Triazole alcohol derivative as well as preparation method and application thereof

A technology of triazole and triazole, applied in the field of medicinal compounds, can solve the problems of large side effects, lack of antifungal drugs against deep fungal drugs, and inability to meet treatment needs.

Active Publication Date: 2020-02-28
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

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 as well as preparation method and application thereof
  • Triazole alcohol derivative as well as preparation method and application thereof
  • Triazole alcohol derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1: (2R,3R)-2-(2,4-difluorophenyl)-3-(prop-2-yn-1-yloxy)-1-(1H-1,2,4- Synthesis of Triazol-1-yl)-butan-2-ol (Compound 12)

[0111] Step 1: the synthesis of compound 3,

[0112]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 ,400MHz)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).

[0113] Step 2: the synthesis of compound 5,

[0114] 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 chl...

Embodiment 2

[0128] Step 1: Dissolve 4-chlorobenzaldehyde (1mmol) in methanol (10mL), add NaHCO 3 (1.1mmol) and NH 2 OH.HCl (1.1mmoL) aqueous solution (10mL), stirred at room temperature for 2h, added water until white solid precipitated, filtered and dried to obtain compound 4-chlorobenzaldehyde oxime.

[0129] Step 2: Dissolve compound 4-chlorobenzaldehyde oxime (1 mmol) in 10 mL of DMF, add NCS (1.1 mmol), and stir at 35° C. for 3 h. After TLC monitors that the reaction is complete, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated NaCl, anhydrous NaCl 2 SO 4 Dried and spin-dried to obtain compound 4-chlorobenzaldehyde oxime chloride.

[0130] Step 3: Compound 4-chlorobenzaldehyde oxime chloride (1mmoL) and (2R,3R)-2-(2,4-difluorophenyl)-3-(prop-2-yn-1-yloxy )-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol (1mmol) was dissolved in THF (10mL), vacuumized under nitrogen protection, and TEA (1mmoL ), stirred at 35°C for 12h. After TLC monitors that t...

Embodiment 3

[0132] Step 1: Dissolve 2-chlorobenzaldehyde (1mmol) in methanol (10mL), add NaHCO 3 (1.1mmol) and NH 2 OH.HCl (1.1mmoL) aqueous solution (10mL), stirred at room temperature for 2h, added water until white solid precipitated, filtered and dried to obtain compound 2-chlorobenzaldehyde oxime.

[0133] Step 2: Dissolve the compound 2-chlorobenzaldehyde oxime (1 mmol) in 10 mL of DMF, add NCS (1.1 mmol), and stir at 35° C. for 3 h. After TLC monitors that the reaction is complete, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated NaCl, anhydrous NaCl 2 SO 4 Dry and spin dry to obtain compound 2-chlorobenzaldehyde oxime chloride.

[0134] Step 3: Compound 2-chlorobenzaldoxime chloride (1mmoL) and (2R,3R)-2-(2,4-difluorophenyl)-3-(prop-2-yn-1-yloxy )-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol (1mmol) was dissolved in THF (10mL), vacuumized under nitrogen protection, and TEA (1mmoL ), stirred at 35°C for 12h. After TLC monitors that the rea...

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PUM

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Abstract

The invention relates to a triazole alcohol derivative as well as a preparation method and application thereof. The chemical structure of the triazole alcohol derivative is shown as a formula I, R1 represents a benzene ring or a substituted benzene ring, and substituent groups of the substituted benzene ring can be located at all positions of the benzene ring, can be mono-substituted or multi-substituted, and can be selected from a) halogen which is F and Cl; b) an electron withdrawing group which is cyano or trifluoromethyl; c ) a lower alkyl of 1-4 carbon atoms or a halogen substituted loweralkyl; and d) lower alkoxy of 1-4 carbon atoms or halogen substituted lower alkoxy. The compound of the invention has strong antifungal activity, has the advantages of low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal drugs.

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): C07D413/12A61P31/10A61K31/422
CPCC07D413/12A61P31/10
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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