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15-membered clarithromycin derivative as well as preparation method and application thereof

A technology of clarithromycin and hydroxyclarithromycin, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of lack of chemical reactivity and difficult structural modification.

Pending Publication Date: 2021-06-01
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above reports are all conventional modifications on the macrocyclic core or branched chain sugars, and the literature (J.Antibiot., 2005, 58, 167-177 and J. Antibiot., 2006, 59, 392-401) reported on the C12 and C13 positions The modification can greatly improve the anti-drug-resistant bacteria activity of the derivative, but the inventors have found through research that it is difficult to directly carry out structural modification at this position due to the lack of chemical reactivity

Method used

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  • 15-membered clarithromycin derivative as well as preparation method and application thereof
  • 15-membered clarithromycin derivative as well as preparation method and application thereof
  • 15-membered clarithromycin derivative as well as preparation method and application thereof

Examples

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Effect test

Embodiment 1

[0172] Preparation of 9(S)-hydroxy-6-O-methylerythromycin A(2)

[0173] Dissolve clarithromycin (20 g, 26.8 mmol) in a mixed solvent of anhydrous tetrahydrofuran (150 mL) and methanol (300 mL). In an ice bath, dissolve NaBH within 1 h 4 (6 g, 158.6 mmol) was added to the above solution in 3 batches. After the addition was complete, the reaction solution was stirred at room temperature for 24 h. After the reaction was complete, the reaction solution was concentrated, and then DCM (200 mL) and saturated NH 4 Cl solution (200 mL) was added to the concentrated residue. Stir well, stand still for liquid separation, wash the aqueous phase with DCM (100 mL×2), and combine the organic phases. The organic phase was anhydrous Na 2 SO 4 Dry, filter with suction, concentrate to obtain the crude product, and then through column chromatography (DCM / CH 3 OH / NH 3 ·H 2 O=30:1:0.1~20:1:0.1~10:1:0.1) isolated to obtain 10.5 g of white solid with a yield of 52%. Melting point 208–210°C;...

Embodiment 2

[0175] Preparation of 2',4",9(S)-triethylsilyloxy-6-O-methylerythromycin A(3)

[0176] 9(S)-Hydroxy-6-O-methylerythromycin A (2) (8 g, 10.7 mmol) and imidazole (7.2 g, 105.8 mmol) were dissolved in N,N-dimethylformamide (100 mL) middle. Under an ice bath, triethylchlorosilane (5.5 g, 36.5 mmol) was slowly added dropwise to the above solution. After the drop was completed, the reaction was stirred at room temperature for 18 h under the protection of nitrogen. After the reaction is complete, add water (100mL) to the reaction solution to quench the reaction, then add EtOAc (100mL) and n-hexane (100mL), stir evenly, leave to separate the liquids, and the organic phase is washed with saturated NH 4 Cl solution (100 mL) washed. The organic phase was anhydrous Na 2 SO 4 Dry, filter with suction, and concentrate to obtain a crude product, which is then separated by column chromatography (petroleum ether / acetone = 80:1-50:1-30:1-10:1) to obtain 7.9 g of a white foamy solid with a y...

Embodiment 3

[0178] Preparation of ring-opening intermediate (6)

[0179] 2',4",9(S)-triethylsilyloxy-6-O-methylerythromycin A (3) (2g, 1.83mmol) was dissolved in chloroform (20mL). Under ice bath, Lead tetraacetate (0.97g, 2.19mmol) was slowly added to the above solution, and after the addition was complete, the reaction solution was stirred and reacted for 0.5h in an ice bath to obtain a chloroform solution of the ring-opening intermediate (4). Under an ice bath, ethanolamine (5 ) (224mg, 3.67mmol) and sodium triacetoxyborohydride (1.16g, 5.47mmol) were slowly added to the above solution, after the addition was complete, the reaction solution was stirred at room temperature for 4h. After the reaction was completed, saturated NaHCO was added to the reaction solution 3 (20 mL) solution to quench the reaction. Stir evenly, let stand to separate the layers, wash the aqueous phase with DCM (20 mL×2), and combine the organic phases. The organic phase was anhydrous Na 2 SO 4 Dry, filter wit...

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Abstract

The invention discloses a 15-membered clarithromycin derivative as well as a preparation method and application thereof. The 15-membered clarithromycin derivative has a structure as shown in a general formula I, II or III (shown in the description), wherein R1 is selected from hydrogen, saturated or unsaturated alkyl, saturated or unsaturated alkoxy and halogen; R2 is selected from hydrogen, an acetyl group, a benzoyl group or a triethyl siloxy group; R3 is selected from a saturated or unsaturated alkyl group and a saturated or unsaturated alkoxy group; x is 1; and y is 1. The 15-membered clarithromycin derivative provided by the invention has excellent antibacterial activity, particularly has a good inhibition effect on drug-resistant staphylococcus aureus, ermB drug-resistant streptococcus pneumoniae, ermB + mefA drug-resistant streptococcus pneumoniae and drug-resistant streptococcus pyogenes, and can be used for preparing drugs for treating bacterial infection.

Description

technical field [0001] The invention relates to a 15-membered clarithromycin derivative, its preparation method and application. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Macrolide antibiotics refer to 14- to 16-membered macrolide antibiotics. By blocking the activity of peptidyltransferase in 50S ribosomes, interfering with the extension of nascent peptide chains, and inhibiting bacterial protein synthesis, they exert antibacterial effects. Belongs to rapid antibacterial agent. These antibiotics are mainly used to treat aerobic Gram-positive and negative cocci, certain anaerobic bacteria, and infections such as Legionella, Mycoplasma, and Chlamydia. Because of it...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00A61K31/7052A61P31/04
CPCC07H17/00C07H1/00A61P31/04
Inventor 马淑涛秦银辉宋迪
Owner SHANDONG UNIV
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