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Synthesis method of ambroxol hydrochloride

A technology of ambroxol hydrochloride and a synthetic method, applied in the field of drug synthesis, can solve problems such as increased risk, many side reactions, and increased cost, and achieve the effects of simplifying production process, low product cost, and improving yield

Active Publication Date: 2015-07-22
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Although the raw materials of this route are easy to obtain, there are many side reactions when the final product is synthesized, the product has poor purity and low yield, and is not suitable for large-scale production
[0014] In the preparation method of ambroxol hydrochloride disclosed by CN103012167A, with 2-amino-3,5-dibromobenzaldehyde and trans-4-aminocyclohexanol as raw materials, adopt "one pot method" to carry out, although the route is operated Simple, short reaction time, but using lithium aluminum hydride or sodium borohydride to carry out the reduction reaction increases the risk of the reaction and increases the cost, so it is not suitable for industrial production
Although the method reaction route is shorter, the reaction time is longer, and the use of sodium borohydride aqueous solution increases the risk of reaction

Method used

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  • Synthesis method of ambroxol hydrochloride
  • Synthesis method of ambroxol hydrochloride
  • Synthesis method of ambroxol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Add 20g of o-nitrobenzaldehyde and 50ml of methanol into the reaction flask in turn, stir, and add 23.26g of bromine dropwise while keeping the temperature at 40°C. After the dropwise addition, continue to react at this temperature for 3h. Filtration, the filter cake was recrystallized with methanol, and dried to obtain 39.37g of compound IV, with a yield of 96.5%;

[0035] (2) Add 30.89g of compound IV obtained in step (1), 12.67g of trans-4-aminocyclohexanol and 308.9ml of toluene into the reaction flask in sequence, stir, heat up to reflux, and react for 5h. After the reaction, cool down , crystallized at 3°C ​​for 1h, filtered, washed with toluene, and dried in vacuo at 50°C to obtain 40.16g of compound III, with a yield of 98.9%;

[0036] (3) Add 38.00g of compound III obtained in step (2), 380ml of methanol and 0.38g of catalyst Pd / C into the autoclave. After ventilation, fill with hydrogen to a pressure of 25kg, raise the temperature to 70°C, and keep stirrin...

Embodiment 2

[0039] (1) Add 20g of o-nitrobenzaldehyde and 50ml of methanol into the reaction flask in turn, stir, and add 23.26g of bromine dropwise while keeping the temperature at 50°C. After the dropwise addition, continue to react at this temperature for 3 hours. After filtration, the filter cake was recrystallized with methanol, and dried to obtain 39.41 g of compound IV, with a yield of 96.6%;

[0040] (2) Add 30.89g of compound IV obtained in step (1), 17.28g of trans-4-aminocyclohexanol and 308.9ml of toluene into the reaction flask in sequence, stir, heat up to reflux, and react for 3h. After the reaction, cool down , crystallized at 3°C ​​for 1h, filtered, washed with toluene, and dried in vacuo at 50°C to obtain 40.20g of compound III, with a yield of 99.0%;

[0041] (3) Add 38.00g of compound III obtained in step (2), 380ml of ethanol and 0.38g of catalyst Pd / C into the autoclave. After ventilation, fill with hydrogen to a pressure of 25kg, raise the temperature to 70°C, and k...

Embodiment 3

[0044] (1) Add 20g of o-nitrobenzaldehyde and 50ml of methanol into the reaction flask in turn, stir, and add 23.26g of bromine dropwise while keeping the temperature at 20°C. After the dropwise addition, continue to react at this temperature for 3 hours. Filtration, the filter cake was recrystallized with methanol, and dried to obtain 38.57g of compound IV, with a yield of 94.6%;

[0045] (2) Add 30.89g of compound IV obtained in step (1), 14.97g of trans-4-aminocyclohexanol and 308.9ml of toluene into the reaction flask in turn, stir, heat up to reflux, and react for 8h. After the reaction is completed, cool down , crystallized at 3°C ​​for 1 h, filtered, washed with toluene, and dried the solid under vacuum at 50°C to obtain 39.73g of compound III, with a yield of 97.8%;

[0046] (3) Add 38.00g of compound III obtained in step (2), 380ml of isopropanol and 0.38g of catalyst Pd / C into the autoclave. After ventilation, fill with hydrogen to a pressure of 25kg, raise the tempe...

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Abstract

The invention belongs to the field of pharmaceutical synthesis and particularly discloses a synthesis method of ambroxol hydrochloride. The synthesis method comprises the steps of brominating o-nitrobenzaldehyde serving as a starting raw material to obtain 2-nitro-3, 5-dibromobenzaldehyde; reacting the obtained 2-nitro-3, 5-dibromobenzaldehyde and trans-4-aminocyclohexanol; and then, reducing and salifying hydrochloride to finally prepare ambroxol hydrochloride. The synthesis method disclosed by the invention is low in raw material cost, simple in operation, safe and environment-friendly, capable of simplifying the production process and increasing the yield and purity of products and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, in particular to a synthesis method of ambroxol hydrochloride. technical background [0002] Ambroxol hydrochloride (CAS: 23828-92-4), chemical name: trans-4-[(2-amino-3.5-dibromobenzyl) amino] cyclohexanol hydrochloride, English name: Ambroxol Hydrochloride, Its chemical structural formula is as follows: [0003] . [0004] Ambroxol hydrochloride was developed by the German Boehritl geritlgelhein company and first listed in 1984. Ambroxol hydrochloride has the characteristics of promoting mucus elimination and dissolving secretions. It can promote the elimination of viscous secretions in the respiratory tract and reduce the retention of mucus. , thus significantly promoting expectoration and improving respiratory conditions. Now it has become a good expectorant new drug approved by many countries in the world. [0005] The synthetic method of ambroxol hydrochloride has been reported multi...

Claims

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Application Information

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IPC IPC(8): C07C215/44C07C213/02C07C213/08
Inventor 张颖刘元鑫宋柱文朱玉正高国锐
Owner JINAN KANGHE MEDICAL TECH
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