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Azithromycin 4-phenproester derivative, its production and medicinal composition

A technology of drugs and compounds, applied in the field of azithromycin derivatives and its preparation, can solve the problems of not describing azithromycin 4″-carbamate derivatives

Inactive Publication Date: 2007-11-21
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] According to the known and established prior art, no acceptable formulas derived from azithromycin 4"-carbamate derivatives, intermediate derivatives and processes related to their preparation, related to their formation with inorganic or organic acids have been described so far. Addition salt, preparation method related to pharmaceutical composition and use of pharmaceutical composition for treating bacterial infection

Method used

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  • Azithromycin 4-phenproester derivative, its production and medicinal composition
  • Azithromycin 4-phenproester derivative, its production and medicinal composition
  • Azithromycin 4-phenproester derivative, its production and medicinal composition

Examples

Experimental program
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Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of the first intermediate

[0052] a) Preparation of 2′-O-acetyl-azithromycin

[0053] Dissolve azithromycin (2.0 g, 2.67 mmol) in anhydrous dichloromethane (20 mL), add acetic anhydride (0.75 mL, 7.96 mmol) and triethylamine (3.00 mL, 21.6 mmol), and stir at room temperature for 24 h. After the reaction was completed, an equal volume of 5% sodium bicarbonate solution was added, the layers were separated, extracted with dichloromethane (10 mL×2), the organic layers were combined, and dried over anhydrous sodium sulfate. It was filtered and evaporated to dryness under reduced pressure to obtain a white foamy solid, which was recrystallized from acetone-water (2:1) to obtain the white target product (1.84 g), with a yield of 92%. Melting point 167~170℃, R f It was 0.522 (the developing solvent was dichloromethane:methanol=10:1). Molecular formula is C 40 h 74 N 2 o 13 , molecular weight is 791.0, MS is 792.0 (M+H + ).

[0054] b) Pre...

Embodiment 2

[0056] Example 2: Preparation of the second intermediate 4″-O-(1-H-imidazole-1-carbonyl)-2′-O-acetyl-azithromycin

[0057] Dissolve 2′-O-acetyl-azithromycin (1.5 g, 1.90 mmol) in anhydrous toluene (20 mL), add triethylamine (0.60 mL, 4.33 mmol) and N, N′-dicarbonylimidazole (CDI) ( 0.672g, 3.80mmol), stirred at room temperature for 48h. After the reaction was completed, a saturated sodium bicarbonate solution (20 mL) was added, the layers were separated, extracted with toluene (6 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate. Filter and evaporate to dryness under reduced pressure to obtain 1.6 g of white foamy solid with a yield of 95.4%. Melting point 147~150℃, R f It was 0.592 (the developing solvent was dichloromethane:methanol=10:1). Molecular formula is C 44 h 76 N 4 o 14 , molecular weight is 884.5, MS is 885.5 (M+H + ).

Embodiment 3

[0058] Embodiment 3: Preparation of target product azithromycin 4 "-carbamate derivative

[0059] a) Preparation of 4″-O-propylcarbamoyl-2′-O-acetyl-azithromycin (target product)

[0060] 4″-O-(1-H-imidazole-1-carbonyl)-2′-O-acetyl-azithromycin (1.33 g, 1.50 mmol) was dissolved in N,N-dimethylformamide (DMF) (15 mL ), add DBU (0.33mL, 2.25mmol) and n-propylamine (0.25mL, 2.25mmol), and stir at room temperature for 12h. After the reaction is complete, add water (30mL), extract with ethyl acetate (15mL×3), combine the organic layers, Wash with saturated brine (15mL×3), dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain 1.15g of white foamy solid, yield 87.3%. Melting point 143~145°C, R f It was 0.611 (the developing solvent was dichloromethane:methanol=10:1). Molecular formula is C 44 h 81 N 3 o 14 , molecular weight is 876.1, MS is 877.1 (M+H + ).

[0061] b) Preparation of 4″-O-benzylcarbamoyl-2′-O-acetyl-azithromycin (target p...

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Abstract

A compound with general formula (I), accepted additional salt formed of inorganic and organic acids, its production, medicinal composition and usage are disclosed. It belongs to azithromycin pentadecenic macrolide derivative, R1 represents hydrogen or acetyl or methane; R2 represents fatty hydrocarbon, substituted aromatic fatty hydrocarbon or substituted aromatic heterocyclic fatty hydrocarbon. It can be used to prepare medicines in treatment of bacterial infections.

Description

technical field [0001] The present invention relates to azithromycin derivatives and preparation thereof, in particular to azithromycin 4"-carbamate derivatives, preparation method and pharmaceutical composition thereof. Background technique [0002] Macrolide antibiotics are a class of antibiotics that can be taken orally and have antibacterial activity against pathogenic bacteria of respiratory tract infections. As the first generation of macrolide antibiotics, erythromycin has been widely used, but its application is limited due to its instability to acid medium. The second-generation macrolide antibiotics represented by azithromycin have solved this problem and have greatly improved their efficacy and pharmacokinetics. Azithromycin (9-deoxy-9a-methyl-9a-aza-9a-homoerythromycin A) is the first 15-membered macrocycle discovered by Bright (US Patent 4,474,768) and Kobrehel (US Patent 4,517,357) Lactone antibiotics. It is a kind of special macrolide antibiotic obtained by...

Claims

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Application Information

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IPC IPC(8): C07H17/08A61K31/7052A61P31/04
Inventor 马淑涛咸瑞卿娄红祥王辉
Owner SHANDONG UNIV
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