Preparation method of bromhexine hydrochloride

Abstract

The invention discloses a preparation method of bromhexine hydrochloride, which comprises the following steps: sequentially reacting 2-amino-3, 5-dibromobenzaldehyde as shown in a formula (I) with monomethylamine and sodium borohydride to obtain an intermediate as shown in a formula (II), then reacting with cyclohexanone to obtain an intermediate as shown in a formula (IV), and then reacting with sodium borohydride and acetic acid to obtain bromhexine as shown in a formula (V), and finally acidifying bromhexine with hydrochloric acid to obtain the bromhexine hydrochloride product shown in the formula VI. The intermediate II can directly participate in synthesis of the intermediate IV without purification, and the obtained intermediate IV and intermediate V can be obtained through simple crystallization and filtration. And upstream process impurities are prevented from being introduced or accumulated into a final product, namely impurity removal and industrial production in the process are facilitated. Besides, the use of expensive N-methylcyclohexylamine is avoided in the process, and the used cyclohexanone and methylamine can be easily removed by drying or filtering in the subsequent process, so that the quality of the finished product is ensured.

Description

Technical Field

[0001] The invention relates to a preparation method of bromhexine hydrochloride and belongs to the technical field of medicines. Background Art

[0002] Bromhexine Hydrochloride (N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine hydrochloride) is an expectorant developed by Boehringer Ingelheim. It is mainly used for patients with bronchitis, asthma, emphysema and other sticky sputum that is difficult to cough up. It is a white or off-white crystalline powder. Its structure is as follows:

[0003]

[0004] There are many documents reporting on the synthesis method and process of bromhexine hydrochloride. Among them, patent CN106631828A (2017.5.10) announced that 2-amino-3,5-dibromobenzaldehyde and methylcyclohexylamine were used as starting materials, and the two were condensed under the catalysis of tetraisopropyl titanate to obtain Schiff base, and then directly reduced with sodium borohydride to prepare bromhexine product, and then acidified with hydrochloric acid to prepare bromhexine hydrochloride product, with a total yield of up to 81% (see route 1). Titanate reagents are used in this process, and a large amount of insoluble matter is produced during the post-treatment process, which brings inconvenience to industrial operation.

[0005]

[0006] Patent CN111470983A (2020.7.31) announced that 2-amino-3,5-dibromobenzaldehyde is used as the starting material, reduced by sodium borohydride, chlorinated by dichlorothionyl, and then condensed with N-methylcyclohexylamine to form a bromhexine product, which is then acidified with hydrochloric acid to obtain a new bromhexine hydrochloride product, with a maximum total yield of 63.25% and a finished product purity of 99.93% (see route 2). During the first step of the reduction reaction of this process, bromine atoms are easily removed, resulting in monobromine or bromine-free impurities; in the subsequent use of SOCl 2 During chlorination, a side reaction occurs in which chlorine atoms replace bromine atoms, generating chlorinated impurities. These impurities have similar polarity to the product and are difficult to remove by recrystallization. They will continue to be introduced into the final product, affecting its quality.

[0007]

[0008]

[0009] Patent WO2023 / 058050 discloses a method of using cheap o-nitrobenzyl bromide as a starting material, undergoing nucleophilic substitution with cyclohexylmethylamine, and then undergoing Raney nickel catalytic hydrogenation reduction, liquid bromine bromination, and hydrochloric acid acidification to obtain a new product of bromhexyl hydrochloride (route 3). Although the starting material o-nitrobenzyl bromide used in this process is relatively cheap, the bromination step is close to the step of synthesizing the target product, and the monobrominated or isomeric brominated impurities produced during the bromination process are difficult to remove in the latter step of the salt formation process, and the oxidizing property of bromine will cause aniline to form N-oxide impurities, and the total molar yield is up to 43%.

[0010]

[0011] Patent CN103333074A (2013.10.2) discloses a method for preparing bromhexine hydrochloride (route 4), which uses 2-amino-3,5-dibromobenzyl alcohol as a raw material, dehydrates and condenses with methylcyclohexylamine at a high temperature of 180°C to obtain a bromhexine product, and then acidifies with hydrochloric acid to obtain a new bromhexine hydrochloride product. This process requires strict high temperature resistance requirements for equipment, and the generated water needs to be continuously removed during the reaction. The reaction time is long, and after the reaction is completed, the excess N-methylcyclohexylamine needs to be evaporated under high vacuum and reduced pressure, which is not conducive to industrial production.

