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Tryptanthrin derivative containing olefine acid, and preparation method and application thereof

A derivative, the technology of tryptanthrin, which is applied in the field of preparation of tryptanthrin derivatives, achieves the effects of simple operation, increased water solubility, and easy industrial production

Active Publication Date: 2019-11-12
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Scientists have also done a lot of research on improving the water solubility of tryptanthrin, which is still challenging

Method used

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  • Tryptanthrin derivative containing olefine acid, and preparation method and application thereof
  • Tryptanthrin derivative containing olefine acid, and preparation method and application thereof
  • Tryptanthrin derivative containing olefine acid, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment example 1

[0064] Step 1: Synthesis of 5-methylisatoic anhydride

[0065]

[0066] Suspend 1000.0 mg (6.213 mmol) of 5-methylisatin 1 in 20 mL of dry dichloromethane, add 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid at 0°C, and stir at room temperature for 2 to 4 Hour; After the TLC detection reaction was completed, the orange solid obtained by filtering the reaction solution was washed with (5mL×3) ethyl acetate to obtain 5-methylisatoic anhydride 2;

[0067] Step 2: Synthesis of 2-methyl-8-fluorotryptanthrin

[0068]

[0069] Suspend 1000.0mg (5.650mmol) of 5-methylisatoic anhydride 2 and 932.9mg (5.650mmol) of 5-fluoroisatin in 10mL of dry acetonitrile solvent, add 2.35mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4 to 4.5 hours, cool to room temperature, filter, and wash the filter cake with (5mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptanthin 3;

[0070] Characterization data:

[0071] 1 HNMR (600MHz, CDCl 3 )δ8.63(d...

Embodiment 2

[0083] Step 1: Synthesis of 5-methylisatoic anhydride

[0084]

[0085] Suspend 1000.0 mg (6.213 mmol) of 5-methylisatin 1 in 20 mL of dry dichloromethane, add 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid at 0°C, and stir at room temperature for 2 to 4 Hour; After the TLC detection reaction was completed, the orange solid obtained by filtering the reaction solution was washed with (5mL×3) ethyl acetate to obtain 5-methylisatoic anhydride 2;

[0086] Step 2: Synthesis of 2-methyl-8-fluorotryptanthrin

[0087]

[0088] Suspend 1000.0mg (5.650mmol) of 5-methylisatoic anhydride 2 and 932.9mg (5.650mmol) of 5-fluoroisatin in 10mL of dry acetonitrile solvent, add 2.35mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4 to 4.5 hours, cool to room temperature, filter, and wash the filter cake with (5mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptanthin 3;

[0089] Step 3: Synthesis of 2-bromomethyl-8-fluorotryptanthrin

[0090] ...

Embodiment example 3

[0096] Step 1: Synthesis of 5-methylisatoic anhydride

[0097]

[0098] Suspend 1000.0 mg (6.213 mmol) of 5-methylisatin 1 in 20 mL of dry dichloromethane, add 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid at 0°C, and stir at room temperature for 2 to 4 Hour; After the TLC detection reaction was completed, the orange solid obtained by filtering the reaction solution was washed with (5mL×3) ethyl acetate to obtain 5-methylisatoic anhydride 2;

[0099] Step 2: Synthesis of 2-methyl-8-fluorotryptanthrin

[0100]

[0101] Suspend 1000.0mg (5.650mmol) of 5-methylisatoic anhydride 2 and 932.9mg (5.650mmol) of 5-fluoroisatin in 10mL of dry acetonitrile solvent, add 2.35mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4 to 4.5 hours, cool to room temperature, filter, and wash the filter cake with (5mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptanthin 3;

[0102] Step 3: Synthesis of 2-bromomethyl-8-fluorotryptanthrin

[0103] ...

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Abstract

The invention discloses a tryptanthrin derivative, and a preparation method and application thereof. The preparation method comprises the following steps: with 5-methylisatin as a raw material, oxidizing 5-methylisatin into 5-methylisatoic anhydride; under the weak alkaline condition of triethylamine, subjecting 5-methylisatoic anhydride and 5-fluoroisatin to reflux with acetonitrile as a solvent,and carrying out filtration and washing to obtain 2-methyl-8-fluorotryptanthrin; subjecting 2-methyl-8-fluorotryptanthrin and N-bromosuccinimide to reflux in a carbon tetrachloride solvent; and reacting a concentrated product with malonic acid in pyridine, and carrying out acidification, washing and filtering to obtain the desired tryptanthrin derivative. The tryptanthrin derivative of the invention has excellent inhibitory activity against indoleamine-2,3-dioxygenase (IDO), increases the water solubility of tryptanthrin, has broad application prospects and can be used for treating diseases with pathological features of the IDO-mediated tryptanthrin metabolism pathway, e.g., cancer, Alzheimer's disease, depression and cataract. The preparation method of the invention has the advantages ofsimple operation, mild conditions and the like, and is easy to be industrialized.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a preparation method and application of tryptanthrin derivatives containing aldehyde groups and tryptanthrin derivatives containing enoic acid. Background technique [0002] With the development of the world and changes in people's lives, the incidence of human cancer is also increasing. Tumor immune escape is one of the main hallmarks of cancer and a major factor in tumorigenesis, growth, invasion, and migration. With the gradual deepening of research on the mechanism of tumor immunity, tumor immunotherapy has gradually entered people's field of vision. Indoleamine-2,3-dioxygenase (IDO), which is also a tumor immune checkpoint, has also received widespread attention. [0003] Indoleamine-2,3-dioxygenase (IDO) is the only rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway, except in the liver. The overexpression of IDO will ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P25/28A61P25/24A61P27/12A61P3/00A61K31/519
CPCC07D487/04A61P35/00A61P25/28A61P25/24A61P27/12A61P3/00
Inventor 匡春香李缘圆
Owner TONGJI UNIV
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