Synthesis method of bromhexine hydrochloride

Abstract

The invention discloses a synthesis method of bromhexine hydrochloride, particularly relates to the technical field of chemical drug synthesis, and relates to a synthesis method of bromhexine hydrochloride. The bromhexine hydrochloride is composed of an aniline derivative and N-methylcyclohexylamine; the bromhexine hydrochloride is prepared from the following raw materials in parts by weight: 3-5 parts of aniline derivative and 6 parts of N-methylcyclohexylamine. According to the Grignard reagent-coupling-salifying method disclosed by the invention, the key intermediate is directly synthesized through one-step coupling reaction, and then the target product can be obtained through salifying reaction, so that the reaction steps are relatively few, the treatment and conversion time of the intermediate is shortened, and the synthesis route is remarkably simplified.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug synthesis, and more specifically, to a method for synthesizing bromhexine hydrochloride. Background Art

[0002] Bromhexine hydrochloride is an important drug intermediate, which is widely used in the medical field, especially in the treatment of respiratory diseases. It can directly act on bronchial glands, increase the secretion of serous glands in the respiratory mucosa, and reduce the secretion of mucous glands, thereby reducing the viscosity of sputum, making it easier to cough up, and has an expectorant and ventilating effect. Therefore, it is of great significance to provide a new synthesis method of bromhexine hydrochloride.

[0003] Bromhexine hydrochloride in the related technology mainly includes bromhexine hydrochloride, benzoic acid, ethylparaben, polysorbate 20, citric acid and purified water; among them, bromhexine hydrochloride reduces the viscosity of sputum and makes sputum easier to cough up by promoting the synthesis and secretion of pulmonary surfactant and inhibiting the secretion of mucus glands; benzoic acid and ethylparaben are used as preservatives to prevent the drug from being contaminated by microorganisms during the preparation and storage process; polysorbate 20 is used as a surfactant to help the dispersion and absorption of the drug in the body; citric acid is used to adjust the pH value of the drug to ensure that it exerts the best effect under appropriate pH; purified water is used as a solvent to dissolve and dilute the drug ingredients to ensure the stability and effectiveness of the drug.

[0004] However, in actual use, it still has some disadvantages, such as complex reaction steps. The bromhexine hydrochloride in the related technology involves various types of reactions, including substitution, addition, oxidation, and reduction. Each step requires specific reaction conditions and operations, which increases the complexity and uncertainty of the entire preparation process; low environmental protection, producing more by-products and wastes, producing a variety of by-products and wastes, and using toxic and harmful solvents, resulting in low environmental protection; low yield. Traditional synthesis methods require harsh reaction conditions including high temperature, high pressure, strong acid and strong base. These conditions not only increase the risk and energy consumption of the reaction, but also may affect the reaction rate and the yield of the product, resulting in its low yield. Summary of the invention

[0005] In order to improve the above problems, reduce the complexity of reaction steps, low environmental protection and low yield, the present invention provides a synthesis method of bromhexine hydrochloride to solve the problems raised in the above background technology.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A bromhexine hydrochloride, composed of an aniline derivative and N-methylcyclohexylamine;

[0008] Described a kind of synthetic method of bromhexine hydrochloride is as follows, comprises the following steps:

[0009] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat to reflux for 2 hours at a temperature of 80-85° C. and a stirring speed of 200-600 r / min; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate with ethanol for 3 times to obtain a crude product of bromhexine hydrochloride;

[0010] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 volumes of methanol and place in a reactor, heat at 70°C and stirring at 300-600 r / min for 10-30 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surfaces with cold methanol to remove impurities, then place them in a drying oven and heat at 60-801°C for 2 h to obtain bromhexine hydrochloride.

[0011] Preferably, the components and weight proportions of the raw materials for preparing bromhexine hydrochloride are as follows:

[0012] 3-5 parts of aniline derivative and 6 parts of N-methylcyclohexylamine.

[0013] Preferably, the aniline derivative consists of 3,5-dibromo-2-aminobenzaldehyde and a Grignard reagent.

[0014] Preferably, the synthesis method of the aniline derivative is as follows:

[0015] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, stir evenly, and place it in a reaction apparatus;

[0016] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a drop rate of 10-30 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 30° C. for 2 h to obtain a coupling reaction solution.

[0017] B3. The coupling reaction solution obtained in B2 is added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 1-2 drops / s at 500-900 r / min to quench the reaction. After the addition, stirring is continued for 15 min. The quenched reaction mixture is then transferred to a separatory funnel, the organic layer is separated, washed with water twice, and then washed once with saturated brine. After each washing, the organic layer is transferred back to the separatory funnel, and the water layer is discharged. Subsequently, 50 g of desiccant is added and stirred and dried at a stirring speed of 200-500 r / min for 5-30 min. After drying, it is filtered to obtain an aniline derivative.

[0018] Preferably, the aniline derivative is composed of 3,5-dibromo-2-aminobenzaldehyde and Grignard reagent in a molar ratio of 1:(1.1-1.5).

