Environment-friendly preparation method of bromhexine hydrochloride

Abstract

The application discloses a green and environment-friendly preparation method of brocresine hydrochloride, and belongs to the technical field of medicine and chemical industry. The method comprises the following synthesis steps: reduction, bromination, condensation, salt formation and refining, and recycling processes such as ethanol recovery, hydrobromic acid recovery, potassium sulfate by-product and toluene recovery. Ethanol is recovered by distillation and reused through collection of ethanol-containing mother liquor generated in each process; hydrobromic acid is recovered by acidification, decolorization and concentration of the combined hydrogen bromide-containing aqueous phase, and the potassium sulfate is by-produced; and toluene is recovered by neutralization and distillation of the toluene-containing mother liquor and reused. The application realizes efficient recycling of solvents and bromine resources, greatly reduces the consumption of organic solvents, acids and salts, reduces the discharge of three wastes, increases economic benefits through by-production of potassium sulfate, has the advantages of green environmental protection and economic efficiency, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a green and environmentally friendly preparation method for bromhexine hydrochloride. Background Technology

[0002] Bromhexine hydrochloride has a strong mucolytic effect. It primarily acts on mucus-producing cells of the tracheal and bronchial mucosa, inhibiting the synthesis of acidic mucopolysaccharides in sputum and breaking down mucoprotein fibers in sputum. This restores the normal rheological properties of tracheal and bronchial secretions, reducing sputum viscosity and making it easier to cough up. It is used for patients with chronic bronchitis, asthma, bronchiectasis, silicosis, and other conditions where sputum is sticky and difficult to expectorate. Bromhexine hydrochloride has good oral safety, definite efficacy, and wide application. However, the current production process for bromhexine hydrochloride involves harsh reaction conditions, and the equipment is often insufficient to meet production needs, resulting in poor reaction quality, low yield, and severe environmental pollution. Furthermore, the production process generates large amounts of organic solvents (such as toluene and ethanol) and acidic wastewater (containing hydrogen bromide and potassium bromide), which lack effective recycling methods, leading to high solvent consumption, excessive emissions of waste gas, wastewater, and solid waste, and high environmental costs.

[0003] Chinese Patent Publication No. CN104003887A reports a method using 3,5-dibromo-o-aminobenzaldehyde as a starting material, which is reduced with sodium borohydride to obtain 3,5-dibromo-o-aminobenzyl alcohol. Following the reaction of 3,5-dibromo-o-aminobenzyl alcohol with solid phosgene (triphosgene), bromhexine hydrochloride is synthesized in a one-pot process via amination and salt formation. While this method uses inexpensive raw materials, the reaction process employs highly toxic triphosgene, increasing the experimental risk. It requires special protective equipment, is cumbersome to operate, and generates large amounts of corrosive hydrogen chloride gas, affecting the lifespan of production equipment and polluting the environment.

[0004] Chinese Patent Publication No. CN104628577A discloses a method for synthesizing bromhexine free base using 2-amino-3,5-dibromobenzaldehyde and N-methylcyclohexylamine as raw materials, in the presence of sulfonic acid catalyst macroporous resin 15(H) and reducing agent sodium borohydride or potassium borohydride in one step. The generated bromhexine free base is then reacted with a hydrogen chloride salt-forming reagent to obtain the product. However, this method has an overall yield of less than 30%, which is unsatisfactory. Furthermore, the use of macroporous resin may introduce new impurities, affecting product quality.

