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Method for preparing benzbromarone

A technology of benzbromarone and catalyst, which is applied in the field of pharmaceutical chemical synthesis, and can solve problems that are unfavorable to labor protection and unfavorable industrialized production of benzbromarone.

Active Publication Date: 2013-08-14
HEFEI IND PHARMA INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Colorless and highly toxic phosgene and highly corrosive bromine are used in this route, which is not conducive to labor protection
[0012] The preparation methods of the above three benzbromarones carry out bromination reaction in the last step without exception, which cannot avoid the generation of impurity I and impurity II clearly mentioned in the 2010 edition of Chinese Pharmacopoeia, and impurity I is a monobromide: (3 -bromo-4-hydroxyphenyl)-(2-ethyl-3-benzofuryl)methanone; impurity II is tribromide: (6-bromo-2-ethyl-3-benzofuryl) -(3,5-dibromo-4-hydroxyphenyl) ketone, so it is necessary to purify benzbromarone several times to control the content of impurity I and impurity II, which is not conducive to the industrialization of benzbromarone Production

Method used

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  • Method for preparing benzbromarone
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  • Method for preparing benzbromarone

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Preparation of 3,5-dibromo-4-acetoxybenzoic acid (III):

[0024] Add 125ml of dichloromethane and 3.67g of acetic anhydride to the reaction flask, add 10g of 3,5-dibromo-4-hydroxybenzoic acid (II) while stirring, add 5-6 drops of concentrated sulfuric acid, and control the temperature at 30-35°C. React for 2 hours, add 250ml of saturated sodium chloride solution to the reaction flask, stir for 1 hour, let stand to separate layers, discard the water layer, wash the organic layer with saturated sodium chloride until neutral, dry the organic layer with anhydrous magnesium sulfate, filter Inorganic salt, and the filtrate was concentrated to dryness to obtain 10.4 g of 3,5-dibromo-4-acetoxybenzoic acid (III) as a white powder solid, with a yield of 91.23%.

[0025] Melting point: 194~196℃

[0026] 1 H NMR data: (400MHz, DCl 3 , 25°C) δ 2.43 (s, 3H), 8.29 (s, 2H), 11.03 (s, 1H) ppm.

[0027] Preparation of 3,5-dibromo-4-acetoxybenzoyl chloride (IV):

[0028] Add 10g of 3...

Embodiment 2

[0036] Preparation of 3,5-dibromo-4-acetoxybenzoic acid (III):

[0037] Add 50ml of dichloromethane and 5.5g of acetic anhydride to the reaction flask, add 5g of 3,5-dibromo-4-hydroxybenzoic acid (II) while stirring, add 2-3 drops of concentrated sulfuric acid, and control the temperature at 30-35°C. React for 2 hours, add 100ml of saturated sodium chloride solution to the reaction bottle, stir for 1 hour, let stand to separate layers, discard the water layer, wash the organic layer with saturated sodium chloride until neutral, dry the organic layer with anhydrous magnesium sulfate, filter Inorganic salt, the filtrate was concentrated to dryness to obtain 4.62 g of 3,5-dibromo-4-acetoxybenzoic acid (III) as a white powder solid, with a yield of 81%.

[0038] Preparation of 3,5-dibromo-4-acetoxybenzoyl chloride (IV):

[0039] Add 4g of 3,5-dibromo-4-acetoxybenzoic acid (III) and 70ml of thionyl chloride to the reaction flask in sequence, and add a drop of DMF dropwise, and sti...

Embodiment 3

[0045] Preparation of 3,5-dibromo-4-acetoxybenzoic acid (III):

[0046] Add 80ml of dichloromethane and 8g of 3,5-dibromo-4-hydroxybenzoic acid (II) into the reaction flask, add 2-3 drops of concentrated sulfuric acid, control the temperature at 30-35°C, add 10.6g of acetyl chloride dropwise, and react 2h, add 200ml of saturated sodium chloride solution to the reaction flask, stir for 1h, let stand to separate layers, discard the water layer, wash the organic layer with saturated sodium chloride until neutral, dry the organic layer with anhydrous magnesium sulfate, filter out the inorganic salt, and the filtrate was concentrated to dryness to obtain 7.1 g of 3,5-dibromo-4-acetoxybenzoic acid (III) as a white powder solid, with a yield of 77.7%. Preparation of 3,5-dibromo-4-acetoxybenzoyl chloride (IV):

[0047] Add 7g of 3,5-dibromo-4-acetoxybenzoic acid (III) and 150ml of thionyl chloride to the reaction flask in sequence, and add a drop of DMF dropwise, and stir for 0.5 hou...

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Abstract

The invention relates to the field of drug synthesis and in particular relates to a method for preparing benzbromarone. The method for preparing benzbromarone is characterized by comprising the steps of carrying out an acetylation reaction, a Friedel-Craft reaction, a hydrolysis reaction and the like to prepare the benzbromarone by using 3,5-dibromo-4-hydroxybenzoic acid and 2-ethyl benzofuran as raw materials. The preparation method disclosed by the invention has the advantages of being simple and safe to operate, convenient for post-treatment, high in product purity, low in economic cost, small in environment pollution, easier to realize industrialization and the like.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing benzbromarone. Background technique [0002] Benzbromarone is an excellent drug for the treatment of gout. With the improvement of people's living standards, the incidence of gout is on the rise. Benzbromarone is a powerful uric acid-removing benzofuran derivative. This compound can not only inhibit the reabsorption of uric acid by renal tubules and promote the excretion of uric acid, but also is a good purine oxidase inhibitor, which can inhibit the production of uric acid. It has a dual function of reducing blood uric acid concentration. [0003] WO2012048058 reports a preparation method of benzbromarone, the process route is as follows: [0004] [0005] The first step of this route uses chloroacetone, which will decompose and release colorless and highly toxic phosgene when heated; the second step, the reduction reaction temperatur...

Claims

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Application Information

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IPC IPC(8): C07D307/80
Inventor 何广卫吴强张磊张强王奎李丰
Owner HEFEI IND PHARMA INST
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