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Preparation method of ambroxol hydrochloride

A technology of ambroxol hydrochloride and salt formation, which is applied in the field of drug synthesis, can solve the problems of industrial equipment corrosion, high risk, and increased risk, and achieve the effects of reduced service life, simple reaction steps, and improved utilization

Active Publication Date: 2020-04-28
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This method uses LiAlH 4 Reduction reaction, high risk; when molecular bromine is used as bromination reagent, the theoretical utilization rate of molecular bromine in the reaction process is only 50%, which is a waste of resources in terms of industrial production, and the other half of molecular bromine is in the reaction process Corrosive hydrogen bromide is generated in the process, which causes serious corrosion to industrial equipment and greatly reduces the service life of industrial equipment, which is not conducive to large-scale production
[0015] 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 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

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0034] Embodiment 1: the synthesis of compound 3

[0035] Dissolve 50mmol (7.556g) of o-nitrobenzaldehyde, 60mmol of ethylene glycol, and 0.25mmol of p-toluenesulfonic acid monohydrate in 100mL of toluene, heat to reflux for 1.5h, and separate water with a Dean-Stark separator. After the reaction, the solution Rotary evaporate, add 100mL of ethyl acetate to dissolve, wash with 50mL of sodium bicarbonate aqueous solution twice, and dry to obtain the crude product. Dissolve the crude product in 100mL THF, then add the catalyst 1g NiCoB / TiO 2 , 7g of hydrazine hydrate, under the protection of nitrogen, start stirring, raise the temperature to 50-55°C, react for 90min, and monitor the reaction progress by TLC. After the reaction, the catalyst was filtered, the solvent was removed by rotary evaporation, 50 mL of diethyl ether was added to stir and crystallize for 20 min, and 7.815 g of compound 3 was obtained after suction filtration and drying, with a yield of 94.50% and a purity...

Embodiment 2

[0036] Embodiment 2: the synthesis of compound 3

[0037] Dissolve 50mmol (7.556g) of o-nitrobenzaldehyde, 50mmol of ethylene glycol, and 0.1mmol of p-toluenesulfonic acid monohydrate in 100mL of toluene, heat to reflux for 1.5h, and separate water with a Dean-Stark separator. After the reaction is complete, the solution Rotary evaporate, add 100mL of ethyl acetate to dissolve, wash with 50mL of sodium bicarbonate aqueous solution twice, and dry to obtain the crude product. Dissolve the crude product in 100mL THF, then add the catalyst 1g NiCoB / TiO 2 , 7g of hydrazine hydrate, under the protection of nitrogen, start stirring, raise the temperature to 50-55°C, react for 90min, and monitor the reaction progress by TLC. After the reaction, the catalyst was filtered, the solvent was removed by rotary evaporation, 50 mL of diethyl ether was added to stir and crystallize for 20 min, and 7.339 g of compound 3 was obtained after suction filtration and drying, with a yield of 88.24% a...

Embodiment 3

[0038] Embodiment 3: the synthesis of compound 3

[0039] Dissolve 50mmol (7.556g) of o-nitrobenzaldehyde, 70mmol of ethylene glycol, and 0.4mmol of p-toluenesulfonic acid monohydrate in 100mL of toluene, heat to reflux for 1.5h, and separate the water with a Dean-Stark separator. After the reaction, the solution Rotary evaporate, add 100mL of ethyl acetate to dissolve, wash with 50mL of sodium bicarbonate aqueous solution twice, and dry to obtain the crude product. Dissolve the crude product in 100mL THF, then add the catalyst 1g NiCoB / TiO 2 , 7g of hydrazine hydrate, under the protection of nitrogen, start stirring, raise the temperature to 50-55°C, react for 90min, and monitor the reaction progress by TLC. After the reaction, the catalyst was filtered, the solvent was removed by rotary evaporation, 50 mL of diethyl ether was added to stir and crystallize for 20 min, and 7.352 g of compound 3 was obtained after suction filtration and drying, with a yield of 89.36% and a pur...

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Abstract

The invention relates to a preparation method of ambroxol hydrochloride, and the method comprises the following steps: carrying out aldehyde group protection on o-nitrobenzaldehyde, and reducing hydrazine hydrate in the presence of a catalyst NiCoB / TiO2 to obtain a compound 3; carrying out bromination reaction on the compound 3 under the action of molecular bromine and hydrogen peroxide, and carrying out deprotection to generate a compound 2; and carrying out aldehyde reductive amination reaction with trans-4-aminocyclohexanol under the action of catalysts NaBH (OAc) 3 and LiClO4, and salifying to obtain the ambroxol hydrochloride. The method has the advantages of mild conditions, simple steps, environmental friendliness, easily stored raw materials and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of ambroxol hydrochloride. Background technique [0002] Ambroxol hydrochloride, the chemical name is: trans-4-[(2-amino-3,5-dibromobenzyl) amino]-cyclohexanol hydrochloride, the chemical structure is: [0003] [0004] Ambroxol hydrochloride is a mucolytic agent developed by Boehringer Ingelheim, Germany. It is used for the expectorant treatment of various acute and chronic respiratory diseases accompanied by abnormal sputum secretion and poor expectoration function. low merit. Ambroxol hydrochloride can act on secretory cells, regulate the secretion of serous and mucus, increase the secretion of serous, dissolve and dilute mucus, strengthen the swing of cilia, increase the removal ability of mucus transport system, and make sputum easy to discharge. [0005] Ambroxol hydrochloride is also a protective agent for the respiratory system, which has the functi...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C213/08C07C215/44C07C221/00C07C223/06C07D317/28
CPCC07C213/02C07C213/08C07C221/00C07D317/28C07C2601/14C07B2200/07C07C215/44C07C223/06
Inventor 孙松曹传镇周燕朱玉青徐桂超
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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