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Preparation method of bromhexine hydrochloride

A technology of bromhexine hydrochloride and bromhexine hydrochloride, applied in the field of pharmaceutical synthesis, can solve the problems of high requirements on reaction equipment, existence of safety risks, incomplete reaction and the like, and achieves the effects of less impurity content, easy operation and shortened reaction steps.

Inactive Publication Date: 2017-05-10
CHENGDU SINO STRONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the toluene water separation step of this route requires high-temperature reaction, and high-speed reaction equipment is required; at the same time, there is also the risk of incomplete reaction, and there is a safety risk in industrial production.

Method used

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  • Preparation method of bromhexine hydrochloride
  • Preparation method of bromhexine hydrochloride
  • Preparation method of bromhexine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The raw materials in this example are all commercially available. Dissolve 2.0g of 2-amino-3,5-dibromobenzaldehyde and 1.2g of N-methylcyclohexylamine in 20ml of methanol, slowly drop 4g of tetraisopropyl titanate into the reaction solution while stirring at room temperature After the addition, continue to stir at room temperature for 5 h; add 0.3 g of sodium borohydride to the reaction solution in batches, and stir for 2 h at room temperature. TLC detects that the reaction is complete. After the reaction was over, add 20ml of water to the reaction solution to quench the reaction, a large amount of solids were separated out, filtered, the filter cake was washed 3 times with ethyl acetate, the filtrate and washings were combined, extracted with ethyl acetate to obtain an organic phase, which was successively washed with sodium carbonate solution , and saturated brine to wash the organic phase.

[0033] At room temperature, under stirring conditions, 5ml of 6N hydrochlo...

Embodiment 2

[0035] The raw materials in this example are all commercially available. Dissolve 2.0g of 2-amino-3,5-dibromobenzaldehyde and 4g of N-methylcyclohexylamine in 20ml of methanol, slowly drop 2g of tetraisopropyl titanate into the reaction solution while stirring at 10°C After the addition, continue to stir and react at 10° C. for 5 h; add 0.3 g of sodium borohydride to the reaction liquid in batches, and stir and react at room temperature for 2 h. TLC detects that the reaction is complete. After the reaction was over, add 20ml of water to the reaction solution to quench the reaction, a large amount of solids were separated out, filtered, the filter cake was washed 3 times with ethyl acetate, the filtrate and washings were combined, extracted with ethyl acetate to obtain an organic phase, which was successively washed with sodium carbonate solution , and saturated brine to wash the organic phase.

[0036] Under the condition of stirring at 10°C, 10ml of 6N hydrochloric acid was...

Embodiment 3

[0038] The raw materials in this example are all commercially available. Dissolve 2.0g of 2-amino-3,5-dibromobenzaldehyde and 1.2g of N-methylcyclohexylamine in 20ml of isopropanol, and slowly drop 4g of tetraisopropyl titanate under stirring at 30°C Added to the reaction solution, after the addition, continued to stir at room temperature for 5 h; added 0.3 g of sodium borohydride to the reaction solution in batches, and stirred at 30° C. for 2 h. TLC detects that the reaction is complete. After the reaction was over, add 20ml of water to the reaction solution to quench the reaction, a large amount of solids were separated out, filtered, the filter cake was washed 3 times with ethyl acetate, the filtrate and washings were combined, extracted with ethyl acetate to obtain an organic phase, which was successively washed with sodium carbonate solution , and saturated brine to wash the organic phase.

[0039] Under the condition of stirring at 30°C, 5ml of 6N hydrochloric acid wa...

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Abstract

The invention provides a preparation method of bromhexine hydrochloride. The method comprises the steps that 2-amino-3, 5-dibromo-benzene and N-methyl cyclohexane are used as the raw material, and bromhexine hydrochloride is obtained after reductive amination and salification. The reaction process comprises the steps that the transient state is generated by the reaction in-situ of 2-amino-3, 5-dibromo-benzene and N-methyl cyclohexane, and N-methyl cyclohexane and titanate; the generated transient state and a reducing agent create a reduction reaction, and bromhexine free alkaili is generated; the bromhexine free alkaili is salified and bromhexine hydrochloride is prepared. The reaction steps of the bromhexine hydrochloride are reduced by the method, the process is simple, easy to operate, and the reaction condition is mild, the required raw materials are easily obtainable, and industrial production is facilitated; the bromhexine hydrochloride is good in yield, high in purity, less in impurity content, and the safety and the effectiveness of drugs are guaranteed.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of bromhexine hydrochloride. Background technique [0002] Bromhexine Hydrochloride (Bromhexine Hydrochloride, N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine hydrochloride) is a drug developed by Boehringer Ingelheim, used clinically It is used for the treatment of acute and chronic bronchitis, asthma, bronchiectasis, and emphysema, especially for those who have difficulty coughing up white sticky phlegm, and for shortness of breath caused by extensive obstruction of small bronchi by sputum. [0003] At present, there are many reports on the synthetic technique of bromhexine hydrochloride, and comprehensive literature analysis finds that the synthetic method of reported bromhexine hydrochloride includes the following, and its synthetic route is as follows: [0004] route one [0005] route two [0006] route three [0007] Most of th...

Claims

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Application Information

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IPC IPC(8): C07C211/52C07C209/28C07C209/00
CPCC07C209/28C07C209/00C07C211/52
Inventor 张善军关文捷李佳匡建明
Owner CHENGDU SINO STRONG PHARMA
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