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Method for synthesis of 5-cyano-1H-pyrazolo[3,4-b]pyridine

A technology of pyrazolo and 4-b, which is applied in the field of medicinal chemistry, can solve problems such as easy generation of impurities, high synthesis cost, and cumbersome steps, and achieve the effects of improving purity, reducing impurity content, and simplifying synthesis steps

Active Publication Date: 2014-08-13
HAIMEN RUIYI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, the method for synthesizing 5-cyano-1H-pyrazolo[3,4-b]pyridine uses ethyl acetate to extract and concentrate the intermediate in the synthesis and then participates in the next step reaction. It is unstable under heated and concentrated conditions, and impurities are easily produced; when synthesizing intermediate 2, intermediate 1 and anhydrous hydrazine are directly ring-closed in ethanol, and anhydrous hydrazine is a poisonous and flammable liquid, so that the product is The safety in transportation and production is not well guaranteed; and the target product synthesized with intermediate 2 as a raw material is not easily soluble in conventional solvents, which makes the target product difficult to purify, low yield, high synthesis cost and other disadvantages

Method used

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  • Method for synthesis of 5-cyano-1H-pyrazolo[3,4-b]pyridine
  • Method for synthesis of 5-cyano-1H-pyrazolo[3,4-b]pyridine
  • Method for synthesis of 5-cyano-1H-pyrazolo[3,4-b]pyridine

Examples

Experimental program
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Embodiment 1

[0025] In a 50L reactor, blow nitrogen, add 2380g of diisopropylamine and THF solvent, and stir evenly; cool down to -30°C, add 1983g of n-butyllithium dropwise, and react for 0.5h; cool down to -65°C, add dropwise 3110g of 2-fluoro - Mixed solution of 5-bromopyridine and THF, reacted for 2.5h; added dropwise 1308g ethyl formate, reacted for 5min, then added dropwise a mixed solution of 1630g citric acid and THF; HPLC control reaction ended; 8.7L of water, stirred for 15min; standing still to separate the liquid, the aqueous layer was extracted with THF, and the organic phase was combined to obtain a THF solution containing the intermediate 5-bromo-2-fluoro-3-formylpyridine.

[0026] In a 50L reaction kettle, add the above-mentioned THF solution containing intermediate 1 and 2.8kg of hydrazine hydrate, stir, raise the temperature to 45°C, and control the reaction in TLC until the reaction is complete; the reaction solution is concentrated to a paste by rotary evaporation; add a...

Embodiment 2

[0028] In a 50L reactor, blow nitrogen, add 2380g of diisopropylamine and THF solvent, stir well; cool down to -30°C, add 1258g of n-butyllithium dropwise, and react for 0.5h; cool down to -65°C, add dropwise 3110g of 2-fluoro - Mixed solution of 5-bromopyridine and THF, reacted for 2.5h; dropwise added 1970g ethyl formate, reacted for 5min, then added dropwise a mixed solution of 1630g citric acid and THF; HPLC control reaction ended; 8.7L of water, stirred for 15min; standing still to separate the liquid, the aqueous layer was extracted with THF, and the organic phase was combined to obtain a THF solution containing the intermediate 5-bromo-2-fluoro-3-formylpyridine.

[0029] In a 50L reaction kettle, add the above-mentioned THF solution containing intermediate 1 and 2.8kg of hydrazine hydrate, stir, raise the temperature to 45°C, and control the reaction in TLC until the reaction is complete; the reaction solution is concentrated to a paste by rotary evaporation; add absolut...

Embodiment 3

[0031] In a 50L reactor, blow nitrogen, add 2380g of diisopropylamine and THF solvent, stir well; cool down to -30°C, add 1161g of n-butyllithium dropwise, and react for 0.5h; cool down to -65°C, add dropwise 3110g of 2-fluoro - Mixed solution of 5-bromopyridine and THF, reacted for 2.5h; added dropwise 2615g of ethyl formate, reacted for 5min, then added dropwise a solution of 1630g of citric acid and THF; the reaction was completed in HPLC; at a temperature of 0°C, 8.7 L of water, stirred for 15 minutes; standing still to separate the layers, the aqueous layer was extracted with THF, and the organic phases were combined to obtain a THF solution containing the intermediate 5-bromo-2-fluoro-3-formylpyridine.

[0032] In a 50L reaction kettle, add the above-mentioned THF solution containing intermediate 1 and 2.8kg of hydrazine hydrate, stir, raise the temperature to 45°C, and control the reaction in TLC until the reaction is complete; the reaction solution is concentrated to a ...

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Abstract

The invention discloses a method for synthesis of 5-cyano-1H-pyrazolo[3,4-b]pyridine. The method comprises the following steps of synthesizing LDA, synthesizing an intermediate I, synthesizing an intermediate II, synthesizing a 5-cyano-1H-pyrazolo[3,4-b]pyridine finished product and carrying out follow-up purification treatment. The method utilizes cheap and easily available raw materials, greatly reduces a production cost, has a reasonable raw material ratio, simple and short processes and mild conditions, is safe and reliable, can prepare a target product having high purity and is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for synthesizing 5-cyano-1H-pyrazolo[3,4-b]pyridine. Background technique [0002] 5-cyano-1H-pyrazolo[3,4-b]pyridine is a key intermediate of some cancer drugs. In recent years, due to the deteriorating living environment and the impact of food hygiene and other issues, the incidence of cancer has become higher and higher. Therefore, the demand for drugs for the treatment of cancer has increased, and the research on key intermediates of cancer drugs has also increased. Pay attention to. [0003] At present, the method for synthesizing 5-cyano-1H-pyrazolo[3,4-b]pyridine uses ethyl acetate to extract and concentrate the intermediate in the synthesis and then participates in the next step reaction. It is unstable under heated and concentrated conditions, and impurities are easily produced; when synthesizing intermediate 2, intermediate 1 and anhy...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 薛嵩周文俊
Owner HAIMEN RUIYI MEDICAL TECH
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