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11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition

A technology for medicines and compounds, applied in the field of azithromycin derivatives and their preparation, can solve problems such as no description

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

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Problems solved by technology

[0005] According to the known and established prior art, no intermediate product derivatives and processes from 11,12-cyclocarbonate-azithromycin 4″-carbamate derivatives, their preparation, their connection with inorganic Or a pharmaceutically acceptable addition salt of an organic acid, a method for preparing a pharmaceutical composition, and an application of the pharmaceutical composition for treating bacterial infections

Method used

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  • 11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition
  • 11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition
  • 11,20-cyclic carbonate-azithromycin 4-phenproester derivative, its production and medicinal composition

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Experimental program
Comparison scheme
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Embodiment 1

[0053] Embodiment 1: the preparation of the first intermediate

[0054] a) Preparation of 2′-O-acetyl-azithromycin

[0055] 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 + ).

[0056] b) Pre...

Embodiment 2

[0058] Example 2: Preparation of the second intermediate 4″-O-(1-H-imidazole-1-carbonyl)-2′-O-acetyl-azithromycin 11,12-cyclocarbonate

[0059] Dissolve 2′-O-acetyl-azithromycin (1.5g, 1.90mmol) in anhydrous toluene (20mL), add triethylamine (0.60mL, 4.33mmol) and 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 was 0.610 (the developing solvent was dichloromethane:methanol=10:1). Molecular formula is C 45 h 74 N 4 o 15 , molecular weight is 911.1, MS is 912.1 (M+H + ).

Embodiment 3

[0060] Embodiment 3: Preparation of target product 11,12-cyclocarbonate-azithromycin 4 "-carbamate derivative

[0061] a) Preparation of 4″-O-propyl-carbamoyl-2′-O-acetyl-azithromycin 11,12-cyclocarbonate (target product)

[0062] 4″-O-(1-H-imidazole-1-carbonyl)-2′-O-acetyl-azithromycin 11,2-cyclocarbonate (1.5 g, 1.65 mmol) was dissolved in N,N-dimethyl In formamide (DMF) (15mL), 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), ethyl acetate (15mL×3 ) extraction, combined organic layers, washed with saturated brine (15mL × 3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 1.35g of white foamy solid, yield 91.0%. Rf is 0.621 (developing agent is dichloromethane: Methanol=10:1), the molecular formula is C 45 h 79 N 3 o 15 , molecular weight is 902.0, MS 903.1 (M+H + ).

[0063] b) Preparation of 4″-O-benzyl-carbamoyl-2′...

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Abstract

A compound with general formula (I), accepted additional salts of inorganic and organic acid medicines, 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 11,12-cyclocarbonate-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 a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08A61K31/7052A61P31/04
CPCY02P20/55
Inventor 马淑涛咸瑞卿娄红祥焦波
Owner SHANDONG UNIV