A process for the preparation of bromhexine hydrochloride

Abstract

This invention discloses a method for synthesizing bromhexine hydrochloride, with the following specific steps: Step (1), using 2-amino-3,5-dibromobenzoic acid as a raw material, reacting it with trimethylacetyl chloride via an anhydride method under the action of an acid-binding agent to obtain compound 2-amino-3,5-dibromobenzoic acid anhydride; Step (2), the 2-amino-3,5-dibromobenzoic acid anhydride obtained in Step 1 undergoes nucleophilic addition with N-methylcyclohexylamine to obtain compound 5, bromhexine hydrochloride intermediate; Step (3), the above compound 5, bromhexine hydrochloride intermediate undergoes amide reduction and salt formation reaction to obtain bromhexine hydrochloride. This process provides a new route for preparing bromhexine hydrochloride, avoiding the heavily regulated chlorination process, reducing the release of toxic gases from strong halogen reagents such as thionyl chloride, significantly reducing safety risks and environmental protection investment, and the reaction itself is safe and fast, which is conducive to industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing bromhexine hydrochloride. Background Technology

[0002] Bromhexine hydrochloride is an expectorant and antitussive developed by Boehringer Ingelheim and marketed in 1965. It is primarily used for patients with chronic bronchitis, asthma, and other conditions that cause thick, sticky sputum that is difficult to expectorate. It works by differentiating and breaking down mucopolysaccharide fibers in sputum and inhibiting mucopolysaccharide synthesis, thereby reducing sputum viscosity, making it easier to cough up, and improving airway obstruction, with significant clinical efficacy. Improvements in its synthesis process are of great significance in reducing safety risks and environmental pollution.

[0003] Based on publicly available patents and literature, existing synthetic routes mainly fall into the following five categories:

[0004] Route 1: Chlorination condensation method.

[0005] Pu et al. reported in the Chinese Journal of Pharmaceutical Industry that bromohexene hydrochloride can be prepared by using 2-amino-3,5-dibromobenzaldehyde as a raw material, reducing it with sodium borohydride to produce 2-amino-3,5-dibromobenzyl alcohol, then chlorinating it with thionyl chloride to produce 2,4-dibromo-6-chloromethylaniline, and finally ammonifying it with N-methylcyclohexylamine to form a salt.

[0006]

[0007] The reactions along this route are relatively simple, but they involve a chlorination process with significant safety risks. The halogenated reagent thionyl chloride releases toxic gases such as sulfur dioxide during the reaction. In addition, the intermediate 2,4-dibromo-6-chloromethylaniline is highly reactive and prone to self-condensation side reactions, which can affect product quality.

[0008] CN104003887B also reports the preparation of bromhexine free base by using 2-amino-3,5-dibromobenzyl alcohol as an intermediate, using solid phosgene instead of thionyl chloride for the reaction, and then condensing it with N-methylcyclohexylamine.

[0009]

[0010] Solid phosgene decomposes into phosgene during the reaction, resulting in high waste gas treatment costs, and the process requires strict anhydrous operation.

[0011] Route 2: Catalytic condensation method.

[0012] Under acetic acid catalysis, the raw material 2-amino-3,5-dibromobenzyl alcohol and N-methylcyclohexylamine undergo a condensation reaction via toluene dehydration, and are finally acidified to form a salt to obtain bromhexine hydrochloride.

[0013]

[0014] This route avoids chlorination reagents and reduces the release of toxic gases, but it requires sophisticated equipment, including an oil-water separator; toluene dehydration requires high temperatures and consumes a lot of energy; the condensation reaction is incomplete, and toluene solvent recovery is difficult, which does not conform to the trend of green chemistry.

[0015] Route 3: Reductive amination and methylation.

[0016] In 2014, Huang et al. reported in CN104447355A that 2-amino-3,5-dibromobenzaldehyde was used as the starting material, which reacted with cyclohexylamine to obtain the corresponding Schiff base. The base was then reduced with sodium borohydride to obtain a secondary amine, which was then methylated on the N-position of the secondary amine with dimethyl sulfate. The product was acidified with hydrochloric acid to obtain bromhexine hydrochloride.

[0017]

[0018] The methylating agent used in this route, dimethyl sulfate, is a Group 1 carcinogen with strict residue control; it has poor methylation selectivity and easily generates methylation byproducts on the N-side of aniline.

[0019] Route 4: Condensation and Reduction Method.

