阅读说明：本技术 一种盐酸氨溴索生产工艺 (Ambroxol hydrochloride production process ) 是由 陈学荣 吴兴起 于 2021-06-29 设计创作，主要内容包括：本申请涉及一种盐酸氨溴索生产工艺,包括以下步骤：在反式-对氨基环己醇中滴加邻硝基溴苄进行缩合反应,得N-(邻硝基苯基)-反式-4-氨基环己醇氯仿反应液,加入盐酸后分液,得N-(邻硝基苯基)-反式-4-氨基环己醇盐酸盐水溶液；将甲苯加入盐酸盐水溶液,得N-(邻氨基苯基)-反式-4-氨基环己醇甲苯反应液；在甲苯反应液中加入硫酸得N-(邻氨基苯基)-反式-4-氨基环己醇硫酸反应液；在硫酸反应液中进行溴化反应,滤出2-氨基-3,5-二溴-N-(反式-4-羟基环己基)苄胺盐,将苄胺盐溶解提纯精制得盐酸氨溴索。本申请采用邻硝基溴苄作为起始原料,与反式-对氨基环己醇缩合、还原、溴化并成盐精制,得到盐酸氨溴索,总收率达到85％以上,且原料易得,操作便捷,能节约原料成本40-50％。(The application relates to an ambroxol hydrochloride production process, which comprises the following steps: dropwise adding o-nitrobenzyl bromide into trans-p-aminocyclohexanol for condensation reaction to obtain N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid, adding hydrochloric acid, and separating liquid to obtain N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride aqueous solution; adding toluene into a hydrochloride aqueous solution to obtain an N- (o-aminophenyl) -trans-4-aminocyclohexanol toluene reaction solution; adding sulfuric acid into the toluene reaction solution to obtain N- (o-aminophenyl) -trans-4-aminocyclohexanol sulfuric acid reaction solution; carrying out bromination reaction in sulfuric acid reaction liquid, filtering out 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt, dissolving the benzylamine salt, purifying and refining to obtain the ambroxol hydrochloride. According to the method, the ambroxol hydrochloride is obtained by adopting the o-nitrobenzyl bromide as an initial raw material, condensing with trans-p-aminocyclohexanol, reducing, brominating and salifying for refining, the total yield reaches over 85%, the raw materials are easy to obtain, the operation is convenient and fast, and the raw material cost can be saved by 40-50%.)

1. The production process of ambroxol hydrochloride is characterized by comprising the following steps:

s1, adding trans-p-aminocyclohexanol into a sodium hydroxide solution, stirring and dissolving, dropwise adding an o-nitrobenzyl bromide chloroform solution at the temperature of 10-50 ℃, and stirring for condensation reaction; stopping dripping the o-nitrobenzyl bromide chloroform solution when the content of the N- (di-o-nitrophenyl) -trans-4-aminocyclohexanol is more than or equal to 0.5 percent, stirring for 5-30min, and standing and separating to obtain an N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid and a water liquid layer;

s2, supplementing trans-p-aminocyclohexanol and a sodium hydroxide solution into the water solution layer, repeatedly carrying out the condensation reaction in S1, mixing the N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid subjected to multiple condensation separation with the N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid in S1, adjusting the pH of the chloroform reaction liquid to be 1-3, stirring for 5-30min, standing for layering, and separating out an N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride water solution; adding concentrated hydrochloric acid into the chloroform reaction solution to adjust the pH value to be 1-3;

s3, adding active iron powder into hydrochloric acid, stirring for 30min, adding toluene and the aqueous solution of N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride in S2, heating and refluxing to react until the reaction is finished, adjusting the pH of the reaction solution to be 7-9, and standing and layering to separate out the N- (o-aminophenyl) -trans-4-aminocyclohexanol toluene reaction solution;

