Cephalosporin compound, crystal thereof, and preparation method and application thereof

A compound and crystal technology, applied in the field of chemical pharmaceuticals, can solve problems such as bacterial resistance

Active Publication Date: 2013-05-15
GUANGZHOU BAIYUNSHAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, with the increasingly widespread use, the phenomenon of bacterial resistance gradually appears, which requires the further development of new types of antibiotics

Method used

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  • Cephalosporin compound, crystal thereof, and preparation method and application thereof
  • Cephalosporin compound, crystal thereof, and preparation method and application thereof
  • Cephalosporin compound, crystal thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Preparation of 7-bromoacetamido-3-[(acetoxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 - Formic acid (Intermediate A)

[0035] At room temperature, 30 g (0.11 mol) of 7-ACA was added to 300 ml of water, and triethylamine was slowly added dropwise under stirring at 120 rpm until 7-ACA was completely dissolved to obtain a clear solution. Add 50ml of dichloromethane to the above clear solution, adjust the temperature to 0-5°C, add dropwise sodium bicarbonate solution (24g dissolved in 250ml water) and 13ml bromoacetyl bromide (0.15mol). Keep warm at 0-5°C, react for 30-60 minutes, let stand to separate layers, separate the water phase, slowly add 3mol / L sulfuric acid solution to the water phase, keep the temperature at 0-5°C, and start to precipitate solids when the pH is about 2.5 , until the pH is about 1.0 to 1.5 as the titration end point, and continue to grow crystals for 1h. After suction filtration, the filter residue was washed three times wit...

Embodiment 2

[0036] Embodiment 2: Preparation of Intermediate A

[0037] At room temperature, 30 g (0.11 mol) of 7-ACA was added to 500 ml of water, and sodium bicarbonate solution (27.6 g dissolved in 250 ml of water) was added dropwise with stirring until 7-ACA was completely dissolved to obtain a clear solution. Add 100ml of toluene to the above clear solution, adjust the temperature to 30-35°C, continue to add dropwise the remaining sodium bicarbonate solution and 12ml of bromoacetyl bromide (0.138mol). Keep warm at 30-35°C, react for 30-60 minutes, let stand to separate layers, separate the water phase, adjust the temperature of the water phase to room temperature, slowly add 3mol / L hydrochloric acid to the water phase, and start to precipitate when the pH is about 2.5 Solid, until the pH is about 1.0-1.5 is the titration end point, and continue to grow crystals for 1h. After suction filtration, the filter residue was washed three times with water and dried in vacuum to obtain about ...

Embodiment 3

[0038] Embodiment 3: preparation compound I

[0039] Adjust the temperature of 500ml of dichloromethane to 15-20°C, add 39.3g (0.1mol) of intermediate A, and slowly add triethylamine dropwise until intermediate A is completely dissolved to obtain a clear solution, then add N,N'-di Cyclohexylthiourea 36g (0.15mol), slowly adjust the temperature to 25-30°C. After reacting for 2h, suction filtered, and the filter residue was washed 3 times with dichloromethane. After vacuum drying at room temperature, about 39 g of compound I was finally obtained. The purity was determined to be 93.2% by HPLC method.

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PUM

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Abstract

The invention relates to a (6R, 7R)-3-[(acetyloxy) methyl]-7-[alpha-(N, N'-dicyclohexyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo [4, 2, 0]-oct-2-ene-2-carboxylic acid, a crystal thereof, and a preparation method and application thereof. Under alkaline conditions, 7-ACA reacts with bromoacetyl bromide to obtain a 7-bromo acetamino-3-[(acetyloxy) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 formic acid intermediate A; and the intermediate A reacts with N, N '- dicyclohexyl thiourea to obtain the compound provided by the invention. The compound is further refined to obtain the crystal with high purity and good stability of the compound provided by the invention. The compound and the crystal thereof have antibacterial effect on Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis, and are potential antimicrobial drugs with promising application prospect.

Description

technical field [0001] The present invention belongs to the field of chemical pharmacy, and more specifically relates to a cephalosporin compound, its crystal and its preparation method and application, especially to (6R, 7R)-3-[(acetyloxy)methyl]-7 -[α-(N,N'-dicyclohexylamidinothio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-ene -2-formic acid betaine crystal and its preparation method and use. Background technique [0002] Cefathiamidine, whose structural formula is as follows, is the first generation of β-lactam antibiotics, and its antibacterial spectrum is similar to that of cephalothin. Cefathiamidine has antibacterial activity against Gram-positive bacteria and some negative bacteria, especially against Gram-positive cocci. It has good antibacterial effect on Streptococcus viridans, Hemolytic Streptococcus, Non-hemolytic Streptococcus, Bacillus diphtheriae, Clostridium perfringens, Bacillus tetani and Bacillus anthracis. [0003] [0004] However, as th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/04A61K31/545A61P31/04
Inventor 冯胜昔姚柳端刘丹青王峰波关晴曾慧周勤
Owner GUANGZHOU BAIYUNSHAN PHARM CO LTD
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