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Triazole alcohol antifungal compounds with nitrogen-containing side chains, preparation method thereof and application thereof

A technology of triazole and compound, applied in the field of medicine, can solve the problems of large side effects, narrow antibacterial spectrum, easy generation of drug resistance and the like

Inactive Publication Date: 2012-01-11
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

However, as far as its clinical application is concerned, the existing antifungal drugs have problems such as large side effects, narrow antibacterial spectrum, and easy drug resistance, which are far from meeting the needs of clinical treatment.

Method used

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  • Triazole alcohol antifungal compounds with nitrogen-containing side chains, preparation method thereof and application thereof
  • Triazole alcohol antifungal compounds with nitrogen-containing side chains, preparation method thereof and application thereof
  • Triazole alcohol antifungal compounds with nitrogen-containing side chains, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Example 1: Preparation of 2-chloro-2', 4'-difluoroacetophenone (II)

[0108] 100g (0.747mol) of anhydrous aluminum trichloride and 75.33g (0.667mol) of m-difluorobenzene were placed in a 500mol three-necked flask, stirred at room temperature, and 75.33g (0.667mol) of chloroacetyl chloride was slowly added dropwise. After the completion, continue to stir at room temperature for 30 minutes, slowly raise the temperature to 50°C, continue to stir at this temperature for 5 hours, pour the reaction solution into ice water, precipitate crystals, filter to obtain a solid, and divide the filtrate twice with 400ml of dichloromethane Extract, 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 methanol to obtain 2-chloro-2',4'-difluoro Acetophenone 107.38g, yield 87.2%, melting point: 46-47°C.

Embodiment 2

[0109] Example 2: Preparation of 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (III)

[0110] Triazole 27.2g (0.4mol), TEBA 0.4g, anhydrous K 2 CO 3 Add 180ml of CH to 41.56g (0.3mol) 2 Cl 2 Suspension was obtained; 2-chloro-2', 4'-difluoroacetophenone (II) 38.2g (0.2mol) was dissolved in 60mlCH 2 Cl 2 Add it dropwise to the above-mentioned 180ml suspension under ice-bath conditions, and drop it in about 1.5 hours. After the drop, react at 0-5°C for 5 hours, and react at room temperature for 24 hours. Then filter, filter cake with CH 2 Cl 2 Wash several times, collect the filtrate, wash the filtrate 3 times with water, each 100ml, anhydrous Na 2 SO4 dried, filtered, distilled CH 2 Cl 2 , dissolve the residue in 100ml of anhydrous ethyl acetate, stir and add concentrated nitric acid dropwise until the yellow solid no longer precipitates, filter, wash the filter cake several times with a small amount of ethyl acetate, dry it, dissolve it in 100ml of water, Use 3...

Embodiment 3

[0111] Example 3: Preparation of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV)

[0112]Get 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (III) 29.8g (0.115mol), trimethyl iodine oxysulfide 25.3g ( 0.115mol), 1.6g of trimethylhexadecylammonium bromide, put into a 500ml three-necked flask, add 180ml of toluene and 225ml of 20% sodium hydroxide solution (w / w), heat at 60°C for 3 hours, and the reaction is completed Finally, the toluene layer is separated, the water layer is extracted with toluene (100mlX2), the toluene layers are combined, washed with water until neutral, and most of the toluene is recovered, the residual solution is diluted with 120ml of ethyl acetate, and 8.3g of 2ml of ethyl acetate of methanesulfonic acid precipitated a pale yellow solid, which was filtered and recrystallized from methanol to obtain 21.71g of compound IV with a yield of 56.7% and a melting point of 128-129°C.

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Abstract

The invention relates to the technical field of medicines. Present antifungal medicines which have problems of large side effect, narrow antimicrobial spectrum, easy generation of the drug resistance and the like cannot satisfy clinical treatment needs. The invention provides novel triazole alcohol antifungal compounds with high efficiency, low toxicity and wide spectrum and pharmaceutically acceptable salts thereof. The compounds are 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(nitrogen-containing side chain substituted)-2-propanol compounds, and the general structure of the compounds is shown in the specification. The invention also provides a preparation method of the compounds and an application of the compounds in the preparation of antifungal medicines.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a novel triazole alcohol antifungal compound-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluoro Phenyl)-3-substituted-2-propanol compounds and salts thereof, as well as preparation methods and applications. Background technique [0002] In recent years, with the extensive application of broad-spectrum antibiotics, antineoplastic drugs, and immunosuppressants, the widespread implementation of radiotherapy and organ transplantation, the widespread development of catheters and intubations, and the rapid increase in immunocompromised patients, especially AIDS patients, have resulted in Fungal infections, especially deep fungal infections, have risen sharply, and deep fungal infections have become the main cause of death from major diseases such as AIDS and tumors. Existing antifungal drugs mainly include amphotericin B that acts on fungal cell membrane lipids, nitrogen azoles that act on la...

Claims

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Application Information

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IPC IPC(8): C07D249/08C07D409/12C07D405/12C07D401/12C07D403/12C07D413/12C07D417/12A61K31/4196A61K31/4709A61K31/4439A61K31/423A61K31/496A61P31/10
Inventor 张万年盛春泉王胜正王文雅缪震元姚建忠
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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