[0012]

[0013] Patent CN104610073A (2015.5.13) announced that 2-aminobenzoic acid methyl ester was used as raw material, bromination by liquid bromination, KBH 4 Reduction, dehydration condensation, and hydrochloric acid acidification give the new bromhexine hydrochloride product. This process is consistent with the dehydration condensation step in patent CN103333074A, and also uses high-temperature dehydration for condensation to prepare the bromhexine product. This process inevitably causes the production of by-products due to the significantly high temperature, such as: the bromine atom in the intermediate 2-amino-3,5-dibromobenzyl alcohol undergoes a substitution reaction with methylcyclohexylamine, or the bromine substitution reaction occurs between the molecules of 2-amino-3,5-dibromobenzyl alcohol itself, etc. These impurity generation steps are adjacent to the finished product preparation steps, which poses a high risk to the finished product quality control.

[0014]

[0015] The existing method mainly uses methylcyclohexylamine as one of the main raw materials when preparing bromhexine hydrochloride, and its market price is high, resulting in a higher finished product of the new bromhexine hydrochloride. In addition, the existing process has no relevant reports on debromination process impurities (see formula VII, formula VIII and formula IX), and these process impurities are introduced into the new bromhexine hydrochloride product and are difficult to remove by conventional filtration or crystallization, and must be controlled in the process of the process or in the upstream intermediate.

[0016] Summary of the invention

[0017] The technical problem to be solved by the present invention is to provide a new preparation method of bromhexine hydrochloride, which has the characteristics of high yield and high purity, and the indicators of the obtained new bromhexine hydrochloride product meet the requirements of domestic and foreign pharmacopoeia standards, and the intermediate IV (formula IV) and the intermediate V (formula V) in the preparation process are both solid, which is conducive to purification and removal of process impurities through a crystallization and filtration method, and is conducive to obtaining products that meet quality standards in industrial production, and meets the current QbD principle of drug development of raw materials.

[0018] In order to solve the above technical problems, the present invention discloses a method for preparing bromhexine hydrochloride. The method comprises the following steps: 2-amino-3,5-dibromobenzaldehyde as shown in formula (I) reacts with monomethylamine and sodium borohydride in sequence to obtain an intermediate as shown in formula (II); the intermediate is then reacted with cyclohexanone to obtain an intermediate as shown in formula (IV); the intermediate is then reacted with sodium borohydride and acetic acid to obtain bromhexine as shown in formula (V); and the bromhexine is finally acidified with hydrochloric acid to obtain a bromhexine hydrochloride product as shown in formula (VI).

[0019]

[0020] Further, the method comprises the following steps,

[0021] (1) 2-amino-3,5-dibromobenzaldehyde and methanol or ethanol as shown in formula (I) are added to a reaction vessel, stirring is started, and after the solution is dissolved, a methanol or ethanol solution of monomethylamine is added, and the temperature is raised to 40-50° C. for reaction. After the reaction is complete (the compound as shown in formula (I) disappears completely by TLC detection), the temperature is lowered to 0-10° C., and sodium borohydride is added in batches at the same temperature for reaction. After the reaction is complete (the intermediate product methylamine Schiff base generated by TLC detection disappears completely), 5-10 wt % hydrochloric acid or saturated ammonium chloride solution is added dropwise to the reaction solution for quenching, and the pH value of the solution is adjusted to 6-7. The solution The mixture is concentrated to dryness under reduced pressure, toluene and pure water are added to the residue, stirred for 10 to 20 minutes, filtered, and the filtrate is adjusted to pH 9 to 10 with a 20 to 30 wt % alkali metal hydroxide solution, allowed to stand, the organic phase is separated, washed with water, dried, filtered, and concentrated to obtain a yellow viscous substance, which is the intermediate represented by formula (II); in the step (1), after the sodium borohydride is added to react completely, the use of hydrochloric acid during quenching is more conducive to subsequent stratification; the alkali metal hydroxide solution can be a sodium hydroxide solution, a potassium hydroxide solution, or a lithium hydroxide solution; the molar yield of this step is greater than 94%, and the purity measured by HPLC is greater than 97.5%;

