Synthesis method of ivabradine intermediate compound

Abstract

The invention discloses a method for synthesizing an ivabradine intermediate compound, and belongs to the technical field of drug synthesis, the method comprises the following steps: mixing IVBB-2 with water, concentrated hydrochloric acid and chloroform, extracting, washing an organic phase, adding N, N-dimethylformamide and thionyl chloride, carrying out reflux reaction to obtain an IVBB-2 chloroform solution, cooling the solution, introducing monomethylamine, carrying out reaction, quenching, extracting, and purifying to obtain the ivabradine intermediate compound. Washing, pulping and crystallizing an organic phase, and centrifugally drying to obtain an intermediate IVBB-3, dissolving the intermediate IVBB-3 in tetrahydrofuran, carrying out reduction reaction with sodium borohydride and boron trifluoride tetrahydrofuran complex, quenching with diluted hydrochloric acid, adding alkali to separate out free amine, extracting with dichloromethane, salifying with a hydrogen chloride isopropanol solution, and purifying to obtain the intermediate IVBB-3. The ivabradine intermediate compound is obtained through crystallization, centrifugation and drying, high-yield and high-optical-purity preparation of the ivabradine key intermediate is achieved, and solvent residues in the product are remarkably reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing an intermediate compound of ivabradine. Background Technology

[0002] Ivabradine intermediates are key intermediates in the synthesis of ivabradine, an antianginal and heart failure drug that selectively inhibits sinoatrial node If current. They are generated through multiple steps of reaction, including condensation, reduction, cyclization, and amidation, starting from substituted benzaldehyde, piperazine compounds, and chiral amines.

[0003] These intermediates contain the core active skeleton of the drug, consisting of a (S)-3-(3-methoxypropyl)-1-[3,4-dimethoxyphenyl]-piperazine ring and an acetamide side chain. They are mainly divided into three categories: chiral piperazines, substituted phenethylamines, and amides. Among them, chiral piperazine intermediates, due to the presence of the S-configuration asymmetric carbon atom essential for drug efficacy, are the core control object in synthesis. Their core functions include constructing the active skeleton of the drug, regulating reaction selectivity, ensuring drug quality and safety, and controlling the economics of large-scale production. Currently, these intermediates suffer from problems such as lengthy synthetic routes, low overall yield, low chiral synthesis efficiency, and difficulty in achieving stable purity of over 99%.

[0004] Chinese invention patent application CN104447553A discloses a method for preparing ivabradine and its intermediates. Part of the raw materials are dissolved in dimethylformamide or dimethyl sulfoxide, sulfonic acid is added and stirred, and then other raw materials and a composite phase transfer catalyst are added. After reaction and purification, the intermediate dehydrogenated ivabradine is obtained. This method uses a composite phase transfer catalyst system, which shortens the reaction time and improves the purity of the product.

[0005] However, the above scheme uses polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide. These solvents have high boiling points, high energy consumption for recovery, and a high risk of solvent residue. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing ivabradine intermediates. By replacing the key solvent, which is high-boiling-point and highly toxic dimethylformamide or dimethyl sulfoxide, with low-boiling-point and easily recyclable tetrahydrofuran, and by using a "sodium borohydride / boron trifluoride-tetrahydrofuran complex" reduction system, the safety risks are significantly reduced by avoiding the use of expensive chiral catalysts.

[0007] The objective of this invention can be achieved through the following technical solutions: A method for synthesizing an intermediate compound of ivabradine includes the following steps: Step 1: First, IVBB-2 is mixed with water, concentrated hydrochloric acid and chloroform for extraction. After washing the organic phase, DMF catalyst and thionyl chloride are added and refluxed to obtain IVBB-2 chloroform solution. Then, after cooling the solution, monomethylamine is passed through it to react, quench and extract. The organic phase is washed, pulped and crystallized, and centrifuged and dried to obtain intermediate IVBB-3.