[0005] Therefore, there is a need to develop a new method for preparing bromhexyl hydrochloride that is high-yield, high-purity, environmentally friendly, and allows for resource recycling. Summary of the Invention

[0006] The purpose of this invention is to provide a green and environmentally friendly preparation method for bromhexine hydrochloride. This method, while ensuring product yield and purity, significantly reduces the consumption of organic solvents and acids / salts by integrating solvent recovery and by-product resource utilization, thereby reducing the emission of waste gas, wastewater, and solid waste and achieving clean production.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A green and environmentally friendly preparation method for bromhexine hydrochloride includes the following steps: (1) 3,5-Dibromo-o-aminobenzaldehyde is reacted with potassium borohydride in ethanol. After the reaction is completed, nitrogen gas is used to pressurize the mixture into a crystallization vessel. The mixture is cooled to 0-5°C using chilled water and crystallized for 1-2 hours. After crystallization, the crystallized liquid is centrifuged to obtain centrifuged mother liquor and filter cake. The filter cake is rinsed with water and dried to obtain 3,5-dibromo-o-aminobenzaldehyde. The centrifuged mother liquor and rinsing liquid are pumped into the ethanol recovery process. (2) 3,5-Dibromo-o-aminobenzyl alcohol is reacted with 40-50% hydrobromic acid in toluene at a temperature of 85-90℃ for 7-9 hours. After the reaction is completed, the mixture is pumped into the separation process. The organic phase obtained by separation is washed with water to obtain a 3,5-dibromo-o-aminobenzyl bromide organic phase solution. (3) Press the 3,5-dibromo-o-aminobenzyl bromide organic phase solution into the condensation reactor, control the temperature inside the reactor at 5-10℃, add N-methylcyclohexylamine dropwise and stir for 0.5-1h, then slowly add potassium carbonate solution dropwise, keep the reaction at 20-25℃ for 5-7h, and after the reaction is complete, pump it into the separation process, wash the organic phase obtained by separation with water to obtain the bromide organic phase solution; (4) Slowly add 25-30% hydrochloric acid to the organic phase solution of bromhexine, control the pH to 2-3, and the bromhexine hydrochloride generated by the reaction precipitates from the toluene solution. Then, after centrifugation, washing and drying, crude bromhexine hydrochloride is obtained. (5) The crude bromhexine hydrochloride is dissolved in ethanol and water, decolorized, centrifuged, crystallized, dried and pulverized to obtain the refined bromhexine hydrochloride.

[0008] Preferably, in step (1), the mass ratio of 3,5-dibromo-o-aminobenzaldehyde to potassium borohydride is 20:1-2.

[0009] Preferably, in step (2), the mass ratio of 3,5-dibromo-o-aminobenzyl alcohol to hydrogen bromide is 10:3-5.

[0010] Preferably, in step (3), the mass ratio of 3,5-dibromo-o-aminobenzyl bromide, N-methylcycloamine, and potassium carbonate is 4-6:1-2:1.

[0011] Preferably, the mass ratio of bromhexine to hydrochloric acid in step (4) is 9-11:1.

[0012] Preferably, the method further includes the following solvent recovery and byproduct recovery steps: (A) Ethanol recovery: Collect the centrifugal mother liquor and eluent generated in steps (1) and (5), distill and condense at 75-80℃ under normal pressure to obtain an aqueous ethanol solution, which is then recycled for steps (1) and (5). (B) Hydrobromic acid recovery and potassium sulfate recovery: Collect the aqueous phase containing hydrogen bromide generated in steps (2) and (3) by separation, acidify, decolorize, filter and concentrate, recover hydrobromic acid and recycle it for step (2), press the concentrated residue into the alcohol precipitation vessel with air, pump the recovered ethanol into the vessel, stir thoroughly and cool the vessel liquid to below 10°C until potassium sulfate crystals precipitate, and obtain potassium sulfate by centrifugation and drying; (C) Toluene recovery: Collect the toluene-containing mother liquor generated by centrifugation in step (4) and the washing liquid generated by washing and pump them into the neutralization process. Water and 25-30% liquid alkali are pumped in sequentially and stirred to neutralize until the pH is greater than 7. After neutralization and separation, the upper organic phase is distilled and condensed under reduced pressure at 70-80℃ and -0.08MPa to recover toluene. The recovered toluene is recycled for step (2).