[0022] (2) adding a solvent to the intermediate of formula (II) obtained in step (1) at room temperature, stirring until completely dissolved, then adding cyclohexanone and acetic acid, reacting at 30-55° C., after the reaction is complete (TLC detection shows that the intermediate of formula (II) disappears completely), crystallizing at 0-20° C., filtering and drying to obtain a white solid powder, namely the intermediate of formula (IV), with a melting point of 103.7-105.9° C., a molar yield of 94.3%, and an HPLC yield of greater than 99.9%;

[0023] (3) adding the intermediate represented by formula (IV) obtained in step (2) and the solvent to a reaction vessel, cooling the temperature to -5 to 5°C, adding sodium borohydride in batches, then adding acetic acid dropwise, heating the temperature to 20 to 30°C, and after the reaction is complete (the intermediate (IV) disappears completely as detected by TLC), cooling the solution to -5 to 5°C, adding pure water (for quenching sodium borohydride), and then adjusting the pH to 10 to 12 with a 20 to 30 wt % alkali metal hydroxide solution, standing, separating, washing the organic layer with water, drying, and filtering, and concentrating the filtrate under reduced pressure to obtain an oily residue; adding C to the oily residue; 1 ~C 4 The solution is heated to reflux and stirred for 20 to 30 minutes, slowly cooled to 30 to 36°C and stirred at a constant temperature for 20 to 30 minutes, then cooled to 0 to 15°C and stirred for crystallization, filtered and dried to obtain a white powder solid, which is bromhexine shown in formula (V), with a melting point of 47.3 to 50.8°C, a molar yield of 93 to 95%, and an HPLC rate of more than 99.5%;

[0024] (4) Add the bromhexine of formula (V) obtained in step (3) and a solvent into a reaction vessel, add concentrated hydrochloric acid dropwise at room temperature, stir for 1 to 2 hours after the addition is complete, crystallize at 0 to 20° C., filter, and dry to obtain a white powder solid, which is the bromhexine hydrochloride product of formula (VI), with a melting point of 239.8 to 241.7° C., a molar yield of greater than 98%, and an HPLC yield of greater than 99.85%.

[0025] Furthermore, in step (1), the molar ratio of 2-amino-3,5-dibromobenzaldehyde represented by formula (I) to monomethylamine contained in the methanol or ethanol solution of monomethylamine is 1.0:1.05-1.3; the molar ratio of 2-amino-3,5-dibromobenzaldehyde represented by formula (I) to sodium borohydride is 1.0:0.75-0.90.

[0026] Furthermore, the solvent used in step (2) is methanol or ethanol, or a mixture of methanol and ethanol in any ratio, and the volume mass ratio of the intermediate represented by formula (II) is 3.0-5.0 mL:1.0 g. In the present invention, since the intermediate IV is relatively stable, even if there is a small amount of water in the solvent, it has no significant effect on the present invention, but anhydrous methanol or anhydrous ethanol is still better, with a mass concentration of at least not less than 95%.

[0027] Furthermore, in step (2), the molar ratio of the cyclohexanone to the intermediate represented by formula (II) is 1.1-1.2:1.0; and the mass of the acetic acid is 0.3-0.5% of the mass of the intermediate represented by formula (II).

[0028] Furthermore, in step (3), the solvent is toluene, cyclohexane or n-heptane. When toluene is used, the conversion rate is the highest. The volume mass ratio of the solvent to the intermediate represented by formula (IV) is 4 to 6 mL: 1 g, preferably 6 mL: 1 g.

[0029] Furthermore, in step (3), the molar ratio of sodium borohydride to the intermediate represented by formula (IV) is 0.8-1.0:1.0, and the molar ratio of acetic acid to the intermediate represented by formula (IV) is 3.7-4.0:1.0.

[0030] Furthermore, in step (3), C 1 ~C 4 The alcohol solvent is 95-100 wt% methanol, 95-100 wt% ethanol or 95-100 wt% isopropanol, or pure butanol. 1 ~C 4 The volume mass ratio of the alcohol solvent to the intermediate represented by formula (IV) is 1.5-2.5 mL:1.0 g; the volume mass ratio of the added pure water to the intermediate represented by formula (IV) is 3-5 mL:1 g.

[0031] Furthermore, in step (3), the slow cooling rate is 1-2°C / min.

[0032] Furthermore, in step (4), the solvent is acetone or ethyl acetate, and the volume mass ratio of the solvent to bromhexine shown in formula (V) is 2 to 8 mL:1 g, and the crystallization yield and quality are optimal when the ratio is 6 mL:1 g.

