A method for preparing a key intermediate of ambroxol hydrochloride

Abstract

This invention belongs to the field of organic synthesis technology and provides a method for preparing a key intermediate of ambroxol hydrochloride. The method includes the following steps: methyl 2-aminobenzoate reacts with a brominating reagent under the action of an initiator to generate methyl 2-amino-3,5-dibromobenzoate via a bromination reaction; subsequently, methyl 2-amino-3,5-dibromobenzoate is reduced to 2-amino-3,5-dibromobenzyl alcohol in a reduction system; finally, under the action of an oxidizing agent, 2-amino-3,5-dibromobenzyl alcohol is further oxidized to form the target compound 2-amino-3,5-dibromobenzaldehyde. The optimized process has mild reaction conditions, conforms to green and environmentally friendly principles, significantly improves route safety, uses inexpensive and readily available raw materials, and achieves high product yield and purity, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology and provides a method for preparing a key intermediate of the expectorant drug ambroxol hydrochloride. Background Technology

[0002] Ambroxol hydrochloride has been widely recognized and used clinically since 1970 as a mucolytic agent to promote the expectoration of sputum in the respiratory tract. If sputum remains in the airway, it can cause airway obstruction and lung infection. In severe cases, sputum accumulation can lead to tracheal mucus plugs, causing symptoms such as hypoxia and suffocation. Therefore, expectorants are an important adjunct to the treatment of airway inflammation. 2-Amino-3,5-dibromobenzaldehyde is a key intermediate in the synthesis of ambroxol hydrochloride, and optimizing its process is of significant research and application value. The chemical structure of 2-amino-3,5-dibromobenzaldehyde (denoted as compound P, formula I) is shown below:

[0003] Formula I The main synthetic routes for 2-amino-3,5-dibromobenzaldehyde (P) reported in the literature are as follows: In 2010, B. Latli and his colleagues ( J . Labelled . Compd . Rad 2010, 53 (15.) reported a method for synthesizing ambroxol hydrochloride based on 2-aminobenzoic acid. This route uses lithium aluminum hydride (LiAlH4) as a reducing agent to reduce 2-aminobenzoic acid to 2-aminobenzyl alcohol; subsequently, using liquid bromine as a brominating agent, 2-aminobenzyl alcohol is converted to 2-amino-3,5-dibromobenzyl alcohol via a bromination reaction; finally, using manganese dioxide as an oxidizing agent, 2-amino-3,5-dibromobenzyl alcohol is oxidized to 2-amino-3,5-dibromobenzaldehyde. The synthetic route is shown in Formula II. However, this route has a relatively low overall yield, uses LiAlH4 as a reducing agent, has relatively harsh reaction conditions, and the post-processing is also quite cumbersome.

[0004]

[0005] Formula II In 2012, Yu Qian and others ( Modern Applied Pharmacy, China , 2012, 29(230.) reported a method for synthesizing ambroxol hydrochloride based on methyl 2-aminobenzoate. This route converts methyl 2-aminobenzoate to methyl 2-amino-3,5-dibromobenzoate via bromination using liquid bromine as the brominating agent. Subsequently, methyl 2-amino-3,5-dibromobenzoate is reduced to methyl 2-amino-3,5-dibromobenzyl alcohol using sodium borohydride, zinc chloride, and triethylamine as the reducing system. Finally, 2-amino-3,5-dibromobenzyl alcohol is oxidized to 2-amino-3,5-dibromobenzaldehyde using manganese dioxide as the oxidant. The synthetic route is shown in Formula III. Although this route has a high overall yield, the use of liquid bromine as the brominating agent results in lower safety.

[0006]

[0007] Formula III In 2015, S. Picard and his colleagues ( Tetrahedron, 2015, 71 , 1088.) with N - Bromosuccinimide is used as a brominating agent to convert 2-amino-5-iodobenzaldehyde to 2-amino-3,5-dibromobenzaldehyde via bromination, as shown in Formula IV. This route has a long reaction time and produces the byproduct 2-amino-3-bromo-5-iodobenzaldehyde (6), resulting in poor selectivity.