[0008] Step 2: The intermediate IVBB-3 was dissolved in tetrahydrofuran, and after reduction reaction with sodium borohydride and boron trifluoride tetrahydrofuran complex, it was quenched with dilute hydrochloric acid, and the free amine was precipitated by adding alkali. After extraction with dichloromethane, it was salted with isopropanol hydrochloride solution, crystallized, centrifuged and dried to obtain the ivabradine intermediate compound.

[0009] Furthermore, the general structural formula of the ivabradine intermediate compound is shown in Formula 1: Formula 1.

[0010] Furthermore, the specific preparation steps for the IVBB-2 chloroform solution are as follows: IVBB-2 and water were added to a reaction vessel and stirred for 20 minutes. Concentrated hydrochloric acid and chloroform were slowly added, and the mixture was stirred thoroughly before extraction. The mixture was allowed to stand and separate into layers. The lower aqueous phase was removed, and the organic phase was retained. The organic phase was washed with water 3-5 times until the water content of IPC-1 was <0.3% as detected by the central control. Then, N,N-dimethylformamide was added as a catalyst. Thionyl chloride was slowly added dropwise while stirring at room temperature. After the addition was complete, the temperature was raised to 60-65℃ and refluxed. The reaction was maintained at this temperature until the reaction was complete, yielding an IVBB-2 chloroform solution.

[0011] Furthermore, the mass ratio of IVBB-2, water, concentrated hydrochloric acid, chloroform, N,N-dimethylformamide and thionyl chloride is 44-46:198-202:23-25:297-303:0.6-0.8:26-28.

[0012] Furthermore, the specific preparation steps for intermediate IVBB-3 are as follows: The IVBB-2 chloroform solution was cooled to 0-10℃. Methylamine was slowly introduced with stirring until the reaction was complete. Excess amine was quenched with water, and chloroform was used for further extraction. All organic phases were combined and washed with water. The washed organic phases were then slurried and crystallized with isopropanol and methyl tert-butyl ether. After centrifugation and separation, a wet cake was obtained. The wet cake was washed 3-5 times with methyl tert-butyl ether, vacuum dried, and pulverized to obtain the intermediate IVBB-3. The reaction process is shown below: Furthermore, the mass ratio of IVBB-2 chloroform solution, monomethylamine, water, isopropanol and methyl tert-butyl ether is 340-350:40-42:89-91:26-28:98-100.

[0013] Furthermore, the specific preparation steps of the ivabradine intermediate compound are as follows: The reduction reaction mixture was cooled to 0°C, and dilute hydrochloric acid was slowly added for quenching. After quenching, the mixture was stirred for 20 min, and 32% liquid alkali was slowly added dropwise to adjust the pH value to >10, so that the target product precipitated in the form of free amine. Dichloromethane was then added for extraction, and the mixture was stirred thoroughly and allowed to stand for separation. The lower organic phase (containing free amine) was separated, and the aqueous phase was extracted a second time with dichloromethane. The organic phases were combined and transferred to a salting vessel. Isopropanol was added, and a solution of isopropanol hydrochloride was slowly added dropwise while stirring. The addition of isopropanol promoted crystallization. The mixture was centrifuged, washed with isopropanol, and dried under vacuum to obtain the ivabradine intermediate compound.

[0014] Furthermore, the mass ratio of the reduction reaction mixture, dilute hydrochloric acid, 32% liquid alkali, dichloromethane, isopropanol, and isopropanol hydrochloride solution is 22:73-77:181-185:347-353:127-134:17.3-17.7.

[0015] Furthermore, the specific preparation steps of the reduction reaction mixture are as follows: Intermediate IVBB-3 and tetrahydrofuran were added to a reaction vessel and stirred until completely dissolved. Sodium borohydride was slowly added while stirring for 20 minutes. The mixture was then cooled to 0-10°C, and the boron trifluoride tetrahydrofuran complex was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 50-60°C and the reaction was maintained until complete to obtain the reduction reaction mixture.

