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3-bromo-2-fluoronitrobenzene preparation method

A technology of fluoronitrobenzene and nitrophenyl, which is applied in the field of preparation of 3-bromo-2-fluoronitrobenzene, can solve the problems of low product purity, difficult to purify, unsuitable for industrial production and the like, and achieves high product purity , high conversion rate, easy to operate

Active Publication Date: 2019-10-08
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Because the fluorinated reagents used in this method are expensive and the reaction conversion rate is low, the cost rises; in addition, the product has low purity and is not easy to purify, so it is not suitable for industrial production

Method used

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Experimental program
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Effect test

Embodiment 1

[0052] The preparation of embodiment 1 N-(2-bromophenyl) acetamide

[0053] Dichloromethane (260 mL) and 2-bromoaniline (86 g, 0.5 mol) were added to a 1 L reaction flask. Triethylamine (63.3 g, 0.63 mol) was added with stirring. Cool down to 0°C.

[0054] Acetyl chloride (42.7 mL, 0.6 mol) was added dropwise at 0°C. Keep the temperature at 0-10°C. 1h dropwise addition is complete. Rise to room temperature and stir for 4h.

[0055] Water (300 mL) and dichloromethane (200 mL) were added. Stir for 10min and separate the liquids. The aqueous phase was extracted once with dichloromethane (400 mL). Combine the organic phases. Wash with water (300mL), evaporate the organic phase to dryness under reduced pressure, add n-heptane (300mL) for recrystallization, and obtain solid N-(2-bromophenyl)acetamide (100.5g, yield 93.7%), mp=97 ~100°C, Rf=0.5 (PE:EA=2:1).

Embodiment 2

[0056] The preparation of embodiment 2 N-(2-bromophenyl) acetamide

[0057] Dichloromethane (260 mL) and 2-bromoaniline (86 g, 0.5 mol) were added to a 1 L reaction flask. Triethylamine (63.3 g, 0.63 mol) was added with stirring. Cool down to 0°C.

[0058] Acetyl chloride (42.7 mL, 0.6 mol) was added dropwise at 0°C. Keep the temperature at 0-10°C. 1h dropwise addition is complete. Rise to room temperature and stir for 4h.

[0059]Water (300 mL) and dichloromethane (200 mL) were added. Stir for 10min and separate the liquids. The aqueous phase was extracted once with dichloromethane (400 mL). Combine the organic phases. Wash with water (300mL), evaporate the organic phase to dryness under reduced pressure, add n-hexane (300mL) for recrystallization, filter, and blow dry to obtain solid N-(2-bromophenyl)acetamide (99.2g, yield 92.7% ), mp=97~100°C, Rf=0.5 (PE:EA=2:1).

Embodiment 3

[0060] The preparation of embodiment 3 N-(2-bromophenyl) acetamide

[0061] Dichloromethane (260 mL) and 2-bromoaniline (86 g, 0.5 mol) were added to a 1 L reaction flask. Triethylamine (63.3 g, 0.63 mol) was added with stirring. Cool down to 0°C.

[0062] Acetyl chloride (99.2 mL, 1.40 mol) was added dropwise at 0°C. Keep the temperature at 0-10°C. 1h dropwise addition is complete. Rise to room temperature and stir for 4h.

[0063] Water (300 mL) and dichloromethane (200 mL) were added. Stir for 10min and separate the liquids. The aqueous phase was extracted once with dichloromethane (400 mL). Combine the organic phases. Wash with water (300mL), evaporate the organic phase to dryness under reduced pressure, add cyclohexane (300mL) for recrystallization, and obtain solid N-(2-bromophenyl)acetamide (102.0g, yield 95.3%), mp=97 ~100°C, Rf=0.5 (PE:EA=2:1).

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Abstract

The invention discloses a 3-bromo-2-fluoronitrobenzene preparation method. The method includes steps: (1) under the alkali action, subjecting bromoaniline and acetyl chloride to acetylation to obtainN-(2-bromophenyl)acetamide; (2) subjecting N-(2-bromophenyl)acetamide and nitric acid to nitration reaction to obtain N-(2-bromo-6-nitrophenyl)acetamide; (3) subjecting N-(2-bromo-6-nitrophenyl)acetamide to hydrolysis reaction to obtain 2-bromo-6-nitroaniline; (4) subjecting 2-bromo-6-nitroaniline, a fluoride and a nitro compound to diazotization to obtain a diazonium salt intermediate, and decomposing the diazonium salt intermediate under a heating condition to obtain 3-bromo-2-fluoronitrobenzene. In a reaction process, the cheap raw materials are used, consumption of expensive fluorination reagents (KF and CsF) is avoided, and the method has advantages of simplicity and convenience in operation, high conversion rate, high product purity, high quality, suitableness for industrial production and the like.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of 3-bromo-2-fluoronitrobenzene. Background technique [0002] 3-bromo-2-fluoronitrobenzene is an important pharmaceutical intermediate, which can be used in the synthesis of anticancer drugs; in addition, there are literature reports that this compound can also be used in the synthesis of azilsartan. However, there are few synthetic methods for this compound at present, among which WO2004069832 reports that 3-bromo-2-chloronitrobenzene is used as a raw material, prepared under the action of 2 equivalents of KF and 1 equivalent of CsF, and the yield is 73%. Although separated by column chromatography, the purity is only 80%, and the unreacted raw material 3-bromo-2-chloronitrobenzene is difficult to remove, and the specific reaction formula is as follows: [0003] [0004] Because the fluorinating reagent used in this method is ex...

Claims

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Application Information

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IPC IPC(8): C07C201/12C07C205/12
CPCC07C201/12C07C209/50C07C231/12C07C231/02C07C205/12C07C211/52C07C233/15
Inventor 张波马群周雄飞唐小平
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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