A process for the preparation of bromhexine hydrochloride

Abstract

The application relates to a preparation method of bromhexine hydrochloride, which comprises the following steps: adding 3,5-dibromo-o-amino benzaldehyde, N-methyl cyclohexylamine and a water absorbent into a reaction solvent, stirring under a protective atmosphere, adding a reducing agent in batches at low temperature, continuing to stir under the condition of rising to room temperature, adding a quenching solvent after the reaction is completed, performing suction filtration, rotating and drying the filtrate, adding purified water and an organic solvent, adding concentrated hydrochloric acid under the condition of room temperature to adjust the pH to 0.5-4.0, stirring, performing suction filtration, washing, drying and obtaining bromhexine hydrochloride. The preparation method provided by the application is high in yield and purity, mild in conditions, simple in operation and suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a preparation method of bromhexine hydrochloride. BACKGROUND

[0002] Sputum, as a metabolic product after inflammation of respiratory diseases, can stimulate respiratory mucosa and induce symptoms such as cough, and further aggravate the disease. In recent years, with the continuous deterioration of the ecological environment, the number of patients with respiratory diseases is increasing, and the drugs for treating respiratory inflammation have also attracted widespread attention in clinical medicine. According to different modes of action, expectorants can be divided into solubility-regulating expectorants, stimulating expectorants, and nauseating expectorants. Stimulating expectorants are often administered in the form of steam volatilization, which is relatively troublesome; nauseating expectorants have a large stimulating effect and are not easy to use alone; and solubility-regulating expectorants make mucus more easily coughed out by reducing sputum viscosity, and are more suitable for a wider range of people.

[0003] Bromhexine hydrochloride (compound I), also known as bromhexane hydrochloride, is a solubility-regulating expectorant developed by Boehringer Ingelheim in Germany and was launched in Japan in 1966 in the form of tablets. Bromhexine hydrochloride can directly act on bronchial glands to increase the secretion of lysosomes in mucus cells, differentiate glycosaminoglycan fibers in sputum, and also accelerate the secretion of low-viscosity small-molecule mucin, thereby reducing the viscosity of sputum and making it easier to cough out. At present, it is reported that the synthesis of bromhexine hydrochloride has the problems of difficulty in preparation of intermediates, low yield, and inability to realize industrial production, so improving the synthesis method has become the current demand.

[0004] The structure of bromhexine hydrochloride is as follows:

[0005]

[0006] The existing reported preparation processes and their advantages and disadvantages are as follows:

[0007] CN103333074A uses 2-amino-3,5-dibromobenzyl alcohol as a starting material, and obtains the product bromhexine hydrochloride through condensation reaction and salt formation. Although the synthesis route is relatively short, the reaction temperature of the second condensation reaction is as high as 180℃, and the reaction needs to be crystallized under negative pressure after the reaction is completed, which is harsh and dangerous in operation.

[0008]

[0009] CN104003887A reported that 3,5-dibromo-o-aminobenzaldehyde was used as a starting material, and 3,5-dibromo-o-aminobenzyl alcohol was obtained by sodium borohydride reduction. After the reaction of 3,5-dibromo-o-aminobenzyl alcohol with solid phosgene (triphosgene), the one-pot synthesis of bromhexine hydrochloride was carried out by amination reaction and salt formation reaction. Although the raw material used in this scheme is cheap, the reaction process uses highly toxic triphosgene, which increases the experimental risk factor and requires special protective equipment. The operation is complicated, and a large amount of corrosive hydrogen chloride gas is produced during the reaction, which affects the service life of the production equipment in the workshop and also pollutes the environment.

[0010]

[0011] CN102617359A reported that 3,5-dibromo-o-aminobenzaldehyde was used as a starting material, and the target compound bromhexine hydrochloride was finally synthesized by reduction reaction, chlorination reaction, nucleophilic substitution reaction and salt formation reaction. The reaction process route, production cycle is long, the operation is complicated, and the total yield is not high; in addition, the use of thionyl chloride in the chlorination reaction will produce sulfur dioxide gas which will cause certain harm to the environment, and also introduce chlorinated impurities which are difficult to remove, increasing the purification cost.

