A method for preparing ambroxol hydrochloride

Abstract

This invention discloses a method for preparing ambroxol hydrochloride, belonging to the field of pharmaceutical and chemical technology. Using 3,5-dibromo-o-aminobenzaldehyde and trans-p-aminocyclohexanol as raw materials, the finished product is obtained through only three steps: condensation, reduction, and salt formation. This eliminates steps such as protection, deprotection, and stepwise hydrogenation, significantly shortening the cycle and reducing costs. Furthermore, the reduction is carried out at atmospheric pressure and low temperature, eliminating the need for high-temperature and high-pressure equipment. It also avoids the use of halogenated hydrocarbons and highly corrosive reagents, significantly reducing waste and meeting green chemical requirements.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and specifically relates to a method for preparing ambroxol hydrochloride. Background Technology

[0002] Ambroxol hydrochloride, chemically named trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride, is a widely used mucolytic agent in clinical practice. It promotes respiratory mucosal serous secretion, reduces sputum viscosity, enhances ciliary movement and sputum expectoration, and is suitable for treating acute and chronic respiratory diseases accompanied by thick sputum and difficulty in expectoration. Current synthetic routes for ambroxol hydrochloride are mainly divided into two categories: one uses o-nitrobenzaldehyde or methyl o-aminobenzoate as starting materials, and prepares it through multiple steps including bromination, reduction, condensation, reductive amination, and salt formation; the other uses 3,5-dibromo-o-aminobenzaldehyde as an intermediate, which is condensed with trans-p-aminocyclohexanol and then reduced to form a salt. The publicly disclosed processes generally suffer from the following problems: lengthy reaction steps, numerous side reactions, and low overall yield; harsh reduction systems (high temperature and pressure, highly corrosive reagents), resulting in large amounts of waste; insufficient product purity, and difficulty in controlling isomers and heavy metal residues; and poor safety and economic efficiency for industrial scale-up.

[0003] Chinese Patent Publication No. CN118834135A discloses a method for preparing ambroxol hydrochloride, which involves bromination of o-nitrobenzaldehyde, condensation with trans-p-aminocyclohexanol, catalytic hydrogenation reduction, and salt formation. However, it has the following drawbacks: the nitro reduction and imine reduction are carried out in steps, resulting in a long reaction cycle; the hydrogenation pressure is high, and the equipment requirements are stringent; the bromination selectivity is poor, and impurities are difficult to remove.

[0004] Chinese Patent Publication No. CN111072500B discloses a method for preparing ambroxol hydrochloride, which adopts an aldehyde protection, reduction, deprotection, condensation, and salt formation route. However, it has the following drawbacks: the protection and deprotection processes add two steps, resulting in poor atom economy. It also requires the use of halogenated hydrocarbon solvents and special salt catalysts, leading to complex post-processing, high environmental pressure, and room for improvement in overall yield and purity.

[0005] Therefore, it is of great significance to develop a method for preparing ambroxol hydrochloride that is short in steps, mild in conditions, high in yield, high in purity, and suitable for industrial application. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing ambroxol hydrochloride using 3,5-dibromo-o-aminobenzaldehyde and trans-p-aminocyclohexanol as raw materials. Through an integrated process of condensation, mild reduction, and directional salt formation, a high-yield, high-purity, low-cost, green and safe preparation method is achieved.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing ambroxol hydrochloride specifically includes the following steps: (1) Condensation reaction: 3,5-dibromo-o-aminobenzaldehyde and trans-p-aminocyclohexanol were heated under reflux in a solvent and catalyzed by organic acid to give trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol; (2) Reduction reaction: trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol is reduced in a low alcohol with a mild reducing agent at atmospheric pressure to give ambroxol; (3) Salt formation and refining: Ambroxol is salted with hydrochloric acid in an alcohol solvent, and crystallized by gradient cooling and drying to obtain the finished product of ambroxol hydrochloride.

[0008] Preferably, in step (1), the solvent is one or more of toluene, isopropanol, ethyl acetate, and methyltetrahydrofuran; and the organic acid catalyst is one of formic acid, acetic acid, p-toluenesulfonic acid, and citric acid.

[0009] Preferably, in step (1), the molar ratio of 3,5-dibromo-o-aminobenzaldehyde to trans-p-aminocyclohexanol is 1:1-2; the condensation reaction temperature is 70-110℃, and the time is 4-8h.

[0010] Preferably, in step (2), the low alcohol is one or more of methanol, ethanol, and isopropanol; the mild reducing agent is one of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, and the molar ratio of the reducing agent to trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol is 0.8-1.5:1.

[0011] Preferably, in step (2), the reduction temperature is 20-60℃ and the reaction is carried out at normal pressure for 3-6 hours.

