Preparation method of hydroxyphenylboronic acid

A technology of hydroxybenzene boronic acid and boronic acid ester, applied in chemical instruments and methods, compounds containing periodic table Group 3/13 elements, production of bulk chemicals, etc. Competitiveness, high cost, easy protection and deprotection, easy industrial scale-up, and good process stability

Active Publication Date: 2020-04-28
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In view of the above method, in the route of using bromophenol as raw material, the protecting group is mainly THP or tert-butyldimethylsilane, and these two protecting groups are easily dissolved in water after the reaction is completed and the protecting group is removed. Difficulties in biochemical treatment
The cost of other reaction routes is too high, and they do not have cost advantages and core competitiveness when they are adopted industrially

Method used

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  • Preparation method of hydroxyphenylboronic acid
  • Preparation method of hydroxyphenylboronic acid
  • Preparation method of hydroxyphenylboronic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] In the reaction flask, add p-bromophenol (17.3g, 0.1mol), potassium carbonate (18.0g, 0.13mol), benzyl bromide (18.8g, 0.11mol) and dioxane 140mL, after stirring evenly, heat up to 40 React at -45°C for 10 hours. After detecting the completion of the reaction, evaporate the solvent to dryness, add water and ethyl acetate to separate layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers and wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, evaporate to dryness, and ethanol / heptane The mixed solvent was beaten to obtain 24.7 g of off-white solid, with a yield of 94%.

[0025] Under the protection of nitrogen, add 24.7g (0.094mol) of the above solid into 80mL of tetrahydrofuran, dissolve it completely under stirring, cool to -10°C to 0°C, and start to dropwise add 1.3M isopropylmagnesium chloride-lithium chloride / tetrahydrofuran solution (94mL , 0.122mol), the dropwise addition was completed, and the he...

Embodiment 2

[0027]

[0028] In the reaction flask, add m-bromophenol (17.3g, 0.1mol), potassium carbonate (20.7g, 0.15mol), benzyl chloride (15.2g, 0.12mol) and dioxane 130mL, after stirring evenly, heat up to 40 React at -45°C for 10 hours. After detecting the completion of the reaction, evaporate the solvent to dryness, add water and ethyl acetate to separate layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers and wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, evaporate to dryness, and ethanol / heptane The mixed solvent was beaten to obtain 24.9 g of off-white solid, with a yield of 95%.

[0029] Under the protection of nitrogen, add 24.9 g (0.095 mol) of the above solid into 80 mL of tetrahydrofuran, dissolve it completely under stirring, cool to -10°C to 0°C, and start to dropwise add 1.3M isopropylmagnesium chloride-lithium chloride / tetrahydrofuran solution (94mL , 0.122mol), the dropwise addition was completed, and th...

Embodiment 3

[0031]

[0032] In the reaction flask, m-bromophenol (17.3g, 0.1mol), ammonium chloride (0.3g) and 110mL of hexamethyldisilazane were added, stirred evenly, and heated to reflux for overnight reaction. After the completion of the detection reaction, the solvent was evaporated to dryness, and then the temperature was raised to 40-50° C. for 40 minutes under reduced pressure and vacuum pumping, and 24.6 g of oily liquid was obtained in the reaction bottle, with a yield of 100%.

[0033] Under the protection of nitrogen, the above oily liquid was added into 150 mL of tetrahydrofuran and dissolved completely under stirring, then triisopropyl borate (24.4 g, 0.13 mol) was added. Then it was cooled to -60°C, and 2.5M n-butyllithium hexane solution (44mL, 0.11mol) was added dropwise. After the dropwise addition was completed, the reaction was kept for 2 hours, and then the temperature was slowly raised to -10°C. After the detection reaction is completed, the temperature is controlle...

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Abstract

The invention discloses a preparation method of hydroxyphenylboronic acid, which belongs to the technical field of boric acid synthesis in medical intermediates. The method comprises the following steps: starting from bromophenol, carrying out BOC, trimethylsilyl or benzyl protection, forming a Grignard reagent, reacting with borate, or carrying out one-pot reaction with borate and n-butyllithium,and hydrolyzing to obtain hydroxyphenylboronic acid. According to the invention, cheap and easily available protecting groups are adopted, so that the protecting groups are easy to remove during boronation reaction hydrolysis, industrial amplification is easy to realize, batch production is carried out on the scale of dozens of kilograms, and the process stability is good.

Description

technical field [0001] The invention relates to the preparation of organic boric acid as a pharmaceutical intermediate, in particular to a preparation method of hydroxyphenylboronic acid, which belongs to the technical field of organic synthesis. Background technique [0002] Hydroxyphenylboronic acid, white powder or crystalline solid, including 2-hydroxyphenylboronic acid, 4-hydroxyphenylboronic acid and 4-hydroxyphenylboronic acid, are mainly used in the development of high-end innovative clinical drugs. Taking 3-hydroxyphenylboronic acid and 4-hydroxyphenylboronic acid as examples, the application conditions are as follows: 3-hydroxyphenylboronic acid, used for URB-597, is currently in Phase I clinical trials, targeting FAAH2, and the indication is schizophrenia; and Zotiraciclib, currently in Phase II clinical trials, targets CDK1-2, 9, JAK2, FLT3, CDK7, etc., and its indications are keratinoma and anaplastic astrocytoma. 4-Hydroxyphenylboronic acid, used for Honokiol,...

Claims

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Application Information

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IPC IPC(8): C07F5/02
CPCC07F5/025Y02P20/55
Inventor 张世红刘增仁张朋岳于伟东
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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