A process for the preparation of bromhexine hydrochloride
Patent Information
- Application Number
- CN202611428743.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-09-15
- Publication Date
- 2026-10-23
AI Technical Summary
其中，氯代反应使用了氯化亚砜作为氯代试剂，反应中会产生大量刺激性气体，对反应设备及管路具有较强的腐蚀作用
[0046]通过设计新的制备路线，先制备得到邻位为氨基的酰胺类中间体，利用氨基及酰胺基团的强定位效应并配合优选的溴代催化体系，可以直接进行双溴代反应，使得反应具有更强的指向性及转化率，还避免了同一位点可能产生的副反应。同时，配合后续的还原体系及重结晶体系优化，使得整体上物料利用率更高，反应更高效，操作更便捷，对环境更友好，利于盐酸溴己新原料药大规模制备。
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing bromhexine hydrochloride, and more particularly to a method for preparing bromhexine hydrochloride that is suitable for industrial application, belonging to the pharmaceutical field. Background Technology
[0002] Bromhexine hydrochloride is a commonly used clinical drug for respiratory system diseases. It has several preparation methods, the most common of which are as follows:
[0003] .
[0004] This method uses dibromoaminobenzaldehyde as the starting material (starting material 1), and obtains crude bromhexine hydrochloride through reduction, chlorination, substitution, and salt formation reactions, followed by purification to obtain the refined product. The chlorination reaction uses thionyl chloride as the chlorinating reagent, which generates a large amount of irritating gas that has a strong corrosive effect on the reaction equipment and pipelines. Simultaneously, the chlorination reaction also involves a side reaction where bromine on the benzene ring is replaced by chlorine, reducing the utilization rate of the material. Furthermore, when using methanol alone for recrystallization, the purification efficiency and yield are insufficient. Summary of the Invention
[0005] Purpose of the invention: The present invention aims to provide a novel synthetic route for the preparation of bromhexine hydrochloride that is easy to apply on a large scale.
[0006] Technical solution: The preparation method of bromhexine hydrochloride according to the present invention includes the following steps:
[0007] ,
[0008] (1) Compound SMA reacts with methylcyclohexylamine via a condensation reaction to obtain intermediate 1;
[0009] (2) Intermediate 1 is brominated to give intermediate 2;
[0010] (3) Intermediate 2 is reduced to obtain crude bromhexine hydrochloride, and then post-processed to obtain refined bromhexine hydrochloride.
[0011] This invention uses anthranilic acid as a starting material, which first undergoes condensation with methylcyclohexylamine to form amino and amide dual-directing groups at adjacent positions on the benzene ring. This creates an enhanced ortho- and meta-directing effect, resulting in more precise site selection and higher conversion rates in the subsequent dibromination reaction. Combined with a preferred reduction system and purification system, the overall reaction is more efficient and requires no special operating conditions or equipment.
[0012] Preferably, the condensation reagent used in step (1) is selected from HATU / DIPEA, NCS / PPh3 or HOBT / DMAP.
[0013] Further preferred, the condensation reagent used in step (1) is HATU / DIPEA.
[0014] More preferably, the molar ratio of compounds SMA, HATU and DIPEA in step (1) is 1:1.1~1.5:1.5~2.
[0015] Further optimization is made by setting the molar ratio of compounds SMA, HATU and DIPEA in step (1) to 1:1.1:1.5.
[0016] Preferably, the molar ratio of compound SMA to methylcyclohexylamine in step (1) is 1:1.3~2.
[0017] Further preferred, the molar ratio of compound SMA to methylcyclohexylamine in step (1) is 1:1.3.
[0018] Preferably, the reaction solvent for the condensation reaction in step (1) is selected from DMF, DMSO or NMP.
[0019] Further preferred, the reaction solvent for the condensation reaction in step (1) is DMF.
[0020] Preferably, the reaction temperature of the condensation reaction in step (1) is 20~50℃.
[0021] Further optimization is that the reaction temperature of the condensation reaction in step (1) is 45~50℃.
[0022] Preferably, the brominating reagent used in step (2) is NBS / FeBr3, and the molar ratio between intermediate 1, NBS and FeBr3 is 1:2.5~3:0.1~0.2.
[0023] Further optimization is that the molar ratio between intermediate 1, NBS and FeBr3 in step (2) is 1:2.5:0.2.
[0024] Preferably, the reaction solvent for the bromination reaction in step (2) is selected from DMF, DMSO, NMP or DMAc.