[0012] Preferably, in step (3), the alcohol solvent is at least one of ethanol and isopropanol, the salt formation reaction temperature is 40-70℃, the hydrochloric acid mass concentration is 35-40%, and the pH is adjusted to 1-3.

[0013] Preferably, the gradient cooling procedure in step (3) is to keep the temperature at 60°C for 1 hour, then reduce the temperature to 30°C at a rate of 5-10°C / hour, and then reduce the temperature to 0-5°C at a rate of 3-5°C / hour for 2-4 hours to allow crystal growth.

[0014] Compared with the prior art, the present invention has the following advantages: This invention uses 3,5-dibromo-o-aminobenzaldehyde and trans-p-aminocyclohexanol as raw materials, and obtains the finished product through only three steps: condensation, reduction, and salt formation. This eliminates the need for protection, deprotection, and stepwise hydrogenation steps, significantly shortening the cycle and reducing costs. At the same time, the reduction is carried out at normal pressure and low temperature, eliminating the need for high-temperature and high-pressure equipment. It does not use halogenated hydrocarbons or highly corrosive reagents, significantly reducing the amount of waste and meeting the requirements of green chemical industry. The method of this invention has a total yield of ≥90%, a purity of ≥99.8%, and a single impurity of ≤0.05%. The raw materials used are inexpensive and readily available, the equipment is universal, the operation is simple, the crystallization process is controllable, and the reproducibility is good, making it suitable for continuous industrial production. 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 method for preparing ambroxol hydrochloride includes the following steps: (1) Condensation reaction: 280g of 3,5-dibromo-o-aminobenzaldehyde, 125g of trans-p-aminocyclohexanol, 560mL of toluene, 140mL of isopropanol, and 7g of p-toluenesulfonic acid were added to a 1 L reaction flask. The mixture was stirred and heated to 90-95℃ and refluxed for 6h. The reaction was monitored by TLC until the starting material disappeared. The mixture was then cooled to 20℃, filtered, and washed with a small amount of isopropanol to obtain 378.5g of trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol wet product, with a yield of 96.2%. (2) Reduction reaction: The wet product of trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol was added to a 1L reaction flask, 750mL of ethanol was added, and the mixture was stirred and dispersed. 42g of sodium borohydride was added in portions, and the reaction was carried out at atmospheric pressure for 4h while maintaining the temperature at 35-45℃. The intermediate was monitored by TLC for complete conversion. The mixture was concentrated under reduced pressure to 1 / 3 of its original volume, 500mL of water was added, and the mixture was stirred and crystallized for 1h. After filtration, 356.2g of wet product of ambroxol was obtained. (3) Salt purification: Add 800 mL of wet ambroxol to ethanol, heat to 60 °C to dissolve, add 36% concentrated hydrochloric acid to adjust pH to 1.5-2.5, keep warm at 60 °C for 1 h, lower the temperature to 30 °C at 8 °C / h, then lower it to 0-5 °C at 4 °C / h, crystallize for 3 h, filter, wash with cold ethanol, and vacuum dry at 55 °C until the moisture content is ≤0.5%, to obtain 342.8 g of ambroxol hydrochloride product.

[0017] The overall yield was 90.5%, the purity was 99.86%, and the single impurity was ≤0.04%. Example

[0018] A method for preparing ambroxol hydrochloride includes the following steps: (1) Condensation reaction: 560g of 3,5-dibromo-o-aminobenzaldehyde, 246g of trans-p-aminocyclohexanol, 350mL of toluene, 700mL of methyltetrahydrofuran, and 19g of citric acid were added to a 1 L reaction flask. The mixture was stirred and heated to 90-95℃ and refluxed for 7h. The reaction was monitored by TLC until the starting material disappeared. The mixture was then cooled to 25℃ and filtered. The filter cake was washed three times with 150mL of methyltetrahydrofuran each time to obtain 762.8g of trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol wet product, with a yield of 96.2%. (2) Reduction reaction: The wet product of trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol was put into a 1L reaction flask, 1200mL of methanol was added, and the mixture was stirred and dispersed. 126g of sodium cyanoborohydride was added in batches. The temperature was controlled at 30-35℃ and the reaction was carried out at atmospheric pressure for 6h. The complete conversion was monitored by TLC. The product was concentrated under reduced pressure to 1 / 3 of the original volume. 800mL of water was added, and the mixture was stirred and crystallized for 2h. After filtration, 708.3g of wet product of ambroxol was obtained. (3) Salt purification: Add 1500 mL of wet ambroxol to ethanol, heat to 65°C to dissolve, add 37% concentrated hydrochloric acid to adjust pH to 2.5-3, keep warm at 65°C for 1.5 h, lower the temperature to 30°C at 10°C / h, then lower it to 0-5°C at 5°C / h, crystallize for 2 h, filter, wash with cold ethanol, and vacuum dry at 60°C until the moisture content is ≤0.5%, to obtain 690.2 g of ambroxol hydrochloride product.