[0019] Preferably, the Grignard reagent consists of magnesium and ethyl bromide.

[0020] Preferably, the synthesis method of the Grignard reagent is as follows:

[0021] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0022] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0023] C3. Under the condition of stirring at a speed of 200-1000 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 3-10 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0024] Preferably, the Grignard reagent is composed of magnesium and ethyl bromide in a weight ratio of (2-10):1.

[0025] Preferably, the catalyst is cuprous iodide; the ligand is triphenylphosphine; the desiccant is anhydrous sodium sulfate; and the initiator is cuprous iodide.

[0026] Technical effects and advantages of the present invention:

[0027] 1. The Grignard reagent-coupling-salting method of the present invention directly synthesizes the key intermediate through a one-step coupling reaction, and then obtains the target product through a salt-forming reaction. The reaction steps are relatively few, which reduces the processing and conversion time of the intermediate and significantly simplifies the synthesis route;

[0028] 2. The present invention uses a Grignard reagent to carry out a coupling reaction with a substrate under relatively mild reaction conditions, which reduces the safety risk during the reaction and avoids the use of toxic and harmful solvents, thereby further improving the environmental friendliness of the preparation process;

[0029] 3. The present invention uses a Grignard reagent to carry out a coupling reaction with a substrate. The Grignard reagent can react with a variety of functional groups including a carbonyl group, an ester group, and an acyl halide, which helps to construct complex molecules under mild conditions and achieve a highly selective coupling reaction, thereby reducing the generation of by-products and improving the purity and yield of the product. DETAILED DESCRIPTION

[0030] The present invention is further described in detail below in conjunction with the embodiments of the present invention. The raw materials used in the examples and embodiments of the present invention are all commercially available common materials unless otherwise specified below.

[0031] Preparation Example 1-5

[0032] A Grignard reagent, the raw material components and their corresponding weights of which are shown below, is prepared by the following synthesis method:

[0033] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0034] The reaction device comprises a three-necked flask, a stirrer, a constant pressure dropping funnel and a reflux condenser with a drying tube;

[0035] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0036] C3. Under the condition of stirring at a speed of 200 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 3 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0037] The initiator is cuprous iodide;

[0038] Table: Raw material components and their weights in Preparation Examples 1-5 (g)

[0039]

[0040] A Grignard reagent, which is different from Preparation Example 1 in that the specific preparation steps are as follows:

[0041] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0042] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0043] C3. Under the condition of stirring at a speed of 350 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 4 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0044] Preparation Example 7

[0045] A Grignard reagent, which is different from Preparation Example 1 in that the specific preparation steps are as follows:

[0046] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0047] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0048] C3. Under the condition of stirring at a speed of 500 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 6 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0049] Preparation Example 8

[0050] A Grignard reagent, which is different from Preparation Example 1 in that the specific preparation steps are as follows:

[0051] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0052] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0053] C3. Under the condition of stirring at a speed of 650 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 7 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0054] Preparation Example 9

[0055] A Grignard reagent, which is different from Preparation Example 1 in that the specific preparation steps are as follows:

[0056] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0057] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0058] C3. Under the condition of stirring at a speed of 800 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 9 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0059] Preparation Example 10

[0060] A Grignard reagent, which is different from Preparation Example 1 in that the specific preparation steps are as follows:

[0061] C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A;

[0062] C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B;

[0063] C3. Under the condition of stirring at a speed of 1000 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 10 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

[0064] Preparation Examples 11-15

[0065] An aniline derivative, the raw material components and their corresponding weights of which are shown below, is prepared by the following synthesis method:

[0066] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, stir evenly, and place it in a reaction apparatus;

[0067] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a drop rate of 30 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 30° C. for 2 h to obtain a coupling reaction solution.

[0068] The Grignard reagent is prepared as in Preparation Example 1;

[0069] The catalyst is cuprous iodide;

[0070] The ligand is triphenylphosphine;

[0071] B3. The coupling reaction solution obtained in B2 was added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 1 drop / s at 500 r / min to quench the reaction. After the addition, stirring was continued for 15 min. The quenched reaction mixture was then transferred to a separatory funnel. The organic layer was separated, washed with water twice, and then washed with saturated brine once. After each washing, the organic layer was transferred back to the separatory funnel, and the aqueous layer was discharged. Subsequently, 50 g of desiccant was added and stirred and dried at a stirring speed of 200 r / min for 5 min. After drying, it was filtered to obtain an aniline derivative.

[0072] The desiccant is anhydrous sodium sulfate;

[0073] Table: Raw material components and their mol ratios in Preparation Examples 11-15

[0074]

[0075] An aniline derivative, which is different from Preparation Example 11 in that the specific preparation steps are as follows:

[0076] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, and place it in a reaction apparatus;

[0077] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a drop rate of 25 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 32° C. for 2 h to obtain a coupling reaction solution.