[0012]

[0013] CN112194585A also used 3,5-dibromo-o-aminobenzaldehyde as a starting material, added palladium on carbon and N-methylcyclopropylamine, and then added formic acid dropwise for amination reduction reaction. After pressure filtration and concentration, salt formation reaction was carried out with hydrogen chloride ethanol solution, and finally bromhexine hydrochloride was obtained. This scheme needs to add a large amount of formic acid dropwise at high temperature for a long time, which has a certain risk, and after the reaction is completed, the palladium on carbon needs to be treated by pressure filtration and vacuum concentration. The steps are complex, and the risk of introducing heavy metal palladium is increased, which is not conducive to large-scale industrial production.

[0014]

[0015] CN 116514666 A reported that in the presence of formic acid, 3,5-dibromo-2-aminobenzaldehyde and N-methylcyclohexylamine were subjected to reductive amination reaction, and then hydrochloric acid was added for salt formation reaction to obtain crude bromhexine hydrochloride, which was refined to obtain the reaction still cannot avoid the use of a large amount of formic acid.

[0016] CN104628577A discloses that 2-amino-3,5-dibromobenzaldehyde and N-methylcyclohexylamine are used as raw materials, and a macroporous resin 15(H) and reducing agent sodium borohydride or potassium borohydride, the resulting bromhexine free base is reacted with a salt forming agent of hydrogen chloride to obtain the bromhexine hydrochloride, the total yield of this scheme is less than 30%, which is not ideal, and the use of macroporous resin may introduce new impurities, affecting the product quality.

[0017]

[0018] Therefore, it is necessary to invent a method which is mild, cost-saving and suitable for large-scale production. SUMMARY

[0019] The present application aims to overcome the defects in the prior art, and provide a preparation method of bromhexine hydrochloride, which has the advantages of mild conditions, cost-saving, high reaction yield and suitability for industrial production.

[0020] To achieve the above-mentioned object, the technical scheme adopted by the present application is as follows:

[0021] A preparation method of bromhexine hydrochloride, comprising the following steps:

[0022] 3,5-dibromo-o-aminobenzaldehyde, N-methylcyclohexylamine and a water absorbent are added to a reaction solvent, stirred under a protective atmosphere for 0.5-1h, and a reducing agent is added in batches at low temperature, and the stirring is continued at room temperature for 5-6h, then a quenching solvent is added after the reaction is completed, and stirred for 15-35min, then filtered, the filter cake is washed with the quenching solvent, the filtrate is rotary dried to obtain bromhexine free base, purified water and an organic solvent are added and stirred for 0.5-1h, concentrated hydrochloric acid is added at room temperature to adjust the pH to 0.5-4.0, stirred for 0.5-1.5h, filtered, washed and dried to obtain bromhexine hydrochloride.

[0023] As a further improvement of the present application, the molar ratio of 3,5-dibromo-o-aminobenzaldehyde, N-methylcyclohexylamine and reducing agent is 1:1-5:2-5, and the mass ratio of 3,5-dibromo-o-aminobenzaldehyde to water absorbent is 1:0.25-0.75.

[0024] As a further improvement of the present application, the water absorbent is selected from one or a combination of two or more of 4A molecular sieve, 5A molecular sieve, sodium sulfate, magnesium sulfate and calcium chloride.

[0025] As a further improvement of the present application, the reducing agent is added in two batches, and stirred for 30-60min after each batch is added, and the amount of each batch is half of the total amount.

[0026] As a further improvement of the present application, the reducing agent is selected from one or a combination of two or more of sodium triacetoxyborohydride, sodium borohydride and potassium borohydride.

[0027] As a further improvement of the present application, the mass-volume ratio of the 3,5-dibromo-o-aminobenzaldehyde and the reaction solvent is 1:5-15.

[0028] As a further improvement of the present application, the room temperature is 10-35℃; and the low temperature is 0-10℃.

[0029] As a further improvement of the present application, the reaction solvent is selected from tetrahydrofuran, acetonitrile, trichloromethane, dichloromethane; and the quenching solvent is selected from methanol, ethanol, isopropanol, n-propanol.

[0030] As a further improvement of the present application, the mass-volume ratio of the bromhexine free base, purified water and the organic solvent is 1:6-16:6-14.

[0031] As a further improvement of the present application, the organic solvent is selected from dichloromethane, trichloromethane, benzene or toluene.

