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Selective fluorination method for isatin hydrazones compounds

A compound, the technology of isatin hydrazone, which is applied in the field of synthesis of fluorine-containing drug intermediates, can solve the problems of poor substrate adaptability, harsh reaction conditions, and low yield

Inactive Publication Date: 2018-07-20
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second is to start from indole and obtain the 3-position difluorinated product under the action of N-fluorobisbenzenesulfonamide (NFSI) reagent. This reaction also has the characteristics of poor substrate adaptability, harsh reaction conditions, and low yield.
These deficiencies largely limit the application of existing reactions in drug development and make it impossible for chemists to meet the needs of indole fluorination products.

Method used

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  • Selective fluorination method for isatin hydrazones compounds
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  • Selective fluorination method for isatin hydrazones compounds

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Experimental program
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Effect test

Embodiment 1

[0084] Synthesis, separation and purification of 3-fluoro-2-indolinone: add isatin hydrazone (0.5mmol, 1eq), Selectfluor (354.3mg, 1mmol, 2eq), acetic acid in a 100mL round bottom flask equipped with a magnetic stirrer Lithium (197.8mg, 3mmol, 6eq) was sealed with a rubber stopper; then ethylene dichloride (13mL) was added with a syringe as a solvent; the reaction bottle was placed in an oil bath at 70°C and heated and stirred for 18 hours. Layer chromatography (TLC) monitoring. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was extracted twice with 40 mL of ethyl acetate, the organic phases were combined and washed with saturated brine, and then anhydrous sodium sulfate was added to dry the organic phase. After drying, the organic phase was spin-dried to dry the organic solvent under reduced pressure to obtain a crude product. The crude product was separated by column using 9:1 petroleum ether and ethyl acetate as eluent to obta...

Embodiment 2

[0089] Synthesis, separation and purification of 3-fluoro-1-isopropyl-2-indolone: ​​1-isopropyl-isatin hydrazone (0.5mmol, 1eq) was added to a 25mL round bottom flask equipped with a magnetic stirrer , Selectfluor (354.3mg, 1mmol, 2eq), lithium acetate (197.8mg, 2mmol, 6eq) and seal with a rubber stopper; then add dichloroethane (3mL) as a solvent with a syringe; the reaction bottle is placed in an oil bath at 80°C The reaction was heated and stirred in a pot for 16 hours, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, it was cooled to room temperature, and the reaction mixture was extracted twice with 20 mL of ethyl acetate, the organic phases were combined and washed with saturated brine, and then anhydrous sodium sulfate was added to dry the organic phase. After drying, the organic phase was spin-dried to dry the organic solvent under reduced pressure to obtain a crude product. The crude product was separated b...

Embodiment 3

[0095] Synthesis, separation and purification of 3-fluoro-1-allyl-2-indolinone: 1-allyl-isatin hydrazone (0.5mmol, 1eq) was added to a 25mL round bottom flask equipped with a magnetic stirrer , Selectfluor (354.3mg, 1mmol, 2eq), lithium acetate (197.8mg, 2mmol, 6eq) and seal with a rubber stopper; then add dichloroethane (3mL) as a solvent with a syringe; the reaction bottle is placed in an oil bath at 80°C The reaction was heated and stirred in a pot for 16 hours, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, it was cooled to room temperature, and the reaction mixture was extracted twice with 20 mL of ethyl acetate, the organic phases were combined and washed with saturated brine, and then anhydrous sodium sulfate was added to dry the organic phase. After drying, the organic phase was spin-dried to dry the organic solvent under reduced pressure to obtain a crude product. The crude product was separated by column...

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Abstract

The invention discloses a selective fluorination method for an isatin hydrazones compound. The method comprises the steps that one pot reaction is carried out on isatin hydrazone, 1-chloromethyl-4-fluorine-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and alkali compounds, corresponding 3,3-difluoro indolone and fluorooxindole fluorination products are selectively synthesized; the method fills up technical gaps in the prior art that isatin hydrazones compound is selectively synthesized by using a three-position single fluorination or double fluorination technology starting fromisatin, the operation is simple, the process is short, the product yield is high, and industrial production requirements are met.

Description

technical field [0001] The invention relates to a method for selective fluorination of isatin hydrazone compounds, belonging to the field of synthesis of fluorine-containing drug intermediates. Background technique [0002] Fluorine-containing organic compounds are the core skeleton of many drug molecules. Up to now, at least 20% to 35% of clinical drug molecules contain a fluorine atom or a fluorine-containing group. In various disease treatment fields, fluorine-containing compounds cover many aspects, such as anti-inflammatory, anti-viral, sedative, anti-tumor, etc. Due to the strongest electronegativity, smaller atomic radius and lower polarizability of fluorine atoms, the introduction of fluorine atoms will lead to unique physical, chemical and physiological properties of compounds. Indole derivatives are widely distributed in nature. Many natural compounds contain indole rings in their structures. Some indole derivatives are closely related to life activities. Indole i...

Claims

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Application Information

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IPC IPC(8): C07B39/00C07D209/34
CPCC07B39/00C07D209/34
Inventor 唐真宇杨琼代国丽李佳威
Owner CENT SOUTH UNIV
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