Novel azole antifungal compound and preparation method and application thereof

A compound, nitrogen azole technology, applied in the field of novel nitrogen azole antifungal compound and its preparation, achieving high yield, strong antifungal activity and good effect

Inactive Publication Date: 2012-11-28
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And so far no azole compounds with antifungal activity 1-(1 H -1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(1-substituted benzyloxyethyl-1 H Report on -1,2,3triazol-4-yl)-2-ol

Method used

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  • Novel azole antifungal compound and preparation method and application thereof
  • Novel azole antifungal compound and preparation method and application thereof
  • Novel azole antifungal compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 R group and proton nuclear magnetic spectrum data of some compounds of the present invention

[0036] See Table 1 for the R groups and H NMR spectrum data of some compounds of the present invention.

[0037] Table 1 R group and proton nuclear magnetic spectrum data table of some compounds of the present invention

[0038] serial number R 1 HNMR (300MHz, CDCl 3 ) 7a 2-F 8.27 (1H, s, 1,2,4-triazole-H), 7.75 (1H, s, 1,2,4-triazole-H), 7.58 (1H, s, 1,2,3-triazole-H) , 7.27-6.77 (7H, m, Ar-H), 5.98 (1H, s, OH), 4.69-4.48 (2H, dd, J =14.4Hz, 1,2,4-triazole-CH 2 ), 4.44 (2H, s, CH 2 * CH 2 O), 4.40 (2H, s, ArCH 2 O), 3.74-3.71 (2H, t, CH 2 CH 2 * O), 3.35-3.10 (2H, dd, J =15.0Hz, 1,2,3-triazole-CH 2 * C(OH)) . 7b 3-F 8.27 (1H, s, 1,2,4-triazole-H), 7.75 (1H, s, 1,2,4-triazole-H), 7.60 (1H, s, 1,2,3-triazole-H) , 7.35-6.77 (7H, m, Ar-H), 5.98 (1H, s, OH), 4.69-4.49 (2H, dd, J =14.1Hz, 1,2,4-triazole-CH 2 ), 4.4...

Embodiment 2

[0040] Embodiment 2 The preparation of the intermediate of compound of the present invention

[0041] 1. Preparation of 2-chloro-2′, 4′-difluoroacetophenone

[0042] Put 200 g (1.494 mol) of anhydrous aluminum trichloride and 150 g (1.30 mol) of m-difluorobenzene into a 1000 mL three-neck flask, stir at room temperature, and slowly add 150 g (1.30 mol) of chloroacetyl chloride dropwise, After the dropwise addition, continue to stir at room temperature for 30 minutes, slowly raise the temperature to 45°C, and continue to stir at this temperature for 4.5 hours. Pour the reaction solution into ice water as usual, precipitate solids, and filter; the filtrate is dichloromethane 800 mL Extract twice, combine the dichloromethane extracts, wash with water until neutral, dry over anhydrous sodium sulfate, filter, recover the solvent to obtain a solid, combine the solid obtained twice and recrystallize with ethanol to obtain 2-chloro 2',4' - Difluoroacetophenone 215 g, yield 88...

Embodiment 3

[0051] Embodiment 3 Preparation of some compounds of the present invention

[0052] 1, preparation 1-(1 H -1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[1-(2-fluorobenzyloxy)ethyl-1 H -1,2,3triazol-4-yl)]-2-ol (7a)

[0053] Get the compound 1-(1 that embodiment 2 prepares H -1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[1-hydroxyethyl-1 H -1,2,3triazol-4-yl)]-2-ol 350 mg (1.0 mmol) in 20 mL dry CH 2 Cl 2 Add 26 mg (1.1 mmol) of NaH slowly under ice bath conditions, keep stirring in the ice bath for half an hour, then add 0.13 mL (1.2 mmol) of o-fluorobenzyl bromide, the reaction conditions remain unchanged, and the reaction ends in about 2 hours. At the end, add 20 mL CH 2 Cl 2 Dilute, add a small amount of methanol slowly under ice bath to remove the remaining NaH, then wash with water and saturated brine, evaporate the solvent to dryness, and purify by column chromatography (developing solvent: ethyl acetate:petroleum ether=1:1) to obtain white Solid target compoun...

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Abstract

The invention provides a novel azole antifungal compound. According to the azole antifungal compound, a structural general formula is shown in the specification, wherein X is hydroxyl, Ar is 2,4-difluoro phenyl, and R is selected from hydrogen, alkyl, halogen, cyano-group, nitryl, amino or alkoxy and can be positioned at the ortho-position, meta-position or para-position of a benzene ring and can be mono-substituted or multi-substituted; the alkyl has 1 to 4 carbon atoms; the halogen is selected from F, Cl, Br and I; the amino is selected from -NH2, one or two aminos substituted by the alkyl and cyclic amino; and the alkoxy is selected from methoxyl, ethyoxyl and tert-butyl oxygroup. The invention also provides a method for preparing the compound and application of the compound to preparation of antifungal medicines. Compared with the conventional antifungal medicines which are applied clinically, the azole antifungal compound has the advantages of high antifungal activity on invasive fungi, high efficiency, low toxicity, broad spectrum and the like; and the method is simple and high in yield, and the prepared compound has a good antifungal effect.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, in particular to a novel azole antifungal compound and its preparation method and application. Background technique [0002] In recent years, with the widespread application of broad-spectrum antibiotics, antineoplastic drugs, and immunosuppressants, the widespread development of peritoneal dialysis, organ transplantation, and radiotherapy, and the rapid spread of immunodeficiency diseases, especially AIDS, Candida albicans, Cryptography neoformans The incidence of opportunistic deep fungal infections such as coccus and Aspergillus fumigatus has increased dramatically. Deep fungal infection has risen to the third largest infectious disease clinically, seriously threatening human life and health. Existing antifungal drugs are mainly allylamines that act on squalene cyclooxygenase and act on lanosterol 14 a -Azole demethylases, as well as acting on the cell wall and -1,3- β Lipo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K31/4196A61P31/10
Inventor 邹燕赵庆杰吴秋业廖俊汪亭胡宏岗俞世冲柴晓云黄生军
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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