[0008]

[0009] Formula IV In 2019, Li Conghao and others ( Synthetic Chemistry , 2019, 27 (820.) Using liquid bromine as the brominating agent, methyl 2-aminobenzoate is converted to methyl 2-amino-3,5-dibromobenzoate via bromination. Subsequently, using red aluminum (Red-Al) as the reducing agent, methyl 2-amino-3,5-dibromobenzoate is reduced to 2-amino-3,5-dibromobenzaldehyde, as shown in Formula V. This route has a high overall yield, but the cost of using red aluminum as the reducing agent is high, making the route less economical.

[0010]

[0011] Formula V In the aforementioned routes, B. Latli, Yu Qian, S. Picard, and Li Conghao all used liquid bromine as the brominating reagent. Liquid bromine is extremely toxic and corrosive, resulting in low safety for these routes. Furthermore, they utilize hazardous compounds such as LiAlH4 or Red-Al. In recent years, safety issues in industrial production have undoubtedly been a core and crucial focus. Therefore, developing a simple, safe, reliable, low-cost synthetic method suitable for industrial production is particularly important, addressing the shortcomings of existing processes. Summary of the Invention

[0012] In view of this, the present invention aims to improve the defects of existing processes, implement the concept of green environmental protection, and provide a new method for the efficient synthesis of 2-amino-3,5-dibromobenzaldehyde (P), a key intermediate of ambroxol hydrochloride.

[0013] To achieve the above objectives, the technical solution of the present invention is as follows: A novel method for preparing compound P, the reaction route of which is shown in Formula VI:

[0014] Style VI The preparation method of compound P includes the following steps: S1. Methyl 2-aminobenzoate (hereinafter referred to as Compound 1), brominating reagent and initiator are placed in an organic solvent to carry out bromination reaction to obtain methyl 2-amino-3,5-dibromobenzoate (hereinafter referred to as Compound 2). S2. Compound 2, the reducing agent and Lewis acid are placed in an organic solvent to carry out a reduction reaction to obtain 2-amino-3,5-dibromobenzyl alcohol (hereinafter referred to as compound 3). S3. Compound 3 and an oxidizing agent are placed in an organic solvent to carry out an oxidation reaction, thereby obtaining compound P.

[0015] Furthermore, in the preparation method of compound P, the organic solvent in step S1 is any one or a mixture of several of methanol, ethanol, acetonitrile, 1,4-dioxane and tetrahydrofuran.

[0016] Furthermore, in the preparation method of compound P, the bromine reagent in step S1 is... N- The brominated reagent is either bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin, with 1,3-dibromo-5,5-dimethylhydantoin being the most suitable.

[0017] Furthermore, in the preparation method of compound P, the initiator in step S1 is any one of 1,3-dimethylthiourea, ammonium persulfate, diisobutyronitrile, and benzoyl peroxide, wherein 1,3-dimethylthiourea is the preferred initiator.

[0018] Furthermore, in the preparation method of compound P, the molar ratio of compound 1, brominated reagent and initiator in step S1 is 1.0:(1.0~2.3):0.1, wherein when the brominated reagent is 1,3-dibromo-5,5-dimethylhydantoin, the molar ratio is optimal at 1.0:1.3:0.1.

[0019] Furthermore, in the preparation method of compound P, the organic solvent in step S2 is any one or a mixture of several of tetrahydrofuran, acetonitrile and 1,4-dioxane.

[0020] Furthermore, in the preparation method of compound P, the reducing agent in step S2 is sodium borohydride.

[0021] Furthermore, in the preparation method of compound P, the Lewis acid mentioned in step S2 is any one of zinc chloride, aluminum trichloride, and boron trifluoride diethyl ether, with zinc chloride being the preferred Lewis acid.

[0022] Furthermore, in the preparation method of compound P, the molar ratio of compound 2, sodium borohydride and Lewis acid in step S2 is 1.0:(1.0~2.5):1.0, wherein the optimal molar ratio is 1.0:2.0:1.0; the reaction time is 0.5~2.5 h, wherein the optimal reduction reaction time is 2 h.

