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Preparation method of 2-bromo-6-fluoroanisole

A technology of fluoroanisole and difluoronitrobenzene, which is applied in the field of preparation of 2-bromo-6-fluoroanisole, can solve the problems that are not conducive to industrial scale-up and generation, and a large amount of waste water, and achieve low price and easy disposal , the effect of little pollution

Active Publication Date: 2021-09-10
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-mentioned synthetic method, in the process of synthesizing 2-bromo-6-fluoroanisole compound I, the first step reaction used the explosive reagent nitric acid for nitration, and produced a large amount of waste water; the second step reaction used highly toxic Methyl iodide is added to the product reagent, which is not conducive to industrial scale-up

Method used

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  • Preparation method of 2-bromo-6-fluoroanisole
  • Preparation method of 2-bromo-6-fluoroanisole
  • Preparation method of 2-bromo-6-fluoroanisole

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Embodiment 1

[0026] A preparation method of 2-bromo-6-fluoroanisole, the preparation method comprises the steps:

[0027] (1) Synthesis of compound III

[0028] Add 159g (1mol) 3,4-difluoronitrobenzene, 500g concentrated sulfuric acid (mass concentration 98%) to the reaction flask, add 195.8g (1.1mol) bromosuccinimide in batches at 40°C, and finish adding Keep stirring for 12 hours, follow the reaction by HPLC until the reaction of 3,4-difluoronitrobenzene is complete; quench into 2000ml ice water, filter, and recrystallize the filter cake with acetone-water system to obtain 194.3g of compound III, molar yield: 82 %.

[0029] (2) Synthesis of Compound IV

[0030] Add 118.5g (0.5mol) compound III, 700ml methanol, 29.7g (0.55mol) sodium methoxide into the reaction flask, stir at 60°C for 6 hours, follow the reaction by HPLC until the compound III reaction is complete; quench into 2000ml ice water, Filter and dry to obtain 103.3 g of compound IV, molar yield: 83%.

[0031] (3) Synthesis o...

Embodiment 2

[0038] A preparation method of 2-bromo-6-fluoroanisole, the preparation method comprises the steps:

[0039] (1) Synthesis of compound III

[0040] To the reaction flask, add 159g (1mol) 3,4-difluoronitrobenzene, 500g concentrated sulfuric acid (mass concentration 98%), add 231.4g (1.3mol) bromosuccinimide in batches at 60°C, and finish adding Keep stirring for 6 hours, follow the reaction by HPLC until the reaction of 3,4-difluoronitrobenzene is complete; quench into 2000ml ice water, filter, and recrystallize the filter cake with acetone-water system to obtain 199.1g of compound III, molar yield: 84 %.

[0041] (2) Synthesis of Compound IV

[0042] Add 118.5g (0.5mol) of compound III, 700ml of methanol, 35.1g (0.65mol) of sodium methoxide into the reaction flask, stir at 50°C for 4 hours, follow the reaction by HPLC until the reaction of compound III is complete; quench into 2000ml of ice water, Filter and dry to obtain 109.5 g of compound IV, molar yield: 88%.

[0043] ...

Embodiment 3

[0048] A preparation method of 2-bromo-6-fluoroanisole, the preparation method comprises the steps:

[0049] (1) Synthesis of compound III

[0050] To the reaction flask, add 159g (1mol) 3,4-difluoronitrobenzene, 500g concentrated sulfuric acid (mass concentration 98%), add 267g (1.5mol) bromosuccinimide in batches at 20°C, add the insulation Stir for 12 hours, follow the reaction by HPLC until the reaction of 3,4-difluoronitrobenzene is complete; quench into 2000ml of ice water, filter, and recrystallize the filter cake with acetone-water system to obtain 189.6g of compound III, molar yield: 80% .

[0051] (2) Synthesis of Compound IV

[0052] Add 118.5g (0.5mol) of compound III, 700ml of methanol, 40.5g (0.75mol) of sodium methoxide into the reaction flask, stir at 40°C for 2 hours, follow the reaction by HPLC until the reaction of compound III is complete; quench into 2000ml of ice water, Filter and dry to obtain 99.6 g of compound IV, molar yield: 80%.

[0053] (3) Syn...

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Abstract

The invention discloses a preparation method of 2-bromine-6-fluoroanisole, the preparation method comprises the following specific steps: (1) carrying out electrophilic substitution reaction on 3, 4-difluoronitrobenzene and bromosuccinimide to generate a compound III; (2) reacting the compound III with sodium methoxide to generate a compound IV; (3) reducing the compound IV by sodium hydrosulfite to generate a compound V; (4) performing diazotization deamination on the compound V to generate a compound I; the obtained product is 2-bromo-6-fluoroanisole. The preparation method is higher in yield.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of 2-bromo-6-fluoroanisole. Background technique [0002] 2-Bromo-6-fluoroanisole is a kind of key intermediate, WO2013 / 28474, WO2014 / 126944, EP2744499 disclose the following route for synthesizing 2-bromo-6-fluoroanisole compound I: [0003] [0004] In the above-mentioned synthetic method, in the process of synthesizing 2-bromo-6-fluoroanisole compound I, the first step reaction used the explosive reagent nitric acid to do nitration, and a large amount of waste water was produced simultaneously; the second step reaction used the highly toxic The product reagent methyl iodide is not conducive to industrial amplification. SUMMARY OF THE INVENTION [0005] In view of the above problems existing in the prior art, the present invention provides a preparation method of 2-bromo-6-fluoroanisole. The yield of the preparation method of t...

Claims

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Application Information

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IPC IPC(8): C07C41/18C07C43/225C07C201/12C07C205/12C07C205/37
CPCC07C41/18C07C201/12C07C205/12C07C205/37C07C43/225
Inventor 张国强王昌军秦英
Owner 无锡双启科技有限公司
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