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Preparation method of bromhexine hydrochloride

A technology of bromhexine hydrochloride and salt-forming reaction, which is applied in the preparation of organic compounds, preparation of amino compounds, chemical instruments and methods, etc., can solve the problems of large environmental pollution, easy decomposition, and demand, and achieve low environmental pollution and high product quality. The effect of high purity and simple steps

Pending Publication Date: 2020-07-31
INCREASEPHARM TIANJIN INST CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This preparation method uses a large amount of thionyl chloride, and thionyl chloride is not only used as a reactant but also as a reaction solvent, which is relatively polluting to the environment, and 2,4-dibromo-6-chloromethylaniline is extremely unstable and easily Decomposition; and this reaction also needs petroleum ether crystallization steps, not only increases the operation steps, and petroleum ether is also a flammable and explosive solvent that is taboo in industrial production, and in actual large-scale production, material loss is also considerable, so The operation is not suitable for mass production

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0066] Example 1 Bromhexine Hydrochloride Pilot Synthesis Experiment and Purification

[0067] Add 450g of 2-amino-3,5-dibromobenzaldehyde into 1.8kg of absolute ethanol and stir thoroughly. Control the temperature below 30°C and add 25g of sodium borohydride in batches, and stir at room temperature for 1 hour. Adjust the pH to 6-7 with hydrochloric acid, filter, add the filter cake to 1.8 kg of tetrahydrofuran to dissolve, dry to remove water, filter, and store the filtrate temporarily.

[0068] Add 356g of thionyl chloride and 2kg of tetrahydrofuran into another 5L reaction flask, and stir evenly. The temperature is controlled below 30°C, and the above filtrate is added dropwise to the system. After the dropwise addition was completed, the reaction was carried out at room temperature for 1 hour, and the system was concentrated under reduced pressure to remove tetrahydrofuran. After the concentration was complete, 2.7 kg of dichloromethane was added to the residue and stir...

Embodiment 2

[0073] Embodiment 2 bromhexine hydrochloride industrialized production and industrialized purification

[0074] Add 4.5kg of 2-amino-3,5-dibromobenzaldehyde into 18kg of absolute ethanol and stir thoroughly. Control the temperature below 30°C and add 0.25 kg of sodium borohydride in batches, and stir at room temperature for 1 hour. Adjust the pH to 6-7 with hydrochloric acid, filter, add the filter cake to 18 kg of tetrahydrofuran to dissolve, dry to remove water, filter, and store the filtrate temporarily.

[0075] Add 3.56kg of thionyl chloride and 20kg of tetrahydrofuran into another 100L reactor, and stir evenly. The temperature is controlled below 30°C, and the above filtrate is added dropwise to the system. After the dropwise addition was completed, the reaction was carried out at room temperature for 1 hour, and the system was concentrated under reduced pressure to remove tetrahydrofuran. After the concentration was complete, 27 kg of dichloromethane was added to the...

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a bromhexine hydrochloride synthesis method. The synthesis method comprises following steps: step A, carrying out a reduction reaction between 2-amino-3,5-dibromobenzaldehyde and a reducing agent to generate 2-amino-3,5-dibromobenzyl alcohol; step B, reacting 2-amino-3,5-dibromobenzyl alcohol obtained in the step A with thionyl chloride to generate 2,4-bromo-6-chloromethyl aniline; and step C, carrying out an amination reaction between 2, 4-bromo-6-chloromethyl aniline obtained in the step B and N-methyl cyclohexyl amine, and then carrying out a salt forming reaction with an HCl salifying reagent to obtain bromhexine hydrochloride. According to the preparation method, thionyl chloride is only used as a reactant; in addition, the steps are simple, the intermediates obtained in the steps A and B do not need to be purified and directly used for the next step of reactions, therefore, the working hours required by the whole production route are remarkably shortened, the final yield is increased by 5% or above, and the method is particularly suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of bromhexine hydrochloride. Background technique [0002] Bromhexine hydrochloride: N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine hydrochloride, CAS number 611-75-6, molecular formula C 14 h 21 Br 2 ClN 2 , the structural formula is as follows: [0003] [0004] Bromhexine hydrochloride, the earliest active ingredient of Indian folk expectorant and cough medicine Duckbill, has a strong mucus-dissolving effect. It mainly acts on the mucus-producing cells of the trachea and bronchial mucosa, inhibits the synthesis of acidic mucopolysaccharide proteins in sputum, and can break the mucin fibers in sputum, thus restoring the rheological properties of trachea and bronchial secretion to normal, and sticky sputum Reduced, sputum diluted and easy to cough up. It is used for patients with chronic bronchus, asthma, bronchiectasis,...

Claims

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Application Information

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IPC IPC(8): C07C211/52C07C209/74C07C209/08C07C215/68C07C213/00
CPCC07C209/74C07C209/08C07C213/00C07C2601/14C07C215/68C07C211/52
Inventor 张保献胡杰王学元杨荣珍李岩杨秀伟
Owner INCREASEPHARM TIANJIN INST CO LTD
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