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Preparation method of 4-bromo-5-methyl-1H-indazole

A technology of methyl and indazole, which is applied in the field of preparation of 4-bromo-5-methyl-1H-indazole, can solve the problems of easy flushing, high production cost, and danger, and achieve low pollution and easy handling Effect

Inactive Publication Date: 2021-02-05
无锡双启科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the above synthetic method, in the process of synthesizing 4-bromo-5-methyl-1H-indazole compound I, the first step reaction generates 2-bromo-1,3-dimethyl-4-nitrobenzene with sulfuric acid , nitric acid nitration, it is easy to punch materials during amplification, which is dangerous, and produces a large amount of waste acid, which is not friendly to the environment; at the same time, the yield in the final step of diazotization ring closure is low, which makes the production cost very high, which is not conducive to industrial scale-up generate

Method used

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  • Preparation method of 4-bromo-5-methyl-1H-indazole

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Embodiment 1

[0024] A kind of preparation method of 4-bromo-5-methyl-1H-indazole, described preparation method comprises the steps:

[0025] (1) Synthesis of compound III

[0026] Add 189g (1mol) 2-bromo-4-fluorotoluene and 1000ml tetrahydrofuran to the reaction flask, cool down to -78°C, add 500ml (1mol) 2.0M LDA solution dropwise, keep the temperature for 2 hours after the dropwise addition, drop Add 73g (1mol) of N,N-dimethylformamide, slowly return to room temperature and stir for 2 hours after dropping, and follow the reaction by HPLC until the reaction of 2-bromo-4-fluorotoluene is complete; quench into saturated ammonium chloride aqueous solution, 2000ml of ethyl acetate was extracted and separated, and the organic phase was dried and concentrated to obtain 190g of compound III with a molar yield of 87.6%.

[0027] (2) Synthesis of Compound IV

[0028] Add 108.5g (500mmol) of compound III, 41.8g (500mmol) of methoxyamine hydrochloride, 69g (500mmol) of potassium carbonate, and 500...

Embodiment 2

[0034] A kind of preparation method of 4-bromo-5-methyl-1H-indazole, described preparation method comprises the steps:

[0035] (1) Synthesis of compound III

[0036] Add 189g (1mol) 2-bromo-4-fluorotoluene and 1000ml tetrahydrofuran to the reaction flask, cool down to -78°C, add 600ml (1.2mol) 2.0M LDA solution dropwise, keep the temperature for 1.5 hours after the dropwise addition, Add 87.6g (1.2mol) N, N-dimethylformamide dropwise, slowly return to room temperature and stir for 1.5 hours after dropping, HPLC follows the reaction until the reaction of 2-bromo-4-fluorotoluene is complete; quenched to saturated ammonium chloride In the aqueous solution, 2000ml of ethyl acetate was extracted and separated, and the organic phase was dried and concentrated to obtain 195g of compound III, with a molar yield of 89.9%.

[0037] (2) Synthesis of Compound IV

[0038] Add 108.5g (500mmol) compound III, 50.1g (600mmol) methoxylamine hydrochloride, 82.8g (600mmol) potassium carbonate,...

Embodiment 3

[0042] A kind of preparation method of 4-bromo-5-methyl-1H-indazole, described preparation method comprises the steps:

[0043] (1) Synthesis of compound III

[0044] Add 189g (1mol) 2-bromo-4-fluorotoluene and 1000ml tetrahydrofuran to the reaction flask, cool down to -78°C, add 750ml (1.5mol) 2.0M LDA solution dropwise, keep the temperature for 1 hour after the dropwise addition, Add 109.5g (1.5mol) N, N-dimethylformamide dropwise, slowly return to room temperature and stir for 1 hour after dropping, HPLC follows the reaction until the reaction of 2-bromo-4-fluorotoluene is complete; quenched to saturated ammonium chloride In the aqueous solution, 2000ml of ethyl acetate was extracted and separated, and the organic phase was dried and concentrated to obtain 198g of compound III, with a molar yield of 91.3%.

[0045] (2) Synthesis of Compound IV

[0046] Add 108.5g (500mmol) compound III, 62.7g (750mmol) methoxyamine hydrochloride, 103.5g (750mmol) potassium carbonate, 500m...

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Abstract

The invention discloses a preparation method of 4-bromo-5-methyl-1H-indazole, wherein the preparation method comprises the specific steps: (1) reacting a compound (II) in the presence of lithium diisopropylamide to generate a lithium reagent, and reacting the lithium reagent with dimethylformamide to generate a compound (III); (2) reacting the compound (III) with methoxyamine hydrochloride and potassium carbonate to obtain a compound (IV); and (3) cyclizing the compound (IV) under the participation of hydrazine hydrate to generate a compound (I). The preparation method is higher in yield.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of 4-bromo-5-methyl-1H-indazole. Background technique [0002] 4-bromo-5-methyl-1H-indazole is a class of key intermediates. WO2007 / 21937 discloses the following route for the synthesis of 4-bromo-5-methyl-1H-indazole compound I: [0003] [0004] In the above synthetic method, in the process of synthesizing 4-bromo-5-methyl-1H-indazole compound I, the first step reaction generates 2-bromo-1,3-dimethyl-4-nitrobenzene with sulfuric acid , nitric acid nitration, it is easy to punch materials during amplification, which is dangerous, and produces a large amount of waste acid, which is not friendly to the environment; at the same time, the yield in the final step of diazotization ring closure is low, which makes the production cost very high, which is not conducive to industrial scale-up generate. Contents of the invention [0005] In view of ...

Claims

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Application Information

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IPC IPC(8): C07D231/56
CPCC07D231/56
Inventor 张国强
Owner 无锡双启科技有限公司
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