s4, placing the N- (o-aminophenyl) -trans-4-aminocyclohexanol toluene reaction solution in an environment with the temperature of 5-10 ℃, adding 10-50% of sulfuric acid solution, stirring for 10-30min, and standing for layering to separate out the N- (o-aminophenyl) -trans-4-aminocyclohexanol sulfuric acid reaction solution; adding hydrobromic acid into the sulfuric acid reaction liquid, uniformly stirring, dropwise adding bromogen and an oxidant, stirring, filtering to obtain 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt when the bromine content is less than or equal to 0.5%, dissolving the benzylamine salt, adjusting the pH value to be 8-9, stirring, filtering to obtain a crude ambroxol product;

s5, adding the ambroxol crude product in the S4 into the refined solvent, stirring and dissolving the solution to be clear, adding hydrochloric acid to adjust the pH value of the reaction solution to be 1-3, stirring the solution for 10-60min, and filtering the solution at the temperature of 0-5 ℃ to obtain the ambroxol crude product; dissolving the crude ambroxol hydrochloride, adding a decolorizing agent, stirring and decolorizing at 70-95 ℃ for 30-60min, filtering out filtrate, cooling to 0-2 ℃, and filtering out ambroxol hydrochloride.

2. The production process according to claim 1, characterized in that: and in the S4, standing and separating liquid to obtain N- (o-aminophenyl) -trans-4-aminocyclohexanol sulfuric acid reaction liquid and toluene mother liquid, wherein the toluene mother liquid can be washed by water and heated for recovery.

3. The production process according to claim 1, characterized in that: in the S4, after filtering out 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt, obtaining acid mother liquor, wherein the acid mother liquor can be adsorbed and recycled in a decolorable manner.

4. The production process according to claim 1, characterized in that: in S4, the benzylamine salt is added to the methanol solution when the benzylamine salt is dissolved.

5. The production process according to claim 1, characterized in that: in the step S4, the bromine source is bromine, and the oxidant is hydrogen peroxide.

6. The production process according to claim 55, wherein: in the step S4, when the bromoogen and the oxidizing agent are dropwise added, the bromoogen is dropwise added first, and then the oxidizing agent is dropwise added.

7. The production process according to claim 1, characterized in that: in the S5, the refining solvent is one of acetone, ethanol and chloroform.

8. The production process according to claim 1, characterized in that: the decolorizing agent is activated carbon.

Technical Field

The application relates to the technical field of pharmaceutical chemical synthesis, in particular to a production process of ambroxol hydrochloride.

Background

Ambroxol hydrochloride with the chemical name of 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine and the chemical formula of C₁₃H₁₈Br₂N₂O HCl, an organic compound having a molecular weight of 414.56, CAS: 23828-92-2, a white to yellowish crystalline powder, almost odorless. It can promote the discharge of viscous secretion in respiratory tract and reduce the retention of mucus, so that it has obvious effect of promoting sputum excretion and is suitable for sputumAcute and chronic respiratory diseases with abnormal secretion and dysfunction of expectoration, good phlegm dissolving effect, and respiratory tract lubricating effect.

The prior domestic synthesis of the mature industrial mass production of the ambroxol hydrochloride mainly uses 2-amino-3, 5-dibromobenzaldehyde as a raw material for synthesis, and the reaction process is as follows: putting solvent anhydrous toluene or anhydrous methanol and ethanol into a dry and clean reaction kettle, putting reaction main raw materials of 2-amino-3, 5-dibromobenzaldehyde and trans-p-aminocyclohexanol into the reaction kettle, wherein the trans-p-aminocyclohexanol is excessively put into the reaction kettle, heating and condensing the reaction until the 2-amino-3, 5-dibromobenzaldehyde finishes reacting, reducing the reaction product in the methanol or the ethanol by sodium borohydride or potassium borohydride to obtain ambroxol, salifying the product by hydrochloric acid to obtain a crude product of ambroxol hydrochloride, and refining the crude product to obtain a refined product of ambroxol hydrochloride, wherein the reaction process is shown as the following formula:

however, the raw materials of the above process are expensive, the production cost is high in mass production, and the waste of raw materials is caused, which is not favorable for environmental protection.

