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Preparation method of cefodizime sodium

A technology for cefodizime and cefodizime acid, applied in the field of drug synthesis, can solve the problems of many operation steps, low recovery rate, high price and the like, and achieve the effects of ensuring product quality and yield, improving yield and simple operation

Inactive Publication Date: 2012-01-04
TIANJIN GREENPINE PHARMA
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] At present, cefodizime sodium is mainly prepared by cefodizime acid, and U.S. Patent U5126445 discloses that cefodizime acid is suspended in water, dissolved by adding triethylamine dropwise, and isocaprylic acid sodium solution is added dropwise in the clear solution to separate out cefodizime Sodium, the color of the product is darker, need to be refined, affecting product quality and yield
U.S. Patent No. 4,590,267 discloses dissolving cefodizime acid with sodium bicarbonate, adding dropwise alcohol to separate out cefodizime sodium, and dissolving it with sodium bicarbonate. The dissolution time is long, and the resulting product easily contains undissolved sodium bicarbonate, which affects the product. quality
Chinese patent CN101239985 discloses suspending cefodizime acid in a two-phase system, adding salt-forming agent sodium isooctanoate and stirring to completely dissolve, layering, adding alcohol to the water layer to precipitate cefodizime sodium, and the two-phase system is selected from dichloro Methane / water, carbon tetrachloride / water, toluene / water or ethyl acetate / water use a large amount of organic solvents in this method, and recovery rate is low, pollutes environment, and cost is higher, and operating steps is many and complicated, and Product purity is low
The method uses boron trifluoride gas or boron trifluoride complex, which is expensive and pollutes the environment. It also needs to use a large amount of organic solvents, and the recovery rate is low and the cost is high.

Method used

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  • Preparation method of cefodizime sodium

Examples

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Embodiment 1

[0042] Synthesis of 7-amino-3-(5-carboxymethyl-4-methyl-1,3-thiazole-2-mercaptomethyl)cephalosporin-2-ene-2carboxylic acid (Ⅳ)

[0043] In a 1000ml three-neck reaction flask, add 300ml of distilled water, 7-ACA (54.4g, 0.2mol) and sodium bicarbonate (16.8g, 0.2mol), and add 2-mercapto-4-methyl-5-thiazoleacetic acid ( 41.4g, 0.2mol), sodium bicarbonate (16.8g, 0.2mol) distilled water 200ml, adjust the pH to 6.5 with saturated sodium bicarbonate solution and keep it until the end of the reaction, react at 40-45°C for 2h, cool to room temperature, add 30ml For n-butanol, adjust the pH to 5.5 with 15% dilute sulfuric acid, stir for 20 minutes, further adjust the pH to 4, stir for 1 hour, filter with suction, wash with distilled water, isopropanol, and n-hexane in turn, and dry to obtain 65.0 g of off-white crystalline powder. Yield 80.9%.

Embodiment 2

[0045] Synthesis of Cefodizime Acid (Ⅵ)

[0046] Add 300ml of dichloromethane into a 500ml reaction flask, add intermediate (IV) (40.1g, 0.1mol), 28ml of triethylamine and AE active ester (42.0g, 0.12mol) while stirring at room temperature, and react at the same temperature for 2h. Add water 200ml×3 for extraction, combine the water layers, decolorize with activated carbon, filter, adjust the pH of the filtrate to 3.5 with hydrochloric acid, stir for 1.5h, filter with suction, wash with 250ml of water and 100ml of isopropanol, and dry to obtain an off-white solid 53.0 g, yield 90.6%.

Embodiment 3

[0048] Synthesis of Cefodizime Sodium (Ⅰ)

[0049] At 8-10°C, add 35.04g of cefodizime acid and 18ml of triethylamine to 250ml of ethanol in turn, add dropwise 15ml of water, then add 1g of activated carbon and stir for 20min, filter with suction, and dissolve 20.3g of sodium isooctanoate in In 90ml of ethanol, add the above-mentioned sodium isooctanoate solution dropwise to the obtained filtrate at 10-20°C for 1 hour. After the dropwise addition is completed, continue stirring at room temperature for 1.5 hours, filter with suction, wash with 200ml of ethanol, and dry in vacuo at 45°C , to obtain cefodizime sodium 32.3g, yield 85.0%.

[0050] The structure was confirmed by NMR and mass spectrometry

[0051] 1 H-NMR (DMSO-d 6 )δ: 9.59(1H, d), 7.29(2H, s), 6.74(1H, s), 5.62(1H, m), 5.02(1H, d), 4.09, 4.63(2H, m), 3.85(3H , s), 3.35(4H, m), 2.18(3H, s).

[0052] 13 C-NMR (DMSO-d 6 ) δ: 172.5, 168.0, 164.5, 162.5, 159.3, 148.5, 145.6, 142.0, 132.5, 128.8, 115.9, 108.6, 61.4...

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Abstract

The invention relates to a preparation method of cefodizime sodium. The preparation method comprises the following steps: reacting 7-ACA (7-aminocephalosporanic acid) (II) with 2-sulfydryl-4-methyl-5-thiazoleacetic acid (III) under the alkaline condition so as to obtain an intermediate (IV); acting the intermediate (IV) with AE (active ester) (V) so as to obtain cefodizime acid (VI); and acting cefodizime acid (VI) in the presence of a salifying agent so as to generate the product cefodizime sodium (I). According to the invention, the preparation method of cefodizime sodium has low cost, is simple to operate and is suitable for industrial production, and the yield of cefodizime sodium is up to 63.7%; and the product is white or of white-like color and dose not need to be refined, thus ensuring the quality and yield of the product.

Description

[0001] technical field [0002] The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of cephalosporins, more specifically to a preparation method of cefodizime sodium. Background technique [0003] Cefodizime sodium is a third-generation cephalosporin antibacterial drug developed by Hoechst, Germany. It has dual properties of antibacterial and immune regulation, and is widely used in clinical practice. Its chemical name is: (6R,7R)-7-[(2-amino-4-thiazolyl)-(methoxyimino)acetamido]-3-[[(5-carboxymethyl-4-methyl -2-thiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt, molecular formula: C 20 h 18 N 6 Na 2 o 7 S 4 , molecular weight: 628.64, structural formula: [0004] [0005] At present, cefodizime sodium is mainly prepared by cefodizime acid, and U.S. Patent U5126445 discloses that cefodizime acid is suspended in water, dissolved by adding triethylamine dropwise, and iso...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/04
Inventor 郑林海
Owner TIANJIN GREENPINE PHARMA
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