[0078] B3. The coupling reaction solution obtained in B2 was added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 1 drop / s at 600 r / min to quench the reaction. After the addition, stirring was continued for 15 min. The quenched reaction mixture was then transferred to a separatory funnel. The organic layer was separated, washed with water twice, and then washed with saturated brine once. After each washing, the organic layer was transferred back to the separatory funnel, and the water layer was discharged. Subsequently, 50 g of desiccant was added and the mixture was stirred and dried at a stirring speed of 260 r / min for 10 min. After drying, it was filtered to obtain an aniline derivative.

[0079] Preparation Example 17

[0080] An aniline derivative, which is different from Preparation Example 11 in that the specific preparation steps are as follows:

[0081] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, and place it in a reaction apparatus;

[0082] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a drop rate of 20 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 34 °C for 2 h to obtain a coupling reaction solution.

[0083] B3. The coupling reaction solution obtained in B2 was added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 1 drop / s at 700 r / min to quench the reaction. After the addition, stirring was continued for 15 min. The quenched reaction mixture was then transferred to a separatory funnel. The organic layer was separated, washed with water twice, and then washed with saturated brine once. After each washing, the organic layer was transferred back to the separatory funnel, and the water layer was discharged. Subsequently, 50 g of desiccant was added and the mixture was stirred and dried at a stirring speed of 320 r / min for 15 min. After drying, it was filtered to obtain an aniline derivative.

[0084] Preparation Example 18

[0085] An aniline derivative, which is different from Preparation Example 11 in that the specific preparation steps are as follows:

[0086] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, and place it in a reaction apparatus;

[0087] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a dropping speed of 15 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 36 °C for 2 h to obtain a coupling reaction solution.

[0088] B3. The coupling reaction solution obtained in B2 was added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 2 drops / s at 800 r / min to quench the reaction. After the addition, stirring was continued for 15 min. The quenched reaction mixture was then transferred to a separatory funnel. The organic layer was separated, washed with water twice, and then washed with saturated brine once. After each washing, the organic layer was transferred back to the separatory funnel, and the water layer was discharged. Subsequently, 50 g of desiccant was added and the mixture was stirred and dried at a stirring speed of 380 r / min for 20 min. After drying, it was filtered to obtain an aniline derivative.

[0089] Preparation Example 19

[0090] An aniline derivative, which is different from Preparation Example 11 in that the specific preparation steps are as follows:

[0091] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, and place it in a reaction apparatus;

[0092] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a dropping speed of 10 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 38° C. for 2 h to obtain a coupling reaction solution.

[0093] B3. The coupling reaction solution obtained in B2 was added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 2 drops / s at 900 r / min to quench the reaction. After the addition, stirring was continued for 15 min. The quenched reaction mixture was then transferred to a separatory funnel, and the organic layer was separated. The organic layer was washed with water twice and then with saturated brine once. After each washing, the organic layer was transferred back to the separatory funnel, and the aqueous layer was discharged. Subsequently, 50 g of desiccant was added and the mixture was stirred and dried at a stirring speed of 440 r / min for 25 min. After drying, it was filtered to obtain an aniline derivative.

[0094] Preparation Example 20

[0095] An aniline derivative, which is different from Preparation Example 11 in that the specific preparation steps are as follows:

[0096] B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, and place it in a reaction apparatus;

[0097] B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a dropping speed of 5 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux and heat at 40° C. to perform coupling reaction for 2 h to obtain a coupling reaction solution;

[0098] B3. The coupling reaction solution obtained in B2 was added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 2 drops / s at 1000 r / min to quench the reaction. After the addition, stirring was continued for 15 min. The quenched reaction mixture was then transferred to a separatory funnel, and the organic layer was separated. The organic layer was washed with water twice and then with saturated brine once. After each washing, the organic layer was transferred back to the separatory funnel, and the aqueous layer was discharged. Subsequently, 50 g of desiccant was added and the mixture was stirred and dried at a stirring speed of 500 r / min for 30 min. After drying, it was filtered to obtain an aniline derivative.

[0099] Preparation Examples 21-29

[0100] An aniline derivative, which is different from Preparation Example 11 in that the usage of the Grignard reagent used in its components is different, and the specific corresponding relationship is shown in the following table.

[0101] Table: Comparison of Grignard reagent usage in preparation examples 21-29

[0102] Group Grignard reagent Preparation Example 21 Prepared from Preparation Example 2 Preparation Example 22 Prepared from Preparation Example 3 Preparation Example 23 Prepared by Preparation Example 4 Preparation Example 24 Prepared from Preparation Example 5 Preparation Example 25 Prepared from Preparation Example 6 Preparation Example 26 Prepared from Preparation Example 7 Preparation Example 27 Prepared from Preparation Example 8 Preparation Example 28 Prepared from Preparation Example 9 Preparation Example 29 Prepared from Preparation Example 10

[0103] Preparation Examples 30-34

[0104] A kind of bromhexine hydrochloride, its raw material components and their corresponding weights are as follows, and it is prepared by the following synthesis method:

[0105] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat under reflux for 2 hours at a temperature of 80° C. and a stirring speed of 200 r / min; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate with ethanol for 3 times to obtain a crude product of bromhexine hydrochloride;

[0106] The aniline derivative is prepared by Preparation Example 11;

[0107] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 times the volume of methanol and place in a reactor, heat at 70°C and stirring at 300 r / min for 10 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surface with cold methanol to remove impurities, then place them in a drying oven and heat at 60°C for 2 h to obtain bromhexine hydrochloride.

