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Synthesis and impurity identification method of bromhexine hydrochloride process impurity positioning reference substance

A technology of bromhexine hydrochloride and process impurities, which is applied in the field of quality inspection of bromhexine hydrochloride, can solve the problem of lack of impurity positioning reference substances and impurity structure confirmation of process impurity by-products, difficulty in monitoring drug quality, and limited quality control of bromhexine hydrochloride. And other issues

Inactive Publication Date: 2020-12-04
JIANGSU YUNYANG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process impurity by-products produced during the synthesis of bromhexine hydrochloride lacks reference substances for impurity positioning and impurity structure confirmation, resulting in limited quality control of bromhexine hydrochloride and difficulty in monitoring drug quality

Method used

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  • Synthesis and impurity identification method of bromhexine hydrochloride process impurity positioning reference substance
  • Synthesis and impurity identification method of bromhexine hydrochloride process impurity positioning reference substance
  • Synthesis and impurity identification method of bromhexine hydrochloride process impurity positioning reference substance

Examples

Experimental program
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Effect test

Embodiment 1

[0017] A kind of synthetic method of bromhexine hydrochloride process impurity, its synthetic route is as follows:

[0018]

[0019] The specific synthesis steps are: add 50g of N-methylcyclohexylamine to the reaction flask, cool down to 10°C, add 100g of 2,4-dibromo-6-chloromethylaniline in batches and control the addition temperature to be less than or equal to 50°C until the Complete, keep the temperature at 45-50°C for stirring reaction for 3h, add 300ml of ethanol to continue stirring and keep the temperature at 45-50°C for 1h, filter while hot and collect the filtrate into the reaction bottle, add 200ml of ethanol and drop hydrochloric acid After adjusting the pH to 4, stir at room temperature for 12 hours, take the concentrated filtrate by suction filtration, separate the slightly viscous product by column chromatography, add acetonitrile to solidify, and dry to obtain N,N-bis(2-amino- 3,5-dibromophenyl)-N-methylcyclohexyl ammonium chloride 14g, as the impurity posit...

Embodiment 2

[0021] An identification method of bromhexine hydrochloride process impurities, its identification method is as follows: Synthesize N, N-di(2-amino-3,5-dibromophenyl)-N-methanol according to any one of the above synthetic methods Cyclohexyl ammonium chloride is used as a reference substance for positioning; when preparing bromhexine hydrochloride, the material obtained by column chromatography separation from the mother liquor is slightly viscous, solidified, filtered, and dried to obtain a light yellow solid process impurity sample. Resonance spectrum and liquid phase-mass spectrometry for qualitative analysis of positioning reference substances and process impurity samples:

[0022] When using Bruker AvanceⅢ400 nuclear magnetic resonance instrument for nuclear magnetic resonance spectrum analysis: deuterated methanol MeOD is used as the test solvent to prepare process impurity samples and place them in nuclear magnetic tubes; measurement temperature: room temperature 20-35 °C...

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Abstract

The invention relates to a synthesis and identification method of bromhexine hydrochloride process impurities, which comprises the following steps: reacting 2, 4-dibromo-6-chloromethylaniline with N-methylcyclohexylamine to synthesize N,N-di(2-amino 3, 5-dibromo phenyl)-N-methylcyclohexylammonium chloride as an impurity positioning reference substance for quality research of bromhexine hydrochloride; separating from bromhexine hydrochloride, curing, filtering and drying a sample, identifying the number of process impurities H, the characteristicsof a resonance peak and chemical shift through anuclear magnetic resonance spectrum and liquid chromatography-mass spectrometry analysis, and identifying isotope ion peaks of cation parts of the process impurities through liquid chromatography-mass spectrometry, and ensuring the molecular formula and the chemical structure of the impurity are consistent with those of a positioning reference substance, which is used for bromhexine hydrochloridequality control.

Description

technical field [0001] The invention relates to a method for synthesizing and identifying process impurities of bromhexine hydrochloride, and belongs to the technical field of bromhexine hydrochloride quality detection methods. Background technique [0002] Bromhexine hydrochloride can directly act on bronchial glands, promote the release of lysosomes of mucus-secreting cells, and differentiate and crack the sticky sugar fibers in sputum; it can also inhibit the synthesis of acid glycoproteins in mucous glands and goblet cells, Make it secrete low-viscosity small molecule glycoproteins, thereby reducing the viscosity of sputum and making it easy to cough up. It can also stimulate the gastric mucosa to reflexively increase the secretion of respiratory glands, dilute the sputum, and target bronchial Inflammation, asthma, emphysema and other drugs that are difficult to cough up with sticky phlegm. The process impurity by-products produced during the synthesis of bromhexine hyd...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/63C07C209/12G01N24/08G01N30/02
CPCC07C209/12G01N24/087G01N30/02C07C2601/14
Inventor 李贞奇董少华岳明邹翔黄岳王国华廖红剑郭兵吴豪
Owner JIANGSU YUNYANG PHARMA GRP
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