Triazole alcohol derivative and preparation method and application thereof

A triazole alcohol and triazole technology, applied in the field of pharmaceutical compounds, can solve the problems of narrow antibacterial spectrum, lack of antifungal drugs and deep fungal drugs, and large side effects

Active Publication Date: 2017-01-18
YANGTZE RIVER PHARM GRP CO LTD
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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

[0122] Example 1: (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4- Synthesis of Pentyn-2-ol

[0123] Step 1: Synthesis of (R)-3-butyn-2-ol mesylate.

[0124] Dissolve (R)-3-butyn-2-ol (50mmol) in dichloromethane, add triethylamine (100mmol), add methanesulfonyl chloride (55mmol) dropwise at -78°C, after the reaction is complete, pour into an aqueous solution of sodium bicarbonate, extracted twice with dichloromethane, and the organic phase was washed twice with water, dried over anhydrous sodium sulfate, spin-dried and used directly in the next step. 1 H NMR (300MHz, CDCl 3 )δ5.29(q,1H),3.13(s,3H),2.71(s,1H),1.66(d,3H).

[0125] Step 2: Synthesis of (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-methyl-4-pentyn-2-ol.

[0126] Pd(CH 3 EN) 2 Cl 2 (5mmol) was dissolved in tetrahydrofuran, triphenylphosphine (12.5mmol) was added, and after 10 minutes of reaction, 2-chloro-2', 4'-difluoroacetophenone (50mmol) and (R)-3-butyne were added -2-alcohol mesylate (5...

Embodiment 2

[0129] Example 2: (2R,3S)-2-(2,5-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4- Synthesis of Pentyn-2-ol

[0130] Step 1: Synthesis of (R)-3-butyn-2-ol mesylate.

[0131] Dissolve (R)-3-butyn-2-ol (50mmol) in dichloromethane, add triethylamine (100mmol), add methanesulfonyl chloride (55mmol) dropwise at -78°C, after the reaction is complete, pour into an aqueous solution of sodium bicarbonate, extracted twice with dichloromethane, and the organic phase was washed twice with water, dried over anhydrous sodium sulfate, spin-dried and used directly in the next step. 1 H NMR (300MHz, CDCl 3 )δ5.29(q,1H),3.13(s,3H),2.71(s,1H),1.66(d,3H).

[0132] Step 2: Synthesis of (2R,3S)-1-chloro-2-(2,5-difluorophenyl)-3-methyl-4-pentyn-2-ol.

[0133] Pd(CH 3 EN) 2 Cl 2 (5mmol) was dissolved in tetrahydrofuran, triphenylphosphine (12.5mmol) was added, and after 10 minutes of reaction, 2-chloro-2', 4'-difluoroacetophenone (50mmol) and (R)-3-butyne were added -2-alcohol mesylate (5...

Embodiment 3

[0136] Embodiment 3: the synthesis of compound 7a

[0137] Dissolve compound 5 (1mmol), compound p-bromobenzotrifluoride (1mmol) in NMP (10mL), add CuI (20mmol%), Pd (PPh3) 2 Cl 2 (5 mmol%), DIEA (5 mmol). Under the protection of nitrogen, react at 60°C for 12h. After TCL 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. After spin-drying, compound 7a was obtained after column chromatography.

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PUM

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Abstract

The invention relates to a triazole alcohol derivative and a preparation method and application thereof. The chemical structure of the triazole alcohol derivative is as shown in the formula I. The invention also provides salt of the compound, a pharmaceutical composition, a preparation method and application. The compound of the invention has strong antifungal activity, has advantages of low toxicity and wide antimicrobial spectrum, and can be used for preparation of 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. The existing antifungal drugs are mainly allylamines that act on squalene epoxidase, azoles that act on lanosterol 14a demethylase, and b-(1,3)-glucans that act on the cell wall. Lipopeptides of sugar synthase, etc. However, as far as t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08C07D409/06C07D403/06C07D401/06C07D413/06A61K31/4196A61K31/506A61K31/4439A61K31/422A61P31/10
CPCC07D249/08C07D401/06C07D403/06C07D409/06C07D413/06
Inventor 张大志姜远英倪廷峻弘蔡瞻庞磊谢斐李冉韩海冰何焱由守谊仰振球齐东绮
Owner YANGTZE RIVER PHARM GRP CO LTD
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