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4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof

A technology of azithromycin and carbamoyl, which is applied in the field of azithromycin derivatives and its preparation, and can solve problems such as no description

Inactive Publication Date: 2009-05-06
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 compounds derived from 4", 11-dicarbamate azithromycin derivatives, intermediates and processes for their preparation, their formation with inorganic or organic acids have been described so far. The addition salt of the invention, the preparation method related to the pharmaceutical composition and the use of the pharmaceutical composition for treating bacterial infection

Method used

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  • 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof
  • 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof
  • 4'',11-diamino formic ether azithromycin derivates, preparation method and medicament composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] a) Preparation of 2′-O-acetyl-azithromycin

[0075] 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 (1.84g), with a yield of 92%. Melting point 167~170℃, R f It is 0.522 (the developing solvent is dichloromethane:methanol=10:1). Molecular formula is C 40 h 74 N 2 o 13 , molecular weight 791.0, MS 792.0 (M+H + ).

[0076] b) Preparation of 2'-O-benzoyl-azithromycin

[0077] Dissolve azithromycin (2.0g...

Embodiment 2

[0079] Preparation of 4"-O-(1-H-imidazole-1-carbonyl)-2'-O-acetyl-azithromycin 11,12-cyclocarbonate

[0080] Dissolve 2′-O-acetyl-azithromycin (1.5g, 1.90mmol) in anhydrous toluene (20mL), add triethylamine (0.60mL, 4.33mmol) and N,N′-dicarbonylimidazole (CDI) ( N,N'-dicarbonylimidazole) (1.23g, 7.6mmol), heated and stirred at 110°C for 2h. After the reaction is complete, add saturated sodium bicarbonate solution (40 mL), separate the layers, extract with toluene (6 mL×2), combine the organic layers, and dry over anhydrous sodium sulfate. Filter and evaporate to dryness under reduced pressure to obtain 1.65 g of white foamy solid with a yield of 95.5%. Melting point 117~120℃, R f It is 0.610 (the developing solvent is dichloromethane:methanol=10:1). Molecular formula is C 45 h 74 N 4 o 15 , molecular weight is 911.1, MS 912.1 (M+H + ).

Embodiment 3

[0082] a): Preparation of 4"-O-(4-hydroxyphenethyl-carbamoyl)-2'-O-acetyl-azithromycin 11,12-cyclocarbonate 4"-O-(1-H- Imidazole-1-carbonyl)-2′-O-acetyl-azithromycin 11,12-cyclocarbonate (1.5 g, 1.65 mmol) was dissolved in N, N-dimethylformamide (DMF) (15 mL), added 1. 8-diazabicyclo(5.4.0)undecene-7(DBU) (0.33mL, 2.25mmol) and 4-hydroxyphenethylamine (0.31g, 2.25mmol), stirred at room temperature for 12h. After the reaction is complete, add water (30 mL), extract with ethyl acetate (15 mL×3), combine the organic layers, wash with saturated brine (15 mL×3), dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain 1.33 g of a white foamy solid , yield 82.0%. The melting point is 155-157°C, the Rf is 0.556 (the developing agent is dichloromethane:methanol=10:1), and the molecular formula is C 50 h 81 N 3 o 16 , molecular weight is 980.2, MS 981.1 (M+H + ).

[0083] b): Preparation of 4"-O-(4-methoxybenzyl-carbamoyl)-2'-O-acetyl azithrom...

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Abstract

The invention relates to a novel fifteen-member macrolide derivative which has a general formula (I) and comes from azithromycin, wherein R1 represents hydrogen, acetyl or benzoyl, and R2 and R3 represent an aliphatic group, a substituted aroma aliphatic group or a substituted aroma heterocycle aliphatic group respectively. The invention also relates to an intermediate product and a preparation method thereof, acceptable addition salts formed by the fifteen-member macrolide derivative together with inorganic acid or organic acid, and a preparation method for a medicine compound and the application of the medicine compound to the treatment of bacterial infection.

Description

technical field [0001] The present invention relates to azithromycin derivatives and preparation thereof, in particular to 4", 11-dicarbamate azithromycin derivatives, preparation method and pharmaceutical composition thereof. Background technique [0002] Macrolide antibiotics, as an important class of anti-infective drugs, have become second only to β-lactams in clinical application because of their good antibacterial activity, no allergic reactions, few side effects, and high safety. Antibiotics are the second largest class of anti-infective drugs and play an important role in clinical treatment. As the first generation of macrolide antibiotics, erythromycin 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. Instability limits its application. The second-generation macrolide antibiotics represented by azithromycin hav...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08A61K31/7052A61P31/04
Inventor 马淑涛咸瑞卿
Owner SHANDONG UNIV
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