Preparation method of ambroxol hydrochloride impurity reference substance

Abstract

The invention discloses a preparation method of an ambroxol hydrochloride impurity reference substance. The method comprises the following steps: firstly, dissolving ambroxol hydrochloride in an appropriate amount of dichloromethane solution, then adding a quantitative aqueous solution of sodium hydrogencarbonate for uniform stirring to obtain free ambroxol, separating, drying and concentrating the organic phase, dissolving the concentrated solution in the alcohol solution, then refluxing with excess orthoformate to obtain a crude product of (1R, 4R)-4-(6,8-dibromo-3,4-dihydroquinazoline)-cyclohexanol after condensation, and obtaining a pure product after the crude product is purified by silica gel column chromatography. The invention has the creative application of orthoformate as a condensing agent. Compared with other condensing agents reported in the literature, the orthoformate has the advantages such as good stability, high safety, low cost, high product yield and easy purification.

Description

technical field [0001] The present invention relates to chemical pharmaceutical field, be specifically related to a kind of preparation method of ambroxol hydrochloride impurity reference substance. Background technique [0002] Ambroxol Hydrochloride is an active product of bromhexine metabolized in vivo, and is mainly used as a mucolytic agent. It can increase the secretion of serous glands in the mucous membrane of the respiratory tract, reduce the formation of mucopolysaccharide fibers in sputum, reduce the viscosity of sputum, and thin the sputum, making it easy to cough up. It is widely used clinically in the treatment of acute and chronic respiratory diseases such as abnormal sputum secretion and poor expectoration function. It can also be used in the treatment of premature infants, neonatal respiratory distress syndrome and preventive treatment of surgical lung internal complications. Ambroxol hydrochloride, as a new generation mucolytic agent, is by far the most w...

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Problems solved by technology

According to relevant literature reports, this impurity is the degradation impurity of ambroxol hydrochloride, although relevant literature reports the synthetic method of this impurity at present, still there is experimental process complexity in synthetic process, a series of problems such as low experiment repetition rate

Disclosed a kind of preparation method of ambroxol hydrochloride impurity standard substance as Chinese patent CN106478524, the strong base solution such as sodium hydroxide adopted in this patent carries out ambroxol hydrochloride free, adopts formic acid ester as condensation agent simultaneously, at high temperature The impurity is synthesized at 80-100 degrees, but because the formate ester condensing agent is easily decomposed into formic acid and corresponding alcohols when heated in the presence of a catalytic amount of inorganic base, so it is not only necessary to ensure that the excess in the free process is fully removed during the experiment Inorganic strong base, to avoid being brought into the next condensation reaction, it is also necessary to ensure that the solvent and free ambroxol are anhydrous during the condensation process, the water in the solvent and a small amount of alkali during the reaction will cause the condensation agent Decompose rapidly under the environment, so the reaction conditions are relatively harsh and the repetition rate is low

At the same time, the formate condensing agent used in this patent generally has low boiling point (n-propyl formate boiling point 81.3 degrees, isopropyl formate boiling point 70.8 degrees) and other problems, and the reaction temperature described in this patent often needs 80-100 Therefore, the risk of the experiment is greatly increased; therefore, it is of great significance to find a method for this impurity that has a simple synthesis method, easy-to-obtain raw materials, high yield, and safe production process.

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