Disclosure of Invention

In order to obtain the ambroxol hydrochloride synthesis process with simple and easily obtained raw materials and low cost, the application provides a production process of ambroxol hydrochloride.

The application provides a production process of ambroxol hydrochloride, which adopts the following technical scheme:

a production process of ambroxol hydrochloride comprises the following steps:

s1, adding trans-p-aminocyclohexanol into a sodium hydroxide solution, stirring and dissolving, dropwise adding an o-nitrobenzyl bromide chloroform solution at the temperature of 10-50 ℃, and stirring for condensation reaction; stopping dripping the o-nitrobenzyl bromide chloroform solution when the content of the N- (di-o-nitrophenyl) -trans-4-aminocyclohexanol is more than or equal to 0.5 percent, stirring for 5-30min, and standing and separating to obtain an N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid and a water liquid layer;

s2, supplementing trans-p-aminocyclohexanol and a sodium hydroxide solution into the water solution layer, repeatedly carrying out the condensation reaction in S1, mixing the N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid subjected to multiple condensation separation with the N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid in S1, adjusting the pH of the chloroform reaction liquid to be 1-3, stirring for 5-30min, standing for layering, and separating out an N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride water solution; adding concentrated hydrochloric acid into the chloroform reaction solution to adjust the pH value to be 1-3;

s3, adding active iron powder into hydrochloric acid, stirring for 30min, adding toluene and the aqueous solution of N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride in S2, heating and refluxing to react until the reaction is finished, adjusting the pH of the reaction solution to be 7-9, and standing and layering to separate out the N- (o-aminophenyl) -trans-4-aminocyclohexanol toluene reaction solution;

s4, placing the N- (o-aminophenyl) -trans-4-aminocyclohexanol toluene reaction solution in an environment with the temperature of 5-10 ℃, adding 10-50% of sulfuric acid solution, stirring for 10-30min, and standing for layering to separate out the N- (o-aminophenyl) -trans-4-aminocyclohexanol sulfuric acid reaction solution; adding hydrobromic acid into the sulfuric acid reaction liquid, uniformly stirring, dropwise adding bromogen and an oxidant, stirring, filtering to obtain 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt when the bromine content is less than or equal to 0.5%, dissolving the benzylamine salt, adjusting the pH value to be 8-9, stirring, filtering to obtain a crude ambroxol product;

s5, adding the ambroxol crude product in the S4 into the refined solvent, stirring and dissolving the solution to be clear, adding hydrochloric acid to adjust the pH value of the reaction solution to be 1-3, stirring the solution for 10-60min, and filtering the solution at the temperature of 0-5 ℃ to obtain the ambroxol crude product; dissolving the crude ambroxol hydrochloride, adding a decolorizing agent, stirring and decolorizing at 70-95 ℃ for 30-60min, filtering out filtrate, cooling to 0-2 ℃, and filtering out ambroxol hydrochloride.

Preferably, in S4, the reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol sulfuric acid and the toluene mother liquor are obtained by standing and separating, and the toluene mother liquor can be washed with water and heated for recovery.

Preferably, in the S4, after filtering out the 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt, an acid mother liquor is obtained, and the acid mother liquor can be adsorbed and recovered in a decolorable manner.

Preferably, in S4, the benzylamine salt is added to the methanol solution when the benzylamine salt is dissolved.

Preferably, in S4, the bromine source is bromine, and the oxidant is hydrogen peroxide.

Preferably, in S4, when the bromogen and the oxidizing agent are dropwise added, the bromogen is firstly dropwise added, and then the oxidizing agent is dropwise added.

Preferably, in S5, the purification solvent is one of acetone, ethanol and chloroform.

Preferably, the decolorizing agent is activated carbon.

