Preparation method of ceftizoxime sodium

A technology of ceftizoxime sodium and ceftizoxime acid, which is applied in the field of preparation of ceftizoxime sodium, can solve the problems of increasing operating procedures and production costs, many side reactions, prolonging reaction steps, etc., and achieves a simple and easy preparation process, Low cost, high purity effect

Inactive Publication Date: 2012-07-25
苏州盛达药业有限公司
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Problems solved by technology

[0005] Regarding the synthesis of ceftizoxime sodium, there are two synthetic routes in the prior art: the first is to use p-methoxybenzyl 7-phenylacetamido-3-cephalosporin-4-carboxylate as raw material at C7 2-cis-methoxyimino-2-(2-formylamino) thiazole acetic acid is introduced into the side chain at the C4 position, and then the protecting group introduced into the side chain at the C4 position is removed to obtain ceftizoxime acid, which is prepared with a salt-forming agent Obtain ceftizoxime sodium, this route repeatedly sloughs off protecting group, prolongs reaction step, has increased operation procedure and production cost; 7-ANCA) is directly condensed with aminothioxime acetic acid as a raw material to obtain ceftizoxime acid and then salted. This route has many side reactions, and the resulting product needs to be purified by column chromatography

Method used

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  • Preparation method of ceftizoxime sodium
  • Preparation method of ceftizoxime sodium
  • Preparation method of ceftizoxime sodium

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[0018] A preparation method of ceftizoxime sodium, comprising (1) 7-ANCA as a raw material, and 2-(2-amino-4-thiazolyl)-2-methoxyimine-acetyl-benzothiazole thioester (AE -Active ester) is condensed in a solvent and in the presence of an alkali to obtain the ceftizoxime acid intermediate; (2) the ceftizoxime acid intermediate is reacted with the salt-forming agent sodium hydroxide to obtain ceftizoxime sodium,

[0019] In step (1), the specific process is to add 7-ANCA to the solvent, cool down to 0-5°C, add AE-active ester, raise the temperature to 20-40°C, and react for 4-5h. After the reaction, the reaction liquid Pour into ethyl acetate to stir, let stand to separate layers, extract the organic layer with water twice, combine the water layer, add the adsorbent, continue to stir for 2-3h, filter, and the filtrate is at 0-5°C. Adjust the pH to 5-6 with 10-15% hydrochloric acid, and precipitate a white solid. Stir the cultured crystals in an ice bath at 0-5°C for 2-3 hours, fi...

Embodiment 1

[0026] Synthesis of ceftizoxamic acid:

[0027] Take a 200ml three-necked flask, add 4g of 7-ANCA, add a mixture of 25ml of water and 40ml of tetrahydrofuran, stir and cool down to 0°C, add 4.7g of triethylamine dropwise and the solution becomes clear, and then add 14.6g of AE active ester , heated up to 20°C, stirred for 4 hours, poured the reaction solution into 100ml of ethyl acetate and stirred, statically separated the liquid, extracted the organic layer twice with 100ml of water, combined the aqueous layer, added the adsorbent, and continued to stir for 2- 3h, filter, the filtrate is at 0-5°C, use hydrochloric acid with a mass percent solubility of 10-15% to adjust the pH to 5-6, and a white solid is precipitated, stir the crystals in an ice bath at 0-5°C for 2-3h, filter , 50 milliliters of water and 50 milliliters of acetone washed the filter cake successively to obtain 6.58 g of ceftizoxamic acid intermediate, with a yield of 86% and a purity of 99.12% by HPLC norm...

Embodiment 2

[0029] Ceftizoxime Sodium

[0030] Add 1 clozoxamic acid and 20ml ethanol to a 200ml single-mouth bottle, add 1N sodium hydroxide dropwise under ice bath, adjust the pH to 8, at this time the solution is clear, then slowly add 160ml of acetone dropwise, white crystals are precipitated, stir for 30 minutes, filtered with suction, washed with acetone, and dried to obtain 0.84 g of a white solid with a yield of 80% and a purity of 99.05% by HPLC normalization method.

[0031] 1H-NMR (DMSO-d6) δ: 3.35(2H, m), 3.47(3H, s), 4.95(1H, d, J=3.9 Hz), 5.62(1H, dd, J = 3. 8 Hz, 6. 6 Hz), 5. 96 (1H, m), 6. 71 (1H, s), 7. 23 (2H, s), 9. 51 (1H, d, J =6. 6 Hz).

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Abstract

The invention discloses a preparation method of ceftizoxime sodium. The method comprises the following steps of: condensing 7-ANCA serving as a raw material with 2-(2-amino-4-thiazolyl)-2-methoxyimine-acetyl-benzothiazole thioester (AE-active ester) in a solvent in the presence of an alkali to obtain a ceftizoxime acid intermediate; and (2) reacting the ceftizoxime acid intermediate with sodium hydrate serving as a salting agent to obtain ceftizoxime sodium. Compared with the prior art, the method has the advantages of easy, convenient and practicable preparation process, mild reaction conditions, low cost, high yield, high product purity and suitability for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of ceftizoxime sodium. Background technique [0002] Ceftizoxime sodium, the English name is: Ceftizoxime Sodium, the trade name is ceftizox, the chemical name is: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methyl Oxyiminoacetamido]-8-oxo-5-thia-1-aminobicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, molecular formula: C 13 h 12 N 5 NaO 5 S 2 , molecular weight: 405.38, structural formula: [0003] [0004] Ceftizoxime sodium was developed by Tengze Pharmaceutical Co., Ltd. of Japan, and was first listed in Japan in 1982. This product is a third-generation cephalosporin antibiotic with broad-spectrum, high efficiency, enzyme resistance, low toxicity and ability to pass through the blood and brain. The characteristics of the barrier are widely used clinically to treat various moderate and severe infections. [0005] Regarding the synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/20C07D501/04
Inventor 曾润保王芳罗新祖
Owner 苏州盛达药业有限公司
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