[0020] Larsen et al. reported in J.Label.Compd.Radiopharm a preparation method using 2-amino-3,5-dibromobenzoic acid as a raw material. The method involves activation with dicyclohexylcarbodiimide (DCC) as a condensing agent and 4-dimethylaminopyridine (DMAP) as a catalyst, followed by condensation with N-methylcyclohexylamine to obtain 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide. The amide is then reduced by lithium borohydride and finally reacted with hydrochloric acid to obtain bromhexine hydrochloride.

[0021]

[0022] The condensation reagent used in this method is expensive, and it is mainly used in situations where the raw materials are expensive or the structure is complex. Furthermore, the byproduct dicyclohexylurea is difficult to remove.

[0023] Route 5: Coordination chemical synthesis.

[0024] CN102531922B reports the reaction of triacetate borate with 2-amino-3,5-dibromobenzyl alcohol to form a 2-amino-3,5-dibromobenzyl alcohol chelate, which then reacts with N-methylcyclohexylamine to form a free base of bromhexine, which is finally salted to form bromhexine hydrochloride.

[0025]

[0026] The process involves high costs for triacetate borate and the formation of chelates, which increases the complexity of the process. The overall yield is less than 50%, resulting in low industrial feasibility. Summary of the Invention

[0027] The purpose of this invention is to solve the problems existing in the above-mentioned routes and find a safe, environmentally friendly, easy-to-operate, high-yield route suitable for industrial production. Bromohexine hydrochloride is synthesized from 2-amino-3,5-dibromobenzoic acid via the anhydride method.

[0028] The present invention adopts the following technical solution:

[0029] A method for synthesizing bromhexine hydrochloride, the reaction equation is as follows:

[0030]

[0031] The specific steps are as follows:

[0032] Step (1): Using 2-amino-3,5-dibromobenzoic acid as a raw material, 2-amino-3,5-dibromobenzoic acid anhydride (compound 3) is obtained by reacting it with trimethylacetyl chloride via the anhydride method.

[0033] In step (2), 2-amino-3,5-dibromobenzoic anhydride (compound 3) from step 1 undergoes nucleophilic addition with N-methylcyclohexylamine to obtain bromhexine hydrochloride intermediate (compound 5);

[0034] Step (3): The above-mentioned bromhexine hydrochloride intermediate (compound 5) is reduced by amide and salted to obtain bromhexine hydrochloride.

[0035] In the method, preferably, step (1) involves adding an acid-binding agent before or after the reaction, wherein the acid-binding agent is at least one of triethylamine and N,N-diisopropylethylamine.

[0036] Preferably, the molar ratio of 2-amino-3,5-dibromobenzoic acid, trimethylacetyl chloride and acid-binding agent in step (1) is 1:1.2-2.0:1.2-2.0; the reaction solvent is at least one of dichloromethane, tetrahydrofuran and acetone; the reaction temperature is 0℃~10℃; and the reaction time is 1h~2h.

[0037] Preferably, in step (2), the molar ratio of 2-amino-3,5-dibromobenzoic anhydride (compound 3) to N-methylcyclohexylamine is 1:2.0-3.0; the reaction solvent is at least one of dichloromethane, tetrahydrofuran, and acetone; the reaction temperature is 0℃ to 10℃; and the reaction time is 1h to 2h.

[0038] Preferably, a reducing agent is added in step (3), wherein the reducing agent is a sodium borohydride and a boron trifluoride tetrahydrofuran complex; the molar ratio of the bromhexine hydrochloride intermediate (compound 5), the reducing agent sodium borohydride, and the reducing agent boron trifluoride tetrahydrofuran complex is 1:2.0:2.0-3.0; the reaction solvent is tetrahydrofuran; the reaction temperature is 30℃~40℃; and the reaction time is 2h.

[0039] Compared with existing processes, the present invention has the following technical advantages:

[0040] (1) It avoids the chlorination process, which is subject to key supervision, does not use hazardous reagents such as thionyl chloride and light-fixing agents, and does not produce toxic waste gas, thus significantly reducing safety risks and environmental protection investment.

[0041] (2) It does not use expensive condensation reagents such as DCC / DMAP, and has a high reaction yield, which has high economic value.

[0042] (3) The reaction is mild and there is no high-temperature reaction. Ordinary equipment can meet the process requirements and it is suitable for large-scale production.

