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Preparation method for benzbromarone

A technology of benzbromarone and bromine salt, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as equipment corrosion, high production cost, and high price, and achieve the effects of avoiding the formation of impurities, improving the utilization rate of bromine, and improving selectivity

Inactive Publication Date: 2018-09-28
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

US5266711 and WO2012048058 respectively report the method for preparing benzbromarone by bromination of (4-hydroxyphenyl)-(2-ethylbenzofuran-3-yl)methanone (II) and bromine in acetic acid, the The method uses bromine as the brominating agent, which is prone to equipment corrosion, environmental pollution, and unavoidable generation of (3-bromo-4-hydroxyphenyl)-(2-ethylbenzofuran-3-yl)methanone and By-products such as (6-bromo-2-ethyl-3-benzofuryl)-(3,5-dibromo-4-hydroxyphenyl)methanone bring troubles to the purification of products
CN102659727 report uses bromosuccinimide (NBS) as bromination agent to carry out the preparation of bromination reaction benzbromarone, yield 86%, but NBS price is more expensive, and production cost is higher

Method used

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  • Preparation method for benzbromarone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Weigh 2mmol of 15-crown-5, 4.4mmol of LiBr and 4.4mmol of NaClO, dissolve them in 7mL of water respectively, mix and stir the three solutions at room temperature for 30min, filter, wash with water 3 times, and dry to obtain yellow Solid 15-crown-5·bromine, yield 87%.

[0016] Dissolve 2.0 mmol of 15-crown-5 bromine in 15 mL of HOAc, slowly add 1 mmol of (4-hydroxyphenyl)-(2-ethylbenzofuran-3-yl)methanone under stirring 10 mL of HOAc solution. React at room temperature for 10 hours, raise the temperature to 40°C, stir for 30 minutes, cool to room temperature, filter, and recrystallize from 95% ethanol to obtain benzbromarone with a yield of 91%. mp151-152°C.

[0017] During the reaction process, 10% LiOH solution was used to absorb the HBr produced by the reaction to neutrality to prepare LiBr, and the content of LiBr was determined by silver nitrate titration.

[0018] The filtrate was evaporated to remove HOAc under reduced pressure, and 15 mL of water was added to ...

Embodiment 2

[0020] Weigh 2mmol of dibenzo-18-crown-6 and 4.4mmol of NaBr respectively, dissolve them in 7mL of water, and then weigh 4.4mmol of 30% H 2 o 2 , at room temperature, the three solutions were mixed and stirred for 30 min, filtered, washed 3 times with water, and dried to obtain a yellow solid dibenzo-18-crown-6 bromide with a yield of 88%.

[0021] Dissolve 2.03 mmol of dibenzo-18-crown-6 bromide in 15 mL of HOAc, slowly add 1 mmol of (4-hydroxyphenyl)-(2-ethylbenzofuran-3-yl) under stirring ) ketone in 10 mL of HOAc solution. React at room temperature for 10 hours, raise the temperature to 40°C, stir for 30 minutes, cool to room temperature, filter, and recrystallize from 95% ethanol to obtain benzbromarone with a yield of 94%. mp152-153°C.

[0022] During the reaction process, the HBr produced by the reaction was absorbed with 20% NaOH solution to neutrality to prepare NaBr, and the content of NaBr was determined by silver nitrate titration.

[0023] The filtrate was eva...

Embodiment 3

[0025] Weigh 2mmol of dicyclohexane and 18-crown ether-6, 2.2mmol of MgBr 2 and 4.4mmol of t-BuOOH were dissolved in 10mL of water respectively. At room temperature, the three solutions were mixed and stirred for 30min, filtered, washed 3 times with water, and dried to obtain a yellow solid dicyclohexane and 18-crown-6 bromide , yield 90%.

[0026] Dissolve 2.0 mmol of dicyclohexane 18-crown-6 bromide in 15 mL of HOAc, slowly add 1 mmol of (4-hydroxyphenyl)-(2-ethylbenzofuran-3- base) ketone in 10 mL of HOAc solution. React at room temperature for 10 hours, raise the temperature to 40°C, stir for 30 minutes, cool to room temperature, filter, and recrystallize from 95% ethanol to obtain benzbromarone with a yield of 91.5%. mp152-153°C.

[0027] During the reaction, use 15% Mg(OH) 2 The solution absorbs the HBr produced by the reaction to neutrality and prepares MgBr 2 , Determination of MgBr by silver nitrate titration 2 content.

[0028] The filtrate was evaporated unde...

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Abstract

The invention discloses a preparation method for benzbromarone (formula I). The preparation method comprises the following steps: using (4- hydroxyphenyl)-(2-ethylbenzofuran-3-yl) ketone (formula II)as a raw material, using crown ether-bromine as a brominating agent, and preparing the benzbromarone in a room temperature through a bromination reaction. A by-product HBr is absorbed by diluted alkali solution for salifying, and used for preparing the crown ether-bromine. The beneficial effect is that the crown ether-bromine is used as the brominating agent, a utilization ratio of bromine is high, generated impurities are less, the reaction conditions are moderate, and crown ether and HBr can be recycled.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of benzbromarone. Background technique [0002] Benzbromarone (benzbromarone) is a uric acid excretion agent, which was first successfully developed by the French Labaz company in the 1960s. It was launched in Germany in 1971 and is clinically used to accelerate the excretion of uric acid and the treatment of gout. US5266711 and WO2012048058 respectively report the method for preparing benzbromarone by bromination of (4-hydroxyphenyl)-(2-ethylbenzofuran-3-yl)methanone (II) and bromine in acetic acid, the The method uses bromine as the brominating agent, which is prone to equipment corrosion, environmental pollution, and unavoidable generation of (3-bromo-4-hydroxyphenyl)-(2-ethylbenzofuran-3-yl)methanone and By-products such as (6-bromo-2-ethyl-3-benzofuryl)-(3,5-dibromo-4-hydroxyphenyl)methanone bring troubles to the purification of the prod...

Claims

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Application Information

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IPC IPC(8): C07D307/80
CPCC07D307/80
Inventor 张宝华张冀男史兰香
Owner SHIJIAZHUANG UNIVERSITY
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