[0025] Further preferred, the reaction solvent for the bromination reaction in step (2) is DMF.
[0026] Preferably, the reaction temperature of the bromination reaction in step (2) is 0~10℃.
[0027] Further optimization is that the reaction temperature of the bromination reaction in step (2) is 0~5℃.
[0028] Preferably, the intermediate 2 obtained in step (2) is first recrystallized and then subjected to a subsequent reduction reaction.
[0029] Further optimization, the intermediate 2 obtained in step (2) is recrystallized using n-heptane-ethanol at a volume ratio of 9:1.
[0030] Preferably, the reducing agent used in step (3) is selected from NaBH4 / BF3, NaBH4 / ZnI2 or LiBH4 / SnCl2.
[0031] Further preferred, the reducing agent used in step (3) is NaBH4 / BF3.
[0032] In a further preferred embodiment, the molar ratio between intermediate 2, NaBH4, and BF3 in step (3) is 1:3~4:2.5~3.
[0033] Further optimization is made, in step (3), the molar ratio between intermediate 2, NaBH4 and BF3 is 1:3:2.5.
[0034] Even more preferably, BF3 is used in the form of a BF3-THF solution, wherein the concentration of BF3 is 1 mol / L (1M).
[0035] Preferably, the reaction solvent for the reduction reaction in step (3) is selected from THF, methyltetrahydrofuran, diethyl ether or 1,4-dioxane.
[0036] Further preferred, the reaction solvent for the reduction reaction in step (3) is THF.
[0037] Preferably, the reaction temperature of the reduction reaction in step (3) is 0~15℃.
[0038] Further optimization is that the reaction temperature of the reduction reaction in step (3) is 0~5℃.
[0039] Preferably, the post-processing in step (3) includes hydrochloride formation and purification steps.
[0040] Further preferred, in step (3), methanol / methyl tert-butyl ether with a volume ratio of 1:1 is used for recrystallization.
[0041] Further preferred, the pH value of the hydrochloride salt in step (3) is 2~3.
[0042] In a further preferred embodiment, 1N hydrochloric acid is used for salt formation in step (3).
[0043] The most preferred preparation method of this invention is as follows:
[0044] .
[0045] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:
[0046] By designing a novel preparation route, an amide intermediate with an ortho-amino group was first prepared. Utilizing the strong directing effect of the amino and amide groups, and in conjunction with an optimized bromination catalytic system, a dibromination reaction can be directly carried out. This results in a more targeted reaction with higher conversion rates, while also avoiding potential side reactions at the same site. Furthermore, optimization of the subsequent reduction and recrystallization systems leads to higher overall material utilization, more efficient reaction, more convenient operation, and greater environmental friendliness, facilitating the large-scale preparation of bromhexine hydrochloride API. Attached Figure Description
[0047] Figure 1 The HPLC chromatogram of intermediate 2 prepared in Example 1 is shown.
[0048] Figure 2 The HPLC chromatogram of the purified product prepared in Example 1 is shown below.
[0049] Figure 3 The HPLC chromatogram of the purified product prepared in Comparative Example 1 is shown.
[0050] Figure 4 The HPLC chromatogram is shown for the purified product prepared in Comparative Example 2. Detailed Implementation
[0051] The technical solution of the present invention will be further described below with reference to the embodiments.
[0052] Example 1
[0053]
[0054] (1) Synthesis of intermediate 1: SMA anthranilic acid (5.48 g, 40 mmol) was dissolved in DMF (27.4 mL) at room temperature, followed by the addition of HATU (16.72 g, 1.1 eq) and DIPEA (7.76 g, 1.5 eq), and stirred at room temperature for 1 h. Methylcyclohexylamine (5.88 g, 1.3 eq) was added to the reaction system, and the temperature was raised to 45 °C for 4 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate (120 mL) was added, followed by 0.1 N hydrochloric acid solution (120 mL), and the mixture was allowed to stand and separate. The organic phase was washed successively with saturated sodium bicarbonate solution (40 mL) and saturated brine (40 mL), and dried over anhydrous sodium sulfate solution. The organic phase was concentrated to dryness under reduced pressure, and the residue was slurried with anhydrous ethanol (40 mL) at room temperature for 1 h, filtered, and dried under vacuum to obtain 8.56 g of off-white intermediate 1 with a purity of 98.87% and a yield of 92.2%.
