Preparation method of 3,5-dibromo-2-aminobenzoic acid

An aminobenzoic acid and bromate technology, which is applied in the preparation of organic compounds, chemical instruments and methods, cyanide reaction preparation, etc., can solve the problems of inconvenient procurement and management, high production cost, high risk and the like of using enterprises, To achieve the effect of simple operation, stable purity and low price

Inactive Publication Date: 2019-01-01
ZHEJIANG NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] But above-mentioned method degrades with liquid bromine / sodium hydroxide, if the bromine negative ion that forms in the reaction can not be reused, and production cost is very high, and the use of liquid bromine, danger is also bigger; Degrade with sodium hypochlorite, because the instability of sodium hypochlorite Sexuality, resulting in low and unstable concentration of commercially available products, a large amount of waste water, and the product is easy to further decarboxylate
In addition, 2-aminobenzoic acid is the first category of precursor chemicals stipulated by the state, and its procurement and storage must be carried out in accordance with the procedures stipulated by the state, which has brought great inconvenience and difficulty to the procurement and management of the users.

Method used

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  • Preparation method of 3,5-dibromo-2-aminobenzoic acid
  • Preparation method of 3,5-dibromo-2-aminobenzoic acid
  • Preparation method of 3,5-dibromo-2-aminobenzoic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Reaction Ⅰ: 6g (0.041mol) phthalimide, 3.67g (0.036mol) NaBr, 2.69g (0.018mol) NaBrO 3 Add it into 100g of water, stir to dissolve, add dropwise 6.64g (0.026mol) of 40% sulfuric acid, stir at room temperature for 12h, filter, and wash the solid with 2×20mL water to obtain a white solid of N-bromophthalimide.

[0040] Reaction II: Add N-bromophthalimide obtained in Reaction I to aqueous sodium hydroxide solution (15.6g, 0.39mol NaOH dissolved in 100g water) in batches at -5°C to 0°C, After the solid was completely dissolved, it was raised to room temperature and kept for 0.5 h.

[0041]Reaction Ⅲ: Add 50mL (0.36mol) of 50% sulfuric acid and 4.96g (0.048mol) of NaBr to the solution obtained in Reaction Ⅱ, cool down to -5°C to 0°C, and add dropwise 19.6g (0.098mol) of 17.1% peroxide Hydrogen aqueous solution, raised to room temperature to continue reaction for 12h after dripping, filtered, washed the solid with 2×20mL water, and dried to obtain 10.90g white solid of 3,5-d...

Embodiment 2

[0043] Reaction Ⅰ: 6g (0.041mol) phthalimide, 3.67g (0.036mol) NaBr, 2.69g (0.018mol) NaBrO 3 Add it into 100g of water, stir to dissolve, add dropwise 6.64g (0.026mol) of 40% sulfuric acid, stir at room temperature for 12h, filter, and wash the solid with 2×20mL water to obtain a white solid of N-bromophthalimide.

[0044] Reaction II: Add the N-bromophthalimide obtained in Reaction I to aqueous sodium hydroxide solution (15.6g, 0.39mol NaOH dissolved in 100g water) in batches at -5°C to 0°C. Solid After complete dissolution, it was raised to room temperature and incubated for 1 h.

[0045] Reaction Ⅲ: Add 61mL (0.73mol) of 36% hydrochloric acid and 4.96g (0.048mol) of NaBr to the solution obtained in reaction Ⅱ respectively, cool down to -5°C to 0°C, and add dropwise 19.6g (0.098mol) of 17.1% peroxide Hydrogen aqueous solution, raised to room temperature to react for 10 h after dripping, filtered, washed the solid with 2×20 mL of water, and dried to obtain 10.78 g of white ...

Embodiment 3

[0047] Reaction Ⅰ: 6g (0.041mol) phthalimide, 4.28g (0.036mol) KBr, 2.99g (0.018mol) KBrO 3 Add it into 100g of water, stir to dissolve, add dropwise 6.64g (0.026mol) of 40% sulfuric acid, stir at room temperature for 12h, filter, and wash the solid with 2×20mL water to obtain a white solid of N-bromophthalimide.

[0048] Reaction II: Add N-bromophthalimide obtained in Reaction I to aqueous sodium hydroxide solution (15.6g, 0.39mol NaOH dissolved in 100g water) in batches at -5°C to 0°C, After the solid was completely dissolved, it was raised to room temperature for 2 h.

[0049] Reaction Ⅲ: Add 50mL (0.36mol) of 50% sulfuric acid and 4.96g (0.048mol) of NaBr to the solution obtained in Reaction Ⅱ, cool down to -5°C to 0°C, and add dropwise 19.6g (0.098mol) of 17.1% peroxide Hydrogen aqueous solution, raised to room temperature to react for 12h after dropping, filtered, washed the solid with 2×25mL water, and dried to obtain 10.65g of white solid of 3,5-dibromo-2-aminobenzoic...

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Abstract

The invention discloses a preparation method of 3,5-dibromo-2-aminobenzoic acid. The preparation method comprises the following steps: (I) performing in-situ oxidation on bromide with an oxidant underan acidic condition, and carrying out a bromination reaction on phthalimide to obtain N-bromophthalimide; (II) performing Hoffmann degradation on the N-bromophthalimide under the action of alkali toobtain 2-aminobenzoic acid and bromoanion; (III) further adding an appropriate amount of bromide and oxidant, and carrying out a bromination reaction on the 2-aminobenzoic acid to obtain the product,namely, 3,5-dibromo-2-aminobenzoic acid. The preparation method has the advantages of environment-friendly reaction system, simple, convenient and safe reaction operation, low cost, high reaction selectivity and high product yield and the like.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a preparation method of 3,5-dibromo-2-aminobenzoic acid. Background technique [0002] Ambroxol hydrochloride, also known as bromhexol hydrochloride, is the active metabolite of bromhexine, an expectorant drug, and has the characteristics of high activity and low toxicity. The drug was launched in Germany in the eighties of the 20th century, and the market prospect is extremely broad. 3,5-dibromo-2-aminobenzoic acid is the key intermediate for the preparation of ambromide hydrochloride. The preparation technology of existing 3,5-dibromo-2-aminobenzoic acid is mainly with 2-aminobenzoic acid as raw material, with liquid bromine (CN106317016, CN103420975), tribromopyridinium salt (Green Chemistry, 2003,5(6 ), 701-703), N-bromosuccinimide (Tetrahedron Letters, 2010, 51(10), 1383-1385) or bromine formed by in situ redox reaction (i.e. sodium bromate, hydrogen peroxide and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/56
CPCC07C227/18C07C227/22C07D209/48C07C229/56
Inventor 肖孝辉王敏超罗虹林霞凌祠昌
Owner ZHEJIANG NORMAL UNIVERSITY
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