The application has at least the following beneficial effects: according to the method, the ambroxol hydrochloride is obtained by adopting the o-nitrobenzyl bromide as an initial raw material, condensing with trans-p-aminocyclohexanol, reducing, brominating and salifying for refining, the total yield reaches over 85%, the raw materials are easy to obtain, the operation is convenient and fast, and the raw material cost can be saved by 40-50%.

Detailed Description

The present application will be described in further detail with reference to examples.

Examples

Example 1

A standard solution containing 0.8682mol of trans-p-aminocyclohexanol, a chloroform standard solution (70 g of chloroform) containing 0.3236mol of o-nitrobenzyl bromide, and a standard solution containing 0.33mol of sodium hydroxide were prepared.

This embodiment 1 includes the following steps:

adding 100ml of water into a reaction bottle, dropwise adding the prepared o-nitrobenzyl bromide chloroform standard solution by 100g of the prepared trans-p-aminocyclohexanol standard solution and 40g of the prepared sodium hydroxide standard solution under the stirring state, controlling the reaction temperature to be 10-40 ℃ in the dropwise adding process, carrying out HPLC detection reaction, stopping dropwise adding the o-nitrobenzyl bromide chloroform standard solution (controlling the dropwise adding time to be 30-120min) when the content of N- (di-o-nitrophenyl) -trans-4-aminocyclohexanol (impurity) is more than or equal to 0.5%, using the non-dropwise added o-nitrobenzyl bromide chloroform standard solution in batches, continuously stirring for 5-30min, standing for layering, and separating an N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction solution and a water liquid layer. And supplementing the reaction amount of trans-p-aminocyclohexanol and sodium hydroxide standard solution in the water liquid layer again, and repeating the steps to obtain 252g of N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid in total.

Adding 150g of water into the N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid, adjusting the pH value to 1-3 by using concentrated hydrochloric acid, stirring for 5-30min, standing for layering, separating an N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride aqueous solution, adding activated carbon, decoloring, stirring for 10-60min, filtering to obtain 320g of an N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride aqueous solution (0.1982mol), detecting the purity by using HPLC (high performance liquid chromatography), and calculating the yield to be 96% by adding the amount of o-nitrobenzyl bromide actually dropwise.

Example 2

A standard solution containing 1.0419mol of trans-p-aminocyclohexanol, a chloroform standard solution (70 g of chloroform) containing 0.3236mol of o-nitrobenzyl bromide, and a standard solution containing 0.33mol of sodium hydroxide were prepared.

This embodiment 2 includes the following steps:

100ml of water, 120g of the prepared trans-p-aminocyclohexanol standard solution and 40g of the prepared sodium hydroxide standard solution are added into a reaction bottle, dropwise adding the prepared o-nitrobenzyl bromide chloroform standard solution under stirring, wherein in the dropwise adding process, the reaction temperature is controlled at 20-30 ℃, and HPLC is used for monitoring the reaction, stopping dripping the o-aminobenzyl bromide chloroform standard solution (controlling the dripping time for 30-120min) when the content of the N- (di-o-nitrophenyl) -trans-4-aminocyclohexanol (impurity) is more than or equal to 0.5 percent, and continuously stirring for 5-30min, adding 50ml of chloroform solution, stirring for reaction for 5-15min, standing for layering, and separating out an N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction solution and an aqueous layer.

Replenishing trans-p-aminocyclohexanol and sodium hydroxide standard solution in the water liquid layer again, repeating the steps to obtain 295g of N- (o-nitrophenyl) -trans-4-aminocyclohexanol chloroform reaction liquid in total, adding 150g of water into the chloroform reaction liquid, adding concentrated hydrochloric acid to adjust the pH value to 1-3, stirring for 5-30min, standing for layering, separating out the N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride aqueous solution, adding activated carbon, decoloring, stirring for 10-60min, filtering to obtain 355.2g of N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride aqueous solution, detecting the purity by HPLC (high performance liquid chromatography) to be 98.5%, and calculating the yield to be 97% by actually adding the o-nitrobenzyl bromide dropwise.