[0032] The beneficial effects produced by the above technical solution are as follows:

[0033] 1. The present application uses cheap 3,5-dibromo-o-aminobenzaldehyde as a starting material, which saves production cost.

[0034] 2. The present application uses reducing agent sodium triacetoxyborohydride in the amination reduction reaction step, and the reaction condition is mild, and the time required for completing the reaction is significantly shortened. The process is safe and simple to operate, the production cycle is shorter, and it is suitable for large-scale industrial production.

[0035] 3. The temperature in the whole reaction process of the present application is not higher than 40℃, and high temperature heating is not required, which is more friendly to industrial production.

[0036] 4. The present application uses a mixed solvent of purified water and an organic solvent in the salting step, directly adds concentrated hydrochloric acid to adjust the pH, saves production cost, and the salting condition is mild and the reaction yield is high.

[0037] 5. The preparation method provided by the present application improves the yield and purity, the condition is mild, the operation is simple, and it is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0038] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings needed to be used in the specific embodiments or prior art description

[0039] Figure 1 is the hydrogen spectrum of hydrochloric acid bromhexine obtained by example 1 of the present application;

[0040] Figure 2 is the carbon spectrum of hydrochloric acid bromhexine obtained by example 1 of the present application;

[0041] Figure 3 is the mass spectrum of bromhexine hydrochloride obtained in Example 1 of the present application;

[0042] Figure 4 is the HPLC chart of bromhexine hydrochloride obtained in Example 1 of the present application. DETAILED DESCRIPTION

[0043] In order to make the object, technical scheme and advantages of the present application more clear, the present application will be described in detail below with specific examples.

[0044] In each example, the reaction route is as follows:

[0045]

[0046] Preparation of bromhexine hydrochloride in Example 1

[0047] 1) Amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added into a 5000 ml three-necked flask, stirred at 25°C for 10 min, 121.5 g of N-methylcyclohexylamine (1.07 mol) and 50.0 g of 4A sieve were added, and stirred at normal temperature under nitrogen protection for 1 h, the temperature was controlled to 5°C, 114.0 g of sodium triacetoxyborohydride STAB (0.54 mol) was added and stirred, 114.0 g of STAB (0.54 mol) was added again after 1 h, and stirred for 30 min, the temperature was increased to 25°C, and stirred under nitrogen protection for 6 h to obtain compound III.

[0048] 2) Post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25°C and stirred for 1 h, and filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled to 20-30°C, concentrated hydrochloric acid was added to adjust the pH to 1, and stirred for 60 min. The filter cake was washed with 100 ml of DCM, and then washed with 200 ml of anhydrous ethanol, and the filter cake was dried in a blast drying oven for 8 h to obtain a white powder solid (compound I), with a yield of 93.2% and a purity of 99.96%.

[0049] Preparation of bromhexine hydrochloride in Example 2

[0050] 1) amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added into a 5000 ml flask, stirred at 25 °C for 10 min, 121.5 g of N-methylcyclohexylamine (114, 1.07 mol) and 50.0 g of 4A sieve were added, stirred at room temperature under nitrogen protection for 1 h, the temperature was controlled to 5 °C, 20.41 g of sodium borohydride (0.54 mol) was added and stirred, 20.41 g of sodium borohydride (0.54 mol) was added again after 1 h, stirred for 30 min, the temperature was increased to 25 °C, stirred under nitrogen protection for 6 h, to obtain compound III.

[0051] 2) post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25 °C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled at 20-30 °C, concentrated hydrochloric acid was added to adjust the pH to 1, stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of anhydrous ethanol, the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I), the yield was 88.1%, the purity was 99.35%.

[0052] Preparation of bromocriptine hydrochloride in Example 3

[0053] 1) amination reduction reaction: 100 g of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added into a 5000 ml flask, stirred at 25 °C for 10 min, 121.5 g of N-methylcyclohexylamine and 50.0 g of 4A sieve were added, stirred at room temperature under nitrogen protection for 1 h, the temperature was controlled to 5 °C, 20.41 g of sodium borohydride (0.54 mol) was added and stirred, 20.41 g of sodium borohydride (0.54 mol) was added again after 1 h, stirred for 30 min, the temperature was increased to 25 °C, stirred under nitrogen protection for 6 h, to obtain compound III.

