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Azithromycin derivative, preparation method and intermediate thereof

A technology for azithromycin and derivatives, applied in the field of azithromycin derivatives, preparation and intermediates, which can solve problems such as side effects and increased toxicity, steric hindrance effects, and excessively long side chain lengths

Inactive Publication Date: 2010-12-01
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there are disadvantages of too long side chain length and too large aromatic heterocycle
When the compound extends into the polypeptide channel and binds to the action site of the ribosome, the length of the side chain at the 4″ position is too long to easily cause the side chain fragments to accumulate, which may affect the 2′ hydroxyl group on the deoxyamino sugar and the A2058 Or the combination of A2059, thus affecting the antibacterial activity; if the aromatic heterocycle is too large, there will be a steric hindrance effect, which will also affect the combination of macrolide antibiotics and ribosomes, affecting antibacterial activity
In addition, in some existing patents, side chains containing ester bonds, ether bonds, and thioether bonds are introduced at C-4″. The ester bonds are easily hydrolyzed by esterases in vivo, while the ether bonds and thioether bonds are prone to oxidation. , which increases the inactive substances in the body, which not only reduces the antibacterial activity of the compound, but also increases the side effects and toxicity

Method used

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  • Azithromycin derivative, preparation method and intermediate thereof
  • Azithromycin derivative, preparation method and intermediate thereof
  • Azithromycin derivative, preparation method and intermediate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0125] Preparation of Benzoyl Chloride

[0126] Put benzoic acid (1.00g, 8.19mmol) in a 50ml round bottom flask, add thionyl chloride (15ml, 0.20mol), heat and reflux at 80°C for 4 hours, evaporate the thionyl chloride under reduced pressure, and proceed to the next step reaction.

Embodiment 2

[0128] Preparation of Benzoylpiperazine

[0129] Put piperazine (0.7g, 8.19mmol) in a 50ml three-neck flask, add 16ml of water to dissolve it; add 4 drops of methyl orange indicator, and adjust the pH with 2mol / L hydrochloric acid solution to make it just change from yellow to red Add 16ml of acetone, slowly add benzoyl chloride dropwise under stirring in an oil bath at 50°C, and continuously neutralize the generated HCl with 40% sodium acetate solution, so that the pH of the reaction solution remains within the discoloration range of methyl orange; react for 30 Minutes, acetone was evaporated under reduced pressure, pH=12 was adjusted with 40% sodium hydroxide solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and 0.72 g of a colorless oily substance was evaporated to dryness under pressure. Yield 45.2%, Rf It was 0.65 (the developing solvent was dichloromethane:methanol=5:1).

Embodiment 3

[0131] Preparation of 4-(3-aminopropyl)piperazin-1-ylbenzophenone

[0132] Benzoylpiperazine (0.72, 3.78mmol) was placed in a 100ml round-bottomed flask, dissolved in 10ml of isopropanol, chlorpromamine hydrochloride (0.70g, 5.67mmol) and triethylamine (1.06ml, 6.56mmol) were added ), stirred in an oil bath at 50°C for 24h, heated to reflux at 90°C for 24h; evaporated to dryness under pressure, dissolved in water, adjusted to PH=12 with 40% NaOH, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and reduced 0.7 g of the oily matter distilled under high pressure was subjected to silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain a colorless oily matter, which was the target compound A1 (0.3 g, 1.21 mmol), and the yield was 45.2 g. %,R f is 0.16 (the developing solvent is dichloromethane:methanol=5:1).

[0133] Other compounds with similar structures were prepared using the same metho...

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Abstract

The invention discloses an azithromycin derivative shown in the formula (I) and a pharmaceutically acceptable salt thereof, wherein R1 represents hydrogen, acetyl or benzoyl, R2 represents hydrogen, aliphatic hydrocarbon, substituted aromatic alkyl, substituted aromatic heterocyclic alkyl, halogen, nitryl, alkoxy or-AR7, R3 represents OR5, R4 represents hydroxyl; or, R3 and R4 can form a ring with a structure that X represents oxygen and nitrogen; R5 represents nitrogen or CONHR6, R6 represents aliphatic hydrocarbon, substituted aromatic alkyl or substituted aromatic heterocyclic alkyl, and R7 represents aliphatic hydrocarbon, substituted aromatic alkyl or substituted aromatic heterocyclic alkyl; n is from 1 to 6, A is one of -O-,-CO-,-CONR8-,-NHCO- and -S-. The invention further relates to a prepared intermediate and a method thereof, an acceptable salt thereof forming with inorganic or organic acid, a drug composite and application thereof in the treatment of bacterial infection.

Description

technical field [0001] The present invention relates to azithromycin derivatives, their preparation methods, and intermediates. Background technique [0002] Macrolide antibiotics have good antibacterial activity, no allergic reaction, few side effects, and high safety. After nearly 60 years of development, they have become the second largest class of anti-infective drugs after β-lactam antibiotics. Erythromycin, the representative drug of the first generation of macrolide antibiotics, has been widely used to treat infections caused by Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus hemolyticus and Mycoplasma pneumoniae, especially for those who are allergic to penicillin. However, it has the disadvantages of unstable acid medium and low bioavailability, which limits its application. The second-generation macrolide antibiotics represented by azithromycin have solved this problem and have greatly improved their efficacy and pharmacokinetics. Azithromycin (che...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00A61K31/7052A61P31/04
Inventor 马淑涛沈学翠马晓东崔文平张玲
Owner SHANDONG UNIV
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