[0108] Table: Components and weights of raw materials extracted in Preparation Examples 30-34 (g)

[0109]

[0110] A kind of bromhexine hydrochloride, the difference with preparation example 30 is that, the synthetic method is as follows:

[0111] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat under reflux at a temperature of 81° C. and a stirring speed of 300 r / min for 2 h; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate with ethanol for 3 times to obtain a crude product of bromhexine hydrochloride;

[0112] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 volumes of methanol and place in a reactor, heat at 70°C and stirring at 350 r / min for 15 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surfaces with cold methanol to remove impurities, then place them in a drying oven and heat at 65°C for 2 h to obtain bromhexine hydrochloride.

[0113] Preparation Example 36

[0114] A kind of bromhexine hydrochloride, the difference with preparation example 30 is that, the synthetic method is as follows:

[0115] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat under reflux at a temperature of 82° C. and a stirring speed of 350 r / min for 2 h; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate with ethanol for 3 times to obtain a crude product of bromhexine hydrochloride;

[0116] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 times the volume of methanol and place in a reactor, heat at 70°C and stirring at 400 r / min for 20 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surface with cold methanol to remove impurities, then place them in a drying oven and heat at 70°C for 2 h to obtain bromhexine hydrochloride.

[0117] Preparation Example 37

[0118] A kind of bromhexine hydrochloride, the difference with preparation example 30 is that, the synthetic method is as follows:

[0119] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat under reflux at a temperature of 83° C. and a stirring speed of 450 r / min for 2 h; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate 3 times with ethanol to obtain a crude product of bromhexine hydrochloride;

[0120] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 volumes of methanol and place in a reactor, heat at 70°C and stirring at 500 r / min for 20 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surfaces with cold methanol to remove impurities, then place them in a drying oven and heat at 70°C for 2 h to obtain bromhexine hydrochloride.

[0121] Preparation Example 38

[0122] A kind of bromhexine hydrochloride, the difference with preparation example 30 is that, the synthetic method is as follows:

[0123] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat under reflux at 84° C. and stirring speed of 500 r / min for 2 h; after the reaction is completed, cool to room temperature, solid precipitates naturally, filter the reaction mixture, take the filtrate, and wash the filtrate with ethanol for 3 times to obtain a crude product of bromhexine hydrochloride;

[0124] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 times the volume of methanol and place in a reactor, heat at 70°C and 550 r / min with stirring for 25 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surfaces with cold methanol to remove impurities, then place them in a drying oven and heat at 75°C for 2 h to obtain bromhexine hydrochloride.

[0125] Preparation Example 39

[0126] A kind of bromhexine hydrochloride, the difference with preparation example 30 is that, the synthetic method is as follows:

[0127] A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat to reflux for 2 h at a temperature of 85° C. and a stirring speed of 600 r / min; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate 3 times with ethanol to obtain a crude product of bromhexine hydrochloride;

[0128] A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 times the volume of methanol and place in a reactor, heat at 70°C and stirring at 600 r / min for 30 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surface with cold methanol to remove impurities, then place them in a drying oven and heat at 80°C for 2 h to obtain bromhexine hydrochloride.

[0129] Preparation Examples 40-57

[0130] A bromhexine hydrochloride, which is different from Preparation Example 11 in that the usage of the aniline derivatives used in its components is different, and the specific corresponding relationship is shown in the following table.

[0131] Table: Comparison of the use of aniline derivatives in Preparation Examples 40-57

[0132]

[0133]

[0134] Performance testing

[0135] First, 20g corn starch is dissolved in water, and the prepared bromhexine hydrochloride is sampled respectively, and 10 times the volume of boiling water is added to make corn starch slurry, 2g bromhexine hydrochloride, 5g corn starch, 20g powdered sugar, and 5g sodium carboxymethyl starch are mixed evenly, and then the corn starch slurry is added to stir and granulate to obtain a bromhexine hydrochloride preparation;

[0136] Each prepared bromhexine hydrochloride preparation was selected for testing, and the test subjects were mice, with 10 mice in each group. The test mice took the bromhexine hydrochloride preparation and maintained good health;

[0137] Take 5g twice a day and add 20ml of water. Then test the inhibition rate ΔK% of inflammatory factors in mice on the day of taking the drug and after taking it for 30 consecutive days. The specific test steps are as follows:

[0138] Inflammatory factor level inhibition rate ΔK%:

[0139] First, the levels of inflammatory factors were sampled before the test, on the day of taking the drug, and after taking the drug for 30 consecutive days. The rate of change of inflammatory factor levels was calculated based on the ratio of the difference between the levels of inflammatory factors after taking the drug and the levels of inflammatory factors before taking the drug, which was used to characterize the improvement effect of bromhexine hydrochloride on lung function. The inflammatory factor levels detected above only took interleukin and tumor necrosis factor as two typical inflammatory factors as examples. The test results and evaluation criteria are as follows:

[0140] 60%<ΔK% value (considered as significant inhibition);

[0141] 10%<ΔK% value<60% (considered as general inhibition effect);

[0142] ΔK% value <10% (considered as substantially no inhibitory effect).

