Preparing method of 3-hydroxyloxoindole derivatives

A technology for indole derivatives and hydroxyl oxidation, applied in the direction of organic chemistry, can solve the problems of complex product purification process, unfavorable industrial application, long reaction cycle, etc., and achieve the effect of shortening the production cycle, avoiding column chromatography, and simple operation

Inactive Publication Date: 2014-06-18
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above methods have the following disadvantages: one, the use of organic solvents as the reaction medium has high toxicity; two, the cost of raw materials is high, three, the reaction cycle is long; four, the product purification process is complicated, etc.
These disadvantages are not conducive to the industrial application of the method

Method used

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  • Preparing method of 3-hydroxyloxoindole derivatives
  • Preparing method of 3-hydroxyloxoindole derivatives
  • Preparing method of 3-hydroxyloxoindole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] First weigh isatin (1mmol): copper sulfate = 1:0.01 (molar ratio), place it in a 50mL round bottom flask, add 10mL of water to make a mixed solution of isatin and copper sulfate; then, add ethyl diazoacetate (2mmol) mixed with another 10mL of water evenly, then, inject the diazo solution into the mixed solution of isatin and copper sulfate by a peristaltic pump for 1 hour, stir at room temperature for 1-2 hours, and extract with 30mL of petroleum ether to remove the small electrode After extraction with 30 mL of ethyl acetate three times (10 mL / time), the organic layers were combined, washed with 30 mL of saturated brine, dried with anhydrous sodium sulfate for 3 hours, and then 40 ° C rotary evaporation to remove ethyl acetate, the crude product was obtained by volume The pure product of 3-hydroxyoxindole derivative 1a was obtained by recrystallization from petroleum ether and ethyl acetate at a ratio of 1:1. Yield: 90%, dr value: 80:20. 1 H NMR (400MHz, DMSO-d 6 )...

Embodiment 2

[0026] First weigh 4-bromoisatin (1mmol):rhodium acetate=2:0.01 (molar ratio), place in a 50mL round bottom flask, add 10mL tetrahydrofuran (water) to make isatin and rhodium acetate mixed solution; then, Ethyl diazoacetate (2mmol) was mixed uniformly with another part of 10mL tetrahydrofuran (water), and then, the diazo solution was injected into the mixed solution of isatin and rhodium acetate by a peristaltic pump for 1 hour, and after stirring at room temperature for 1-2 hours, Extract with 30mL of petroleum ether to remove small polar impurities, then extract with 30mL of ethyl acetate three times (10mL / time), combine the organic layers, wash with 30mL of saturated brine, dry with anhydrous sodium sulfate for 3 hours, and then remove by rotary evaporation at 40°C Ethyl acetate, the crude product was recrystallized from petroleum ether and ethyl acetate at a volume ratio of 1:1 to obtain the pure product of 3-hydroxyoxindole derivative 1b. Yield: 40%, dr value: 83:17.

[00...

Embodiment 3

[0030] First weigh 5-methyl isatin (1mmol): ruthenium chloride = 2:0.01 (molar ratio), put it in a 50mL round bottom flask, add 10mL 1,2-dichloroethane (water) to make isatin Mix solution with ruthenium chloride; Next, mix ethyl diazoacetate (2mmol) with another part of 10mL 1,2-dichloroethane (water), and then inject the diazo solution for 1 hour through a peristaltic pump In the mixed solution of isatin and ruthenium chloride, after stirring at room temperature for 1-2 hours, extract with 30mL petroleum ether to remove small polar impurities, and then extract with 30mL ethyl acetate three times (10mL / time), combine the organic layers, and 30mL saturated salt After washing with water, drying with anhydrous sodium sulfate for 3 hours and then rotary evaporation at 40°C to remove ethyl acetate, the crude product was recrystallized from petroleum ether and ethyl acetate at a volume ratio of 1:1 to obtain 3-hydroxyindole derivative 1c pure Taste. Yield: 85%, dr value: 89:11.

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Abstract

The invention discloses a preparing method of 3-hydroxyloxoindole derivatives shown as the formula (I). The 3-hydroxyloxoindole derivatives are prepared from isatin, water and diazonium, and are prepared by one-step catalysis. According to the method, the 3-hydroxyloxoindole derivatives are prepared with high yield by utilization of a reaction with high atom economy and through green operation processes.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of 3-hydroxyindole derivatives, which provides a new potential way for synthesizing anticancer drug molecule TMC-95. Background technique [0002] 3-hydroxyindole derivatives are a class of very important structural units, widely present in compounds with biological activity (as shown in the following structural formula), for example, alkaloids Convolutamydine A-E (Tetrahedron1995, 51, 5523), 3' -Hydroxygluoisatisin (Tetrahedron Lett. 2001, 42, 9015) and anticancer drug TMC-95A-D (PNAS, 2004, 101, 11949) both contain a 3-hydroxyoxindole derivative skeleton. [0003] [0004] In 2000, Kohno and his colleagues isolated and extracted TMC-95A-D for the first time. TMC-95A-D is a highly efficient protease inhibitor with biological activity of inhibiting the growth of cancer cells (J.Org.Chem.2000 65, 990) . Since its separ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/38
CPCC07D209/38
Inventor 胡文浩史滔达荆常城
Owner EAST CHINA NORMAL UNIV
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