[0055] 1H-NMR (400MHz CDCl3): 7.10 (t, 1H), 6.95 (d, 1H), 6.70 (d, 1H), 6.56 (t, 1H), 4.90 (s, 2H), 3.54 (m, 1H), 3.27 (s, 3H), 1.76-1.79 (m, 2H), 1.46-1.56 (m, 6H), 1.19-1.22 (m, 2H).
[0056] (2) Synthesis of intermediate 2: Intermediate 1 (8.56 g, 36.8 mmol) was dissolved in DMF (100 mL) at room temperature, and then ferric bromide (2.18 g, 0.2 eq) was added. The system was cooled to 0 °C. NBS (16.4 g, 2.5 eq) was added in portions at 0 °C. After the addition was complete, the reaction was maintained at this temperature for 3 h. The temperature was then lowered to 0 °C, and ethyl acetate (100 mL) and saturated sodium bicarbonate solution (200 mL) were added. The mixture was allowed to stand and separated. The organic phase was washed successively with 0.1 N hydrochloric acid (40 mL) and saturated brine (40 mL), and concentrated to dryness under reduced pressure. The residue was recrystallized from n-heptane / ethanol (9:1, 60 mL) to give 12.2 g of off-white intermediate 2. Figure 1 As shown, the purity is 99.90% and the yield is 84.9%.
[0057] 1 H-NMR (400MHz CDCl3): 8.10 (s, 1H), 7.95 (s, 1H), 6.62 (s, 2H), 3.54 (m, 1H), 3.27 (s, 3H), 1.76-1.79 (m, 2H), 1.46-1.56 (m, 6H), 1.19-1.22 (m, 2H).
[0058] (3) Synthesis of crude bromhexine hydrochloride: Intermediate 2 (12.2 g, 31.2 mmol) was dissolved in THF (185 mL), cooled to 5 °C, and then sodium borohydride (3.55 g, 3.0 eq) was added. The temperature was controlled at 5 °C, and boron trifluoride / THF solution (1 M, 78.2 mL, 2.5 eq) was added dropwise, with the temperature not exceeding 5 °C during the addition. After the addition was complete, the reaction was maintained at this temperature for 3 h. 1 N hydrochloric acid was added dropwise to the system to adjust the pH to 2.0. The mixture was filtered to obtain 10.12 g of crude bromhexine hydrochloride, with a purity of 99.10% and a yield of 78.4%.
[0059] (4) Synthesis of purified bromhexine hydrochloride: 10.12 g of crude bromhexine hydrochloride was added to a methanol / methyl tert-butyl ether (1:1, 100 mL) mixed solution, heated to reflux, and after the solid dissolved, slowly cooled to room temperature and stirred for 1 h. Then, the temperature was lowered by 5 °C and stirred for another 1 h. After filtration and drying, 9.13 g of purified bromhexine hydrochloride was obtained. Figure 2 As shown, the purity is 99.95% and the yield is 90.2%.
[0060] 1 H-NMR (400MHz CDCl3): 10.00 (br, 1H), 7.67 (s, 2H), 5.98 (br, 2H), 4.38 (d, 1H), 4.26 (d, 1H), 3.28 (m, 1H), 2.54 (s, 3H), 2.17 (m, 2H), 1.83 (m, 2H), 1.62 (m, 1H), 1.50 (m, 2H), 1.25 (m, 2H), 1.14 (m, 1H).
[0061] Example 2
[0062] (1) Synthesis of intermediate 1: 2.74 g (20 mmol) of anthranilic acid was dissolved in 13.7 mL of DMF at room temperature, followed by the addition of HATU (8.36 g, 1.1 eq) and DIPEA (3.88 g, 1.5 eq). The mixture was stirred at room temperature for 1 h. 4.52 g (2.0 eq) of methylcyclohexylamine was added to the reaction system, and the mixture was heated to 50 °C and reacted for 4 h. After the reaction was complete, the mixture was cooled to room temperature, and 60 mL of ethyl acetate and 60 mL of 0.1 N hydrochloric acid solution were added. The mixture was allowed to stand and separate. The organic phase was washed successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, and dried over anhydrous sodium sulfate solution. The organic phase was concentrated to dryness under reduced pressure. The residue was slurried with 20 mL of anhydrous ethanol at room temperature for 1 h, filtered, and dried under vacuum to obtain 4.24 g of off-white intermediate 1 with a purity of 98.52% and a yield of 91.3%.