Example 3

200ml of water, 0.9628mol of active iron powder and 0.0833mol of hydrochloric acid are added into a reaction flask, stirred at normal temperature for 30min, then 320g of the aqueous solution of N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride prepared in example 1 and 100ml of toluene are added, heated and refluxed until the reaction of the raw materials for HPLC detection is completed, the pH of the reaction solution is adjusted to 7-9, the reaction solution is filtered at 60-75 ℃, the filtrate is allowed to stand for layering, and 179.2g of a toluene reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol (containing about 0.4309mol of N- (o-aminophenyl) -trans-4-aminocyclohexanol) is separated, and the purity of the reaction solution is 98.2% by HPLC detection.

Example 4

200ml of water, 1.25mol of active iron powder and 0.0933 mol of hydrochloric acid are added into a reaction flask, stirred at normal temperature for 30min, 355.2g of the aqueous solution of N- (o-nitrophenyl) -trans-4-aminocyclohexanol hydrochloride prepared in example 2 and 100ml of toluene are added, heated and refluxed until the reaction of raw materials for HPLC detection is completed, the pH of the reaction solution is adjusted to 7-9, the reaction solution is filtered at a temperature of 60-75 ℃, the filtrate is allowed to stand for layering, 200g of a toluene reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol (containing about 0.5181mol of N- (o-aminophenyl) -trans-4-aminocyclohexanol) is separated, and the purity of the reaction solution is 98.5% by HPLC detection.

Example 5

179.2g of the toluene reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol prepared in example 3 was put in a reaction flask, and the reaction flask was kept at a temperature of 5 to 10 ℃ and charged with 200ml of a 15% sulfuric acid solution, followed by stirring for 15 minutes, followed by standing to separate 330g of a sulfuric acid reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol and a mother toluene solution, 330g of the above-mentioned sulfuric acid reaction solution was put in the reaction flask, and the mother toluene solution was washed with water and then heated to recover the mother toluene solution.

Adding 50ml of 48% hydrobromic acid into a reaction bottle, stirring in an environment of 5 ℃, dropwise adding 0.8125mol of bromine, controlling the dropwise adding time to be 90min, controlling the reaction temperature to be less than 25 ℃, dropwise adding 27% hydrogen peroxide after the completion of the dropwise adding of the bromine, controlling the reaction temperature to be less than 30 ℃ in the dropwise adding process, and stopping dropwise adding the hydrogen peroxide when the bromine content detected by HPLC (high performance liquid chromatography) is less than or equal to 0.5%. Filtering at the temperature of 2-5 ℃ to obtain 177.8g of 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt and acid mother liquor, and decoloring, adsorbing and recovering the acid mother liquor.

Adding 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt into 200ml of 30% methanol solution, stirring and mixing, adjusting the pH to 8-9, filtering at the temperature of 0-2 ℃ to obtain 177.2g of ambroxol crude wet product (loss on drying of 14.5%), calculating the yield to be 93.1%, detecting the purity to be 97.6% by HPLC, and heating and recovering the filtered low-concentration methanol filtrate.

Example 6

200g of the toluene reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol prepared in example 4 was put in a reaction flask, and the reaction flask was kept at a temperature of 5 to 10 ℃ and then stirred for 15 minutes after 200ml of a 15% sulfuric acid solution was added, and then the mixture was allowed to stand to separate 353g of a sulfuric acid reaction solution of N- (o-aminophenyl) -trans-4-aminocyclohexanol and a toluene mother liquor, and then 353g of the sulfuric acid reaction solution was put in the reaction flask, and the toluene mother liquor was washed with water and then heated and recovered.

