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Production method of bromhexine hydrochloride

A technology of bromhexine hydrochloride and a production method, applied in the production field of bromhexine hydrochloride, can solve the problems of difficult to scale up production and high equipment requirements, and achieve the effects of less generation of by-products, low raw material requirements, and few reaction steps

Active Publication Date: 2013-11-20
江西亿友药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This condition requires high equipment, and it is not easy to scale up production

Method used

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  • Production method of bromhexine hydrochloride
  • Production method of bromhexine hydrochloride
  • Production method of bromhexine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0029] 1. Synthesis of 3,5-dibromo-2-aminobenzyl alcohol (II)

[0030] Add 220Kg of polyethylene glycol 400 to the reaction kettle, add 25Kg of 3,5-dibromo-2-aminobenzoic acid methyl ester, stir and mix well, add 9Kg of sodium borohydride, heat up to 70°C, and stir for 5 hours . After cooling to room temperature, the reaction solution was diluted with 5 times the volume of water, and an off-white solid was precipitated. Shake the filter, and wash the filter cake with water until neutral. Dry off-white solid 3,5-dibromo-2-aminobenzyl alcohol (II): 20Kg, yield 88%.

[0031] 2. Synthesis of bromhexine hydrochloride (III)

[0032] Add 25Kg of N-methylcyclohexylamine into the reaction kettle, add 20Kg of 3,5-dibromo-2-aminobenzyl alcohol under stirring, then add 11Kg of acetic acid, and heat up to reflux for 10 hours. Cool to room temperature, dilute with water while stirring, then add hydrochloric acid and ethyl acetate. Stir, spin filter, wash the filter cake with water, the...

Embodiment 2

[0036] 1. Synthesis of 3,5-dibromo-2-aminobenzyl alcohol (II)

[0037] Add 220Kg of polyethylene glycol 400 to the reaction kettle, add 25Kg of 3,5-dibromo-2-aminobenzoic acid methyl ester, stir and mix well, add 9Kg of sodium borohydride, heat up to 70°C, and stir for 5 hours . After cooling to room temperature, the reaction solution was diluted with water, and an off-white solid was precipitated. Shake the filter, and wash the filter cake with water until neutral. Dry off-white solid 3,5-dibromo-2-aminobenzyl alcohol (II): 20.2Kg, yield 88.9%.

[0038] 2. Synthesis of bromhexine hydrochloride (III)

[0039] Add 25Kg of N-methylcyclohexylamine into the reaction kettle, add 20.2Kg of 3,5-dibromo-2-aminobenzyl alcohol under stirring, then add 11Kg of acetic acid, and heat up to reflux for 10 hours. Cool to room temperature, dilute with water while stirring, then add hydrochloric acid and ethyl acetate. Stir, shake and filter, wash the filter cake with water, wash with acet...

Embodiment 3

[0043] 1. Synthesis of 3,5-dibromo-2-aminobenzyl alcohol (II)

[0044] Add 220Kg of polyethylene glycol 400 into the reaction kettle, add 25Kg of 3,5-dibromo-2-aminobenzoic acid methyl ester, stir and mix, add potassium borohydride 9.5Kg, heat up to 70°C, and stir for 5 Hour. After cooling to room temperature, the reaction solution was diluted with water, and an off-white solid was precipitated. Shake the filter, and wash the filter cake with water until neutral. Dry off-white solid 3,5-dibromo-2-aminobenzyl alcohol (II): 19.7Kg, yield 86.7%.

[0045] 2. Synthesis of bromhexine hydrochloride (III)

[0046] Add 25Kg of N-methylcyclohexylamine into the reaction kettle, add 19.7Kg of 3,5-dibromo-2-aminobenzyl alcohol under stirring, then add 11Kg of acetic acid, and heat up to reflux for 10 hours. Cool to room temperature, dilute with water while stirring, then add hydrochloric acid and ethyl acetate. Stir, spin filter, wash the filter cake with water, then with ethyl acetat...

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Abstract

The invention discloses a production method of bromhexine hydrochloride; 3,5-dibromo-2-amino benzoic acid methyl ester is used as a starting raw material, polyethylene glycol 400 is used as a solvent, 3,5-dibromo-2-amino benzalcohol is obtained by reduction using sodium borohydride or potassium borohydride, bromhexine is obtained by a condensation reaction of the 3,5-dibromo-2-amino benzalcoho and N-methyl cyclohexylamine under the effect of acetic acid, then a crude product of bromhexine hydrochloride is obtained through direct salt forming with hydrochloric acid, and finally a bromhexine hydrochloride fine product is obtained through refining with methanol. Compared with production processes in the prior art, the production method of the bromhexine hydrochloride has the advantages of few reaction steps, convenient refining, simple operation and good quality of products.

Description

technical field [0001] The invention relates to a preparation method of mucophlegm dissolving agent medicine, in particular to a production method of bromhexine hydrochloride. Background technique [0002] Bromhexine hydrochloride was developed by Boehringer Ingelheim in Germany in the last century, and it was also listed in my country in the 1970s. It has been included in the pharmacopoeias of China, Europe, Japan and other countries. [0003] The chemical name of bromhexine hydrochloride is N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine hydrochloride, and the structure is as follows: [0004] [0005] Bromhexine hydrochloride is a mucolytic agent that can directly act on the bronchial glands to promote the release of lysosomes in mucus-secreting cells, which can differentiate and lyse mucopolysaccharide fibers in sputum, dilute the sputum, and make it easier to cough up. Clinically, it is mainly used for acute and chronic bronchitis, asthma, bronchiectasis, and e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/52C07C209/60
Inventor 童元峰杨庆云张嵩张对良
Owner 江西亿友药业有限公司
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