[0063] (2) Synthesis of intermediate 2: Intermediate 1 (4.24 g, 18.2 mmol) was dissolved in DMF (50 mL) at room temperature, and ferric bromide (0.54 g, 0.1 eq) was added. The system was cooled to 5 °C. NBS (9.74 g, 3.0 eq) was added in portions at 5 °C. After the addition was complete, the reaction was maintained at this temperature for 3 h. The temperature was then lowered to 5 °C, and ethyl acetate (50 mL) and saturated sodium bicarbonate solution (100 mL) were added. The mixture was allowed to stand and separated. The organic phase was washed successively with 0.1 N hydrochloric acid (20 mL) and saturated brine (20 mL), and concentrated to dryness under reduced pressure. The residue was recrystallized from n-heptane / ethanol (9:1, 30 mL) to give 5.95 g of off-white intermediate 2 with a purity of 99.82% and a yield of 83.6%.
[0064] (3) Synthesis of crude bromhexine hydrochloride: Take intermediate 2 (5.0g, 12.8mmol) and follow the procedure in step (3) of Example 1 to obtain 4.1g of crude bromhexine hydrochloride with a purity of 99.03% and a yield of 77.5%.
[0065] (4) Synthesis of bromhexine hydrochloride: Take crude bromhexine hydrochloride (4.0g, 9.7mmol) and follow the steps (4) in Example 1 to obtain 3.58g of bromhexine hydrochloride, with a purity of 99.95% and a yield of 89.5%.
[0066] Example 3
[0067] (1) Synthesis of intermediate 1: 2.74 g (20 mmol) of anthranilic acid was dissolved in 13.7 mL of DMF at room temperature, followed by the addition of HATU (8.36 g, 1.1 eq) and DIPEA (3.88 g, 1.5 eq). The mixture was stirred at room temperature for 1 h. 2.94 g (1.3 eq) of methylcyclohexylamine was added to the reaction system, and the mixture was heated to 20 °C and reacted for 8 h. After the reaction was completed, the mixture was cooled to room temperature, and 60 mL of ethyl acetate and 60 mL of 0.1 N hydrochloric acid solution were added. The mixture was allowed to stand and separated. The organic phase was washed successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, and dried over anhydrous sodium sulfate solution. The organic phase was concentrated to dryness under reduced pressure. The residue was slurried with 20 mL of anhydrous ethanol at room temperature for 1 h, filtered, and dried under vacuum to obtain 4.11 g of off-white intermediate 1 with a purity of 98.5% and a yield of 88.5%.
[0068] (2) Synthesis of intermediate 2: Intermediate 1 (4.11 g, 17.7 mmol) was dissolved in DMF (50 mL) at room temperature, and then ferric bromide (1.05 g, 0.2 eq) was added. The system was cooled to 10 °C. NBS (7.87 g, 2.5 eq) was added in portions at 10 °C. After the addition was complete, the reaction was maintained at this temperature for 3 h. The temperature was lowered to 5 °C, and ethyl acetate (50 mL) and saturated sodium bicarbonate solution (100 mL) were added. The mixture was allowed to stand and separated. The organic phase was washed successively with 0.1 N hydrochloric acid (20 mL) and saturated brine (20 mL), and concentrated to dryness under reduced pressure. The residue was recrystallized from n-heptane / ethanol (9:1, 30 mL) to give 5.90 g of off-white intermediate 2 with a purity of 99.73% and a yield of 85.5%.
[0069] (3) Synthesis of crude bromhexine hydrochloride: Intermediate 2 (5.90 g, 15.1 mmol) was dissolved in THF (180 mL), cooled to 15 °C, and then sodium borohydride (2.29 g, 4.0 eq) was added. The temperature was maintained at 15 °C, and boron trifluoride / THF solution (1 M, 45.4 mL, 3.0 eq) was added dropwise, ensuring the temperature did not exceed 15 °C. After the addition was complete, the reaction was maintained at 15 °C for 2 h. 1 N hydrochloric acid was added dropwise to the system to adjust the pH to 2.3. The mixture was filtered to obtain 4.85 g of crude bromhexine hydrochloride with a purity of 98.53% and a yield of 77.7%.
[0070] (4) Synthesis of bromhexine hydrochloride: Take crude bromhexine hydrochloride (4.0g, 9.7mmol) and follow the steps (4) in Example 1 to obtain 3.48g of bromhexine hydrochloride, with a purity of 99.90% and a yield of 87.2%.
