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Preparation method of 4-phenoxyphenylboronic acid

A technology of phenoxybenzene boronic acid and trimethyl borate is applied in the field of preparation of 4-phenoxy benzene boronic acid, and achieves the effects of simple post-processing operation, mild reaction conditions and high yield

Inactive Publication Date: 2016-08-03
BENGBU CHINA SYNCHEM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The industrial production of 4-phenoxyphenylboronic acid has not been reported yet

Method used

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  • Preparation method of 4-phenoxyphenylboronic acid
  • Preparation method of 4-phenoxyphenylboronic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0018] (1) Grignard reagent: First, add 600mL THF and 200g 4-bromodiphenyl ether into a 1000mL three-necked flask and stir to make a solution for later use. Then add 25g of magnesium, 20mL of THF, and a small grain of iodine into a 2000mL three-necked flask, drop 20mL of the THF solution of 4-bromodiphenyl ether that has been prepared, and after heating and triggering, add the remaining 4-bromodiphenyl ether dropwise at 10-20℃ The THF solution of phenyl ether, after the dropwise addition, was kept and stirred at 30-45°C for 1 hour, and the reaction bottle was cooled to below -30°C with liquid nitrogen for later use.

[0019] (2) Boration: Slowly add 110g of trimethyl borate in 600mL THF solution dropwise to the above-mentioned format solution, the dropping process is maintained at -40~-30°C, after the dropping is completed, stir and naturally rise to room temperature, then add 400mL of 10% hydrochloric acid dropwise, Reflux for 1 hour, after THF was distilled off, 500 mL of co...

Embodiment 2

[0022] (1) Grignard reagent: First, add 600mL THF and 200g 4-bromodiphenyl ether into a 1000mL three-necked flask and stir to make a solution for later use. Then add 20.5g of magnesium, 20mL of THF, and a small grain of iodine into a 2000mL three-necked flask, drop 20mL of the prepared THF solution of 4-bromodiphenyl ether into it, and after heating and triggering, add the remaining 4-bromodiphenyl ether dropwise at 10-20°C After the THF solution of diphenyl ether is added dropwise, keep stirring at 30-45° C. for 1 hour, and cool the reaction bottle to below -30° C. with liquid nitrogen for later use.

[0023] (2) Boration: Slowly add 91.8g of trimethyl borate in 600mL THF solution dropwise to the above-mentioned format solution, keep the dropping process below -30°C, stir and naturally rise to room temperature after dropping, add 400mL of 10% hydrochloric acid dropwise, and reflux After 1 hour, THF was distilled off, 500 mL of cold water was added, stirred for 30 minutes, coo...

Embodiment 3

[0026] (1) Grignard reagent: First, add 600mL THF and 200g 4-bromodiphenyl ether into a 1000mL three-necked flask and stir to make a solution for later use. Then add 20.0g of magnesium, 20mL of THF, and a small grain of iodine into a 2000mL three-necked flask, drop 20mL of the prepared THF solution of 4-bromodiphenyl ether into it, and after heating and triggering, add the remaining 4-bromodiphenyl ether dropwise at 45-50°C After the THF solution of diphenyl ether is added dropwise, keep stirring at 45-50° C. for 1 hour, and cool the reaction bottle to below -30° C. with liquid nitrogen for later use.

[0027] (2) Boration: Slowly add 91.8g of trimethyl borate in 600mL THF solution dropwise to the above-mentioned format solution, keep the temperature below -50~-40°C during the dropwise addition process, stir and naturally rise to room temperature after dropping, add 400mL10% solution dropwise Hydrochloric acid was refluxed for 1 hour. After THF was distilled off, 500 mL of col...

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Abstract

The invention discloses a preparation method of 4-phenoxyphenylboronic acid, which relates to the technical field of organic synthesis. It uses 4-bromodiphenyl ether as raw material, tetrahydrofuran as solvent, and reacts with magnesium flakes first to prepare Grignard reagent. The crude product of 4-phenoxyphenylboronic acid is obtained by reacting the reagent with trimethyl borate, and then hydrolyzing with hydrochloric acid. Finally, the finished product of 4-phenoxyphenylboronic acid is obtained after purification. The raw materials used in the invention are cheap and easy to obtain, the reaction conditions are mild, the post-processing operation is simple, the production cost is low, the yield is high, and the method is suitable for industrial production.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-phenoxyphenylboronic acid. Background technique: [0002] The properties of 4-phenoxyphenylboronic acid are white powdery crystals. It is a very versatile chemical intermediate and is widely used in the synthesis of pharmaceuticals, dyes and other fine chemical products. In medicine, anti-cancer drugs can be prepared, such as ibrutinib, which is an oral first-in-class drug called Bruton's tyrosine kinase (BTK) inhibitor, which can bind to the active site of the target protein Btk A cysteine ​​residue (Cys-481) is selectively covalently bound to irreversibly inhibit BTK, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment. The industrial production of 4-phenoxyphenylboronic acid has not been reported yet. Invention content: [0003] The technical problem to be solved by the...

Claims

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Application Information

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IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 杨青刘洪强赵士民徐剑霄
Owner BENGBU CHINA SYNCHEM TECH CO LTD
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