[0016] Furthermore, the mass ratio of intermediate IVBB-3, tetrahydrofuran, sodium borohydride, and the boron trifluoride tetrahydrofuran complex is 24-26:257-263:21-23:90-92. The reaction process is shown below: The beneficial effects of this invention are: 1. This invention utilizes the low boiling point and good chemical inertness of tetrahydrofuran to efficiently and selectively complete the chiral reduction reaction while ensuring that the solvent can be easily and thoroughly removed in the post-processing. This reduces the residual toxic solvent in the final intermediate to an extremely low level. The solvent system not only avoids the side reactions and purification difficulties caused by the chemical instability and strong polarity of dimethylformamide or dimethyl sulfoxide, achieving high overall process yield and chemical purity, but also significantly reduces production energy consumption and environmental pressure due to its easy recovery characteristics.

[0017] 2. The intermediate IVBB-3 in this invention, through process control and strict impurity standards (IPC-3), yielded a powdered solid with high chemical and optical purity. This provides an ideal substrate with a well-defined structure and a clean impurity spectrum for the subsequent stereoselective reduction reaction in tetrahydrofuran, ensuring the high efficiency and selectivity of the reduction reaction. Its synthesis route has effectively removed the trace amounts of high-boiling-point solvent introduced in the early stage through steps such as water washing and crystallization, blocking the transfer of toxic solvent to the final product from the outset. Its powdered solid form facilitates precise feeding and storage, ensuring the reproducibility of the process. Detailed Implementation

[0018] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments in the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0019] Example 1: A method for synthesizing an intermediate compound of ivabradine, comprising the following steps: S1: Add 44 kg IVBB-2 and 198 kg water to a reaction vessel and stir for 20 min. Slowly add 23 kg concentrated hydrochloric acid and 297 kg chloroform. After thorough stirring, extract the mixture, allow it to stand and separate into layers. Remove the lower aqueous phase and retain the organic phase. Wash the organic phase with water three times until the water content of IPC-1 is <0.3% as detected by the central control. Then add 0.6 kg of N,N-dimethylformamide as a catalyst. Under stirring at room temperature, slowly add 26 kg of thionyl chloride. After the addition is complete, heat to 60 °C and reflux. Maintain the temperature until the reaction is complete to obtain an IVBB-2 chloroform solution.

[0020] S2: Cool 340 kg of IVBB-2 chloroform solution to 0°C, slowly introduce 40 kg of monomethylamine while stirring, and stir until the reaction is complete. Add 89 kg of water to quench excess amine, and perform supplementary extraction with chloroform. Combine all organic phases and wash with 134 kg of water. Pulverize and crystallize the washed organic phase with 26 kg of isopropanol and 98 kg of methyl tert-butyl ether. Centrifuge and separate to obtain a wet cake. Wash the wet cake three times with 20 kg of methyl tert-butyl ether and vacuum dry. The IPC-2 drying loss is ≤1.0%. After pulverization, pack into a PE bag and test IPC-3 to obtain intermediate IVBB-3.

[0021] S3: Add 24 kg of intermediate IVBB-3 and 257 kg of tetrahydrofuran to the reactor and stir until completely dissolved. While stirring, slowly add 21 kg of sodium borohydride and stir for 20 min. Cool to 0°C and slowly add 90 kg of boron trifluoride tetrahydrofuran complex. After the addition is complete, slowly raise the temperature to 50°C and keep the reaction at this temperature until complete. The reduction reaction mixture is obtained by monitoring with TLC / HPLC.

[0022] S4: Cool 22 kg of reduction reaction mixture to 0 °C, slowly add 73 kg of dilute hydrochloric acid for quenching, stir for 20 min after quenching, slowly add 181 kg of 32% liquid alkali to adjust the pH value to >10, so that the target product precipitates in the form of free amine, then add 208 kg of dichloromethane for extraction, stir thoroughly and let stand to separate the layers, separate the lower organic phase (containing free amine), and extract the aqueous phase a second time with 139 kg of dichloromethane. Combine the organic phases and transfer to a salting vessel, add 20 kg of isopropanol, and slowly add 17.3 kg of isopropanol hydrochloride solution while stirring. Add 107 kg of isopropanol to promote crystallization, transfer to a centrifuge, centrifuge to separate, and obtain wet solid. Wash with 29 kg of isopropanol, transfer to a double cone drying oven, and vacuum dry. The moisture content of IPC-1 is ≤1.0% as detected by the central control, and the ivabradine intermediate compound is obtained.

