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Method for synthesizing 5-chloro-4-azaindole

A technology for the synthesis of azaindole and its synthesis method, which is applied in the field of synthesis of 5-chloro-4-azaindole, can solve the problems of low synthesis yield, long reaction route, and low reaction yield, and achieve high synthesis yield High, easy separation, high selectivity effect

Inactive Publication Date: 2015-06-03
CHEMFUTURE PHARMATECH JIANGSU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Azaindole compounds have a wide range of biological activities, such as the role of peroxisome proliferator-activated receptor antagonists, of which 5-chloro-4-azaindole is an important synthetic compound Intermediate, the existing reaction route for this compound is very long, and the final reaction yield is low, resulting in expensive products, which are not suitable for large-scale industrial production
Patent document WO2009023844 discloses a method for synthesizing 5-chloro-4-azaindole using 4-azaindole (CAS# 272-49-1) as a raw material. The synthesis yield of this method is low (there is a step The yield is only 29%), and the raw material 4-azaindole used is expensive, which is not conducive to reducing the synthesis cost

Method used

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  • Method for synthesizing 5-chloro-4-azaindole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Add 300g of 2-amino-6-picoline in batches to 1.5L of concentrated sulfuric acid, keep the temperature of the solution below 20°C during the addition process, after the addition, stir for half an hour, add the mixed acid (from 150ml of concentrated sulfuric acid mixed with 150ml concentrated nitric acid), keep the temperature at 0°C during the dropwise addition, after the dropwise addition, raise the temperature to 20°C and stir for 13 hours, then pour the reaction solution into ice water, adjust the pH to neutral, filter, and filter the cake with acetic acid Dissolve ethyl ester, decolorize activated carbon, dry over sodium sulfate, filter, and distill off ethyl acetate under reduced pressure to obtain product 2-amino-5-nitro-6-picoline and by-product 2-amino-3-nitro - Mixtures of 6-picoline. The above mixture was dispersed into 1.5L of toluene, heated to boiling and refluxed for 3 hours, filtered while hot, and the filter cake was dried under normal pressure to obt...

Embodiment 2

[0036] (1) Add 30g of 2-amino-6-picoline in batches to 150mL of concentrated sulfuric acid, keep the temperature of the solution below 20°C when adding, after the addition, stir for half an hour, then add the mixed acid (composed of 15ml of concentrated sulfuric acid and 15ml of concentrated nitric acid), keep the temperature at 0°C when adding the mixed acid dropwise, after the drop, the temperature of the solution rises to 20°C and stir for 12 hours, pour the reaction solution into ice water, adjust the pH to neutral, filter, and use for filter cake Ethyl acetate was dissolved, activated carbon was decolorized, dried over sodium sulfate, filtered, and ethyl acetate was evaporated under reduced pressure to obtain the product 2-amino-5-nitro-6-picoline and by-product 2-amino-3-nitro Base-6-picoline mixture. The above mixture was dispersed into 150mL xylene, heated to boiling and refluxed for 3 hours, filtered while hot, and the filter cake was dried under normal pressure to ob...

Embodiment 3

[0042] (1) According to the step (1) described in Example 2, 19.6 g of the product 2-amino-5-nitro-6-picoline was obtained, the difference is that the product 2-amino-5-nitro-6-picoline And the by-product 2-amino-3-nitro-6-picoline is dispersed in benzene, then heated and filtered for separation.

[0043] (2) Take 19.6g of the product obtained in step (1), add 40mL of water, add 80mL of concentrated sulfuric acid dropwise under ice bath, control the temperature below 20°C, after the addition is complete, cool down to 0°C, add dropwise sodium nitrite aqueous solution (9.8g Sodium nitrite dissolved in 300mL of water), after dropping, the temperature of the reaction solution returned to 20°C and stirred for 2 hours, filtered, and dried under normal pressure to obtain 16g of the product 2-hydroxy-5-nitro-6-picoline, the yield 81%.

[0044] (3) Take the product 2-hydroxy-5-nitro-6-picoline (16g) obtained in step (2) and add 25g of phosphorus pentachloride to 15g of phosphorus oxyc...

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Abstract

The invention discloses a method for synthesizing the 5-chloro-4-azaindole. The method includes reacting 2-amino-6-methylpyridine with nitric acid to perform nitratlon reaction to obtain 2-amino-6-methyl-5-nitropyridine, reacting the obtained 2-amino-6-methyl-5-nitropyridine with sodium nitrite to obtain 2-amino-6-methyl-5-nitropyridine; and with phosphorus pentachloride serving as a chlorinating agent, chlorinating the 2-hydroxy-6-methyl-5-nitropyridine to into 2-chloro-6-methyl-5-nitropyridine in a phosphorus oxychloride solvent, mixing the chlorinated product with N,N-dimethylformamide dimethyl acetal, heating the mixture to 80 DEG C to 110 DEG C to obtain an enamine intermediate, and performing ring closing reaction on the enamine intermediate in a hydrogen atmosphere under the catalysis of a catalyst raney nickel to obtain the 5-chloro-4-azaindole. The method has the advantages of being simple in steps, low in cost, high in synthesis yield and selectivity, and suitable for enlarging production, and resultants obtained in each step are separable.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and in particular relates to a synthesis method of 5-chloro-4-azaindole. Background technique [0002] Azaindole compounds have a wide range of biological activities, such as the role of peroxisome proliferator-activated receptor antagonists, of which 5-chloro-4-azaindole is an important synthetic compound The intermediate has a very long reaction route to synthesize the compound, and the final reaction yield is low, resulting in expensive products, which are not suitable for large-scale industrial production. Patent document WO2009023844 discloses a method for synthesizing 5-chloro-4-azaindole using 4-azaindole (CAS# 272-49-1) as a raw material. The synthesis yield of this method is low (there is a step The yield is only 29%), and the raw material 4-azaindole used is expensive, which is not conducive to reducing the synthesis cost. Contents of the invention [0003] The purpose of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
Inventor 赖文徐骏张浩波史海龙
Owner CHEMFUTURE PHARMATECH JIANGSU