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Preparation method and applications of deuterated isoxazole compound

A compound, the technology of isoxazole, applied in the field of medicinal chemistry, achieves good antifungal activity, improved stability, and improved water solubility

Inactive Publication Date: 2020-02-11
朱允涛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, deuterated isoxazole small molecule antifungal compounds have not been reported

Method used

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  • Preparation method and applications of deuterated isoxazole compound
  • Preparation method and applications of deuterated isoxazole compound
  • Preparation method and applications of deuterated isoxazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Synthesis of Compound D1:

[0068]

[0069] Step 1: Dissolve compound 1 (10mmol) in toluene, add pivaloyl chloride (15mmol) under ice bath, then slowly add triethylamine (16mmol) dropwise, react at room temperature until the raw materials are completely reacted, pour into water, stir and divide layer, and the aqueous phase was adjusted to pH 8-9 with 5N NaOH aqueous solution, then extracted with ethyl acetate, and the organic phases were combined, dried and spin-dried to obtain the crude product 2, which was directly used in the next step.

[0070] Step 2: Dissolve compound 2 (10 mmol) in absolute ethanol, add diethyl oxalate (15 mmol), dropwise add potassium tert-butoxide ethanol solution with a concentration of 22% under ice melting, add hydrochloric acid after the reaction is complete under ice melting Hydroxylamine (20mmol), add a small amount of water after the reaction is complete at room temperature, and then adjust the pH value to 6.5-7 with aqueous sodium hy...

Embodiment 2

[0079] Synthesis of compound D2:

[0080]

[0081] Step 1: Dissolve compound 1 (10 mmol) in anhydrous tetrahydrofuran, add triethylamine (5 mmol), add sodium borodeuteride (20 mmol) in batches under ice bath conditions, add deuterated methanol dropwise, and react at room temperature until complete Then add aqueous sodium hydroxide solution (50 mmol), heat to 60°C until the reaction is complete, adjust the pH value to 7-8 with hydrochloric acid, spin out the methanol, and carry out stirring and crystallization to obtain compound 2.

[0082] Step 2: Dissolve compound 2 (10mmol) in NMP, add thionyl chloride (20mmol), react at room temperature, add water after the reaction is complete, adjust the pH value to neutral with aqueous sodium hydroxide solution, and then use ethyl acetate After extraction, the organic phase was spin-dried to obtain compound 3.

[0083] Step 3: Dissolve compound 3 (10mmol) and 4-dimethylaminopyridine (1mmol) in ethyl acetate, add di-tert-butyl dicarbo...

Embodiment 3

[0086] Synthesis of compound D3:

[0087]

[0088] Step 1: Dissolve compound 1 (2.5g) in heavy water (100mL), add Pd / C (250mg), and react at 180°C for 24 hours in an autoclave or in a microwave reactor for 2 hours. After the reaction is complete, add Diluted with methanol, filtered off palladium carbon, spin-dried, and obtained compound 2 by column chromatography.

[0089] Step 2: Dissolve compound 2 (2 mmol) in 48% hydrobromic acid, add bromine and sodium nitrite aqueous solution under ice cooling, after the reaction is complete under ice cooling, add 30% sodium hydroxide aqueous solution to adjust the pH value, ethyl acetate After ester extraction, the organic phase was spin-dried and column chromatographed to obtain compound 3.

[0090] Step 3: Dissolve compound 4 (10mmol) in tetrahydrofuran, add 3 (12mmol), add potassium tert-butoxide (12mmol) under ice bath, react until complete at room temperature, pour into water, extract with ethyl acetate, dry and spin dry 5 late...

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Abstract

The invention discloses a preparation method and applications of a deuterated isoxazole compound represented by a formula (I) or a prodrug thereof. According to the invention, the deuterated isoxazolecompound and the prodrug thereof can be used as fungus GPI anchoring protein synthetase inhibitors in antifungal infection drugs.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a method for preparing a deuterated isoxazole compound or a pharmaceutically acceptable salt thereof, a prodrug of the compound or a pharmaceutically acceptable salt of the prodrug. The deuterated Use of the compound as an inhibitor of GPI-anchored protein synthase, or a composition comprising it, in antifungal infection. Background technique [0002] Fungal infections are mainly divided into superficial fungal infections and deep fungal infections. At present, there are limited methods for the treatment of invasive fungal infections in clinic, and there are three main types of drugs: polyenes, azoles and echinocandins. There are many problems in the clinical application of existing antifungal drugs, such as the toxicity of polyenes, the resistance of azoles, and the adverse reactions after treatment with echinocandins. At the same time, due to the closer affinity bet...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07F9/6558A61K31/444A61K31/675A61P31/10
CPCC07D413/14C07F9/65583A61K31/444A61K31/675A61P31/10C07B2200/05
Inventor 李爽朱允涛
Owner 朱允涛
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