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Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof

A technology of antibiotics and nitrogen heterocycles, applied in the field of antibiotics, can solve the problems of easily destroying the B-lactam structure, affecting product stability, and reducing product content, etc.

Active Publication Date: 2009-05-20
GUANGZHOU PHARMACEUTICAL INDUSTRIAL RESEARCH INSTITUTE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, if the product purity is to be further improved, the common refining method of cephalosporins is to use acid and alkali to adjust the isoelectric point: while acid and alkali refining methods are easy to destroy the B-lactam structure, such as ring opening, resulting in product degradation, The content of the product will decrease instead, which will affect the stability of the product
In addition, the dissolution method is used, but some impurities cannot be removed.

Method used

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  • Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof
  • Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof
  • Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] In the following examples, 7-bromoacetyl ACT refers to: 7-bromoacetyl-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2 , 4-triazin-3-yl)thio]methyl]-cephalosporanic acid.

[0049] 1. 3-[(Acetoxy)methyl]-7-[α-(N,N-diisopropylamidinothio)acetamido]-8-oxo-5-thia-1-aza Preparation of bicyclo[4,2,0]-oct-2-ene-2-carboxylic acid (II) (refer to Chinese Invention Patent 200410050908.X "C3 methylene nitrogen-containing heterocycle substituted amidothioacetamide group Cephalosporium Elements, preparation methods and applications" method preparation)

[0050] Add 100ml of dichloromethane, 4.9 grams (0.01mol) of 7-bromoacetyl ACT, dropwise add 2.8ml (0.02mol) of triethylamine to dissolve it, add 2.4 grams (0.015 mol) at 30°C until complete reaction; after stirring for 1 hour, the temperature was lowered for 1 hour; suction filtration and vacuum drying gave 4. g of compound (II). The content (HPLC) was 94.3%.

[0051] The pH of its saturated aqueous solution is 3.2.

[0052] 1 HN...

Embodiment 2

[0071] One, the preparation of 7-bromoacetyl ACT is the same as in Example 1

[0072] 2. 3-[(Acetoxy)methyl]-7-[α-(N,N-diisopropylamidinothio)acetamido]-8-oxo-5-thia-1-aza Preparation of bicyclo[4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):

[0073] 5°C, dissolve 0.1 g of sodium carbonate in 5 ml of deionized water in a three-necked flask, add 1 g of compound (II) under rapid stirring at 500 rpm, react for 45 minutes, add activated carbon for decolorization, filter, and the filtrate drops to In 80ml of acetone, adopt on-line particle test analysis instrument to monitor, separate out solid, filter, wash 2 times with acetone, 40 ℃ vacuum-dry for 24 hours to obtain compound (Ia) 0.75 gram, content (HPLC) is 98.35%, pH is 7.3 (concentration 0.1g / ml).

[0074] 1 HNMR (DMSO-d 6 , 500Hz): 1.12(m, 12H, J=6), 3.35(d, 1H, J=17.5), 3.57(d, 1H, J=17.5), 3.50(s, 3H), 3.77(m, 4H) , 4.14(d, 1H, J=13), 4.37(d, 1H, J=13), 4.99(d, 1H, J=5), 5.50(q, 1H), 9.32(d, 1H, J=7.5 )

Embodiment 3

[0076] One, the preparation of 7-bromoacetyl ACT is the same as in Example 1

[0077]2. 3-[(Acetoxy)methyl]-7-[α-(N,N-diisopropylamidinothio)acetamido]-8-oxo-5-thia-1-aza Preparation of bicyclo[4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):

[0078] 5°C, add 1 g of compound (II) obtained above, 4 ml of deionized water, and 4 ml of 95% ethanol into a three-necked flask, stir rapidly at 200 rpm until completely dissolved, drop 1.8 ml of 8% sodium bicarbonate, and react for 30 Minutes, add activated carbon for decolorization, filter and drop the filtrate into 100ml acetone, monitor using an online particle test analyzer, separate out solid, filter, wash 2 times with acetone, and vacuum dry at 40°C for 24 hours to obtain 0.7 grams of compound (Ia). The content (HPLC) was 98.81%.

[0079] 1 HNMR (D 2 O, 400Hz): 1.25(m, 12H, J=6.4), 3.45(d, 1H, J=18), 3.69(d, 1H, J=18), 3.62(s, 3H), 3.98(m, 4H ), 4.07 (d, 1H, J=13.6), 4.32 (d, 1H, J=13.6), 5.12 (d, 1H, J=5), 5.56 (d, 1H, ...

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Abstract

The invention relates to an antibiotic substituted by nitrogen heterocyclic ring, and a preparation method and the application thereof, pertaining to the antibiotic medicament of a human body, and discloses the structural formula (I) of 7-(Alpha-(N, N-bis (1-methylethyl)-thiourea) acetamido)-3-(((2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2, 4-triazine-3-base)sulfo)methyl)-cephalosporin polyhydroxyalkanoate sodium salt and sylvite, and a manufacturing method and the application thereof. The antibiotic has good antibacterial activity, can treat diseases caused by hypersensitive gram positive bacteria and gram negative bacteria, bloodpoisoning, alimentary infection, urinary tract infection, has long half-life of plasma and little toxicity and can reduce times for taking medicaments every day and treatment fees. The compound has good stability and is stored at normal temperature; the manufacturing method is simple; a product obtained by the manufacturing method has high purity and meets medical requirements.

Description

technical field [0001] The present invention relates to a nitrogen-containing heterocyclic substituted antibiotic, in particular to 3-[(acetoxy)methyl]-7-[α-(N,N-diisopropylamidinothio)acetamido]- Sodium and potassium 8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylate and its synthesis method and application. technical background [0002] The chemical name of cefotaxime amidine is (6R,7R)-3-[(acetoxy)methyl]-7-[α-(N,N-diisopropylamidinothio)acetamido]-8-oxo Dai-5-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid is a new cephalosporin compound with the following structure: [0003] [0004] The compound of formula II is the first cefathiamidine analogue created by Chinese invention patent application number 200410050908.X, and has good activity against some Gram-positive bacteria. [0005] The inventors found that the compound of formula II has low water solubility and relatively poor stability, and the pH value of the aqueous solution is 3.2, which is obviousl...

Claims

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Application Information

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IPC IPC(8): C07D501/36A61K31/545A61P31/04
Inventor 朱少璇陈矛刘学斌郑丽真林丽薇刘文坚王玉平杨威李云峰叶放许淑文张小娜
Owner GUANGZHOU PHARMACEUTICAL INDUSTRIAL RESEARCH INSTITUTE
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