[0043] (4) No genotoxic reagents such as dimethyl sulfate are used, the reaction mechanism is clear, there are few side reactions, and the quality of the drug can be guaranteed. Attached Figure Description

[0044] Figure 1 The HPLC chromatogram of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide prepared in Example 1 is shown below.

[0045] Figure 2 The 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide prepared in Example 1 1 H-NMR spectrum;

[0046] Figure 3 The 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide prepared in Example 1 13 C-NMR spectrum;

[0047] Figure 4 The MS spectrum of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide prepared in Example 1;

[0048] Figure 5 The HPLC chromatogram of N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzamine hydrochloride prepared in Example 1;

[0049] Figure 6 The N-methyl-N-cyclohexyl-2-amino-3,5-dibromophenylamine hydrochloride prepared in Example 1 1H-NMR spectrum;

[0050] Figure 7 The N-methyl-N-cyclohexyl-2-amino-3,5-dibromophenylamine hydrochloride prepared in Example 1 13 C-NMR spectrum;

[0051] Figure 8 The MS spectrum of N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine hydrochloride prepared in Example 1;

[0052] Figure 9 The HPLC chromatogram of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide prepared in Example 2 is shown below.

[0053] Figure 10 The HPLC chromatogram of N-methyl-N-cyclohexyl-2-amino-3,5-dibromophenylamine hydrochloride prepared in Example 2 is shown. Detailed Implementation

[0054] Example 1

[0055] Step (1): Synthesis of 2-amino-3,5-dibromobenzoic anhydride (compound 3):

[0056] 50.00 g of 2-amino-3,5-dibromobenzoic acid (1.0 eq) was added to a 1 L three-necked flask, followed by the addition of 150 mL of dichloromethane and stirring. The temperature was maintained between 0 °C and 10 °C. Then, 20.59 g of triethylamine (1.2 eq) was added, and the mixture was kept at this temperature for 0.5 h. Under the conditions of 0 °C to 10 °C, 24.53 g of trimethylacetyl chloride (1.2 eq) was slowly added dropwise, and the reaction was maintained at this temperature for 1 h to 2 h. The reaction of the starting materials was monitored by TLC until complete, yielding a solution of 2-amino-3,5-dibromobenzoic anhydride (compound 3), which was directly transferred to the next step.

[0057] Step (2): Synthesis of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide (compound 5):

[0058] 57.61 g (3.0 eq) of N-methylcyclohexylamine was added to a 1 L three-necked flask and stirred. At 0℃~10℃, the dichloromethane solution of 2-amino-3,5-dibromobenzoic anhydride obtained in step (1) was slowly added dropwise to the flask. After the addition was complete, the reaction was maintained at this temperature for 1-2 hours, and the reaction was monitored by TLC until the reactants were fully reacted. The organic phase was washed with 200 mL of purified water, the aqueous phase was discarded, and the organic phase was washed twice (120 mL * 2) with 5% sodium hydroxide aqueous solution, retaining the organic phase. The organic phase was washed twice (200 mL * 2) with purified water, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a light yellow oily liquid. 280 mL of n-heptane was added, the mixture was heated and stirred for 30 min, then cooled to 0℃~5℃, and crystallization was allowed to occur for 2 hours. After filtration, a filter cake was obtained. The temperature was controlled at 60℃±5℃ and the vacuum degree was ≤-0.09Mpa. The cake was then vacuum dried for 6 hours to obtain a white solid, which was 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide (compound 5) (43.26g, 65.41%), with a purity of 99.83%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 1.04~1.19(m,3H), 1.47~1.60(m,3H), 1.69~1.78(m,4H), 2.79(s,3H), 3.77(br s,1H),5.14(s,2H),7.17(d,J=2.24Hz,1H),7.62(d,J=2.28Hz,1H); 13 C-NMR (100MHz, DMSO-d6) δ (ppm): 25.35, 25.78, 27.50, 29.46, 30.63, 52.98, 58.32, 106.85, 109.82, 124.63, 129.12, 134.69, 141.98, 167.15. ES-MSm / z: 390.84[M+H]+.