Adding 50ml of 48% hydrobromic acid into a reaction bottle, stirring in an environment of 5 ℃, dropwise adding 1.025mol of bromine, controlling the dropwise adding time to be 90min, controlling the reaction temperature to be less than 25 ℃, dropwise adding 27% hydrogen peroxide after the completion of the dropwise adding of the bromine, controlling the reaction temperature to be less than 30 ℃ in the dropwise adding process, and stopping dropwise adding the hydrogen peroxide when the bromine content is less than or equal to 0.5% by HPLC (high performance liquid chromatography). Filtering at the temperature of 2-5 ℃ to obtain 262g of 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt and acid mother liquor, and decoloring, adsorbing and recovering the acid mother liquor.

Adding 2-amino-3, 5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine salt into 250ml of 30% ethanol solution, stirring and mixing, adjusting the pH to 8-9, filtering at the temperature of 0-2 ℃ to obtain 208.5g of ambroxol crude wet product (the drying weight loss is 11.2%), calculating the yield to be 95%, detecting the purity to be 98.6% by HPLC, and heating and recovering the filtered low-concentration methanol filtrate.

Example 7

60g of crude and wet ambroxol prepared in example 5 (weight loss on drying is 11.2%) is added into a reaction bottle, 100ml of acetone is added, after stirring and dissolving the mixture at the temperature of 20-25 ℃ for clearing, hydrochloric acid is added to adjust the pH value of the reaction solution to 3, after stirring and reacting for 20min, heating and refluxing are carried out for 20min, 58.2g of crude ambroxol hydrochloride (weight loss on drying is 5%) is filtered and filtered in an environment below 2 ℃, the yield is calculated to be 98.4%, the purity is 99.8% by HPLC detection, and acetone mother liquor obtained by filtering is heated and recovered.

Example 8

50g of crude wet ambroxol prepared in example 6 (loss on drying of 11.2%) is added into a reaction flask, 100ml of acetone is added, after the mixture is stirred and dissolved at the temperature of 20-25 ℃, hydrochloric acid is added to adjust the pH value of the reaction solution to 3, the mixture is stirred for 30min, 49.3g of crude ambroxol hydrochloride (loss on drying of 5%) is filtered and filtered out in an environment below 2 ℃, the yield is calculated to be 98%, the purity is 99.6% by HPLC (high performance liquid chromatography) detection, and acetone mother liquor obtained by filtering is heated and recovered.

Example 9

50g of crude wet ambroxol prepared in example 6 (loss on drying of 11.2%) was added to a reaction flask, 100ml of acetone was added, after stirring and clearing at 20-25 ℃, hydrochloric acid was added to adjust the pH of the reaction solution to 3, stirring was carried out for 60min, 49.8g of crude ambroxol hydrochloride (loss on drying of 5%) was filtered off in an environment of 2 ℃ or below, the yield was calculated to be 98.6%, the purity was 99.7% by HPLC, and the acetone mother liquor obtained by filtration was recovered by heating.

Example 10

50g of the ambroxol hydrochloride crude product (5% loss on drying) prepared in example 7 is taken and added into a reaction bottle, 450ml of pure water and 2g of medicinal activated carbon are added, the mixture is heated to 95 ℃, stirred and decolored for 30min, filtered to obtain filtrate, the filtrate is stirred and cooled to below 2 ℃, 43g of ambroxol hydrochloride refined product is filtered out, the yield is 90%, and the purity is 99.89% by HPLC detection.

Example 11

50g of the ambroxol hydrochloride crude product (5% loss on drying) prepared in example 7 is taken and added into a reaction bottle, 450ml of pure water and 2g of medicinal activated carbon are added, the mixture is heated to 95 ℃, stirred and decolored for 30min, filtered to obtain filtrate, the filtrate is stirred and cooled to below 2 ℃, 46.5g of ambroxol hydrochloride refined product is filtered out, the yield is calculated to be 98%, and the purity is 99.88% by HPLC detection.

The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.