[0033] The invention uses 2-amino-3,5-dibromobenzaldehyde, methylamine solution and cyclohexanone as key materials to prepare bromhexine hydrochloride, which is a new process for preparing bromhexine hydrochloride. 2-amino-3,5-dibromobenzaldehyde and methylamine solution can quickly generate methylamine Schiff base, which can then be reduced with sodium borohydride to generate intermediate (II). The intermediate (II) obtained after the reaction solution is treated does not need to be further purified, and is directly reacted with cyclohexanone (III) in an alcohol solvent to obtain intermediate (IV). The intermediate (IV) with high purity and high yield can be prepared through crystallization, filtration and drying. When preparing intermediate (IV), excess remaining materials in the reaction process, a small amount of process impurities generated, and process impurities that may be introduced by intermediate (II) can all be effectively removed during filtration, and the HPLC purity of the obtained intermediate (IV) is greater than 99.9%, and the yield is 94-95%. The high-purity intermediate (IV) helps to further control process impurities from the source when preparing the intermediate (V), ensuring that the obtained intermediate (V) has ideal quality and yield, with HPLC purity greater than 99.5% and molar yield of 93-95%. The intermediate (V) can be acidified with hydrochloric acid, filtered and dried to obtain a new product of bromhexyl hydrochloride, with a purity greater than 99.85%, a molar yield greater than 98%, and a total molar yield of the product greater than 80%.

[0034] Generally speaking, the advantage of the present invention is that the intermediate (II) in the technological process can directly participate in the synthesis of the intermediate (IV) without purification, and the obtained intermediate (IV) and the intermediate (V) can be obtained by simple crystallization and filtration. By controlling the quality of the intermediate (V) by crystallization, the new bromhexyl hydrochloride product with high purity and high yield can be effectively obtained, and the upstream process impurities are avoided to be introduced or accumulated in the finished product, i.e., the impurity removal and industrialized production of the technological process are beneficial. In addition, the use of expensive N-methylcyclohexylamine is avoided in the technology, and the pimelinketone and methylamine used can be easily removed by drying or filtering in the subsequent process, thereby ensuring the finished product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the HPLC detection spectrum of intermediate II in Example 1;

[0036] Figure 2 This is the HPLC detection spectrum of intermediate IV in Example 1;

[0037] Figure 3 It is the HPLC detection spectrogram of the intermediate V (bromhexine) of Example 1;

[0038] Figure 4 The HPLC detection spectrogram of the product bromhexine hydrochloride of Example 1;

[0039] Figure 5 The MS detection spectrogram of the product bromhexine hydrochloride of Example 1 DETAILED DESCRIPTION

[0040] The present invention is further explained below in conjunction with the examples. The following examples are only used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0041] Example 1

[0042] (1) Preparation of Intermediate II

[0043] Put 50g of 2-amino-3,5-dibromobenzaldehyde and 300mL of methanol into a 1000mL four-necked bottle and start stirring. After the solution becomes clear, add 19.47g of 30% monomethylamine methanol solution. After the addition, raise the temperature to 50°C and keep the reaction for 6h. Take a sample for TLC analysis to show that no raw material remains. The temperature was lowered to 0-5°C and maintained, 5.07 g of sodium borohydride was added in batches, and the reaction was kept at the same temperature after the addition was completed. Samples were taken for TLC detection and analysis to show that no raw material remained. 10 wt % hydrochloric acid was added dropwise to the solution to adjust the pH of the solution to 6-7, and the solution was concentrated to dryness under reduced pressure. 200 mL of toluene and 100 mL of pure water were added to the residue, stirred for 10 min, filtered, and the pH of the filtrate water layer was adjusted to 9-10 with 30 wt % sodium hydroxide solution. The mixture was allowed to stand, separated, and the organic layer was washed with 200 mL of water, separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 49.8 g of a yellow oily viscous substance, namely intermediate II, with a molar yield of 94.7% and a HPLC purity of 97.67% (see Figure 1 ).

[0044] (2) Preparation of Intermediate IV

[0045] Add 49.8g of intermediate II and 200mL of methanol to the reaction flask, stir until dissolved, add 18.28gg of cyclohexanone, and then add 0.25g of acetic acid. Heat to 46℃ and keep warm for 15 hours until the reaction is complete. Cool the reaction solution to 3℃ and keep warm for crystallization. Filter and dry to obtain 59.7g of white solid product (i.e., intermediate IV), with a molar yield of 94.2%, HPLC: 99.95% (see attached Figure 2 ).