[0143] The prepared bromhexine hydrochloride was selected for testing, and the test subjects were 280 portions of bromhexine hydrochloride, 10 portions in each group, and the content of the prepared bromhexine hydrochloride was determined by high performance liquid chromatography. The test results and evaluation criteria are as follows:

[0144] Content>98% (considered as high preparation content and few impurities);

[0145] Content < 98% (considered as low content in preparation and high impurities)

[0146] It should be specifically noted that the bromhexine hydrochloride prepared above is bromhexine hydrochloride produced in a normal production mode, and the defective bromhexine hydrochloride produced is discarded and not counted.

[0147] Examples 1-5

[0148] A kind of bromhexine hydrochloride, the corresponding relationship of its synthetic method used is shown in the following table.

[0149] Table: Bromhexine hydrochloride usage comparison table in Example 1-5

[0150]

[0151]

[0152] The bromhexine hydrochloride in the above Examples 1-5 was extracted, and its inflammatory factor level inhibition rate ΔK% and its component content were tested according to the above measurement steps and measurement standards. The test results were averaged and recorded in the following table.

[0153] Table: Performance test results of bromhexine hydrochloride in Examples 1-5

[0154]

[0155]

[0156] As can be seen from the above table, the bromhexine hydrochloride prepared in Examples 1-5 has a good effect of improving the lung function ecology, and can achieve the purpose of improving the lung function microenvironment by inhibiting inflammatory factors, improving mucopolysaccharide aggregation, and promoting small molecule mucin secretion;

[0157] In Example 1-5, the inhibition rate ΔK% of interleukin level on the day of administration was 34.7%-36.2%, which was considered to be a general inhibition effect; the inhibition rate ΔK% of tumor necrosis factor level was 44.1%-47.5%, which was considered to be a general inhibition effect;

[0158] After continuous use for 30 days, the inhibition rate of interleukin level ΔK% was 72.2%-74.6%, which was considered significant inhibition; the inhibition rate of tumor necrosis factor level ΔK% was 70.1%-72.9%, which was considered significant inhibition;

[0159] The component contents of Examples 1-5 all exceeded 98%, which was considered to be high in preparation content and low in impurities;

[0160] It can be seen that when the dosage of bromhexine hydrochloride is constant, the effect of bromhexine hydrochloride can be increased by adjusting the proportion of each component. Combined with the data in the above table, it is not difficult to see that when the mol ratio of aniline derivative to N-methylcyclohexylamine is 5:6, the prepared bromhexine hydrochloride has the best effect.

[0161] Examples 6-10

[0162] A kind of bromhexine hydrochloride, the corresponding relationship of its synthetic method used is shown in the following table.

[0163] Table: Comparison table of bromhexine hydrochloride usage in Examples 6-10

[0164] Group Bromhexine Hydrochloride Example 6 Prepared from Preparation Example 35 Example 7 Prepared from Preparation Example 36 Example 8 Prepared from Preparation Example 37 Example 9 Prepared from Preparation Example 38 Example 10 Prepared from Preparation Example 39

[0165] The bromhexine hydrochloride in the above Examples 6-10 was extracted, and its inflammatory factor level inhibition rate ΔK% and its component content were tested according to the above measurement steps and measurement standards. The average value of the test results was recorded in the following table.

[0166] Table: Performance test results of bromhexine hydrochloride in Examples 1, 6-10

[0167]

[0168]

[0169] As can be seen from the above table, the bromhexine hydrochloride prepared in Examples 1 and 6-10 has a good effect of improving the lung function ecology, and can achieve the purpose of improving the lung function microenvironment by inhibiting inflammatory factors, improving mucopolysaccharide aggregation, and promoting small molecule mucin secretion;

[0170] In Examples 1, 6-10, the inhibition rate ΔK% of interleukin level on the day of administration was 34.7%-35.3%, which was considered to be a general inhibition effect; the inhibition rate ΔK% of tumor necrosis factor level was 44.1%-45.5%, which was considered to be a general inhibition effect;

[0171] After continuous use for 30 days, the inhibition rate of interleukin level ΔK% was 72.2%-73.9%, which was considered significant inhibition; the inhibition rate of tumor necrosis factor level ΔK% was 70.1%-71.3%, which was considered significant inhibition;

[0172] The component contents of Examples 6-10 all exceeded 98%, which was considered to be high in preparation content and low in impurities;

[0173] It can be seen that when the amount of bromhexine hydrochloride is certain, the preparation effect of bromhexine hydrochloride can be increased by adjusting the synthesis method. It is not difficult to see from the data in the above table that the temperature and stirring speed of bromhexine hydrochloride when preparing bromhexine hydrochloride are improved; the stirring speed and heating time during thermal dissolution; the temperature during drying can slightly improve the quality of the bromhexine hydrochloride prepared. The reason for this is that increasing the temperature in the preparation process can accelerate the molecular motion of the reactants and increase the collision frequency between molecules, thereby facilitating the reaction; the mass transfer process can be accelerated by the stirring speed, so that the reactants reach the reaction interface faster and improve the reaction efficiency; increasing the heating time may fully convert the reactants into products, while avoiding the decomposition of the products or the occurrence of side reactions, thereby improving the quality of bromhexine hydrochloride.