[0054] 2) post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25 °C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled at 20-30 °C, concentrated hydrochloric acid was added to adjust the pH to 1, stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of anhydrous ethanol, the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I), the yield was 88.1%, the purity was 99.35%.

[0055] Preparation of bromocriptine hydrochloride in Example 4

[0056] 1) amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added into a 5000 ml three-necked flask, stirred at 25 °C for 10 min, 40.5 g of N-methylcyclohexylamine (0.36 mol) and 50.0 g of 4A sieve were added, stirred at room temperature under nitrogen protection for 1 h, the temperature was controlled to 5 °C, 76.3 g of sodium triacetoxyborohydride STAB (0.36 mol) was added and stirred, 76.3 g of STAB (0.36 mol) was added after 1 h, stirred for 30 min, the temperature was increased to 25 °C, stirred under nitrogen protection for 6 h, to obtain compound III.

[0057] 2) post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25 °C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled to 25 °C, concentrated hydrochloric acid was added to adjust the pH to 2, stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of anhydrous ethanol, the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I), the yield was 90.3%, and the purity was 99.61%.

[0058] Preparation of bromocriptine hydrochloride

[0059] 1) amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added into a 5000 ml three-necked flask, stirred at 25 °C for 10 min, 40.5 g of N-methylcyclohexylamine (0.36 mol) and 50.0 g of 4A sieve were added, stirred at room temperature under nitrogen protection for 1 h, the temperature was controlled to 5 °C, 76.3 g of sodium triacetoxyborohydride STAB (0.36 mol) was added and stirred, 76.3 g of STAB (0.36 mol) was added after 1 h, stirred for 30 min, the temperature was increased to 25 °C, stirred under nitrogen protection for 6 h, to obtain compound III.

[0060] 2) post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25 °C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled to 25 °C, concentrated hydrochloric acid was added to adjust the pH to 2, stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of anhydrous ethanol, the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I), the yield was 90.3%, and the purity was 99.61%.

[0061] Preparation of Bromhexine hydrochloride

[0062] 1) Amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of DCM were added into a 5000 ml flask, stirred at 25 °C for 10 min, 121.5 g of N-methylcyclohexylamine (1.07 mol) and 50.0 g of 4A sieve were added, stirred at room temperature for 1 h, the temperature was controlled to 5 °C, 114.0 g of sodium triacetoxyborohydride STAB (0.54 mol) was added and stirred, 114.0 g of STAB (0.54 mol) was added again after 1 h, stirred for 30 min, the temperature was increased to 25 °C, stirred under nitrogen protection for 6 h, to obtain compound III.

[0063] 2) Post-treatment and salt formation reaction: 1000 ml of ethanol was added to compound III at 25 °C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of ethanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of ethyl acetate were added and stirred for 10 min, the temperature was controlled at 20-30 °C, concentrated hydrochloric acid was added to adjust the pH to 1, stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of absolute ethanol, the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I), the yield was 89.8%, the purity was 99.27%.

[0064] Comparative Example 1

[0065] 1) Amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of DCM were added into a 5000 ml flask, stirred at 25 °C for 10 min, 121.5 g of N-methylcyclohexylamine (1.07 mol) and 50.0 g of 4A sieve were added, stirred at room temperature for 1 h, the temperature was controlled to 5 °C, 114.0 g of sodium triacetoxyborohydride STAB (0.54 mol) was added and stirred, 114.0 g of STAB (0.54 mol) was added again after 1 h, stirred for 30 min, the temperature was increased to 25 °C, stirred under nitrogen protection for 6 h, to obtain compound III.

[0066] 2) Post-treatment and salt formation reaction: 1000 ml of ethanol was added to compound III at 25 °C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of ethanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of ethyl acetate were added and stirred for 10 min, the temperature was controlled at 20-30 °C, concentrated hydrochloric acid was added to adjust the pH to 1, stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of absolute ethanol, the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I), the yield was 89.8%, the purity was 99.27%.

[0067] Comparative Example 2

[0068] 1) Amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added to a 5000 ml flask, stirred at 25°C for 10 min, 121.5 g of N-methylcyclohexylamine (1.07 mol) and 50.0 g of 4A sieve were added, stirred at room temperature for 1 h, the temperature was controlled to 5°C, 228.0 g of sodium triacetoxyborohydride STAB (1.08 mol) was added and stirred for 1.5 h, the temperature was raised to 25°C, stirred under nitrogen protection for 6 h to obtain compound III.

