Substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl)urea derivative and preparation method and use thereof

A technology of urea derivatives and isoxazoles, applied in the field of organic synthetic drugs

Active Publication Date: 2018-07-31
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The emergence of these point mutations has brought new challenges to the development of drugs for the treatment of AML

Method used

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  • Substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl)urea derivative and preparation method and use thereof
  • Substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl)urea derivative and preparation method and use thereof
  • Substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl)urea derivative and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1 Preparation of 3-amino-5-tert-butylisoxazole (intermediate 2)

[0089]

[0090] Weigh raw material 1 (4,4-dimethyl-3-oxopentonitrile) (1.25g, 10mM) in a 250mL round bottom flask filled with 100mL of water, then add hydroxylamine hydrochloride (759mg, 11mM) and hydroxide Sodium (440mg, 11mM), the reaction solution was stirred at room temperature for half an hour, then an appropriate amount of sodium hydroxide was added to adjust the pH to 8-9, and then the temperature was raised to 50°C for 10h. After the TCL detection reaction was complete, 100 mL of methyl tert-butyl ether was added into the solution three times for extraction, the organic layer was discarded, and 150 mL of DCM (dichloromethane) was added to the water layer for three times for extraction, and the DCM layer was collected. Wash with saturated brine three times, then add anhydrous sodium sulfate to dry, filter and spin the filtrate to give white solid N'-hydroxy-4,4-dimethyl-3-carbonylpentami...

Embodiment 2

[0094] Example 2 Preparation of 1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-fluoro-4-hydroxyphenyl)urea (Intermediate 3)

[0095]

[0096] Weigh triphosgene (5.282g, 17.8mM) in a 500mL round bottom flask, then add 200mL of ethyl acetate, then slowly add 100mL of intermediate 2 (5g, 35.7mM) ethyl acetate dropwise to the flask in an ice-water bath environment After the ester solution was added dropwise, triethylamine (7.2 g, 71.4 mM) was slowly added dropwise in an ice-water bath environment, and then the temperature was raised to 70° C. to react for three hours. After the reaction was completed, the organic phase was removed directly with a rotary evaporator, and then 200 mL of ethyl acetate solution of 4-amino-2-fluorophenol (4.4 g, 35 mM) was added, and the reaction solution was heated at 70 °C for 5 h, and detected by TCL. After the reaction is complete, remove the organic phase in the reaction liquid with a rotary evaporator, add 200 mL of a saturated aqueous solution of potass...

Embodiment 3

[0098] Preparation of Example 3 tert-butyl (6-fluoropyridin-3-yl) carbamate (intermediate 5)

[0099]

[0100]In a 250mL round-bottomed flask, the intermediate 4(6-fluoropyridin-3-amine) (2g, 15.6mM) and BOC anhydride (di-tert-butyl dicarbonate, 4g, 18.7mM) were added, followed by 150mL of dioxane The ring was used as a solvent, then the temperature was raised to 100°C, and the reaction was carried out for about 8 hours until the reaction was detected by TLC. Then the reaction solution was concentrated under reduced pressure, water and dilute hydrochloric acid were added to adjust the pH to 3-4, and then 150 mL of ethyl acetate was added for extraction, which was added to the water layer in three times, and the ethyl acetate layer was collected. Then the ethyl acetate layer was washed three times with saturated brine, then the ethyl acetate layer was dried with anhydrous sodium sulfate, and after filtering, the filtrate was directly removed with a rotary evaporator to obtai...

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Abstract

The invention belongs to the technical field of organic synthetic medicines, and particularly relates to a substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl) urea derivative, and a preparation methodand use thereof. The substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl) urea derivative has a structural formula shown in Formula I. The invention also provides the preparation method of the substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl) urea derivative and use of the substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl) urea derivative in preparation of FMS-tyrosine kinase 3 inhibitors. A new and effective choice is provided for the preparation of the kinase inhibitors, the preparation of drugs for anti-autoimmune diseases, the preparation of neovascularization inhibitors and anti-tumordrugs in the field, and the substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl) urea derivative has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic synthetic medicines, in particular to substituted 1-(isoxazol-3-yl)-3-(3-fluoro-4-phenyl)urea derivatives and their preparation methods and applications. Background technique [0002] Acute myeloid leukemia (AML) is a hematologic malignancy in which myeloid leukocytes proliferate abnormally. In recent years, with the development of molecular biology and disease genomics, people have discovered some target genes closely related to the occurrence and development of AML, which provides a new option for the effective treatment of AML. Among these target genes, FMS-like tyrosine kinase 3 (FLT3) proved to be the most important one. FLT3 plays an important role in the regulation of the proliferation and differentiation of hematopoietic stem cells, dendritic cells, B cells, and natural killer cell precursors. Studies have shown that about one-third of AML patients have FLT3 gene mutations, among which t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D413/12C07D491/056A61K31/519A61K31/5377A61K31/517A61K31/4439A61K31/437A61P35/00A61P35/02A61P37/06A61P9/00
CPCC07D413/12C07D471/04C07D491/056A61K31/435A61K31/437A61K31/4439A61K31/506A61K31/517A61K31/519A61K31/5377A61P9/00A61P35/00A61P35/02A61P35/04A61P37/02A61P37/06C07D215/22C07D401/14
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV
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