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A kind of preparation method of pentafluorophenol

A technology for pentafluorophenol and pentafluorobenzene boric acid is applied in the field of preparation of pentafluorophenol, can solve the problems of difficult water removal, high recovery cost, troublesome recovery and the like, and achieves the effects of stable process, convenient operation and reduction of operation steps

Active Publication Date: 2020-04-14
DALIAN QIKAI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Since tetrahydrofuran and water are miscible, it is very difficult to remove water, and the recovery cost is very high in industrial production
Use 2-methyltetrahydrofuran as reaction solvent, obtain the yield of pentafluorophenylboronic acid only 78%, and use cyclopentyl methyl ether as the yield of solvent pentafluorophenylboronic acid to have 90%, and 2-methyl Tetrahydrofuran is water-soluble, and its solubility in water at 20°C is 13.1% (W), which brings trouble to recovery

Method used

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  • A kind of preparation method of pentafluorophenol

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Effect test

Embodiment 1

[0034] Step (1): Dry the 1000ml four-necked bottle, replace it with nitrogen, start stirring to maintain good nitrogen protection, add 21.6g (0.891mol) of magnesium chips, 468g of cyclopentyl methyl ether (CPME), 0.02 g iodine, heat up to 40-50°C, add 10g (0.04mol) pentafluorobromobenzene, stir the reaction, after the reaction is triggered, add the remaining 190g (0.77mol) of pentafluorobromobenzene dropwise, after the addition, the temperature rises at 40-50 Incubate at ℃ for 2 hours to obtain Grignard reagent.

[0035] Step (2): Add 133g of cyclopentyl methyl ether and 97g (0.94mol) of trimethyl borate into a 2000ml four-neck flask, cool down to -10-0°C, and drop the Grignard reagent prepared in the above step (1) Add in, then heat to room temperature and keep it warm for 2 hours, then acidify with 10% hydrochloric acid to pH<1, separate layers, and the oil layer is directly used in the next step.

[0036] Step (3): Add the oil layer obtained in step (2) into a 1000ml four-...

Embodiment 2

[0039] Step (1): Dry the 1000ml four-necked bottle, replace it with nitrogen, start stirring to maintain a good nitrogen protection, add 21.6g (0.891mol) of magnesium chips in the four-necked bottle, and recover the cyclopentyl methyl ether (Example 1 The cyclopentyl methyl ether recovered by the method, the water content is 85ppm) 468g, 0.02g iodine, the temperature is raised to 40-50°C, 10g (0.04mol) pentafluorobromobenzene is added, and the reaction is stirred. After the reaction is triggered, the remaining 190 g (0.77 mol) of bromopentafluorobenzene was added, and after the addition was completed, it was incubated at 40-50° C. for 2 hours to obtain the Grignard reagent.

[0040] Step (2): add the cyclopentyl methyl ether that 103g reclaims in the 2000ml four-necked bottle (the cyclopentyl methyl ether that the method described in embodiment 1 reclaims, water content 85ppm) and fresh cyclopentyl methyl ether 30g and 97g (0.94mol) trimethyl borate, lower the temperature to -...

Embodiment 3

[0044] Step (1): Dry the 1000ml four-necked bottle, replace it with nitrogen, start stirring to maintain good nitrogen protection, add 19.7g (0.81mol) of magnesium chips, 468g of cyclopentyl methyl ether (CPME), 0.02 g iodine, heat up to 25-35°C, add 10g (0.04mol) pentafluorobromobenzene, stir the reaction, after the reaction is triggered, add the remaining 190g (0.77mol) of pentafluorobromobenzene dropwise, after the addition is completed, the temperature rises at 25-35 Incubate at ℃ for 2 hours to obtain Grignard reagent.

[0045] Step (2): Add 133g of cyclopentyl methyl ether (CPME) and 83.6g (0.81mol) of trimethyl borate into a 2000ml four-necked bottle, cool down to 0-10°C, and put the lattice prepared in the above step (1) Add the Nitrile reagent dropwise, then heat to room temperature and keep it warm for 2 hours, then acidify with 10% hydrochloric acid to pH<1, separate the layers, and the oil layer is directly used in the next step.

[0046] Step (3): Add the oil lay...

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Abstract

The invention relates to a preparation method for pentafluorophenol, and belongs to the technical field of the compound synthesis. The method comprises the following steps: adding Bromopentafluorobenzene to an organic solvent containing magnesium and iodine dropwise to obtain a Grignard reagent; adding the obtained Grignard reagent to the organic solvent solution of borate B(OR)3 in 20-30 DEG C dropwise, and performing the esterification reaction; enabling the obtained cyclopentyl methyl ether solution of the pentaflubenic acid to react with peroxide in 10-50 DEG C, wherein the organic solvent is the cyclopentyl methyl ether or the recycled cyclopentyl methyl ether. The preparation method is capable of using the cyclopentyl methyl ether or the recycled cyclopentyl methyl ether as the reactive solvent, and the solvent is good for the refined recycling. The provided method has the characteristics of easily obtained raw materials, stable technology, convenient operation and high product purity (greater than or equal to 99.5%).

Description

technical field [0001] The invention relates to a preparation method of pentafluorophenol, which belongs to the field of compound synthesis. Background technique [0002] Pentafluorophenol is an important medicine, pesticide and liquid crystal material intermediate, and because it can activate carboxyl groups and promote the formation of peptide bonds, it is also widely used in peptide synthesis. Pentafluorophenol is a key intermediate in the synthesis of the anti-hepatitis C drug Sofosbuvir. Sofosbuvir is an anti-hepatitis C patent drug newly developed by Gilead Sciences, Inc. (hereinafter referred to as "Gilead"). [0003] Regarding the preparation method of pentafluorophenol, Patent Document 1 (CN 1847210A) discloses a kind of pentafluorobromobenzene as a starting material, using tetrahydrofuran as a solvent to prepare Grignard reagent, then reacting with borate ester at -15°C and then Acidify and distill with hydrochloric acid to obtain pentafluorophenylboronic acid, d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C37/01C07C39/27
CPCC07C37/01C07F3/02C07F5/025C07C39/27
Inventor 杨群山姜殿平张忠赵玉国
Owner DALIAN QIKAI MEDICAL TECH
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