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Preparation method of 5-hydroxy-7-azaindole

An azaindole and hydroxyl technology, which is applied in the field of preparation of 5-hydroxy-7-azaindole, can solve problems such as low yield of 5-hydroxy-7-azaindole, and avoid excessive preparation costs. High, mild reaction conditions, easy to use effect

Pending Publication Date: 2021-06-11
ABA CHEM NANTONG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the deficiencies of the prior art, the present invention provides a preparation method of 5-hydroxy-7-azaindole, which has the advantages of mild reaction and high yield, and solves the problem of preparing 5-hydroxy-7-azaindole in the prior art. The problem of low yield of indole

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment one: a kind of preparation method of 5-hydroxyl-7-azaindole, comprises the following steps:

[0021] 1) Add 150 mL of Grignard reagent to the reaction bottle, add 10 mL of n-butyllithium THF solution dropwise under stirring, and react for 3 minutes. For vinyl magnesium bromide.

[0022] 2) Pour into 200mL of ice water to quench the reaction, extract with 450ml of ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain white Solid 5-hydroxyl-7-azaindole-5-boronic acid, the eluent of silica gel column chromatography in step 2) is ethyl acetate and sherwood oil, and the eluent of silica gel column chromatography in step 4) is dichloromethane , the reaction temperature in step 2) is 0°C.

[0023] 3) Add 60mL of tetrahydrofuran into the reaction flask, stir to dissolve it, add 17mL of sodium h...

Embodiment 2

[0025] Embodiment two: a kind of preparation method of 5-hydroxyl-7-azaindole, comprises the following steps:

[0026] 1) Add 150 mL of Grignard reagent into the reaction bottle, add 10 mL of n-butyllithium THF solution dropwise under stirring, and react for 4 minutes, then add 3 g of trimethyl borate, after adding, react at room temperature for 1 hour, and the Grignard reagent is Vinyl magnesium bromide.

[0027] 2) Pour into 200mL of ice water to quench the reaction, extract with 450ml of ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain white Solid 5-hydroxy-7-azaindole-5-boronic acid, the eluent of silica gel column chromatography in step 2) is ethyl acetate and petroleum ether, and the reaction temperature in step 2) is 2.5°C.

[0028] 3) Add 60mL of tetrahydrofuran into the reaction flask, stir ...

Embodiment 3

[0030] Embodiment three: a kind of preparation method of 5-hydroxyl-7-azaindole, comprises the following steps:

[0031] 1) Add 150 mL of Grignard reagent to the reaction bottle, add 10 mL of n-butyllithium THF solution dropwise under stirring, and react for 5 minutes, add 4 g of trimethyl borate, after adding, react at room temperature for 1.5 h, Grignard reagent For vinyl magnesium bromide.

[0032] 2) Pour into 200mL of ice water to quench the reaction, extract with 450ml of ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain white Solid 5-hydroxy-7-azaindole-5-boronic acid, the eluent of silica gel column chromatography in step 2) is ethyl acetate and petroleum ether, and the reaction temperature in step 2) is 5°C.

[0033] 3) Add 60mL of tetrahydrofuran into the reaction bottle, stir to dissolve it...

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Abstract

The invention relates to the technical field of preparation methods of 5-hydroxy-7-azaindole, and discloses a preparation method of 5-hydroxy-7-azaindole, which comprises the following steps: 1) adding 150mL of Grignard reagent into a reaction flask, dropwise adding 10mL of THF solution of n-butyllithium while stirring, conducting reacting for 3-5min after dropwise adding, adding 2-4g of trimethyl borate, and conducting reacting for 0.5-1.5 h at room temperature after adding. The preparation method of the 5-hydroxy-7-azaindole comprises the following steps: conducting washing with a saturated saline solution, conducting drying with anhydrous sodium sulfate, carrying out vacuum concentration, and carrying out silica gel column chromatography purification on residues to obtain solid 5-hydroxy-7-azaindole. In the reaction process, the usage amount of sodium methoxide is extremely small. A large amount of wastewater is prevented from being generated in the reaction process. Butyl lithium is replaced by n-butyllithium, mild reaction conditions, environment friendliness and higher yield are realized in the reaction process, overhigh preparation cost in the production process is avoided, and the method is more convenient for a user to use.

Description

technical field [0001] The invention relates to the technical field of preparation methods of 5-hydroxy-7-azaindole, in particular to a preparation method of 5-hydroxy-7-azaindole. Background technique [0002] ABT-199 (Venetoclax), chemical name 2-[(1H-pyrrolo[3-B]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4 -Dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]-nitrogen-[3-nitro-4-[[(tetrahydropyran-4-yl)methyl]amino] Benzenesulfonamide]methylbenzoate, is an experimental B-cell lymphoma factor-2 (BCL-2) inhibitor, jointly developed by AbbVie and Roche, BCL-2 is an inhibitor of some cells Apoptotic protein (including lymphocytes), ABT-199 is designed to selectively inhibit the function of BCL-2 factors, restore the communication system of cells, and allow cancer cells to self-destruct, so as to achieve the effect of treating tumors. [0003] The existing preparation method of 5-hydroxyl-7-azaindole usually uses 5-bromo-7-azaindole as a raw material, through amino protection, un...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 蒋信义徐军刘汝章
Owner ABA CHEM NANTONG
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