[0023] Furthermore, in the preparation method of compound P, the organic solvent in step S3 is any one or a mixture of several of tetrahydrofuran, 1,4-dioxane and acetonitrile.

[0024] Furthermore, in the preparation method of compound P, the oxidant in step S3 is any one of manganese dioxide, pyridinium dichromate, and pyridinium chlorochromate, with manganese dioxide being the preferred oxidant.

[0025] Furthermore, in the preparation method of compound P, the molar ratio of compound 3 to oxidant in step S3 is 1.0:(2.0~11.0), wherein when the oxidant is manganese dioxide, the molar ratio is optimal at 1.0:10.0; the reaction time is 10~80 min, wherein the oxidation reaction time is optimal at 60 min.

[0026] In a preferred embodiment of the present invention, methyl 2-aminobenzoate is prepared by bromination of methyl 2-aminobenzoate using 1,3-dibromo-5,5-dimethylhydantoin as the brominating agent; subsequently, methyl 2-amino-3,5-dibromobenzoate is reduced to 2-amino-3,5-dibromobenzyl alcohol using sodium borohydride as the reducing agent; finally, 2-amino-3,5-dibromobenzyl alcohol is oxidized to 2-amino-3,5-dibromobenzaldehyde using manganese dioxide as the oxidizing agent. The raw materials used in the method of the present invention are inexpensive and readily available, and the reaction conditions are mild, safe, and easy to operate. It also conforms to the concept of green environmental protection. Furthermore, the product obtained by the present invention has high yield and purity, making it suitable for industrial production. Attached Figure Description

[0027] Figure 1 Synthetic route for 2-amino-3,5-dibromobenzaldehyde (P), a key intermediate for ambroxol hydrochloride. Figure 2 2-Amino-3,5-Dibromobenzaldehyde (P), a key intermediate for ambroxol hydrochloride 1 H NMR spectrum.

[0028] Figure 3 2-Amino-3,5-Dibromobenzaldehyde (P), a key intermediate for ambroxol hydrochloride 13 C NMR spectrum. Detailed Implementation

[0029] The present invention will be described below with reference to specific embodiments. These embodiments are only used to more clearly illustrate the technical solution of the present invention and should not be construed as limiting the scope of protection of the present invention.

[0030] Unless otherwise specified, the techniques or conditions described in the following examples are based on those described in the literature or the product instructions. Unless otherwise specified, the reagents or instruments used are commercially available conventional products. Example

[0031] (1) Preparation method of compound 2 (methyl 2-amino-3,5-dibromobenzoate) At room temperature, compound 1 (0.500 g, 3.308 mmol) and 1,3-dimethylthiourea (0.0345 g, 0.331 mmol) were added to a 50 mL single-necked flask, and anhydrous ethanol (10 mL) was added and stirred until the solution was clear. 1,3-dibromo-5,5-dimethylhydantoin (1.324 g, 4.631 mmol) was slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 10 min, and monitored by TLC. After the reaction was complete, sodium thiosulfate solution was added to quench excess brominated reagent. The mixture was then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow crude product. Petroleum ether was added to the solid, and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure to give a white solid 2 (1.002 g, yield 97.04%). 1 HNMR (400 MHz, DMSO- d 6): δ 7.84 (s, 2H), 6.80 (s, 2H), 3.83 (s, 3H) ppm. 13 CNMR (100 MHz, DMSO- d 6): δ 166.1, 146.8, 138.7, 132.2, 111.8, 110.6, 104.9,52.2 ppm. (2) Preparation method of compound 2 (methyl 2-amino-3,5-dibromobenzoate) At room temperature, compound 1 (0.500 g, 3.308 mmol) and azobisisobutyronitrile (0.054 g, 0.331 mmol) were added to a 50 mL single-necked flask, and anhydrous ethanol (10 mL) was added and stirred until the solution was clear. The reaction temperature was raised from room temperature to 60 °C, and 1,3-dibromo-5,5-dimethylhydantoin (1.229 g, 4.300 mmol) was slowly added to the reaction system. After the addition was complete, the mixture was stirred at 60 °C for 10 min and monitored by TLC. After the reaction was complete, sodium thiosulfate solution was added to quench excess brominated reagent. The mixture was then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow crude product. Petroleum ether was added to the solid, and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure to give a white solid 2 (0.978 g, yield 95.69%). 1 H NMR and 13 The C NMR data are consistent with those described above.

