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A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto

A technology of mercaptophenylboronic acid and hydroxyl group, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as inability to obtain pure products, and achieve the effects of high yield and high product purity

Active Publication Date: 2015-07-22
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the above synthetic methods, some literatures only obtain protected phenylboronic acid, or the by-product of boric acid oxidation to hydroxyl occurs in the process of removing the protecting group, and the pure product cannot be obtained.

Method used

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  • A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Synthesis of o-hydroxyphenylboronic acid:

[0020] Under the protection of nitrogen, 1.5 kg of 2-methoxyphenylboronic acid, 18 liters of anisole and 1.56 kg of acetyl chloride were added into a 30L glass reactor. After the addition, the reaction solution was cooled to -10-0°C and stirred for 1 hour. Begin to add 133 grams of anhydrous aluminum trichloride in batches. After the addition is completed and naturally rise to room temperature, keep warm and stir the reaction until TLC shows that the raw materials are completely reacted. This process takes about 8 to 10 hours. During this process, the solids of the reaction mixture were gradually dissolved, followed by the gradual precipitation of solids.

[0021] Add 5M potassium hydroxide aqueous solution to quench and adjust the pH to 11-12. At this point the organic layer was separated and discarded. Add 6M hydrochloric acid aqueous solution to the water layer to adjust the pH to 2-3, extract twice with 12 liters of ethy...

Embodiment 2

[0023] Synthesis of p-hydroxyphenylboronic acid:

[0024] Under the protection of nitrogen, add 1.5 kg of 4-methoxyphenylboronic acid, 20 liters of toluene and 1.17 kg of acetyl chloride into a 30L glass reactor. After the addition, cool the reaction solution to -10-0°C and stir for 1 hour. Begin to add 267 grams of anhydrous aluminum trichloride in batches, rise to 80 ° C after the addition is complete, keep warm and stir the reaction until TLC shows that the raw materials have reacted completely, and this process takes about 3 to 5 hours. During this process, the solids of the reaction mixture were gradually dissolved, and then solids were gradually precipitated out.

[0025] Add 2M sodium hydroxide aqueous solution to quench and adjust the pH to 11-12. At this point the organic layer was separated and discarded. Add 6M hydrochloric acid aqueous solution to the water layer to adjust the pH to 2, extract twice with 15 liters of ethyl acetate, combine the organic layers, was...

Embodiment 3

[0027] Synthesis of p-mercaptophenylboronic acid:

[0028] Under nitrogen protection, add 4.2 kg of 4-tert-butylmercaptophenylboronic acid, 25 liters of diphenyl ether and 2.3 kg of acetyl chloride into a 50L glass reactor. After the addition, cool the reaction solution to -10-0°C and stir for 1 hour. Begin to add 267 grams of anhydrous aluminum trichloride in batches, add complete. Raise the reaction solution to 80°C, keep warm and stir the reaction until TLC shows that the reaction of the raw materials is complete, and this process takes about 2 to 3 hours. During this process, the solids of the reaction mixture were gradually dissolved, and then solids were gradually precipitated out.

[0029] Add 2M sodium hydroxide aqueous solution to quench and adjust the pH to 11-12. At this point the organic layer was separated and discarded. Add 6M hydrochloric acid aqueous solution to the water layer to adjust the pH to 2-3, extract twice with 15 liters of ethyl acetate, combine t...

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Abstract

A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto is disclosed. The method includes adding a compound of a formula I into an organic solvent, adding 1.2-2.0 eq of acetyl chloride, lowering the temperature of the solution to a temperature between -10 DEG C and 0 DEG C, adding 0.1-0.3 eq of anhydrous aluminium chloride, heating to 20-120 DEG C, stirring for 2-10 h to obtain a compound of a formula II, adding an alkali to adjust pH to be 11-12 after TLC detection proves that the reaction is finished, layering, removing the organic layer, adding hydrochloric acid into the water layer to adjust pH to be 2-3, extracting with ethyl acetate, subjecting the organic layer to rotary drying, and beating the obtained crude product with a mixture of acetone or dichloromethane and n-heptane to obtain a solid product of a formula III, wherein R in the formula I is methyl or tert-butyl, and M in the formula I, M in the formula II and M in the formula III are oxygen simultaneously or sulfur simultaneously. The product produced by the method is high in purity and high in yield.

Description

technical field [0001] The invention relates to a method for preparing ortho-para-substituted hydroxyl and mercaptophenylboronic acid, which belongs to the field of synthesis of pharmaceutical intermediates. technical background [0002] The Suzuki reaction is used in synthetic chemistry to construct various types of sp 2 One of the important methods of C-C single bond type, the main raw material of this reaction, organoboronic acid, has always maintained a relatively strong market demand, because hydroxy / mercaptoboronic acid can be conveniently introduced into the molecule through Suzuki coupling to introduce phenol / mercapto structural units, so It is also widely used in daily chemical and pharmaceutical synthesis. At the same time, biomolecules containing boron-sulfhydryl groups have also begun to be used in the field of boron neutron capture therapy (BNCT). [0003] At present, the synthetic methods of hydroxyl / mercaptophenylboronic acid mainly include: 1) adopt THP pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 冷延国桂迁张进余锦华
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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