Production method of bromhexine hydrochloride

Abstract

The invention relates to a production method of bromhexine hydrochloride. The production method is characterized by comprising the following steps of: 1) carrying out a condensation reaction between 3,5-dibromo-2-aminobenzalcohol and N-methyl cyclohexane in the presence of glacial acetic acid as a catalyst, thereby generating N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine; 2) salifying the generated N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine with hydrochloric acid to obtain bromhexine hydrochloride; and 3) decoloring and refining the obtained bromhexine hydrochloride in an alcoholic solution to obtain a pure product, wherein an azeotropic water-carrying agent is added to the condensation reaction in the step 1), and water in the reaction mixed solution in the reaction process is removed immediately through distillation.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a production method of bromhexine hydrochloride, an expectorant. Background technique [0002] Bromhexine hydrochloride, alias bromhexine hydrochloride, bisoping, bixiaophlegm, bromhexine hydrochloride, English name is Bromhexine Hydrochloride, chemical name is N-methyl-N-cyclohexyl-2-amino-3, 5-Dibromobenzylamine hydrochloride, molecular formula: C 14 h 20 Br 2 N 2 ·HCl, molecular weight: 412.60, structural formula: [0003] [0004] Bromhexine hydrochloride is a commonly used expectorant at home and abroad. It has a strong mucolytic effect, can decompose and break polysaccharides and cellulose in sputum, inhibit the synthesis of acidic mucopolysaccharide proteins, reduce sputum viscosity, and facilitate coughing. It is clinically suitable for patients with chronic bronchitis, asthma, bronchiectasis, silicosis and other diseases with sticky phlegm that is di...

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Problems solved by technology

[0007] In order to improve the quality stability of bromhexine hydrochloride and improve the safety and effectiveness of medication for patients, the patent CN102775316A adopts the method of decolorizing in a mixed solvent of ethanol and n-butanol, and cooling and crystallizing after adding acetonitrile aqueous solution to the filtrate, with a yield of 87 ~ 90%, content 99.5 ~ 90.8%, and the obtained new crystals are combined with excipients such as mannitol and pH regulators such as citric acid to improve the quality stability of bromhexine hydrochloride. The above method adopts mixed solvent decolorization and Adding a special solvent, acetonitrile, for crystallization brings difficulties in solvent recovery and treatment; patent CN 102924295A uses a method of crystallization with an alcohol solvent with a water content of more than 30%, the recovery rate is greater than 60%, the optimal condition can reach more than 80%, and the product purity reaches 99.8% More than, the new crystalline crystal stability that obtains and the solubility in water are better than the crystal form that prior art produces, help to prepare bromhexine hydrochloride injection dosage form, but this method recovery rate is on the low side, has increased mother liquor treatment quantity and Difficulty; recently published patent CN103145564A adopts decolorization in ethanol and methanol mixed solvent, and cools and crystallizes after adding dropwise acetone aqueous solution in the filtrate, and there is also the problem of difficult recovery and low recovery rate of a large amount of mixed solvent

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