Macrolide antimicrobial compound as well as preparation method and application thereof

A technology of macrolides and compounds, applied in the field of macrolides antibacterial compounds and their preparation, achieving good application prospects, solving the problem of multi-drug resistance, and good antibacterial performance

Active Publication Date: 2016-03-23
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Phase IV clinical studies have found that telithromycin has severe liver toxicity. For safety reasons, the US FDA has restricted the indications of telithromycin to only community-acquired pneumonia. Recent reports have shown that the drug Disabled in most countries around the world

Method used

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  • Macrolide antimicrobial compound as well as preparation method and application thereof
  • Macrolide antimicrobial compound as well as preparation method and application thereof
  • Macrolide antimicrobial compound as well as preparation method and application thereof

Examples

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Embodiment 1

[0033] The present embodiment macrolide antibacterial compound I 1 Synthesis:

[0034] (1) Fluoromycin (70.0 g, 93 mmol) was dissolved in 1200 mL of hydrochloric acid buffer solution with a pH of 1.5, and the reaction was stirred at room temperature for 24 h. The solution was concentrated to 200 mL, and the pH was adjusted to 9 by adding ammonia water. Ethyl acetate was extracted three times (150 mL×3), and the organic phase was successively washed with saturated sodium bicarbonate solution (100 mL×3) and saturated saline solution (100 mL×3), and dried overnight over anhydrous sodium sulfate. Filtration, evaporation of solvent, silica gel column chromatography (developing agent V 二氯甲烷 / V 甲醇 =20:1), the white solid product 3-de(hexylglucopyranosyl)-3-hydroxyfluoroerythromycin (40.0g, 72%) was obtained, and the product identification data were as follows:

[0035] m.p.:118-120℃; 1 H-NMR (400MHz, DMSO-d 6 )δ: 5.11(d, J=7.8Hz, 2H, H-1', 13), 4.48(d, J=7.3Hz, 1H, H-6-OH), 4.1...

Embodiment 2

[0044] The present embodiment macrolide antibacterial compound I 2 Synthetic, the preparation method is the same as in Example 1, p-nitrophenylacetic acid (0.31g, 1.73mmol) is replaced by p-nitrophenylpropionic acid (0.34g, 1.73mmol), and the light yellow solid product 3-de(hexylpyridine) is obtained Glucopyranosyl)-3-p-nitrophenylpropionyl-11,12-cyclocarbonate-fluerythromycin I 2 (0.4g, 36%) product identification data are as follows:

[0045] m.p.:110-113℃; 1 H-NMR (400MHz, CDCl 3 )δ: 8.13(d, J=8.1Hz, 2H, H-2”, 6”), 7.40(d, J=8.2Hz, 2H, H-3”, 5”), 5.81(d, J=10.7 Hz,1H,H-1'),4.94(d,J=9.2Hz,1H,H-13),4.82(s,1H,H-11),4.22(d,J=7.0Hz,1H,H- 3), 3.84(dt, J=13.2, 6.6Hz, 2H, H-7”-CH 2 -),3.45(s,1H,H-5'),3.27-3.07(m,2H,8”-CH 2 -),2.73(ddd,J=23.8,16.4,9.2Hz,4H,H-2,2',10,5,),2.48(d,J=31.8Hz,6H,H-3'-N-( CH 3 ) 2 ), 2.09(q, J=6.5Hz, 1H, H-3'), 1.71(s, 3H, H-6-CH 3 ), 1.61 (d, J=23.1Hz, 4H, H-4'b, 4, 7a, 13- CH 2a CH 3 ),1.48(s,3H,H-8-CH 3 ), 1.19 (d, J=7.2Hz, 3H, H-4'a, 7b, ...

Embodiment 3

[0047] The present embodiment macrolide antibacterial compound I 3 The synthesis of, preparation method is the same as embodiment 1, p-nitrophenylacetic acid (0.31g, 1.73mmol) is replaced by 2-fluorophenylacetic acid (0.27g, 1.73mmol), silica gel column chromatography (developing agent V 二氯甲烷 / V 甲醇 =40:1), the white solid product 3-de(hexyglucopyranosyl)-3-(2-fluoro-phenylacetyl)-11,12-cyclocarbonate-fluerythromycin I was obtained 3 (0.25g, 24%), the product identification data are as follows:

[0048] m.p.:90-92℃; 1 H-NMR (400MHz, DMSO-d 6 )δ:7.68-7.65(m,2H,H-2",6"),7.50(d,J=7.8Hz,2H,H-3",5"),5.86(s,1H,H-1' ),5.59(dd,J=10.0,1.4Hz,1H,H-13),4.88(dd,J=9.8,3.3Hz,1H,H-2'-OH),4.60(s,1H,H-11 ), 4.31(d, J=4.0Hz, 1H, H-3), 4.10(d, J=7.4Hz, 1H, H-6-OH), 3.84(t, J=8.8Hz, 3H, H-7 "-CH 2 -,5'),3.48(dd,J=10.1,5.1Hz,1H,H-5),3.13(dd,J=7.3,1.6Hz,1H,H-2'),3.05-2.98(m,1H ,H-7a),2.72(dd,J=26.1,13.7Hz,2H,H-10,2),2.21(s,6H,H-3'-N-(CH 3 ) 2 ), 1.99(d, J=1.8Hz, 1H, H-7b), 1.96(d, J=6.8Hz, ...

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Abstract

The present invention belongs to the technical field of medicine chemical industry, and discloses a macrolide antimicrobial compound as well as a preparation method and application thereof. The structure of the macrolide antimicrobial compound is shown as formula I, wherein n equals 1 or 2; X is a carbon atom or a nitrogen atom; and R is selected from any one of H, C1-C6 alkyl, nitryl, C1-C6 alkoxy, halogen substituent and C1-C6 haloalkyl substituent. According to the synthesis route, fluorine erythromycin firstly reacts with a hydrochloric acid buffer solution, and the reaction product successively reacts with benzoic anhydride, triphosgene and R-substituted aryl acid or heterocyclic aryl acid, and finally a reflux reaction is performed in an alcohol solvent so as to obtain the macrolide antimicrobial compound. The preparation method disclosed by the present invention is simple in synthesis route and high in synthesis yield; and the obtained product is good in antibacterial performance and high in inhibitory activity of macrolide drug-resistant strains, and has good application prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a macrolide antibacterial compound and its preparation method and application. Background technique [0002] Since erythromycin A, the first macrolide antibiotic developed by Eli Lilly and Company, was launched on the market in 1952, global pharmaceutical companies and major research institutes have been researching on this class of antibiotics for more than 60 years. They can be roughly divided into Three stages: (1) The era from the 1950s to the 1980s was the era of the first generation of macrolide antibiotics, including erythromycin, dirithromycin, mabemycin, josamycin, acetylspiramycin, Midecamycin. It is mainly used to treat diseases such as respiratory tract infections caused by a variety of Gram-positive bacteria, and has strong activity against Chlamydia, Mycoplasma, Campylobacter, and Legionella. This type of compound has definite cu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H17/00C07H1/00A61K31/7048A61K31/706A61P31/04
CPCC07H1/00C07H17/00C07H17/08
Inventor 张雷高蕾李晶关溯张硕
Owner SOUTH CHINA UNIV OF TECH
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