[0174] Examples 11-14

[0175] A kind of bromhexine hydrochloride, the corresponding relationship of its synthetic method used is shown in the following table.

[0176] Table: Bromhexine hydrochloride usage comparison table in Examples 11-14

[0177] Group Bromhexine Hydrochloride Embodiment 11 Prepared from Preparation Example 40 Example 12 Prepared from Preparation Example 41 Example 13 Prepared from Preparation Example 42 Embodiment 14 Prepared from Preparation Example 43

[0178] The bromhexine hydrochloride in the above Examples 11-14 was extracted, and its inflammatory factor level inhibition rate ΔK% and its component content were tested according to the above measurement steps and measurement standards. The average value of the test results was recorded in the following table.

[0179] Table: Performance test results of bromhexine hydrochloride in Examples 1, 11-14

[0180]

[0181]

[0182] As can be seen from the above table, the bromhexine hydrochloride prepared in Examples 1 and 11-14 has a good effect of improving the lung function ecology, and can achieve the purpose of improving the lung function microenvironment by inhibiting inflammatory factors, improving mucopolysaccharide aggregation, and promoting small molecule mucin secretion;

[0183] In Examples 1 and 11-14, the inhibition rate ΔK% of interleukin level on the day of administration was 34.2%-34.7%, which was considered to be a general inhibition effect; the inhibition rate ΔK% of tumor necrosis factor level was 43.7%-44.1%, which was considered to be a general inhibition effect;

[0184] After continuous use for 30 days, the inhibition rate of interleukin level ΔK% was 71.8%-72.2%, which was considered significant inhibition; the inhibition rate of tumor necrosis factor level ΔK% was 69.7%-70.1%, which was considered significant inhibition;

[0185] The component contents of Examples 11-14 all exceeded 98%, which was considered to be high in preparation content and low in impurities;

[0186] It can be seen that when the dosage of bromhexine hydrochloride is constant, the preparation effect of bromhexine hydrochloride can be increased by adjusting the proportion of each component. Combined with the data in the above table, it is not difficult to see that when the mol ratio of 3,5-dibromo-2-aminobenzaldehyde to Grignard reagent is 1:1.1 when preparing aniline derivatives, the prepared Grignard reagent has the best effect.

[0187] Examples 15-19

[0188] A kind of bromhexine hydrochloride, the corresponding relationship of its synthetic method used is shown in the following table.

[0189] Table: Bromhexine hydrochloride usage comparison table in Examples 15-19

[0190] Group Bromhexine Hydrochloride Embodiment 15 Prepared from Preparation Example 44 Example 16 Prepared from Preparation Example 45 Embodiment 17 Prepared from Preparation Example 46 Embodiment 18 Prepared from Preparation Example 47 Embodiment 19 Prepared from Preparation Example 48

[0191] The bromhexine hydrochloride in the above Examples 15-19 was extracted, and its inflammatory factor level inhibition rate ΔK% and its component content were tested according to the above measurement steps and measurement standards. The test results were averaged and recorded in the following table.

[0192] Table: Performance test results of bromhexine hydrochloride in Examples 1, 15-19

[0193]

[0194]

[0195] As can be seen from the above table, the bromhexine hydrochloride prepared in Examples 1 and 15-19 has a good effect of improving the lung function ecology, and can achieve the purpose of improving the lung function microenvironment by inhibiting inflammatory factors, improving mucopolysaccharide aggregation, and promoting small molecule mucin secretion;

[0196] In Examples 1 and 15-19, the inhibition rate ΔK% of interleukin level on the day of administration was 34.7%-35.8%, which was considered to be a general inhibition effect; the inhibition rate ΔK% of tumor necrosis factor level was 44.1%-45.3%, which was considered to be a general inhibition effect;

[0197] After continuous use for 30 days, the inhibition rate of interleukin level ΔK% was 72.2%-73.8%, which was considered significant inhibition; the inhibition rate of tumor necrosis factor level ΔK% was 70.1%-71.4%, which was considered significant inhibition;

[0198] The component contents of Examples 15-19 all exceeded 98%, which was considered to be high in preparation content and low in impurities;

[0199] It can be seen that when the amount of bromhexine hydrochloride is constant, the preparation effect of bromhexine hydrochloride can be increased by adjusting the synthesis method. It is not difficult to see from the data in the above table that increasing the reflux heating temperature of the coupling reaction when preparing aniline derivatives; the stirring speed of the quenching reaction; the stirring speed and time during drying; and reducing the speed of dropping the grignard reagent during the coupling reaction can slightly improve the quality of the prepared bromhexine hydrochloride, but it quickly tends to saturation. The reason for this is that the increase in the heating temperature can accelerate the reaction rate and make the reaction proceed more fully; the increase in the stirring speed can promote mixing and contact between the reactants, thereby improving the reaction efficiency; the stirring during the drying process helps to remove the solvent and moisture, and improve the dryness and purity of the product; reducing the dropping speed can make the reaction proceed more smoothly and reduce the side reactions caused by excessive local concentration.