[0046] (3) Preparation of Intermediate V (Bromhexine)

[0047] 55g of intermediate IV and 300mL of toluene were added to a reaction flask, stirred and cooled to 5°C, 5g of sodium borohydride was added in batches at the same temperature, and then 32.7g of acetic acid was added. After the addition, the solution was heated to 30°C and kept for reaction for 12h. The solution was cooled to 0°C, 165mL of pure water was added, and after the dripping, the pH was adjusted to 10-12 with 30wt% sodium hydroxide solution, and the organic phase was separated, and then washed with 100mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to an oily substance. 82.5mL of 95wt% methanol solution was added to the oily substance, the temperature was raised and refluxed for 10 minutes, the temperature was slowly lowered to 33°C at a rate of 1-2°C / min and stirred at a constant temperature for 25 minutes, then the temperature was lowered to 15°C for crystallization for 30 minutes, filtered, and dried to obtain 51.5g of a white solid product, i.e., bromhexine (intermediate V), with a molar yield of 93.2% and a HPLC purity of 99.72% (see attached Figure 3 ), melting point: 47.5~49.2℃.

[0048] (4) Preparation of Bromhexine Hydrochloride

[0049] At room temperature, 45 g of intermediate IV was added to a reaction flask, 270 mL of acetone was added, and then 13.1 g of 36 wt% concentrated hydrochloric acid was added dropwise. The reaction was kept warm for 80 minutes, the temperature was cooled to 0°C with stirring, suction filtered, and vacuum dried to obtain 48.9 g of white powder solid, i.e., the product of bromhexyl hydrochloride, with a molar yield of 98.9% and a HPLC purity of 99.9% (see attached Figure 4 ), melting point 239.8~240.7℃, MS detection, product characteristic molecular ion peak [M+1]=377.01, consistent with the characteristic peak of bromhexine hydrochloride molecular ion (see attached Figure 5 ).

[0050] Example 2

[0051] (1) Preparation of Intermediate II

[0052] Put 40g of 2-amino-3,5-dibromobenzaldehyde and 300mL of anhydrous ethanol into a 1000mL four-necked bottle and start stirring. After the solution becomes clear, add 17.8g of 30wt% monomethylamine methanol solution. After adding, raise the temperature to 45°C and keep the reaction for 5 hours. Take a sample for TLC analysis to show that no raw material remains. The temperature was lowered to an internal temperature of 0 to 5°C and maintained at this temperature. 4.33 g of sodium borohydride was added in batches. After the addition was completed, the reaction was kept warm. Samples were taken for TLC detection and analysis. No raw material residue was found. The pH of the solution was adjusted to 6 to 7 with 5 wt% hydrochloric acid. The mixture was then concentrated to dryness under reduced pressure. 150 mL of toluene and 150 mL of pure water were added to the residue. The mixture was stirred for 10 minutes and filtered. The pH of the aqueous layer was adjusted to 9 to 10 with 20 wt% NaOH solution. The organic layer was washed with 150 mL of water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 39.8 g of the intermediate shown in formula II as an oily viscous substance with a molar yield of 94.6%. HPLC: 97.62%.

[0053] (2) Preparation of Intermediate IV

[0054] 29.4 g of intermediate II and 90 ml of methanol were added to the reaction flask, and stirring was started. After the solution was dissolved, 11.8 g of cyclohexanone was added, and then 0.088 g of acetic acid was added. The temperature was raised to 50 ° C and the reaction was kept for 8 hours. The reaction was completed. The reaction solution was cooled to 5 ° C and kept for crystallization for 20 minutes. Filtered and dried to obtain 35.1 g of white solid powder, namely intermediate IV, with a molar yield of 93.9%, HPLC: 99.97%.

[0055] (3) Preparation of Intermediate V (Bromhexine)

[0056] 35 g of intermediate IV and 200 mL of toluene were added to a reaction flask, stirred and cooled to 3°C, 2.84 g of sodium borohydride was added in batches at the same temperature, and then 22.6 g of acetic acid was added dropwise. After the addition, the solution was heated to 25°C and reacted for 14 h, then cooled to 5°C, 100 mL of water was added, and after the dropwise addition, the solution pH was adjusted to 10-12 with 20 wt% sodium hydroxide, and the layers were allowed to stand and separated. The organic phase was washed with 80 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to an oil.