[0013] Preferably, the acid used for aqueous phase acidification in step (B) is 98% sulfuric acid. After acidification, the solution is decolorized with activated carbon and filtered under pressure. The filtrate is first distilled off the fore fraction under a vacuum of -0.09 MPa and 55-60°C, and then distilled at 60-80°C to obtain 40-50% hydrobromic acid.

[0014] Compared with the prior art, the present invention has the following advantages: By centrally recovering the ethanol mother liquor generated from reduction and refining processes, ethanol can be recycled, achieving a total ethanol recovery rate of over 95%, significantly reducing ethanol consumption. The aqueous phases containing hydrogen bromide generated from bromination and condensation reactions are combined, acidified, decolorized, and concentrated to obtain hydrobromic acid, which is directly reused in the bromination reaction, realizing the recycling of bromine resources and reducing hydrogen bromide emissions and procurement costs. During the hydrobromic acid recovery process, potassium sulfate is recovered through alcohol precipitation, converting the potassium salt in the waste acid into a high-purity potassium sulfate byproduct, realizing waste resource utilization and increasing economic benefits. The toluene-containing waste liquid generated during salt formation and refining processes is neutralized and subjected to vacuum distillation to recover and recycle toluene, achieving a toluene recovery rate of over 90%, reducing organic solvent volatilization and hazardous waste generation. The entire process organically combines the main reaction with solvent recovery and byproduct recovery, forming a closed-loop production system. This significantly reduces emissions of waste gas, wastewater, and solid waste, meeting the requirements of green chemistry and clean production, and is suitable for large-scale industrial production. Meanwhile, the purity of the bromhexine hydrochloride prepared by this invention is ≥99.5%, and the total yield, calculated based on 3,5-dibromo-o-aminobenzaldehyde, can reach over 88%. Detailed Implementation

[0015] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example

[0016] A green and environmentally friendly preparation method for bromhexine hydrochloride includes the following steps: (1) 300 kg of 3,5-dibromo-o-aminobenzaldehyde was reacted with 16 kg of potassium borohydride in ethanol. After the reaction was completed, nitrogen gas was used to pressurize the mixture into a crystallization vessel. The mixture was cooled to 3°C using chilled water and crystallized for 2 hours. After the crystallization was completed, the crystallized liquid was centrifuged to dry it, and centrifuged mother liquor and filter cake were obtained. The filter cake was rinsed with water and dried to obtain 3,5-dibromo-o-aminobenzyl alcohol. The centrifuged mother liquor and rinsing liquid were pumped into the ethanol recovery process. The reaction equation for 3,5-dibromo-o-aminobenzaldehyde with potassium borohydride is:

[0017] The reaction results are shown in Table 1 below.

[0018] Table 1 above shows that the conversion rate of 3,5-dibromo-o-aminobenzaldehyde is 98.5%.

[0019] (2) 294 kg of 3,5-dibromo-o-aminobenzyl alcohol was reacted with 48% hydrobromic acid in toluene at a temperature of 85-90℃ for 8 h. After the reaction was completed, the mixture was pumped into the separation process. The organic phase obtained by separation was washed with water to obtain an organic phase solution of 3,5-dibromo-o-aminobenzyl bromide. The reaction equation for 3,5-dibromo-o-aminobenzyl alcohol with hydrobromic acid is:

[0020] The reaction results are shown in Table 2 below.

[0021] Table 2 above shows that the conversion rate of 3,5-dibromo-o-aminobenzyl alcohol is 98.5%.

[0022] (3) Press the 3,5-dibromo-o-aminobenzyl bromide organic phase solution into the condensation reactor, control the temperature inside the reactor at 10°C, add N-methylcyclohexylamine dropwise and stir for 0.5 h, then slowly add potassium carbonate solution dropwise, keep the reaction at 20-25°C for 5-7 h, and after the reaction is complete, pump it into the separation process, wash the organic phase obtained by separation with water to obtain the bromide organic phase solution; The reaction equation for 3,5-dibromo-o-aminobenzyl bromide and N-methylcyclohexylamine is:

[0023] The reaction results are shown in Table 3 below.

