Preparation method of ambroxol hydrochloride impurity

A quality and salt-forming technology, which is applied in the field of preparation of ambroxol hydrochloride impurities, achieves the effects of high yield, real operation and few reaction steps

Inactive Publication Date: 2021-06-15
北京新康哌森医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] During the clinical process, it was found that ambroxol hydrochloride is usually well tolerated, but there are also very few adverse reactions, such as gastrointestinal side effects, allergic reactions, and rare acute allergic symptoms

Method used

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  • Preparation method of ambroxol hydrochloride impurity
  • Preparation method of ambroxol hydrochloride impurity
  • Preparation method of ambroxol hydrochloride impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1, the synthesis of AXS-13-01

[0074]

[0075] The specific steps are as follows: First, 10g (0.024mol) of ambroxol hydrochloride was dissolved in 100mL of dichloromethane solvent, 7.23g (0.072mol) of triethylamine was added, 0.29g (0.0024mol) of DMAP was stirred at room temperature for 30min, and then added 5.4g (0.036mol) TBSCl, be warming up to 40 ℃, stir 5 hours, TLC thin-layer chromatographic plate monitors (add DCM to dilute, developer: DCM:MeOH=20:1), treat that ambroxol hydrochloride raw material basically reacts, The reaction solution was lowered to room temperature, added water, stirred for 10 minutes, separated, the organic phase was washed with brine, dried and spin-dried, and purified by wet silica gel column chromatography to obtain the product, AXS-13-01, colorless oil, 10g, HPLC Purity: 99.20%, yield 85%.

Embodiment 2

[0076] Embodiment 2, the synthesis of AXS-13-02

[0077]

[0078] The specific steps are as follows: First, add 10g (0.02mol) AXS-13-01 to 50mL acetonitrile, add 5.26g (0.041mol) DIEA, 1.69g (0.010mol) KI, then dropwise add 4.4g (0.022mol) bromine Tert-butyl acetate, dropwise, warming up to reflux and stirring for 8 hours, TLC thin-layer chromatographic plate monitoring (adding DCM for dilution, developer: PE:EA=1:1) reaction, when the AXS-13-01 raw material completely disappeared The reaction solution was lowered to room temperature, added water and EA, stirred for 10 min, separated, the organic phase was washed with brine, dried and spin-dried, wet silica gel column chromatography, PE: EA = 50: 1, washed out the product, enriched and concentrated to obtain AXS -13-02, yellow oil, 9g, HPLC purity: 98.82%, yield 73%.

Embodiment 3

[0079] Embodiment 3, the synthesis of AXS-13-03

[0080]

[0081] The specific steps are as follows: 9g (0.015mol) AXS-13-02 was added to 90mL THF, 2.5g (0.023mol) t-BuOK was added in batches, stirred at room temperature for 2 hours, and monitored by TLC thin layer chromatography (adding water and EA , take the EA phase, developing agent: PE:EA=2:1), the reaction of the raw material AXS-13-02 is completed. Add saturated ammonium chloride and EA, stir for 10min, separate the layers, wash the organic phase with brine, dry and spin dry to obtain AXS-13-03, yellow solid, 7.64g, HPLC purity: 96.37%, yield 96%, its mass spectrum is as follows: Figure 4 shown.

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Abstract

The invention discloses a preparation method of an ambroxol hydrochloride impurity reference substance. With ambroxol hydrochloride as a raw material, the ambroxol impurity AXS-13 is obtained through hydroxyl protection, amine alkylation, cyclization, carbonyl reduction, deprotection and other reactions. A basis is provided for research of ambroxol hydrochloride related substances. The method is simple, raw materials are easy to obtain, the product is easy to purify, the yield and the purity are high, and the product can be used as a reference substance in impurity detection.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a method for preparing ambroxol hydrochloride impurities. Background technique [0002] Ambroxol Hydrochloride is an active product of bromhexine metabolized in the body and is mainly used as a mucolytic agent. It can increase the secretion of serous glands in the respiratory mucosa, 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 widely used expectorant drug. [0003] During the clinical proc...

Claims

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Application Information

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IPC IPC(8): C07D243/14C07F7/18
CPCC07D243/14C07F7/1804C07F7/188Y02P20/55
Inventor 郑祖爽梁飞宋启义赵国伟刘玉平
Owner 北京新康哌森医药科技有限公司
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