obtained from the step (2) with the organic solvent and then causing the dissolved ceftizoxime alapivoxil to react with tert-butoxycarbonyl-alanine; and (4) causing N-tert-butoxycarbonyl acyl alanyl ceftizoxime alapivoxil obtained from the step (3) to react with HCL / methanol solution by taking methanol as the solvent, and obtaining the final product HCL ceftizoxime alapivoxil. The process has the advantages of easily-available and cheap raw materials, mild reaction conditions, reliable purity, high yield and production cost reduction, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a process for synthesizing cefizoxime propidil hydrochloride. Background technique [0002] Cefizoxime propidil is a prodrug of cefizoxime for injection, and it is a bifunctional ester derivative of cefizoxime, which can be used orally. This product not only improves the oral absorption rate, but also improves the sweetness of this product, which is more suitable for children's medication. [0003] At present, there are three main ways to synthesize cefazoxaproxil. One is to use cefazoxamate or its sodium salt as raw material, through esterification at the 4-position, condensation at the 7-position, and deprotection to form a hydrochloride to prepare cefazomoxime Pilates. The method has many by-products and is not easy to purify. It needs to use column chromatography to separate and refine the product, and the yield is low, which is not suitable for scale-up production. (Dong Chuanming, Zhang Fengxia, Luo Faxin, etc., Study ...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/06
Inventor 吕旭幸洪虹黄冰陈琳胡雄严琴
Owner ZHEJIANG YATAI PHARMA
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