[0200] Examples 20-23

[0201] A kind of bromhexine hydrochloride, the corresponding relationship of its synthetic method used is shown in the following table.

[0202] Table: Comparison table of bromhexine hydrochloride usage in Examples 20-23

[0203] Group Bromhexine Hydrochloride Embodiment 20 Prepared from Preparation Example 49 Embodiment 21 Prepared from Preparation Example 50 Embodiment 22 Prepared from Preparation Example 51 Embodiment 23 Prepared from Preparation Example 52

[0204] The bromhexine hydrochloride in the above Examples 20-23 was extracted, and its inflammatory factor level inhibition rate ΔK% and its component content were tested according to the above measurement steps and measurement standards. The average value of the test results was recorded in the following table.

[0205] Table: Performance test results of bromhexine hydrochloride in Examples 1, 20-23

[0206]

[0207]

[0208] As can be seen from the above table, the bromhexine hydrochloride prepared in Examples 1 and 20-23 has a good effect of improving the lung function ecology, and can achieve the purpose of improving the lung function microenvironment by inhibiting inflammatory factors, improving mucopolysaccharide aggregation, and promoting small molecule mucin secretion;

[0209] In Examples 1 and 20-23, the inhibition rate ΔK% of interleukin level on the day of administration was 34.2%-34.7%, which was considered to be a general inhibition effect; the inhibition rate ΔK% of tumor necrosis factor level was 43.5%-44.1%, which was considered to be a general inhibition effect;

[0210] After continuous use for 30 days, the inhibition rate of interleukin level ΔK% was 71.5%-72.2%, which was considered significant inhibition; the inhibition rate of tumor necrosis factor level ΔK% was 69.5%-70.1%, which was considered significant inhibition;

[0211] The component contents of Examples 20-23 all exceeded 98%, which was considered to be high in preparation content and low in impurities;

[0212] It can be seen that when the dosage of bromhexine hydrochloride is constant, the preparation effect of bromhexine hydrochloride can be increased by adjusting the component ratio. Combined with the data in the above table, it is not difficult to see that when the mol ratio of magnesium to ethyl bromide is 2:1 when preparing the Grignard reagent, the prepared Grignard reagent has the best effect.

[0213] Examples 24-28

[0214] A kind of bromhexine hydrochloride, the corresponding relationship of its synthetic method used is shown in the following table.

[0215] Table: Comparison table of bromhexine hydrochloride usage in Examples 23-28

[0216] Group Bromhexine Hydrochloride Embodiment 24 Prepared from Preparation Example 53 Embodiment 25 Prepared from Preparation Example 54 Embodiment 26 Prepared from Preparation Example 55 Embodiment 27 Prepared from Preparation Example 56 Embodiment 28 Prepared from Preparation Example 57

[0217] The bromhexine hydrochloride in the above Examples 24-28 was extracted, and its inflammatory factor level inhibition rate ΔK% and its component content were tested according to the above measurement steps and measurement standards. The average value of the test results was recorded in the following table.

[0218] Table: Performance test results of bromhexine hydrochloride in Examples 1, 24-28

[0219]

[0220]

[0221] As can be seen from the above table, the bromhexine hydrochloride prepared in Examples 1 and 24-28 has a good effect of improving the lung function ecology, and can achieve the purpose of improving the lung function microenvironment by inhibiting inflammatory factors, improving mucopolysaccharide aggregation, and promoting small molecule mucin secretion;

[0222] In Examples 1 and 24-28, the inhibition rate ΔK% of interleukin level on the day of administration was 34.7%-38.3%, which was considered to be a general inhibition effect; the inhibition rate ΔK% of tumor necrosis factor level was 44.1%-46.6%, which was considered to be a general inhibition effect;

[0223] After continuous use for 30 days, the inhibition rate of interleukin level ΔK% was 72.2%-74.3%, which was considered significant inhibition; the inhibition rate of tumor necrosis factor level ΔK% was 70.1%-72.3%, which was considered significant inhibition;

[0224] The component contents of Examples 24-28 all exceeded 98%, which was considered to be high in preparation content and low in impurities;

[0225] It can be seen that when the amount of bromhexine hydrochloride is certain, the preparation effect of bromhexine hydrochloride can be increased by adjusting the synthesis method. It is not difficult to see from the data in the above table that the quality of the prepared Grignard reagent can be improved by increasing the stirring speed and the dropping rate of ethyl bromide and tetrahydrofuran when preparing the Grignard reagent. The reason for this is that when the stirring speed is increased, the collision frequency between the reactant molecules increases, so that more effective collisions occur, thereby promoting the reaction; when the dropping rate of ethyl bromide and tetrahydrofuran is increased, it can be ensured that the reactants are evenly distributed in the reaction system, avoiding the situation where the local concentration is too high or too low.