[0057] 87.5 mL of 95 wt% ethanol solution was added to the oily substance, the mixture was heated to reflux and stirred for 20 minutes, the temperature was slowly lowered to 40 ° C at a rate of 1 to 2 ° C / min and stirred at a constant temperature for 30 minutes, then the temperature was lowered to 10 ° C for crystallization for 30 minutes, filtered and dried to obtain 32.8 g of a white solid product, i.e. bromhexine (intermediate V), with a molar yield of 92.8%, HPLC purity of 99.73%, and a melting point of 47.7 to 49.1 ° C.

[0058] (4) Preparation of Bromhexine Hydrochloride

[0059] At room temperature, 30 g of intermediate IV was added to a reaction bottle, 120 mL of acetone was added, and then 8.5 g of 36 wt% concentrated hydrochloric acid was added dropwise, and then the reaction was kept warm for 1 hour, stirred and cooled to 20°C, filtered, and vacuum dried to obtain 32.6 g of white powder solid, i.e., the new bromhexyl hydrochloride product, with a molar yield of 98.7%, an HPLC purity of 99.92%, and a melting point of 239.8-240.9°C.

[0060] Example 3

[0061] (1) Preparation of Intermediate II

[0062] 50 g of 2-amino-3,5-dibromobenzaldehyde and 200 mL of anhydrous ethanol were put into a 1000 mL four-necked flask, and 24.1 g of a 30% monomethylamine methanol solution was added. After the addition, the temperature was raised to 47°C, and the mixture was kept warm for 5 hours. After TLC tracking and detection, almost no raw material remained. The solution was cooled to 10°C, and 6.1 g of sodium borohydride was added in batches. After the addition, the mixture was kept warm for 5 hours. After TLC tracking and detection, the reaction was completed, 5 wt% hydrochloric acid solution was added dropwise to the solution to adjust the pH to 6-7, and the solution was concentrated to dryness under reduced pressure. 180 mL of toluene and 150 mL of pure water were added to the residue, stirred, and filtered. The pH of the filtrate was adjusted to 9-10 with a 25% sodium hydroxide solution, and the mixture was allowed to stand and separated. The organic layer was washed with 150 mL of water, allowed to stand, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 50.1 g of an oily and viscous intermediate II product with a molar yield of 95.2%, and HPLC: 97.56%.

[0063] (2) Preparation of Intermediate IV

[0064] 50.1 g of intermediate II and 250.5 ml of ethanol were added to a reaction flask, stirring was started, 19.35 g of cyclohexanone was added, and then 0.175 g of acetic acid was added. The temperature was raised to 35°C for reaction. TLC detection showed that intermediate IV had almost completely disappeared. The reaction solution was cooled to 10°C for crystallization. After suction filtration and drying, 59.7 g of intermediate IV was obtained as a white solid product with a molar yield of 93.9% and HPLC: 99.96%.

[0065] (3) Preparation of Intermediate V (Bromhexine)

[0066] 55g of intermediate IV and 350mL of cyclohexane were added to a reaction flask, stirred and cooled to -5°C, 5.56g of sodium borohydride was added in batches at the same temperature, and then 33.5g of acetic acid was added dropwise. After the addition, the solution was heated to 28°C and kept warm for reaction for 12h. The solution was cooled to 2°C, 275mL of pure water was added, and after the addition was complete, the pH value of the solution was adjusted to 10-12 with 25wt% sodium hydroxide solution. The solution was allowed to stand and the layers were separated. The organic phase was separated and washed with 120mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to an oil. 100.2 mL of 95 wt% isopropanol solution was added to the oil, the mixture was heated to reflux and stirred for 25 minutes, the temperature was slowly lowered to 30° C. at a rate of 1 to 2° C. / min and stirred at a constant temperature for 20 minutes, the temperature was then lowered to 0° C. for crystallization for 60 minutes, the mixture was filtered off with suction, and dried to obtain 51.3 g of a white solid product, i.e., bromhexine (intermediate V), with a molar yield of 92.8%, an HPLC purity of 99.71%, and a melting point of 47.6 to 49.5° C.

