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Synthesis method for forming indazole derivative by activating hydroxylamine

A synthesis method and derivative technology, applied in the direction of organic chemistry, etc., can solve the problems of harsh reaction conditions and narrow application range of reaction conditions, and achieve the effect of simple and convenient purification

Inactive Publication Date: 2012-07-04
常州协丰新材料科技有限公司
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Problems solved by technology

Either the requirements for the reaction conditions are relatively harsh, or the use range of the reaction conditions is relatively narrow

Method used

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  • Synthesis method for forming indazole derivative by activating hydroxylamine
  • Synthesis method for forming indazole derivative by activating hydroxylamine
  • Synthesis method for forming indazole derivative by activating hydroxylamine

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preparation example Construction

[0037] A kind of synthetic method that forms indazole derivative by the activation of hydroxylamine, described indazole derivative is shown in formula (I), and synthetic method comprises the steps:

[0038] a, with o-fluoro aromatic formaldehyde as shown in formula (II) as raw material, tetrahydrofuran as solvent, add methoxylamine hydrochloride and potassium carbonate, react overnight at normal temperature;

[0039] b. The solution obtained in step a is filtered, concentrated, and quantitatively obtained as an intermediate compound such as o-fluoroaromatic methoxyxime shown in formula (III);

[0040] c. Dissolve the intermediate compound (III) obtained in step b in tetrahydrofuran, add hydrazine hydrate, and reflux overnight to obtain a methoxy-substituted indazole derivative as shown in formula (IV);

[0041] d. The methoxy-substituted indazole derivative shown in (IV) obtained in step c is heated to reflux under acidic conditions to remove the methoxy group to obtain the in...

Embodiment

[0051] The present invention has carried out concrete experiment, and its experimental process and result are as follows:

[0052]

[0053] First step reaction: A→B

[0054] 2-Bromo-5-fluoro-4-carbaldehydepyridine (0.98 mol, 200.0 g), methoxylamine hydrochloride (0.98 mol, 81.85 g), and potassium carbonate (1.08 mol, 149.3 g) were added to 1.5 L of THF The solution was stirred at room temperature for 13 hours. The reaction solution was filtered, and the filtrate contained product B, and then the filtrate was concentrated to 1 liter, such as figure 1 Shown is the LCMS profile of the first step reaction.

[0055] Second step reaction: B→C

[0056] Add 400 ml of hydrazine hydrate to the concentrated filtrate in the first step reaction, and reflux overnight. The reaction solution was directly concentrated by a vacuum pump to 500 ml, and 1 liter of distilled water was slowly added to the concentrated solution with constant stirring. A large amount of precipitate was precipit...

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Abstract

The invention relates to a synthesis method for forming indazole derivative by activating hydroxylamine, and belongs to the field of a chemical synthesis method. The method comprises the following steps of: adding methoxylamine hydrochloride and potassium carbonate into fluoro aromatic formaldehyde serving as a raw material and tetrahydrofuran serving as a solvent; reacting at normal temperature for a night; filtering, concentrating and quantifying to obtain an intermediate compound fluoro aromatic methoxyl oxime; dissolving the intermediate into tetrahydrofuran; adding hydrazine hydrate; refluxing for a night to obtain the methoxyl substituted indazole derivative; and heating, refluxing and removing the methoxyl under the acidic condition to obtain high-yield indazole derivative. According to the method, the hydrazine hydrate with low toxicity and low danger serves as a reaction agent, so the method is high in yield and convenient for purification and can be applied to amplification of industrialized production.

Description

technical field [0001] The invention relates to a synthesis method for forming indazole derivatives through activation of hydroxylamine, belonging to the field of chemical synthesis methods. Background technique [0002] Aromatic or heterocyclic indazole derivatives are very important pharmaceutical intermediates with a wide range of applications. The indazole derivative is formed by cyclizing a relatively active halogen fluorine atom and an adjacent aldehyde or ketone on a benzene ring or a pyridine ring under anhydrous hydrazine. It has been reported in the literature that 2-bromo-5-fluoro-acetylpyridine is used as a raw material, ethylene glycol is used as a solvent, and anhydrous hydrazine is reacted at 165°C to generate 5-bromo-3-methyl-1H-pyrazol[3, 4-c]pyridine. However, this method needs to prepare anhydrous hydrazine, which is dangerous, prone to explosion and low in safety. Since anhydrous hydrazine is a flammable and explosive substance, the reaction is dangero...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D471/04
Inventor 程利见王柯康富安
Owner 常州协丰新材料科技有限公司
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