[0069] 2) Post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25°C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled at 20-30°C, concentrated hydrochloric acid was added to adjust the pH to 1, and stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of absolute ethanol, and the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I) with a yield of 87.6% and a purity of 95.15%.

[0070] Comparative Example 3

[0071] 1) Amination reduction reaction: 100 g (0.36 mol) of 3,5-dibromo-o- aminobenzaldehyde (compound II), 1000 ml of tetrahydrofuran were added to a 5000 ml flask, stirred at 25°C for 10 min, 121.5 g of N-methylcyclohexylamine (1.07 mol) and 50.0 g of 4A sieve were added, stirred at room temperature for 1 h, the temperature was controlled to 5°C, 228.0 g of sodium triacetoxyborohydride STAB (1.08 mol) was added and stirred for 1.5 h, the temperature was raised to 25°C, stirred under nitrogen protection for 6 h to obtain compound III.

[0072] 2) Post-treatment and salt formation reaction: 1000 ml of methanol was added to compound III at 25°C and stirred for 1 h, filtered, the filter cake was washed with 50 ml of methanol, the filtrate was rotary evaporated, 1000 ml of purified water and 700 ml of DCM were added and stirred for 10 min, the temperature was controlled at 20-30°C, concentrated hydrochloric acid was added to adjust the pH to 1, and stirred for 60 min. Filtered, the filter cake was first washed with 100 ml of DCM, then washed with 200 ml of absolute ethanol, and the filter cake was dried in a blast drying oven for 8 h to obtain a white powdery solid (compound I) with a yield of 87.6% and a purity of 95.15%.

[0073] It should be pointed out finally that the above embodiments are only used to illustrate the technical solutions of the present application, but not to limit the same; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that the technical solutions recorded in the foregoing embodiments can still be modified, or some technical features therein can be replaced equivalently; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A process for the preparation of brovincamine hydrochloride, characterized in that, It comprises the following steps: 3, 5-dibromo-o-aminobenzaldehyde, N-methylcyclohexylamine and water absorption agent are added into a reaction solvent, stirred under a protective atmosphere for 0.5-1h, a reducing agent is added in batches at low temperature, and stirring is continued at room temperature for 5-6h, methanol or ethanol is added after the reaction is completed, and stirring is continued for 15-35min, filtration is performed, the filter cake is washed with methanol or ethanol, the filtrate is rotary dried to obtain bromhexine free base, purified water and an organic solvent are added and stirred for 0.5-1h, concentrated hydrochloric acid is added at room temperature to adjust the pH to 0.5~4.0, stirring is continued for 0.5-1.5h, filtration is performed, washing and drying are performed to obtain bromhexine hydrochloride; The reducing agent is sodium triacetoxyborohydride; The reaction solvent is selected from tetrahydrofuran, acetonitrile, chloroform, dichloromethane.

2. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized in that, The molar ratio of 3, 5-dibromo-o-aminobenzaldehyde, N-methylcyclohexylamine and the reducing agent is 1∶1 ~ 5∶2 ~ 5, and the mass ratio of 3, 5-dibromo-o-aminobenzaldehyde to the water absorption agent is 1∶0.25 ~ 0.

75.

3. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized by, The water absorption agent is selected from one or a combination of two or more of 4A molecular sieve, 5A molecular sieve, sodium sulfate, magnesium sulfate, and calcium chloride.

4. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized by, The reducing agent is added in two batches, and stirring is continued for 30-60min after each batch is added, and the amount of each batch is half of the total amount.

5. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized by, The mass-volume ratio of 3, 5-dibromo-o-aminobenzaldehyde to the reaction solvent is 1∶5~15.

6. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized by, The room temperature is 10 ~35℃; and the low temperature is 0 ~ 10℃.

7. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized by, The mass-volume ratio of bromhexine free base to purified water and an organic solvent is 1∶6 ~ 16∶6 ~ 14.

8. A process for the preparation of brovincamine hydrochloride according to claim 1, characterized by, The organic solvent is selected from dichloromethane, chloroform, benzene or toluene.

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