[0067] (4) Preparation of Bromhexine Hydrochloride

[0068] At room temperature, 50 g of intermediate IV was added to a reaction flask, 220 mL of acetone was added, and then 14.8 g of 36% concentrated hydrochloric acid was added dropwise to the solution. After the addition, the mixture was reacted at room temperature for 2 hours, the temperature was lowered to 8 ° C for crystallization, suction filtered, and vacuum dried to obtain 48.9 g of a white solid powder product, i.e., bromhexine hydrochloride product, with a molar yield of 98.7%, a purity of 99.96% measured by HPLC, and a melting point of 239.9-240.4 ° C.

[0069] Example 4

[0070] (1) Preparation of Intermediate II

[0071] 50g 2-amino-3,5-dibromobenzaldehyde and 220mL methanol were put into a 1000mL four-necked bottle, and 24.1g of 30wt% monomethylamine methanol solution was added. After the addition, the temperature was raised to 46°C. After TLC tracking detection, there was basically no raw material residue. The solution was cooled to 6°C, and 5.75g sodium borohydride was added in batches. After the addition, the temperature was kept warm for reaction. After TLC tracking detection, 8wt% hydrochloric acid was added dropwise to the solution to adjust the pH of the solution to 6-7, and the solution was concentrated to dryness under reduced pressure. 160mL toluene and 160mL pure water were added to the residue, stirred, filtered, and the pH of the filtrate was adjusted to 9-10 with 20wt% sodium hydroxide solution. The mixture was allowed to stand and separated. The organic layer was washed with 200mL water, stood and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 49.8g of oily viscous intermediate II product with a molar yield of 94.6% and a purity of 97.57% measured by HPLC.

[0072] (2) Preparation of Intermediate IV

[0073] 50 g of intermediate II and 175 ml of ethanol were added to a reaction flask, stirring was started, 19.5 g of cyclohexanone was added, and after the addition, 0.2 g of acetic acid was added. The temperature was raised to 37°C for reaction. TLC detection showed that intermediate IV had almost completely disappeared. The reaction solution was cooled to 10°C for crystallization. After suction filtration and drying, 59.6 g of a white solid product, namely intermediate IV, was obtained. The molar yield was 93.7%. The purity was 99.94% as measured by HPLC.

[0074] (3) Preparation of Intermediate V (Bromhexine)

[0075] 55 g of intermediate IV and 330 mL of n-heptane were added to a reaction flask, stirred and cooled to 3.5°C, 5.5 g of sodium borohydride was added in batches at the same temperature, and then 35 g of acetic acid was added dropwise. After the addition, the solution was heated to 26.5°C and kept warm for 13 hours. The solution was cooled to 3.5°C, 180 mL of pure water was added, and after the addition was complete, the pH value of the solution was adjusted to 10-12 with 20% sodium hydroxide. The layers were allowed to stand and the organic phase was separated. The organic layer was washed with 150 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to an oil. Add 100 mL of anhydrous methanol to the oil, heat up and reflux with stirring for 20 minutes, slowly cool to 38 ° C and stir at a constant temperature for 20 minutes, then cool to 5 ° C for crystallization for 50 minutes, filter and dry to obtain 51.5 g of white solid product, i.e. bromhexine (intermediate V), with a molar yield of 93.0%, HPLC purity of 99.28%, and a melting point of 48.2-49.7 ° C.

[0076] (4) Preparation of Bromhexine Hydrochloride

[0077] At room temperature, 50 g of intermediate IV was added to a reaction flask, 250 mL of ethyl acetate was added, and then 14.5 g of 36 wt% concentrated hydrochloric acid was added dropwise to the solution. After the addition, the mixture was reacted at room temperature for 1.5 hours, the temperature was lowered to 16 ° C for crystallization, suction filtered, and vacuum dried to obtain 54 g of a white solid powder product, i.e., bromhexine hydrochloride product, with a molar yield of 98.4%, an HPLC purity of 99.94%, and a melting point of 240.2-241.3 ° C.

Claims

1. A method for preparing bromhexine hydrochloride, characterized in that: The method comprises the following steps: 2-amino-3,5-dibromobenzaldehyde represented by formula (I) reacts with monomethylamine and sodium borohydride in sequence to obtain an intermediate represented by formula (II); the intermediate reacts with cyclohexanone to obtain an intermediate represented by formula (IV); the intermediate reacts with sodium borohydride and acetic acid to obtain bromhexine represented by formula (V); and the bromhexine is finally acidified with hydrochloric acid to obtain a bromhexine hydrochloride product represented by formula (VI).