[0024] Table 3 above shows that the conversion rate of 3,5-dibromo-o-aminobenzyl bromide is 98.7%.

[0025] Side reactions are:

[0026] The results of the side reactions are shown in Table 4 below.

[0027] (4) Slowly add 25-30% hydrochloric acid to the organic phase solution of bromhexine, control the pH to 2-3, and the bromhexine hydrochloride generated by the reaction precipitates from the toluene solution. Then, after centrifugation, washing and drying, crude bromhexine hydrochloride is obtained. The reaction equation for bromhexine and hydrochloric acid is:

[0028] The reaction results are shown in Table 5 below.

[0029] Table 4 above shows that the conversion rate of bromhexine is 100%.

[0030] (5) 250 kg of crude bromhexine hydrochloride was dissolved in ethanol and water, decolorized, centrifuged, crystallized, dried and pulverized to obtain 245 kg of refined bromhexine hydrochloride. The total yield was 93.8% based on 3,5-dibromo-o-aminobenzaldehyde and the purity was 99.63%.

[0031] Furthermore, the solvent recovery and by-product recovery steps are as follows: (A) Ethanol recovery: Collect the centrifugal mother liquor and eluent generated in steps (1) and (5), distill and condense at 75-80℃ under normal pressure to obtain an aqueous ethanol solution, which is then recycled for steps (1) and (5). (B) Recovery of hydrobromic acid and potassium sulfate: The aqueous phase generated in the separation of steps (2) and (3) is pumped into the acid adjustment process. Stirring is started, and the temperature of the kettle is kept <30℃. Sulfuric acid with a specification of 98% is slowly dripped in. The reaction is stirred for 1-2 hours until the reaction ends. Activated carbon is added, and the decolorization is stirred for 2 hours until the decolorization ends. The decolorized filtrate is pumped into the concentration process through the pressure filter. Vacuum is turned on, and the pre-distillation is carried out at -0.09MPa and 60℃. The distillate is sent to the sewage treatment station for treatment. The distillate is reduced. Then the temperature is raised and the distillation is carried out at 60-80℃ to obtain the azeotrope of hydrogen bromide vapor and water vapor. The condensate is condensed into liquid by the glass-lined anti-corrosion condenser and flows into the hydrobromic acid receiving tank to obtain hydrobromic acid with a detection concentration of about 40%. This is used in step (2). The concentrated residue is pressed into the alcohol precipitation kettle with air. The recovered ethanol is pumped into the kettle. The kettle is stirred thoroughly and the kettle liquid is cooled to below 10℃ until potassium sulfate crystals precipitate. The potassium sulfate is obtained by centrifugation and drying. (C) Toluene recovery: Collect the toluene-containing mother liquor generated by centrifugation in step (4) and the washing liquid generated by washing and pump them into the neutralization process. Water and 30% liquid alkali are pumped in sequentially and stirred until the pH is greater than 7. After stirring for 1 hour, let it stand for 0.5 hours to separate into layers. The upper organic phase is pumped into the distillation process. The upper organic phase is distilled and condensed under reduced pressure at 70-80℃ and -0.08MPa to recover toluene. The recovered toluene is recycled for step (2).

