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Preparation method of 5-bromo-1-methylindazole

A technology of methyl indazole and bromobenzaldehyde, applied in the direction of organic chemistry and the like, can solve problems such as low efficiency, and achieve the effects of high product purity, simple process operation and short synthesis steps

Active Publication Date: 2022-01-11
CANGZHOU PURUI DONGFANG SCI & TECH +1
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  • Abstract
  • Description
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Problems solved by technology

Since the Rf values ​​of 5-bromo-1-methylindazole and 5-bromo-2-methylindazole in this mixture are very close, repeated column chromatography is required to obtain the pure product, and a large amount of solvent is used for washing, and the efficiency is very high. Low, not suitable for industrial scale-up

Method used

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  • Preparation method of 5-bromo-1-methylindazole

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preparation example Construction

[0021] Preparation of formylhydrazine

[0022] In a three-neck flask, ethyl formate (74.1 g, 1.0 mol) and 80% hydrazine hydrate (75.0 g, 1.2 mol) were added to ethanol (250 mL) respectively, and the temperature was raised to reflux for 5 hours. Excess hydrazine hydrate and ethanol solvent were distilled off under reduced pressure to obtain a light yellow oil, which solidified after cooling, and was slurried with a mixed solvent of ethanol and heptane. After drying, 55.4 g of formylhydrazine was obtained, a white crystalline solid with a melting point of 53-55°C.

Embodiment 1

[0024] In the three-necked flask, add 2-fluoro-5-bromobenzaldehyde (20.3g, 0.10mol) and 120mL absolute ethanol, and dissolve completely under stirring. Then 1.2 mL of acetic acid was added, and after cooling down to 0°C, formylhydrazine (6.0 g, 0.10 mol) was added in batches, and the addition was completed in about 20 minutes. Then naturally rise to room temperature and stir for 2 hours, and TLC detects that the reaction is complete. The reaction was directly evaporated to dryness under reduced pressure, and toluene was taken with water once to obtain a viscous solid. Add 150mL DMSO and anhydrous potassium carbonate (27.6g, 0.20mol), stir well, and heat up to 90-100°C to react overnight. TLC detected that the reaction was complete, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to no liquid, added 100 mL of dichloromethane and 55 mL of saturated ammonium chloride, stirred until the system was dissolved and separated, and the aque...

Embodiment 2

[0027] In the three-necked flask, add 2-fluoro-5-bromobenzaldehyde (20.3g, 0.10mol) and 120mL absolute ethanol, and dissolve completely under stirring. Then 1.2 mL of acetic acid was added, and after cooling down to 0°C, formylhydrazine (6.0 g, 0.10 mol) was added in batches, and the addition was completed in about 20 minutes. Then naturally rise to room temperature and stir for 2 hours, and TLC detects that the reaction is complete. The reaction was directly evaporated to dryness under reduced pressure, and toluene was taken with water once to obtain a viscous solid. Add 110mL of dioxane, add sodium hydride (0.16mol) in batches, stir for 5 minutes after each addition, and then add the next batch Second-rate. After all the addition was completed, the temperature was raised to 80-85°C to react overnight. TLC detected that the reaction was complete, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to no liquid, added 100 mL of dich...

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Abstract

The invention relates to a preparation method of 5-bromo-1-methylindazole, belonging to the technical field of medical intermediates. The preparation method comprises the following steps: carrying out condensation reaction on 2-fluoro-5-bromobenzaldehyde and formyl hydrazine, then subjecting a reaction product and alkali to ring closing in a polar aprotic solvent, and finally, carrying out reducing with borane to obtain the 5-bromo-1-methylindazole. According to the method, the problem of isomers in direct methylation reaction of 5-bromoindazole in a traditional process is effectively avoided, synthesis steps are short, and the obtained product is high in purity.

Description

technical field [0001] The invention relates to a preparation method of 5-bromo-1-methylindazole, belonging to the technical field of pharmaceutical intermediates. Background technique [0002] 5-Bromo-1-methylindazole, CAS number: 465529-57-1, melting point 111-112°C, is an important pharmaceutical intermediate, used to synthesize various heterocyclic compounds. [0003] At present, the common synthetic method is mainly to use 5-bromoindazole to react with methyl iodide under alkaline conditions to generate a mixture of 5-bromo-1-methylindazole and 5-bromo-2-methylindazole, Separated by column chromatography. Since the Rf values ​​of 5-bromo-1-methylindazole and 5-bromo-2-methylindazole in this mixture are very close, repeated column chromatography is required to obtain the pure product, and a large amount of solvent is used for washing, and the efficiency is very high. Low, not suitable for industrial scale-up. Contents of the invention [0004] In order to overcome t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56
CPCC07D231/56Y02P20/55
Inventor 张进张朋岳刘增仁田利国王建凯
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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