[0059] Step (3): Synthesis of N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzamine hydrochloride (compound 1):

[0060] 30.00 g (1.0 eq) of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide (compound 5) was dissolved in 100 mL of tetrahydrofuran and added to a 500 mL three-necked flask with stirring. At 0℃–10℃, 5.82 g (2.0 eq) of sodium borohydride was added in portions, maintaining the temperature ≤30℃ after the addition. Then, 21.52 g (2.0 eq) of boron trifluoride tetrahydrofuran complex was added dropwise. After the addition was complete, the temperature was raised and maintained at 30℃–40℃ for 2 h, with TLC monitoring to ensure complete reaction of the starting material. At 10℃–20℃, 120 mL of purified water was added to quench the reaction, and 15 mL of 40% sodium hydroxide aqueous solution was added to adjust the pH to 8–9. The mixture was stirred for 30 min. The mixture was filtered, and the filtrate was extracted with dichloromethane (45 mL * 2). After standing, the liquid was separated, retaining the organic phase. The organic phase was concentrated to dryness under reduced pressure to obtain a colorless oily product. This product was dissolved in 45 mL of dichloromethane, and 11.68 g of concentrated hydrochloric acid was slowly added dropwise at 20℃~30℃ while stirring to form a salt. The temperature was lowered to 0℃~5℃, and crystallization was allowed to occur for 4 hours. The product was then filtered to obtain a filter cake. The cake was dried under vacuum at 60℃±5℃ and a vacuum degree ≤-0.09 MPa for 6 hours to obtain a white solid, which is N-methyl-N-cyclohexyl-2-amino-3,5-dibromophenylamine hydrochloride (compound 1) (23.25 g, 73.28%), with a purity of 99.88%. 1 H-NMR (600MHz, DMSO-d6) δ (ppm): 1.09 ~ 1.16 (m, 1H), 1.21 ~ 1.30 (m, 2H), 1.46 ~ 1.54 (m, 2H), 1.62 (d, J = 13.0Hz, 1H), 1.84 (t, J = 13.5Hz ,2H),2.15(t,J=13.7Hz,2H),2.54(s,3H),3.29(tt,J=12.0Hz,J=3.0Hz,1H),4.26(d,J=13.7Hz,1H),4.38(d,J=13.7Hz,1H),5.89(br s,2H);7.64~7.65(m,1H),7.68(d,J=2.3Hz,1H),9.94(br s,1H); 13 C-NMR (150MHz, DMSO-d6) δ (ppm): 24.42, 24.52, 24.58, 25.28, 26.66, 34.53, 51.49, 64.29, 106.22, 109.90, 116.85, 135.15, 135.18, 144.76. Elemental analysis (C 14 H 20 Measured values ​​(theoretical values, %) of Br2N2·HCl: C 40.89 (40.76), H 5.01 (5.13), N 6.73 (6.79). ES-MS m / z: 375.01 [M-Cl]+.

[0061] Example 2

[0062] Step (1): Synthesis of 2-amino-3,5-dibromobenzoic anhydride (compound 3):

[0063] 50.00 g of 2-amino-3,5-dibromobenzoic acid (1.0 eq) was added to a 1 L three-necked flask, followed by the addition of 150 mL of tetrahydrofuran and stirring. The temperature was maintained between 0 °C and 10 °C. Then, 40.88 g of trimethylacetyl chloride (2.0 eq) was added, and the mixture was kept at this temperature for 0.5 h. At 0 °C to 10 °C, 43.82 g of N,N-diisopropylethylamine (2.0 eq) was slowly added dropwise, and the reaction was maintained at this temperature for 2 h. A large amount of white solid was produced during the dropwise addition. The reaction was monitored by TLC until complete, yielding a solution of 2-amino-3,5-dibromobenzoic anhydride (compound 3), which was directly transferred to the next step.

[0064] Step (2): Synthesis of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide (compound 5):

[0065] Under conditions of 0℃~10℃, 38.41g (2.0eq) of N-methylcyclohexylamine was slowly added dropwise to a tetrahydrofuran solution of 2-amino-3,5-dibromobenzoic anhydride. After the addition was complete, the reaction was maintained at this temperature for 1h~2h, and the reaction was monitored by TLC until the starting material was completely reacted. 150mL of dichloromethane was added to extract the reaction solution, and the organic phase was washed with 200mL of purified water. The aqueous phase was discarded, and the organic phase was washed twice with 5% sodium hydroxide aqueous solution (120mL*2), retaining the organic phase. The organic phase was washed twice with purified water (200mL*2), dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a light yellow oily liquid. 280mL of n-heptane was added, and the mixture was heated and stirred for 30min. The temperature was then lowered to 0℃~5℃, and crystallization was allowed to occur for 2h. After filtration, a filter cake was obtained. The temperature was controlled at 60℃±5℃, and the vacuum degree was ≤-0.09Mpa. The cake was then vacuum dried for 6 hours to obtain a white solid, which was 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide (compound 5) (36.14g, 54.64%), with a purity of 95.42%. The spectral data were the same as in Example 1.