[0032] (3) Preparation method of compound 2 (methyl 2-amino-3,5-dibromobenzoate) At room temperature, compound 1 (0.500 g, 3.308 mmol) and 1,3-dimethylthiourea (0.035 g, 0.331 mmol) were added to a 50 mL single-necked flask, and anhydrous ethanol (10 mL) was added and stirred until the solution was clear. 1,3-dibromo-5,5-dimethylhydantoin (1.135 g, 3.969 mmol) was slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 10 min, and monitored by TLC. After the reaction was complete, excess brominated reagent was quenched with sodium thiosulfate solution. The mixture was then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow crude product. Petroleum ether was added to the solid, and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure to give a white solid 2 (0.907 g, yield 88.75%). 1 HNMR and 13 The C NMR data are consistent with those described above. Example

[0033] (1) Preparation method of compound 3 (2-amino-3,5-dibromobenzyl alcohol) Compound 2 (0.500 g, 1.618 mmol) was added to a 50 mL two-necked flask at room temperature, followed by the addition of tetrahydrofuran (THF, 7.5 mL) and stirring until dissolved. Sodium borohydride (0.153 g, 4.045 mmol) and zinc chloride (0.221 g, 1.618 mmol) were slowly added with stirring. After the addition was complete, the mixture was refluxed at 68 °C with stirring for 2 h, and monitored by TLC. After the reaction was complete, water and hydrochloric acid were added dropwise until no more bubbles were produced. The solution was concentrated under reduced pressure, and dichloromethane was added with stirring. The mixture was then filtered under reduced pressure. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered again. The filtrate was concentrated under reduced pressure to give a white solid 3 (0.46 g, 96.23% yield). Chemical shift assignment: 1 H NMR (400 MHz, DMSO- d 6): δ 7.47 (d, J = 2.40 Hz, 1H), 7.28 (d, J =4.00 Hz, 1H), 5.33 (t, J = 8.00 Hz, 1H), 5.20 (s, 2H), 4.41 (dd, J = 4.00, 2.20 Hz, 2H) ppm. 13 C NMR (100 MHz, DMSO- d 6): δ 142.2, 131.9, 129.3, 128.9,108.4, 106.5, 60.4 ppm. (2) Preparation method of compound 3 (2-amino-3,5-dibromobenzyl alcohol) Compound 2 (0.500 g, 1.618 mmol) was added to a 50 mL two-necked flask at room temperature, and tetrahydrofuran (THF, 7.5 mL) was added and stirred until dissolved. Sodium borohydride (0.122 g, 3.237 mmol) was slowly added while stirring. After the addition was complete, the mixture was refluxed at 68 °C and stirred for 2 h, monitored by TLC. After the reaction was complete, water and hydrochloric acid were added dropwise until no more bubbles were generated. The solution was concentrated under reduced pressure, and dichloromethane was added and stirred. The mixture was filtered under reduced pressure, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give a white solid 3 (0.026 g, yield 4.00%). 1 H NMR and 13 The C NMR data are consistent with those described above.

[0034] (3) Preparation method of compound 3 (2-amino-3,5-dibromobenzyl alcohol) Compound 2 (0.500 g, 1.618 mmol) was added to a 50 mL two-necked flask at room temperature, followed by the addition of tetrahydrofuran (THF, 7.5 mL) and stirring until dissolved. Sodium borohydride (0.0612 g, 1.618 mmol) and zinc chloride (0.220 g, 3.237 mmol) were slowly added with stirring. After the addition was complete, the mixture was refluxed at 68 °C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, water and hydrochloric acid were added dropwise until no more bubbles were produced. The solution was concentrated under reduced pressure, and dichloromethane was added with stirring. The mixture was then filtered under reduced pressure. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered again. The filtrate was concentrated under reduced pressure to give a white solid 3 (0.182 g, yield 40.03%). 1 HNMR and 13 The C NMR data are consistent with those described above. Example

