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Triazole alcohol derivative, and preparation method and application thereof

The technology of triazole and compound is applied in the field of triazole derivatives and preparation thereof, and can solve the problems of lack of antifungal drugs against deep fungus, narrow antibacterial spectrum, large side effects and the like

Active Publication Date: 2020-04-17
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 the antifungal drugs currently in clinical use are concerned, there are problems such as large side effects, narrow antibacterial spectrum, and easy drug resistance. Effective antifungal drugs, especially anti-deep fungal drugs, are very scarce, which are far from meeting the needs of treatment.

Method used

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  • Triazole alcohol derivative, and preparation method and application thereof
  • Triazole alcohol derivative, and preparation method and application thereof
  • Triazole alcohol derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: (2R,3R)-2-(2,4-difluorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)-butane- Synthesis of 2-alcohols

[0110] Step 1: the synthesis of compound 3,

[0111] Dissolve (R)-methyl 2-hydroxypropionate (50mmol) and sodium methoxide (8mmol) in THF, add dropwise morpholine (100mmol), control the temperature at 10°C, stir for 3h, monitor the reaction by TLC, and dichloromethane Extracted twice, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, spin-dried and directly used in the next step. 1 H NMR (CDCl 3 ,300MHz)δ4.43-4.48(m,1H), 3.61-3.83(m,7H),3.42-3.44(m,2H),1.33(d,3H,J=6.8Hz).

[0112] Step 2: the synthesis of compound 5,

[0113]Compound 3 (50mmol) was dissolved in THF, p-toluenesulfonic acid (10mmol) was added, the temperature was controlled at 5°C, 3,4-dihydropyran (80mmol) was added dropwise, and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, two Methyl chloride was extracted ...

Embodiment 2

[0130] Example 2: (compound 17a)

[0131] Anthranilic acid (1mmol) and (2R,3R)-2-(2,4-difluorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl )-butan-2-ol (1mmol) was dissolved in DMF (10ml), added DIEA (2mmol), PyBOP (1.1mmol), reacted at room temperature for 2 hours, after TLC monitored the reaction was complete, extracted three times with ethyl acetate, combined Organic phase, washed twice with saturated NaCl, anhydrous NaCl 2 SO 4 After drying, the crude product was obtained after spin-drying. The crude product was dissolved in MeCN (10ml), and t-BuONO (1.5mmol) was added dropwise at 0°C, and kept at 0°C for 2 hours. After the reaction was monitored by TLC, it was poured into ice water, and the precipitated solid was filtered and weighed with methanol / water. Crystallization yields the product shown above.

Embodiment 3

[0132] Example 3: (compound 17b)

[0133] Mix o-2-amino-6-fluorobenzoic acid (1mmol) with (2R,3R)-2-(2,4-difluorophenyl)-3-amino-1-(1H-1,2,4-tri Azolazol-1-yl)-butan-2-ol (1mmol) was dissolved in DMF (10ml), added DIEA (2mmol), PyBOP (1.1mmol), and reacted at room temperature for 2 hours. Extracted three times with ethyl ester, combined organic phase, washed twice with saturated NaCl, anhydrous NaCl 2 SO 4 After drying, the crude product was obtained after spin-drying. Dissolve the crude product in MeCN (10ml), add t-BuONO (1.5mmol) dropwise at 0°C, keep the reaction at 0°C for 2 hours, monitor the reaction by TLC, pour it into ice water, filter the precipitated solid, and weigh it with methanol / water Crystallization yields the product shown above.

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Abstract

The invention relates to a triazole alcohol derivative, and a preparation method and an application thereof. The chemical structure of the triazole alcohol derivative is represented by formula I, A inthe formula I represents a benzene ring or a substituted benzene ring, and the substituent group of the substituted benzene ring can be located at each position of the benzene ring, is monosubstituted or polysubstituted, and is selected from: a) halogen which is F, Cl, Br or I; b) an electron-withdrawing group, wherein the electron withdrawing group is a cyano group, a nitro group or a trifluoromethyl group; c) a C1-4 low alkyl group or a halogen-substituted low alkyl group; and d) a C1-4 low alkoxy group or a halogen-substituted low alkoxy group. The compound has the advantages of high antifungal activity, low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal medicines.

Description

technical field [0001] The invention relates to the technical field of medical compounds, in particular to a novel triazole alcohol derivative and its preparation method and application. 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. However, as far as the antifungal drugs in clinical use are concerned, there are problems such as large side effects, narrow antibacterial spectrum, and easy drug resistance. Effective antifungal drugs, especially anti-deep fungal drugs, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K31/53A61P31/10
CPCC07D403/06A61P31/10
Inventor 张大志姜远英倪廷峻弘谢斐丁子超郝雨濛王瑞娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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