[0071] Comparative Example 1
[0072] Intermediate 1 (4.0 g, 17.2 mmol) prepared according to the method in Example 1 was added to glacial acetic acid (20 mL) and cooled to 0 °C. Maintaining the temperature at 0 °C, Br2 (5.51 g, 2.0 eq) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 h. Purified water (100 mL) was added, and the pH was adjusted to 7-8 with sodium bisulfite solution (1 M). Extraction was performed with dichloromethane (100 mL * 2), and the organic phase was dried over anhydrous sodium sulfate. Desolventization yielded 5.0 g of intermediate 2, with a purity of 96.34% and a yield of 74.4%.
[0073] Following the preparation methods in steps (3) and (4) of Experimental Example 1, 3.6g of purified bromhexine hydrochloride was obtained, such as... Figure 3 As shown, the purity is 97.88%, and the two-step yield is 68.1%.
[0074] Analysis of the impurity spectrum of the refined product revealed the following traces of impurities, which are products of incomplete bromination.
[0075]
[0076] Comparative Example 2
[0077] Intermediate 2 (3.0 g, 7.7 mmol) prepared according to the method in Example 1 was added to tetrahydrofuran (60 mL) and cooled to below -20 °C. LiAlH4 (1.17 g, 4.0 eq) was added in portions, with the internal temperature controlled not to exceed -20 °C during addition. After the addition was complete, the mixture was kept at this temperature for 0.5 h. Ammonium chloride solution (1 M, 30 mL) was added dropwise at the same temperature, followed by ethyl acetate (50 mL), and the mixture was allowed to stand and separate. The solvent was removed, and the residue was dissolved in methanol (20 mL). Concentrated hydrochloric acid (1 mL) was added, and the mixture was stirred for 1 h. After filtration, the filter cake was dried under vacuum to obtain 2.33 g of crude bromhexine hydrochloride with a purity of 95.76% and a yield of 73.5%.
[0078] 2.0g of purified bromhexine hydrochloride was obtained according to the preparation method in step (4) of Experimental Example 1. Figure 4 As shown, the purity is 97.90% and the yield is 86.3%.
[0079] Analysis of the impurity spectrum of the refined product also revealed impurities with structures of formula 1 and formula 2 as in Comparative Example 1, which were generated by the removal of bromine during reduction. An impurity of formula 3 was also found, which was reported in J Label Compd Radiopharm 2005; 48:429-434.
[0080]
[0081] Comparative Example 3
[0082] The crude bromhexine hydrochloride (10.0 g) prepared according to the method in Example 1 was added to methanol (100 mL), heated to reflux, and after the solid dissolved, it was slowly cooled to room temperature and stirred for 9 h. After filtration and drying, 5.1 g of purified bromhexine hydrochloride with a purity of 99.89% and a yield of 51% was obtained.
Claims
1. A method for preparing bromhexine hydrochloride, characterized in that, Includes the following steps: ， (1) Compound SMA reacts with methylcyclohexylamine via a condensation reaction to obtain intermediate 1; (2) Intermediate 1 is brominated to give intermediate 2; (3) Intermediate 2 is reduced to obtain crude bromhexine hydrochloride, and then post-processed to obtain refined bromhexine hydrochloride.
2. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, The condensation reagent used in step (1) is selected from HATU / DIPEA, NCS / PPh3 or HOBT / DMAP.
3. The method for preparing bromhexine hydrochloride according to claim 2, characterized in that, The condensation reagent used in step (1) is HATU / DIPEA, and the molar ratio between compounds SMA, HATU and DIPEA is 1:1.1~1.5:1.5~2.
4. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, In step (1), the molar ratio of compound SMA to methylcyclohexylamine is 1:1.3~2.
5. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, The reaction temperature of the condensation reaction in step (1) is 20~50℃.
6. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, The brominating agent used in step (2) is NBS / FeBr3, and the molar ratio between intermediate 1, NBS and FeBr3 is 1:2.5~3:0.1~0.
2.
7. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, The reducing reagent used in step (3) is selected from NaBH4 / BF3, NaBH4 / ZnI2 or LiBH4 / SnCl2.
8. The method for preparing bromhexine hydrochloride according to claim 7, characterized in that, The reducing agent used in step (3) is NaBH4 / BF3, and the molar ratio between intermediate 2, NaBH4, and BF3 is 1:3~4:2.5~3.
9. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, The reaction solvent for the reduction reaction in step (3) is selected from THF, methyltetrahydrofuran, diethyl ether or 1,4-dioxane.
10. The method for preparing bromhexine hydrochloride according to claim 1, characterized in that, The post-treatment in step (3) includes recrystallization using methanol / methyl tert-butyl ether at a volume ratio of 1:1.