Method for preparing cefpiramide acid

A technology of cefpiramide and carboxylic acid, applied in the direction of organic chemistry and the like, can solve the problems of inability to guarantee the completeness of the protection reaction, unsuitable for large-scale production, easy to produce oil and agglomerate, and achieves overcoming adverse effects, simple and easy operation. control and protection response

Inactive Publication Date: 2013-04-24
珠海保税区丽珠合成制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the treatment of 7-ATCA in this reaction is usually to add trimethylchlorosilane and triethylamine to carry out trimethylchlorosilyl protection reaction in dichloromethane, and the reaction solution after protection is a suspension, heterogeneous The reaction cannot guarantee the completeness of the protection reaction, and it is easy to affect the effect of the subsequent reaction
In addition, after the reaction is completed, the reaction solution needs to be transferred to the dichloromethane-water mixture for hydrolysis and crystallization. It needs to be stirred quickly, and it is easy to produce oil and agglomerates, which is not suitable for large-scale production.

Method used

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  • Method for preparing cefpiramide acid
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  • Method for preparing cefpiramide acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] This example provides a method for preparing the reactant 7-ATCA used in the method of the present invention.

[0028] Concrete operations are as follows: add 90 grams of 7-aminocephalosporanic acid (7-ACA) in 1000 milliliters of four-necked bottles, 42.1 grams of 1-methyl-1H-tetrazolium-5-mercaptan (MMT), 595 milliliters of acetonitriles, Stir. Add 412.5 ml of boron trifluoride acetonitrile complex (BC) dropwise at room temperature (such as 20-25°C), control the temperature at 28-32°C, and react for 1.5 hours after the addition is complete. 660 ml of purified water, stirred for about 5 minutes to precipitate crystals, stirred slowly for 30 minutes, added dropwise 10% ammonia water to adjust the pH to 2.4-2.6, grown the crystals for 2 hours, filtered, and then used 205 ml of acetonitrile + 90 ml of water, 300 ml mL of water, 300 mL of acetone to wash the crystal. Vacuum-dried at 35-40°C until the water content was less than 1%, to obtain 99 grams of white solid powder...

Embodiment 2

[0037] This example provides a method for preparing the reactant HOPG-NAD-ECF used in the method of the present invention.

[0038]The specific operation is as follows: add 180ml of N,N-dimethylformamide (DMF) to a 250ml three-necked bottle, cool down to below 10°C, add D-α-(6-methyl-4-hydroxynicotinamide)-4-hydroxy Phenylacetic acid (HOPG-NAD) 36g, stirred for 30min, cooled to below -60°C, 20ml of ethyl chloroformate (ECF) was added dropwise for 30min, after the dropwise addition of 13ml of N-methylmorpholine (N-MMP), Stir for 10 minutes after dropping, and cool down to -70°C for later use.

Embodiment 3

[0040] This embodiment provides the method for preparing cefpiramin of the present invention.

[0041] The specific operation is as follows: add 38g of 7-ATCA and 160ml of dichloromethane into a 250ml three-necked flask, add 57ml of BSA dropwise with stirring at room temperature, and stir until the reaction is dissolved; add the obtained reaction solution dropwise into the HOPG-NAD- In the ECF solution, control the temperature at -60°C, react for 4 hours, raise the temperature to 0°C, stir and dropwise add sodium bicarbonate solution (16.7g sodium bicarbonate + 167ml water) for hydrolysis, filter, and let the filtrate stand for stratification, and the organic phase is about 440ml, Add 100ml of water each time, extract twice, combine the obtained aqueous phases to about 360ml, add 360ml of acetone, add hydrochloric acid dropwise to adjust the pH to 1~2 and crystallize, grow the crystals at 0~10°C for 1 hour, filter, and wash with 100ml of water and 100ml of acetone respectively ...

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Abstract

The invention provides a method for preparing cefpiramide acid. The method provided by the invention adopts (6R,R7)-3-[(1-methyl-1H-tetrazolyl-5-yl)thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]octyl-2-alkenyl-2-carboxylic acid as a trimethylchlorosilicyl protective agent. The method provided by the invention is simple to operate, obviously enhances the product purity and yield, and can easily implement industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a method for preparing cefpiramin. Background technique [0002] Cefpiramide (Cefpiramide) is a third-generation cephalosporin antibacterial drug, which was jointly developed by Sumitomo Pharmaceutical Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd., and was first listed in Japan in 1985. Included, suitable for pneumonia, acute bronchitis, chronic bronchitis caused by sensitive G+ and G- bacteria such as Escherichia coli, Proteus, Klebsiella pneumoniae, Pseudomonas aeruginosa, influenza bacillus, pneumococcus, Staphylococcus aureus Acute attack, bronchiectasis complicated with infection, pyelonephritis, cystitis, cholecystitis, cholangitis, peritonitis, uterine annex inflammation and other infectious diseases. [0003] The chemical name of cefpiramide is (6R,7R)-7-[(2R)-(4-hydroxy-6-methyl-3-pyridine)carboxamido-2-(4-hydroxyphenyl)ethyl Amino]-3-[(1-methyl-1H tetrazo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06
Inventor 江跃李显焕肖鸿
Owner 珠海保税区丽珠合成制药有限公司
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