Preparation method of ambroxol hydrochloride impurity reference substance

A technology of ambroxol hydrochloride and impurity reference substances, which is applied in the field of preparation of ambroxol hydrochloride impurity reference substances, can solve the problems of increased risk, low repetition rate, and harsh reaction conditions, so as to reduce experimental risks and increase safety , The effect of stable yield

Active Publication Date: 2018-12-21
SHANGLUO UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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 du

Method used

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  • Preparation method of ambroxol hydrochloride impurity reference substance
  • Preparation method of ambroxol hydrochloride impurity reference substance
  • Preparation method of ambroxol hydrochloride impurity reference substance

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A kind of preparation method of ambroxol hydrochloride impurity reference substance, concrete steps are as follows: first, 1g ambroxol hydrochloride is dissolved in the dichloromethane solvent of 10mL, adds 0.6g saturated sodium bicarbonate solution and pH is adjusted to slightly alkaline , extracted with dichloromethane, the organic phase was concentrated and dried, and then the concentrated solution was dissolved by adding 10 mL of ethanol, then added 715 mg of triethyl orthoformate and reacted at 80°C for 8 hours, and the reaction was detected by TLC thin-layer chromatography. When hydrochloric acid After the ambroxol raw material disappeared completely, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a white solid, which was purified by silica gel column chromatography to obtain (1R, 4R)-4-(6,8-dibromo -3,4-dihydroquinazoline)-cyclohexanol pure product 900mg, yield 96.14%, purity 99.3%.

[0028...

Embodiment 2

[0031] A kind of preparation method of ambroxol hydrochloride impurity reference substance, concrete steps are as follows: first, 0.5g ambroxol hydrochloride is dissolved in the dichloromethane solvent of 8mL, adds 0.3g saturated sodium bicarbonate solution and pH is adjusted to weak base nature, extracted with dichloromethane, concentrated and dried the organic phase, then added 5mL of ethanol to the concentrated solution to dissolve, then added 256mg of trimethyl orthoformate and reacted at 60°C for 8 hours. The reaction was detected by TLC thin-layer chromatography. After the ambroxol raw material disappeared completely, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a white solid, which was purified by silica gel column chromatography to obtain (1R, 4R)-4-(6,8-dibromo -3,4-dihydroquinazoline)-cyclohexanol pure product 430mg, yield 97.86%, purity 99.0%.

Embodiment 3

[0033] A kind of preparation method of ambroxol hydrochloride impurity reference substance, concrete steps are as follows: first, 1g ambroxol hydrochloride is dissolved in the dichloromethane solvent of 5mL, adds 0.6g saturated sodium bicarbonate solution and pH is adjusted to slightly alkaline , extracted with dichloromethane, the organic phase was concentrated and dried, then the concentrated solution was dissolved by adding 5mL of ethanol, and then added 358mg of triethyl orthoformate and reacted at 70°C for 8 hours, and the reaction was detected by TLC thin-layer chromatography. After the bromoxol raw material completely disappeared, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a white solid, which was purified by silica gel column chromatography to obtain (1R,4R)-4-(6,8-dibromo- 849 mg of pure 3,4-dihydroquinazoline)-cyclohexanol, with a yield of 96.69% and a purity of 99.1%.

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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...

Claims

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Application Information

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IPC IPC(8): G01N1/28G01N30/06
CPCG01N1/28G01N30/06
Inventor 宋月红
Owner SHANGLUO UNIV
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