[0226] This specific embodiment is only an explanation of the present invention, not a limitation of the present invention. After reading this specification, those skilled in the art can make non-creative modifications to this embodiment as needed, but as long as it is within the scope of the claims of the present invention, it is protected by the patent law.

Claims

1. A synthetic method for bromhexine hydrochloride, characterized in that, Bromhexine hydrochloride is composed of aniline derivatives and N-methylcyclohexylamine; The synthesis method is as follows: A1. Dissolve the aniline derivative in 200 ml of ethanol, put it into a reaction device, then add N-methylcyclohexylamine and 30 ml of 37% hydrochloric acid by mass, and heat to reflux for 2 hours at a temperature of 80-85° C. and a stirring speed of 200-600 r / min; after the reaction is completed, cool to room temperature, solids precipitate naturally, filter the reaction mixture, take the filtrate, and wash the filtrate with ethanol for 3 times to obtain a crude product of bromhexine hydrochloride; A2. Dissolve the crude bromhexine hydrochloride obtained in A1 in 3 volumes of methanol and place in a reactor, heat at 70°C and stirring at 300-600 r / min for 10-30 min, then remove impurities by hot filtration, take the filtrate, and let the collected filtrate stand at room temperature to naturally cool to room temperature; after crystals precipitate, filter them to separate the crystals from the solution, wash the crystal surfaces with cold methanol to remove impurities, then place them in a drying oven and heat at 60-801°C for 2 h to obtain bromhexine hydrochloride.

2. A kind of bromhexine hydrochloride according to claim 1, characterized in that: The components and weight proportions of the raw materials for preparing bromhexine hydrochloride are as follows: 3-5 parts of aniline derivative and 6 parts of N-methylcyclohexylamine.

3. A kind of bromhexine hydrochloride according to claim 1, characterized in that: The aniline derivative consists of 3,5-dibromo-2-aminobenzaldehyde and a Grignard reagent.

4. A kind of bromhexine hydrochloride according to claim 4, characterized in that: The synthesis method of the aniline derivative is as follows: B1. Add 150 mL of tetrahydrofuran to 3,5-dibromo-2-aminobenzaldehyde to obtain phase C, stir evenly, and place it in a reaction apparatus; B2. In a nitrogen atmosphere, slowly drop the Grignard reagent into phase C at a drop rate of 10-30 ml / min, add 0.5 g of catalyst and 1 g of ligand, and reflux at 30° C. for 2 h to obtain a coupling reaction solution. B3. The coupling reaction solution obtained in B2 is added dropwise to a saturated ammonium chloride solution of twice its volume at a rate of 1-2 drops / s at 500-900 r / min to quench the reaction. After the addition, stirring is continued for 15 min. The quenched reaction mixture is then transferred to a separatory funnel, the organic layer is separated, washed with water twice, and then washed once with saturated brine. After each washing, the organic layer is transferred back to the separatory funnel, and the water layer is discharged. Subsequently, 50 g of desiccant is added and stirred and dried at a stirring speed of 200-500 r / min for 5-30 min. After drying, it is filtered to obtain an aniline derivative.

5. A kind of bromhexine hydrochloride according to claim 4, characterized in that: The aniline derivative is composed of 3,5-dibromo-2-aminobenzaldehyde and a Grignard reagent in a molar ratio of 1:(1.1-1.5).

6. A kind of bromhexine hydrochloride according to claim 4, characterized in that: The Grignard reagent consists of magnesium and ethyl bromide.

7. A kind of bromhexine hydrochloride according to claim 7, characterized in that: The synthesis method of the Grignard reagent is as follows: C1. Add magnesium chips and 50 ml of tetrahydrofuran to the reaction apparatus to immerse the reaction apparatus to obtain phase A; C2, add 50 ml of tetrahydrofuran to ethyl bromide to obtain phase B; C3. Under the condition of stirring at a speed of 200-1000 r / min and full of nitrogen, add 1 mg of initiator to the phase A obtained from C1, and then add the phase B obtained from C2 at a dropping speed of 3-10 drops / s to maintain the reaction system in a slightly boiling state; after the dropping process is completed, continue the reaction for 1 hour to obtain the Grignard reagent.

8. A kind of bromhexine hydrochloride according to claim 7, characterized in that: The Grignard reagent is composed of magnesium and ethyl bromide in a weight ratio of (2-10):

1.

9. A kind of bromhexine hydrochloride according to claim 5, characterized in that: The catalyst is cuprous iodide; the ligand is triphenylphosphine; the desiccant is anhydrous sodium sulfate; and the initiator is cuprous iodide.

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