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11‑o‑aralkylcarbamate clarithromycin derivatives and their preparation methods and applications
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A technology of alkyl carbamate clarithromycin and clarithromycin, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., to achieve good anti-gram-positive bacteria activity and obvious effects of antibacterial effect
Active Publication Date: 2017-07-04
SHANDONG UNIV
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Problems solved by technology
The C-11 position is a very potential modification site for macrolide antibiotics, and there are few reports on the modification of the C-11 position of clarithromycin
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Embodiment 1
[0074] Preparation of 2′,4″-O-diacetyl-clarithromycin
[0075] Dissolve clarithromycin (30g, 40mmol) in dry dichloromethane (180mL), add acetic anhydride (12mL, 127mmol), 4-dimethylaminopyridine (0.1g, 0.82mmol) and triethylamine (13.5mL) , 97.6mmol) and stirred at 30°C for 12h. After the reaction is completed, an equal volume of saturated sodium bicarbonate solution is added to separate the layers, and the organic layer is washed with saturated sodium bicarbonate solution 2-3 times, and then washed with saturated brine. Dry with anhydrous sodium sulfate. It was filtered and evaporated to dryness under reduced pressure to obtain 35.12 g of a white foamy solid with a crude yield of 105%. Rf=0.40 (developing agent: dichloromethane: methanol=15:1; color development with concentrated sulfuric acid-ethanol).
Embodiment 2
[0077] Preparation of 2′,4″-O-bisbenzoyl-clarithromycin
[0078] Dissolve clarithromycin (5g, 6.7mmol) in DMF (25mL), add 4-dimethylaminopyridine (0.9g, 7.4mmol), triethylamine (4.5mL, 32.5mmol) and benzoic anhydride (5.25 g, 23.2mmol), stirred at 45°C for 4h. After the reaction is complete, add 50ml of distilled water and stir for 2h, then add 25% NaOH solution to adjust the pH to 9-10. Suction filtration, take the filter cake, and vacuum dry to obtain 6.36 g of yellow-brown solid, with a crude yield of 99.4%. Rf=0.67 (developer: acetone: cyclohexane=1:2).
Embodiment 3
[0080] Preparation of 2′,4″-O-Diacetyl-11,12-cyclic carbonate-clarithromycin
[0081] Dissolve 2',4″-O-Diacetyl-clarithromycin (35.12g, 42.2mmol) in anhydrous dichloromethane (500mL), add pyridine (32.3mL, 401mmol) and stir at 0°C under nitrogen protection After that, triphosgene (23.81g, 80.18mmol) was dissolved in anhydrous dichloromethane (200mL) and slowly dropped into the above mixed solution. Stir at 0°C for 6h. After the reaction was completed, add an appropriate amount of distilled water to quench the reaction. The layer was washed 2-3 times with saturated sodium bicarbonate solution until it was neutral. Then washed with saturated brine. Dried over anhydrous sodium sulfate. Filtered and evaporated to dryness under reduced pressure to obtain 35.6 g of light yellow foamy solid. The crude product yield was 98. %. Rf=0.56 (developer: dichloromethane:methanol=10:1).
[0082] 2',4"-O-bisbenzoyl-11,12-cyclic carbonate-clarithromycin was prepared according to the above method.
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Abstract
The invention discloses 11-O-aromatic aralkyl carbamate clarithromycin derivatives as well as a preparation method and application thereof. The 11-O-aromatic aralkyl carbamate clarithromycin derivatives are characterized in that a carbamate side chain structure is introduced to a C-11 position, and various substituted substitutive aromatic groups are arranged at the tail end of the carbamate side chain structure; the side chain has a certain flexibility, so that the side chain is favorably combined with nucleotide residues on the surface of a peptide channel of a ribosome 23S rRNA (Ribosomal Robonucleic Acid). On the basis that the series of derivatives are modified at the C-11 position, benzoic acid is introduced to hydroxyl at the C4 position to form a benzoate side chain, and further a secondary acting mechanism is obtained; the determination on in vitro antibacterial activity shows that the introduction of the side chain at the C4 position is extremely important for obtaining the activity of drug-resistant bacteria; the 11-O-aromatic aralkyl carbamate clarithromycin derivatives show excellent activity of resisting gram positive bacteria, wherein some compounds have outstanding properties on in vitro antibacterial activity of ermB type anti-drug streptococcus pneumonia. The 11-O-aromatic aralkyl carbamate clarithromycin derivatives particularly have excellent effect on the activity of drug-resistant bacteria of various streptococcus pneumonia, and can be used for preparing medicines for treating bacterial infection.
Description
Technical field [0001] The invention relates to a class of 11-O-aralkyl carbamate clarithromycin derivatives, a preparation method thereof, and applications in antibacterial. Background technique [0002] Macrolides are a class of weakly basic lipophilic compounds containing 14 to 16 membered macrolide rings. Although it is only a small branch of anti-infective drugs, compared with penicillins and other commonly used antibiotics, it has a positive effect and no serious adverse reactions. It has been widely used in the treatment of respiratory tract, soft tissue infections and urinary system infections. . [0003] The use of antibiotics will inevitably have a selective effect on bacterial mutations and cause bacterial drug resistance, and the rate of bacterial resistance is much faster than the rate of new antibacterial drug development. The semi-synthetic modification targeting macrolides as the backbone has become one of the focus of current antibacterial drug research, and it i...
Claims
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