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Method for preparing cefpiramide

A technology of cefpiramide and methylnicotinamide, applied in the field of medicine, can solve the problems of difficult control of conditions, easy destruction of beta-lactam, low practicability and the like, and achieves the effect of easy operation

Inactive Publication Date: 2013-03-13
苏州盛达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many ways to prepare cefpiramide, for example, by condensing 7-ACA and DHPG at the 7-position, then reacting with 6-methyl-4-hydroxynicotinic acid, and finally condensing with MTTA at the 3-position of the parent Obtain cefpiramide, but, in these methods, generally speaking, the chiral center of DHPG and the β-lactam ring can participate in reaction repeatedly, because DHPG easily racemizes, and the β-lactam of cephalosporin is easily destroyed, and condition is not easy control, and thus less practical

Method used

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  • Method for preparing cefpiramide
  • Method for preparing cefpiramide

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Add D-a-(4-hydroxy-6-methylnicotinamide)-P-hydroxyphenylethylsodium 19.4g, N, N-dimethylacetamide (DMA) 160ml to a 1L three-necked flask, stir until dissolved, Cool down to 0°C and add 0.6 ml of pyridine dropwise, cool the solution to -25°C, control the temperature at -20°C, add 7.2g of pivaloyl chloride dropwise, stir at -20°C for 10 minutes, then add 80 mL of toluene was stirred for 20 minutes to obtain solution (a).

[0018] Add 7-amino-3-(1-methyl-1H-tetrazole-5-thiomethyl)-8-oxo-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylic acid (7-TMCA) 16.4g, dichloromethane 100ml, then add 8.8g hexamethyldisilazane (HMDS) and gradually increase the temperature and reflux for 1-2 hours until the solution is clear and transparent , (or blow nitrogen into the solution and stir at room temperature for 1 hour), and cool the solution to -20°C under the protection of nitrogen to obtain solution (b).

[0019] Slowly add solution (b) to solution (a), wash the wall of the bottle wi...

Embodiment 2

[0023] Add D-a-(4-hydroxy-6-methylnicotinamide)-P-hydroxyphenyl ethyl sodium 19.4g, N, N-dimethylacetamide (DMA) 160ml in sequence in a 1L three-necked flask, stir until dissolved, Cool down to 0°C, add 0.6ml of pyridine dropwise, cool to -25°C, add 7.2g of pivaloyl chloride dropwise at -20°C, stir for 10 minutes at -20°C, add 80ml of toluene dropwise at -20°C, stir After 20 minutes, solution (a) was obtained.

[0024] Add 7-amino-3-(1-methyl-1H-tetrazole-5-thiomethyl)-8-oxo-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylic acid (7-TMCA) 16.4g, acetonitrile 100ml, temperature control less than 25°C, add N, O-bis(trimethylsilyl)acetamide 12.7g, stir at 25°C for 30 Minutes until transparent and clear, cooled to -20°C to obtain solution (b).

[0025] Slowly add solution (b) to solution (a) dropwise, and drop 5.1 g of triethylamine into the reaction system under temperature control at -20°C, stir at -20°C for 15 hours, raise the temperature to 0°C for 2 hours, and then Pour th...

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Abstract

The invention provides a method for preparing cefpiramide. The method is characterized by comprising the following steps: (1) a compound of D-a-(4-hydroxyl-6-methyl nicotinamide)-P-sodium hydroxyphenyl acetate is dissolved in organic solvent and is activated through an activating agent under alkaline catalysis at the temperature of minus 25 to minus 20 DEG C so as to produce mixed acid anhydride solution (a); (2) a compound of 7-amino-3-(1-mehtyl-1H-tetrazole-5-sulfomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is dissolved in the organic solvent, is added with a silylation reagent at the temperature of 20-25 DEG C so as to be subjected to silylation protective reaction and is cooled to the temperature below minus 25 to minus 20 DEG C to obtain solution (b); and (3) the solution (a) and the solution (b) are mixed together, the obtained mixed solution is added with triethylamine to react at the temperature of minus 25 to minus 20 DEG C and is added into aqueous solution after completing the reaction to regulate the pH value, so that the cefpiramide is obtained. The method is simple to operate, the yield and purity of the produced cefpiramide are high, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicines, more particularly to a preparation method of cefpiramide. Background technique [0002] Cefpiramide (Cefpiramide), the chemical name is (6R, 7R)-7-[(R)-2-(4-hydroxy-6-methyl-3-pyridylcarboxylic acid amino)-2-(p-hydroxy Phenyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylic acid, which belongs to the third generation cephalosporin antibacterial drugs, has a strong antibacterial effect on Gram-positive bacteria. Since it was jointly developed by Sumitomo Pharmaceutical Company and Yamanouchi Company, and first listed in Japan in 1985, it has been marketed in many countries around the world. There are many ways to prepare cefpiramide, for example, by condensing 7-ACA and DHPG at the 7-position, then reacting with 6-methyl-4-hydroxynicotinic acid, and finally condensing with MTTA at the 3-position of the parent Obtain cefpiramide, but, in thes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/04
Inventor 曾润保吕德新黄建忠刘士军
Owner 苏州盛达药业有限公司
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