[0023] The dilute hydrochloric acid is prepared by mixing concentrated hydrochloric acid and water in a mass ratio of 1:1.

[0024] Example 2: A method for synthesizing an ivabradine intermediate compound, comprising the following steps: S1: Add 45 kg IVBB-2 and 200 kg water to a reaction vessel and stir for 20 min. Slowly add 24 kg concentrated hydrochloric acid and 300 kg chloroform. After thorough stirring, extract the mixture, allow it to stand and separate into layers. Remove the lower aqueous phase and retain the organic phase. Wash the organic phase with water four times until the water content of IPC-1 is <0.3% as detected by the central control. Then add 0.7 kg N,N-dimethylformamide as a catalyst. Under stirring at room temperature, slowly add 27 kg thionyl chloride. After the addition is complete, heat to 62.5 °C and reflux. Maintain the temperature until the reaction is complete to obtain an IVBB-2 chloroform solution.

[0025] S2: Cool 345 kg of IVBB-2 chloroform solution to 5°C, slowly introduce 41 kg of monomethylamine while stirring, and stir until the reaction is complete. Add 90 kg of water to quench excess amine, and perform supplementary extraction with chloroform. Combine all organic phases and wash with 135 kg of water. Pulverize and crystallize the washed organic phase with 27 kg of isopropanol and 99 kg of methyl tert-butyl ether. Centrifuge and separate to obtain a wet cake. Wash the wet cake four times with 25 kg of methyl tert-butyl ether and vacuum dry. The IPC-2 drying loss is ≤1.0% according to the central control test. After pulverization, pack into a PE bag and obtain intermediate IVBB-3 by the central control test.

[0026] S3: Add 25 kg of intermediate IVBB-3 and 260 kg of tetrahydrofuran to the reactor and stir until completely dissolved. While stirring, slowly add 22 kg of sodium borohydride and stir for 20 min. Cool to 5°C and slowly add 91 kg of boron trifluoride tetrahydrofuran complex. After the addition is complete, slowly raise the temperature to 55°C and keep the reaction at this temperature until complete. The reduction reaction mixture is obtained by monitoring with TLC / HPLC.

[0027] S4: Cool 22 kg of reduction reaction mixture to 0 °C, slowly add 75 kg of dilute hydrochloric acid for quenching, stir for 20 min after quenching, slowly add 183 kg of 32% liquid alkali to adjust the pH value to >10, so that the target product precipitates in the form of free amine, then add 210 kg of dichloromethane for extraction, stir thoroughly and let stand to separate the layers, separate the lower organic phase (containing free amine), and extract the aqueous phase a second time with 140 kg of dichloromethane. Combine the organic phases and transfer them to a salting vessel, add 22.5 kg of isopropanol, and slowly add 17.5 kg of isopropanol hydrochloride solution while stirring. Add 108 kg of isopropanol to promote crystallization, transfer to a centrifuge, centrifuge to separate, and obtain wet solid. Wash with 30 kg of isopropanol, transfer to a double cone drying oven, and vacuum dry. The moisture content of IPC-1 is ≤1.0% as detected by the central control, and the ivabradine intermediate compound is obtained.

[0028] Example 3: A method for synthesizing an intermediate compound of ivabradine, comprising the following steps: S1: Add 46 kg IVBB-2 and 202 kg water to a reaction vessel and stir for 20 min. Slowly add 25 kg concentrated hydrochloric acid and 303 kg chloroform. After thorough stirring, extract the mixture, allow it to stand and separate into layers. Remove the lower aqueous phase and retain the organic phase. Wash the organic phase with water 5 times until the water content of IPC-1 is <0.3% as detected by the central control. Then add 0.8 kg N,N-dimethylformamide as a catalyst. Under stirring at room temperature, slowly add 28 kg thionyl chloride. After the addition is complete, heat to 65 °C and reflux. Maintain the temperature until the reaction is complete to obtain an IVBB-2 chloroform solution.