2. the preparation method of bromhexine hydrochloride according to claim 1, is characterized in that: The method comprises the following steps, (1) Add 2-amino-3,5-dibromobenzaldehyde and methanol or ethanol as shown in formula (I) into a reaction vessel, start stirring, add a methanol or ethanol solution of monomethylamine after the solution becomes clear, heat to 40-50°C for reaction, cool to 0-10°C after the reaction is complete, and add sodium borohydride in batches at the same temperature for reaction, add hydrochloric acid or ammonium chloride solution dropwise to the reaction solution for quenching, and adjust the solution pH to 6-7, concentrate the solution to dryness under reduced pressure, add toluene and pure water to the residue, stir for 10-20 minutes, filter, adjust the filtrate to pH 9-10 with an alkali metal hydroxide solution, let stand, separate the organic phase, wash with water, dry, filter, and concentrate to obtain the intermediate as shown in formula (II); (2) adding a solvent to the intermediate of formula (II) obtained in step (1), stirring until completely dissolved, then adding cyclohexanone and acetic acid, reacting at 30-55° C., crystallizing at 0-20° C. after the reaction is complete, filtering, and drying to obtain the intermediate of formula (IV); (3) adding the intermediate represented by formula (IV) obtained in step (2) and a solvent to a reaction vessel, cooling to -5 to 5°C, adding sodium borohydride in batches, then adding acetic acid dropwise, heating to 20 to 30°C, after the reaction is complete, cooling the solution to -5 to 5°C, adding pure water, and adjusting the pH to 10 to 12 with an alkali metal hydroxide solution, standing, stratifying, washing the organic layer with water, drying, and filtering, and concentrating the filtrate under reduced pressure to obtain an oily residue; adding a C1 to C4 alcohol solvent to the oily residue, heating the solution to reflux and stirring for 20 to 30 minutes, slowly cooling to 30 to 36°C, stirring at a constant temperature for 20 to 30 minutes, and then cooling to 0 to 15°C, stirring and crystallizing, filtering with suction, and drying to obtain bromhexine represented by formula (V); (4) Add the bromhexine of formula (V) obtained in step (3) and a solvent into a reaction vessel, add concentrated hydrochloric acid dropwise at room temperature, stir for 1 to 2 hours after the addition, crystallize at 0 to 20° C., filter, and dry to obtain the bromhexine hydrochloride product of formula (VI).

3. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: In step (1), the molar ratio of 2-amino-3,5-dibromobenzaldehyde represented by formula (I) to monomethylamine contained in the methanol or ethanol solution of monomethylamine is 1.0:1.05-1.3; the molar ratio of 2-amino-3,5-dibromobenzaldehyde represented by formula (I) to sodium borohydride is 1.0:0.75-0.

90.

4. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: The solvent used in step (2) is methanol or ethanol, or a mixture of methanol and ethanol in any ratio, and the volume mass ratio of the solvent to the intermediate represented by formula (II) is 3.0-5.0 mL:1.0 g.

5. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: In step (2), the molar ratio of cyclohexanone to the intermediate represented by formula (II) is 1.1-1.2:1.0; the mass of acetic acid is 0.3-0.5% of the mass of the intermediate represented by formula (II).

6. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: In step (3), the solvent is toluene, cyclohexane or n-heptane, and the volume mass ratio of the solvent to the intermediate represented by formula (IV) is 4-6 mL: 1 g.

7. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: In step (3), the molar ratio of sodium borohydride to the intermediate represented by formula (IV) is 0.8-1.0:1.0, and the molar ratio of acetic acid to the intermediate represented by formula (IV) is 3.7-4.0:1.

0.

8. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: In step (3), the alcohol solvent of C1 to C4 is 95 to 100 wt% methanol, 95 to 100 wt% ethanol or 95 to 100 wt% isopropanol, or pure butanol, and the volume mass ratio of the alcohol solvent of C1 to C4 to the intermediate represented by formula (IV) is 1.5 to 2.5 mL: 1.0 g; the volume mass ratio of the added pure water to the intermediate represented by formula (IV) is 3 to 5 mL: 1 g.

9. the preparation method of bromhexine hydrochloride according to claim 2, is characterized in that: In step (3), the slow cooling rate is 1-2°C / min.

10. The method for preparing bromhexine hydrochloride according to claim 2, wherein: In step (4), the solvent is acetone or ethyl acetate, and the volume mass ratio of the solvent to bromhexine shown in formula (V) is 2-8 mL: 1 g.

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