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Synthetic process of novel cephalosporin anti-infective drug

A synthesis process and technology for cephalosporins, applied in the field of drug synthesis, can solve problems such as being unsuitable for industrialized large-scale production, high industrial production cost, difficult to find purification methods, etc., and achieve reduction of by-products, product cost reduction, and easy post-processing. Effect

Active Publication Date: 2015-11-04
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In the above-mentioned two kinds of processing routes, the synthesis of route one mainly starts from the 7-position of 7-ACA, and route two begins to synthesize from the 3-position of 7-ACA, and route two synthesizes cefzidone yield (71.5 %) is slightly higher than route one (60%), but the weak point of route two is that the by-product of 1-methylthiadiazole-5-mercaptan and 7-ACA reaction is accompanied in the end product always, and it is difficult to Find a suitable purification method, so that its synthesis cost will increase accordingly, and it is not suitable for industrial large-scale production
[0015] In the prior art, the method for synthesizing cefazedone sodium generally has the disadvantages of low yield, poor product color grade and high industrial production cost.
The difficulty of the process makes the price of the preparation expensive, causing an economic burden to the drug users, and the use of highly polluting chemical reagents in the synthesis process causes great damage to the environment

Method used

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  • Synthetic process of novel cephalosporin anti-infective drug
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  • Synthetic process of novel cephalosporin anti-infective drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) Preparation of thioester compound (formula III):

[0037] In a dry reaction flask, add 200ml of tetrahydrofuran, 22.2g of 3,5-dichloro-4-pyridone-1-acetic acid (formula I, 0.1mol) and 2-mercapto-5-methyl-1,3, 14.55 g of 4-thiadiazole (formula II, 0.11 mol), stirred, then added 12.2 g (0.12 mol) of triethylamine, stirred at room temperature for 1 hour, then slowly added dropwise the tetrahydrofuran solution in which the catalyst triethyl phosphite was dissolved (Triethyl phosphite 20g dissolved in 50ml of tetrahydrofuran, 0.12mol), drop it off within 1 hour, control the temperature at 20-25°C and stir the reaction for 1 hour, filter, cool the filtrate to below 10°C, precipitate crystals, filter with suction, Vacuum drying below 40°C yielded 32.7 g of thioester compound (Formula III, 0.097 mol), with a yield of 97% and an HPLC purity of 99.5%.

[0038] (2) Preparation of Cefazedone Sodium (Formula IV):

[0039] Under the protection of nitrogen, add 24.5g (0.09mol) of ...

Embodiment 2

[0041] (1) Preparation of thioester compound (formula III):

[0042] In a dry reaction flask, add 180ml of tetrahydrofuran, 22.2g of 3,5-dichloro-4-pyridone-1-acetic acid (formula I, 0.1mol) and 2-mercapto-5-methyl-1,3, 14.55 g of 4-thiadiazole (formula II, 0.11 mol), stirred, then added 6.1 g (0.06 mol) of triethylamine, 0.8 g (0.01 mol) of pyridine, stirred at room temperature for 1 hour, then slowly added dropwise the dissolved catalyst The tetrahydrofuran solution of isopropyl chloroformate (14.7 g of isopropyl chloroformate dissolved in 50 ml of tetrahydrofuran, 0.12 mol), dripped within 1 hour, stirred and reacted at a temperature of 20-25 ° C for 1 hour, filtered, and the filtrate was cooled to 10 Below ℃, crystals were precipitated, filtered by suction, and dried under vacuum below 40℃ to obtain 32.8 g of thioester compound (Formula III, 0.0966 mol), the yield was 96.6%, and the HPLC purity was 99.2%.

[0043] (2) Preparation of Cefazedone Sodium (Formula IV):

[004...

Embodiment 3

[0046] (1) Preparation of thioester compound (formula III):

[0047] In a dry reaction flask, add 200ml of dichloromethane, 33.3g of 3,5-dichloro-4-pyridone-1-acetic acid (formula I, 0.15mol) and 2-mercapto-5-methyl-1, 20.8 g of 3,4-thiadiazole (formula II, 0.1575 mol), stirred, then added 6.1 g (0.06 mol) of triethylamine, 0.95 g (0.012 mol) of pyridine, stirred at room temperature for 1 hour, then slowly added the dissolved Dichloromethane solution with catalyst triethyl phosphite (triethyl phosphite 14.7g dissolved in 50ml of dichloromethane), drop it off within 1 hour, control the temperature at 20-25°C and stir for 1 hour, filter, and cool the filtrate Cool below 10°C to precipitate crystals, filter with suction, and dry under vacuum below 40°C to obtain 49.3 g of thioester compound (Formula III, 0.1452 mol), with a yield of 96.8% and an HPLC purity of 99.0%.

[0048] (2) Preparation of Cefazedone Sodium (Formula IV):

[0049] Under the protection of nitrogen, add 32.7g...

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Abstract

The invention relates to a synthetic process of a novel cephalosporin anti-infective drug. A thioester compound (formula III) synthesized by adopting 3,5-dichloro-4-pyridone-1-acetic acid and 2-thiol-5-methyl-1,3,4-thiadiazole as raw materials is directly reacted with 7-ACA in one step to successfully prepare cefazedone sodium. According to the synthetic process disclosed by the invention, the operating steps are simplified, so that the production conditions are milder, the generation of byproducts is reduced, and the production technology is simpler; and moreover, the product yield and purity are greatly improved, the cost is reduced, the environmental pollution is little, and the synthetic process is higher in environmental protection, so that the process accords with the requirement of industrialization.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis process of a novel cephalosporin anti-infective drug cefzidone sodium. Background technique [0002] Cefazedone sodium (Cefazedone) belongs to the first generation of injectable cephalosporin antibiotics, and its curative effect on various Gram-positive bacteria and Gram-negative bacteria, including Staphylococcus aureus, Streptococcus, and Enterococcus, is superior to similar drugs— The drug resistance of cefazolin and cephalothin is obviously better than that of the latter. They are classic broad-spectrum antibiotics with broad antibacterial spectrum and wide clinical application. A total of 732 patients in 7 foreign countries and 35 hospitals participated in the clinical research results showed that cefzidome was effective against urinary system infection, respiratory tract infection, surgical-skin infection and gynecological infection caused by gram-positive and nega...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06C07D501/04C07D501/12
CPCC07D501/04C07D501/06C07D501/12C07D501/36
Inventor 何雅官马红娟徐淑周
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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