[0019] The overall yield was 91.1%, the purity was 99.88%, and the single impurity was ≤0.03%. Example

[0020] A method for preparing ambroxol hydrochloride includes the following steps: (1) Condensation reaction: 280g of 3,5-dibromo-o-aminobenzaldehyde, 120g of trans-p-aminocyclohexanol, 600ml of ethyl acetate, and 4g of formic acid were added to a 1 L reaction flask. The mixture was stirred and heated to 80-85℃ and refluxed for 5h. The reaction was monitored by TLC until the starting material disappeared. The mixture was then cooled to 20℃, filtered, and washed with a small amount of ethyl acetate to obtain 376.2g of trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol wet product, with a yield of 95.8%. (2) Reduction reaction: The wet product of trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol was put into a 1L reaction flask, 700mL of isopropanol was added, and the mixture was stirred and dispersed. 105.9g of sodium triacetoxyborohydride was added in batches. The temperature was controlled at 40-45℃, and the mixture was stirred and reacted at normal pressure for 5h. The reaction was monitored by TLC until it was complete. The mixture was concentrated under reduced pressure to 1 / 4 of the original volume, 450mL of water was added, and the mixture was stirred and crystallized for 1.5h. After filtration, 352.5g of wet product of ambroxol was obtained. (3) Salt purification: Add 750 mL of wet ambroxol to ethanol, heat to 55 °C to dissolve, add 35% concentrated hydrochloric acid to adjust pH to 1-1.5, keep warm at 55 °C and stir for 1 h, then lower the temperature to 30 °C at 5 °C / h, then lower it to 0-5 °C at 3 °C / h, crystallize for 4 h, filter, wash with cold ethanol, and vacuum dry at 50 °C until the moisture content is ≤0.5%, to obtain 338.5 g of ambroxol hydrochloride product.

[0021] The overall yield was 90.4%, the purity was 99.83%, and the single impurity was ≤0.05%.

[0022] 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 method for preparing ambroxol hydrochloride, comprising using 3,5-dibromo-o-aminobenzaldehyde and trans-p-aminocyclohexanol as raw materials, and sequentially subjecting them to a condensation reaction, a reduction reaction, hydrochloric acid salt formation, and purification to obtain ambroxol hydrochloride, characterized in that, Specifically, the following steps are included: (1) Condensation reaction: 3,5-dibromo-o-aminobenzaldehyde and trans-p-aminocyclohexanol were heated under reflux in a solvent and catalyzed by organic acid to give trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol; (2) Reduction reaction: trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol is reduced in a low alcohol with a mild reducing agent at ambient pressure to give ambroxol; (3) Salt formation and refining: Ambroxol is salted with hydrochloric acid in an alcohol solvent, and crystallized by gradient cooling and drying to obtain the finished product of ambroxol hydrochloride.

2. The method for preparing ambroxol hydrochloride according to claim 1, characterized in that, In step (1), the solvent is one or more of toluene, isopropanol, ethyl acetate, and methyltetrahydrofuran; the organic acid catalyst is one of formic acid, acetic acid, p-toluenesulfonic acid, and citric acid.

3. The method for preparing ambroxol hydrochloride according to claim 1, characterized in that, In step (1), the molar ratio of 3,5-dibromo-o-aminobenzaldehyde to trans-p-aminocyclohexanol is 1:1-2; the condensation reaction temperature is 70-110℃ and the time is 4-8h.

4. The method for preparing ambroxol hydrochloride according to claim 1, characterized in that, In step (2), the low alcohol is one or more of methanol, ethanol, and isopropanol; the mild reducing agent is one of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, and the molar ratio of the reducing agent to trans-4-[(2-amino-3,5-dibromophenylmethylene)amino]cyclohexanol is 0.8-1.5:

1.

5. The method for preparing ambroxol hydrochloride according to claim 1, characterized in that, In step (2), the reduction temperature is 20-60℃ and the reaction is carried out at normal pressure for 3-6 hours.

6. The method for preparing ambroxol hydrochloride according to claim 1, characterized in that, In step (3), the alcohol solvent is at least one of ethanol and isopropanol, the salt formation reaction temperature is 40-70℃, the hydrochloric acid mass concentration is 35-40%, and the pH is adjusted to 1-3.

7. The method for preparing ambroxol hydrochloride according to claim 1, characterized in that, In step (3), the gradient cooling procedure is to keep the temperature at 60℃ for 1 hour, then reduce it to 30℃ at a rate of 5-10℃ / h, and then reduce it to 0-5℃ at a rate of 3-5℃ / h for 2-4 hours to allow crystal growth.