[0066] Step (3): Synthesis of N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzamine hydrochloride (compound 1):

[0067] 30.00 g (1.0 eq) of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzamide was dissolved in 100 mL of tetrahydrofuran and added to a 500 mL three-necked flask with stirring. 5.82 g (2.0 eq) of sodium borohydride was added in portions at 0℃–10℃, maintaining the temperature ≤30℃ after the addition. Then, 32.28 g (3.0 eq) of boron trifluoride tetrahydrofuran complex was added dropwise. After the addition was complete, the temperature was raised and maintained at 30℃–40℃ for 2 h, with TLC monitoring to ensure complete reaction of the starting material. The reaction was quenched by adding 120 mL of purified water at 10℃–20℃, and the pH was adjusted to 8–9 by adding 15 mL of 40% sodium hydroxide aqueous solution. The mixture was stirred for 30 min. The mixture was filtered, and the filtrate was extracted with dichloromethane (45 mL * 2). After standing, the liquid was separated, retaining the organic phase. The organic phase was concentrated to dryness under reduced pressure to obtain a colorless oily product. This product was dissolved in 45 mL of dichloromethane, and 11.68 g of concentrated hydrochloric acid was slowly added dropwise at 20°C–30°C while stirring to form a salt. The mixture was then cooled to 0°C–5°C and allowed to crystallize for 4 hours. After filtration, a filter cake was obtained. The cake was then vacuum dried at 60°C ± 5°C and a vacuum degree ≤ -0.09 MPa for 6 hours to obtain a white solid, namely N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzamine hydrochloride (compound 1) (22.68 g, 71.48%), with a purity of 97.95%. Spectral data were the same as in Example 1.

[0068] The above embodiments provide a detailed description of a method for synthesizing bromhexine hydrochloride provided by the present invention. Compared with the prior art, the present invention elaborates on its advantages, implementation methods, and preferred conditions. The examples are provided to help understand the method and core ideas of the present invention.

Claims

1. A method for synthesizing bromhexine hydrochloride, characterized in that, The reaction equation is: The specific steps are as follows: Step (1): Using 2-amino-3,5-dibromobenzoic acid as a raw material, the compound 2-amino-3,5-dibromobenzoic acid anhydride is obtained by reacting it with trimethylacetyl chloride via the anhydride method. In step (2), the compound 2-amino-3,5-dibromobenzoic anhydride obtained in step 1 undergoes nucleophilic addition with N-methylcyclohexylamine to obtain compound 5, bromhexine hydrochloride intermediate; Step (3): The above compound 5, bromhexine hydrochloride intermediate, is reduced by amide and salted to obtain bromhexine hydrochloride.

2. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, In step (1), an acid-binding agent is added, wherein the acid-binding agent is at least one of triethylamine and N,N-diisopropylethylamine.

3. The method for synthesizing bromhexine hydrochloride according to claim 2, characterized in that, The molar ratio of 2-amino-3,5-dibromobenzoic acid, trimethylacetyl chloride and acid binder in step (1) is 1:1.2-2.0:1.2-2.

0.

4. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, The reaction solvent in step (1) is at least one of dichloromethane, tetrahydrofuran, and acetone; the reaction temperature is 0℃~10℃; and the reaction time is 1h~2h.

5. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, The molar ratio of the compound 2-amino-3,5-dibromobenzoic anhydride to N-methylcyclohexylamine in step (2) is 1:2.0-3.

0.

6. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, The reaction solvent in step (2) is at least one of dichloromethane, tetrahydrofuran and acetone; the reaction temperature is 0℃~10℃; and the reaction time is 1h~2h.

7. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, In step (3), a reducing agent is added, which is a sodium borohydride and boron trifluoride tetrahydrofuran complex.

8. The method for synthesizing bromhexine hydrochloride according to claim 7, characterized in that, The molar ratio of compound 5, the bromhexine hydrochloride intermediate, sodium borohydride, and the boron trifluoride tetrahydrofuran complex in step (3) is 1:2.0:2.0-3.

0.

9. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, The reaction solvent in step (3) is tetrahydrofuran.

10. The method for synthesizing bromhexine hydrochloride according to claim 1, characterized in that, The reaction temperature in step (3) is 30℃~40℃; the reaction time is 2h.

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