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Preparation method for ambroxol hydrochloride intermediate 3,5-dibromo-2-aminobenzoic acid

A technology of aminobenzoic acid and ammonium bromide hydrochloride, which is applied in the field of preparation of ammonium bromide hydrochloride intermediate 3,5-dibromo-2-aminobenzoic acid, can solve the problems of large environmental pollution and high production cost, and achieve environmental protection Friendly, low production cost, low solubility effect

Inactive Publication Date: 2018-12-28
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Existing methods all use 2-aminobenzoic acid as a starting material, and the preparation of 2-aminobenzoic acid often starts from toluene, and is obtained through multi-step processes such as nitration, separation of ortho-para nitration products, oxidation, reduction, etc., and the production cost is low. High, environmental pollution

Method used

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  • Preparation method for ambroxol hydrochloride intermediate 3,5-dibromo-2-aminobenzoic acid
  • Preparation method for ambroxol hydrochloride intermediate 3,5-dibromo-2-aminobenzoic acid

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Embodiment 1

[0033] At room temperature, dissolve 6.0g (0.041mol) of phthalimide and 15.6g (0.39mol) of NaOH into 80g of water, cool down to -5-0°C, add 2.4mL (0.047mol) of liquid bromine dropwise, and Insulate and react at -5~0°C for 30 minutes. Raise the temperature of the reaction system to 70°C and keep it warm for 5-10 minutes, cool to room temperature, add 50mL (0.36mol) of 50% sulfuric acid dropwise, cool down to -5-0°C, add 9.6g (0.099mol) of 35% hydrogen peroxide dropwise, and The reaction was incubated at -5~0°C for 1 h, and then raised to room temperature to continue the reaction for 11 h. Filtration, the solid was washed with 2×30mL H 2 O was washed and dried to obtain 10.9 g of 3,5-dibromo-2-aminobenzoic acid light yellow solid with a yield of 90.8%.

Embodiment 2

[0035] At room temperature, dissolve 6.0g (0.041mol) of phthalimide and 22.2g (0.39mol) of KOH into 80g of water, cool down to -5-0°C, add 2.4mL (0.047mol) of liquid bromine dropwise, and Insulate and react at -5~0°C for 30 minutes. Raise the temperature of the reaction system to 70°C and keep it warm for 5-10 minutes, cool to room temperature, add 50mL (0.36mol) of 50% sulfuric acid dropwise, cool down to -5-0°C, add 9.6g (0.099mol) of 35% hydrogen peroxide dropwise, and Insulate and react at -5~0°C for 1 h, then rise to room temperature and continue to react for 12 h. After filtration, the solid was washed with 2×30 mL H2O, and dried to obtain 10.7 g of 3,5-dibromo-2-aminobenzoic acid as a pale yellow solid, with a yield of 89.2%.

Embodiment 3

[0037] At room temperature, dissolve 6.0g (0.041mol) of phthalimide and 15.6g (0.39mol) of NaOH into 80g of water, cool down to -5~0°C, add 2.2mL (0.043mol) of liquid bromine dropwise, and Insulate and react at -5~0°C for 30 minutes. Raise the temperature of the reaction system to 70°C and keep it warm for 5-10 minutes, cool to room temperature, add 50mL (0.36mol) of 50% sulfuric acid dropwise, cool down to -5-0°C, add 9.6g (0.099mol) of 35% hydrogen peroxide dropwise, and Insulate the reaction at -5~0°C for 1 h, then rise to room temperature and continue the reaction for 10 h. After filtration, the solid was washed with 2×30 mL H2O, and dried to obtain 10.2 g of 3,5-dibromo-2-aminobenzoic acid as a pale yellow solid, with a yield of 85.0%.

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Abstract

The invention discloses a preparation method for an ambroxol hydrochloride intermediate 3,5-dibromo-2-aminobenzoic acid. The method enables the ambroxol hydrochloride intermediate 3,5-dibromo-2-aminobenzoic acid to be obtained through the following two-step reaction: (1) under the action of alkali and bromine, phthalimide undergoes the Hofmann degradation reaction to obtain 2-amino-benzoate and bromine anion; (2) under acidic conditions, the bromine anion is oxidized in situ to be bromine by hydrogen peroxide, and the bromine further undergoes electrophilic substitution reaction on an aromaticring with 2-aminobenzoic acid to obtain the 3,5-dibromo-2-aminobenzoic acid. The method takes phthalic acid imine as an initiating raw material, the raw material is cheap and easy to obtain, and a production process for the raw material is also more environmentally friendly and saves more energy.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a preparation method of ambromide hydrochloride intermediate 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. [0003] 3,5-dibromo-2-aminobenzoic acid is the key intermediate for the preparation of ambromide hydrochloride. Existing preparation technology has: one, take 2-aminobenzoic acid as raw material, take liquid bromine as bromination reagent [CN106317016, CN103420975]; The bromine formed by the in-situ oxidation of bromide anion is the bromide [Journal of the American Chemical Society, 1903, 25, 935-947; Journal of Chemical Research, Synopses, 1984, 12,...

Claims

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Application Information

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IPC IPC(8): C07C229/56C07C227/16C07C227/12
CPCC07C227/12C07C227/16C07C229/56
Inventor 肖孝辉王敏超罗虹
Owner ZHEJIANG NORMAL UNIVERSITY
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