[0035] (1) Preparation method of compound P (2-amino-3,5-dibromobenzaldehyde) Compound 3 (0.500 g, 1.780 mmol) was added to a 50 mL two-necked flask at room temperature, and tetrahydrofuran (THF, 10 mL) was added and stirred until dissolved. Manganese dioxide (1.547 g, 17.797 mmol) was slowly added with stirring. After the addition was complete, the mixture was refluxed at 68 °C and stirred for 1 h, monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid P (0.490 g, yield 98.71%). Chemical shift assignment: 1 H NMR (400 MHz, DMSO- d6): δ9.79 (s, 1H), 7.86 (d, J = 4.00 Hz, 2H), 7.20 (s, 2H) ppm. 13 C NMR (100 MHz, DMSO- d 6): δ 193.2, 146.1, 139.3, 137.3, 119.8, 109.8, 105.1 ppm. (3) Preparation method of compound P (2-amino-3,5-dibromobenzyl alcohol) 2 Compound 3 (0.500 g, 1.780 mmol) was added to a 50 mL two-necked flask at room temperature, and tetrahydrofuran (THF, 10 mL) was added and stirred until dissolved. Manganese dioxide (1.238 g, 14.238 mmol) was slowly added while stirring. After the addition was complete, the mixture was refluxed at 68 °C for 1 h, and monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid P (0.410 g, yield 82.33%). 1 H NMR and 13 The C NMR data are consistent with those described above.

[0036] (3) Preparation method of compound P (2-amino-3,5-dibromobenzaldehyde) Compound 3 (0.500 g, 1.780 mmol) was added to a 50 mL two-necked flask at room temperature, and tetrahydrofuran (THF, 10 mL) was added and stirred until dissolved. Manganese dioxide (1.547 g, 17.797 mmol) was slowly added while stirring. After the addition was complete, the mixture was refluxed at 68 °C for 20 min, and monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid P (0.359 g, yield 72.58%).

[0037] 1 H NMR and 13 The C NMR data are consistent with those described above.

[0038] It should be noted that the above embodiments are only some embodiments of the present invention, and not all embodiments, and are only used to illustrate the technical solutions of the present invention, not to limit it. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of ambroxol hydrochloride, wherein the 2-amino-3,5-dibromobenzaldehyde is characterized in that, Includes the following steps: S1. Methyl 2-aminobenzoate, a brominating reagent and an initiator are placed in an organic solvent to carry out a bromination reaction to obtain methyl 2-amino-3,5-dibromobenzoate. S2. Methyl 2-amino-3,5-dibromobenzoate, a reducing agent, and a Lewis acid are placed in an organic solvent to carry out a reduction reaction to obtain 2-amino-3,5-dibromobenzyl alcohol. S3. 2-Amino-3,5-dibromobenzyl alcohol and an oxidant are placed in an organic solvent to carry out an oxidation reaction to obtain 2-amino-3,5-dibromobenzaldehyde.

2. The preparation method according to claim 1, characterized in that, In step S1, the organic solvent is any one or a mixture of several of methanol, ethanol, acetonitrile, tetrahydrofuran and 1,4-dioxane.

3. In the preparation method according to claim 1, the characteristic is that, In step S1, the brominating reagent is N Either 1,3-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin.

4. In the preparation method according to claim 1, the characteristic is that, In step S1, the initiator is any one of 1,3-dimethylthiourea, ammonium persulfate, azobisisobutyronitrile, and benzoyl peroxide.

5. The preparation method according to claim 1, characterized in that, In step S1, the molar ratio of methyl 2-aminobenzoate, brominated reagent and initiator is 1.0:(1.0~2.3):0.

1.

6. The preparation method according to claim 1, characterized in that, In step S3, when the oxidant is manganese dioxide, the molar ratio of 2-amino-3,5-dibromobenzyl alcohol to manganese dioxide is 1.0:(8.0~11.0), and the oxidation reaction time is 10~80 min.

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