[0032] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A green and environmentally friendly preparation method for bromhexine hydrochloride, characterized in that, Includes the following steps: (1) 3,5-Dibromo-o-aminobenzaldehyde is reacted with potassium borohydride in ethanol. After the reaction is completed, nitrogen gas is used to pressurize the mixture into a crystallization vessel. The mixture is cooled to 0-5°C using chilled water and crystallized for 1-2 hours. After crystallization, the crystallized liquid is centrifuged to obtain centrifuged mother liquor and filter cake. The filter cake is rinsed with water and dried to obtain 3,5-dibromo-o-aminobenzaldehyde. The centrifuged mother liquor and rinsing liquid are pumped into the ethanol recovery process. (2) 3,5-Dibromo-o-aminobenzyl alcohol is reacted with 40-50% hydrobromic acid in toluene at a temperature of 85-90℃ for 7-9 hours. After the reaction is completed, the mixture is pumped into the separation process. The organic phase obtained by separation is washed with water to obtain a 3,5-dibromo-o-aminobenzyl bromide organic phase solution. (3) Press the 3,5-dibromo-o-aminobenzyl bromide organic phase solution into the condensation reactor, control the temperature inside the reactor at 5-10℃, add N-methylcyclohexylamine dropwise and stir for 0.5-1h, then slowly add potassium carbonate solution dropwise, keep the reaction at 20-25℃ for 5-7h, and after the reaction is complete, pump it into the separation process, wash the organic phase obtained by separation with water to obtain the bromide organic phase solution; (4) Slowly add 25-30% hydrochloric acid to the organic phase solution of bromhexine, control the pH to 2-3, and the bromhexine hydrochloride generated by the reaction precipitates from the toluene solution. Then, after centrifugation, washing and drying, crude bromhexine hydrochloride is obtained. (5) The crude bromhexine hydrochloride is dissolved in ethanol and water, decolorized, centrifuged, crystallized, dried and pulverized to obtain the refined bromhexine hydrochloride.

2. The green and environmentally friendly preparation method of bromhexine hydrochloride according to claim 1, characterized in that, In step (1), the mass ratio of 3,5-dibromo-o-aminobenzaldehyde to potassium borohydride is 20:1-2.

3. The green and environmentally friendly preparation method of bromhexine hydrochloride according to claim 1, characterized in that, In step (2), the mass ratio of 3,5-dibromo-o-aminobenzyl alcohol to hydrogen bromide is 10:3-5.

4. The green and environmentally friendly preparation method of bromhexine hydrochloride according to claim 1, characterized in that, In step (3), the mass ratio of 3,5-dibromo-o-aminobenzyl bromide, N-methylcycloamine, and potassium carbonate is 4-6:1-2:

1.

5. The green and environmentally friendly preparation method of bromhexine hydrochloride according to claim 1, characterized in that, In step (4), the mass ratio of bromhexine to hydrochloric acid is 9-11:

1.

6. The green and environmentally friendly preparation method of bromhexine hydrochloride according to claim 1, characterized in that, The method also includes the following solvent recovery and byproduct recovery steps: (A) Ethanol recovery: Collect the centrifugal mother liquor and eluent generated in steps (1) and (5), distill and condense at 75-80℃ under normal pressure to obtain an aqueous ethanol solution, which is then recycled for steps (1) and (5). (B) Hydrobromic acid recovery and potassium sulfate recovery: Collect the aqueous phase containing hydrogen bromide generated in steps (2) and (3) by separation, acidify, decolorize, filter and concentrate, recover hydrobromic acid and recycle it for step (2), press the concentrated residue into the alcohol precipitation vessel with air, pump the recovered ethanol into the vessel, stir thoroughly and cool the vessel liquid to below 10°C until potassium sulfate crystals precipitate, and obtain potassium sulfate by centrifugation and drying; (C) Toluene recovery: Collect the toluene-containing mother liquor generated by centrifugation in step (4) and the washing liquid generated by washing and pump them into the neutralization process. Water and 25-30% liquid alkali are pumped in sequentially and stirred to neutralize until the pH is greater than 7. After neutralization and separation, the upper organic phase is distilled and condensed under reduced pressure at 70-80℃ and -0.08MPa to recover toluene. The recovered toluene is recycled for step (2).

7. The green and environmentally friendly preparation method of bromhexine hydrochloride according to claim 6, characterized in that, In step (B), the acid used for aqueous phase acidification is 98% sulfuric acid. After acidification, the solution is decolorized by activated carbon and filtered under pressure. The filtrate is first distilled off the fore fraction under a vacuum of -0.09 MPa and 55-60℃, and then distilled at 60-80℃ to obtain 40-50% hydrobromic acid.

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