[0029] S2: Cool 350 kg of IVBB-2 chloroform solution to 10 °C. Slowly introduce 42 kg of monomethylamine while stirring. Stir until the reaction is complete. Add 91 kg of water to quench excess amine. Perform supplementary extraction with chloroform. Combine all organic phases and wash with 136 kg of water. Pulverize and crystallize the washed organic phase with 28 kg of isopropanol and 100 kg of methyl tert-butyl ether. Centrifuge and separate to obtain a wet cake. Wash the wet cake 5 times with 30 kg of methyl tert-butyl ether and vacuum dry. The IPC-2 drying loss is ≤1.0%. After pulverization, pack into a PE bag and test IPC-3 to obtain intermediate IVBB-3.

[0030] S3: Add 26 kg of intermediate IVBB-3 and 263 kg of tetrahydrofuran to the reactor and stir until completely dissolved. While stirring, slowly add 23 kg of sodium borohydride and stir for 20 min. Cool to 10°C and slowly add 92 kg of boron trifluoride tetrahydrofuran complex. After the addition is complete, slowly raise the temperature to 60°C and keep the reaction at this temperature until complete. The reduction reaction mixture is obtained by monitoring with TLC / HPLC.

[0031] S4: Cool 22 kg of the reduction reaction mixture to 0 °C, slowly add 77 kg of dilute hydrochloric acid for quenching, stir for 20 min after quenching, slowly add 185 kg of 32% liquid alkali to adjust the pH value to >10, so that the target product precipitates in the form of free amine, then add 212 kg of dichloromethane for extraction, stir thoroughly and let stand to separate the layers, separate the lower organic phase (containing free amine), and extract the aqueous phase a second time with 141 kg of dichloromethane. Combine the organic phases and transfer them to a salting vessel, add 25 kg of isopropanol, and slowly add 17.7 kg of isopropanol hydrochloride solution while stirring. Add 109 kg of isopropanol to promote crystallization, transfer to a centrifuge, centrifuge to separate, and obtain a wet solid. Wash with 31 kg of isopropanol, transfer to a double cone drying oven, and vacuum dry. The moisture content of IPC-1 is ≤1.0% as detected by the central control, and the ivabradine intermediate compound is obtained.

[0032] The IPC-3 testing standard is that the powder is off-white to light yellow in appearance, and the content of IVBB-3-impurity 1 is ≤0.5%, IVBB-3-impurity 3 is ≤0.5%, IVBB-3-impurity 6 is ≤1.0%, the maximum single impurity content is ≤0.5%, and the total impurity content is ≤3.0%. Among them, 1 is (S)-4,5-dimethoxybenzocyclobutane-1-carboxylic acid; 2 is 3-(3,4-dimethoxyphenyl)-N-methylpropionamide; and 3 is (S)-4,5-dimethoxy-N,N-dimethyl-1,2-benzocyclobutene-1-carboxamide.

[0033] In Examples 1-3, IVBB-2 was 4,5-dimethoxybenzocyclobutane-1-carboxylic acid, selected from Wuhan Yuancheng Chemical Co., Ltd., model YC-250128; chloroform was selected from Hubei Langbowan Biomedical Co., Ltd., CAS number 865-49-6, model LBW-8766; thionyl chloride was selected from Aozun Composite New Materials Co., Ltd., CAS number 7719-09-7; monomethylamine was selected from Shandong Qiancheng New Materials Co., Ltd.; methyl tert-butyl ether was selected from Shandong Junfeng New Materials Co., Ltd., CAS number 1634-04-4; boron trifluoride tetrahydrofuran complex was selected from Shandong Heyi Gas Co., Ltd., CAS number 462-34-0; liquid alkali was selected from Jinan Jiaxu Chemical Technology Co., Ltd.; dichloromethane was selected from Shandong Haocheng Chemical New Materials Co., Ltd.; isopropanol hydrochloride solution was selected from Henan Danlan Chemical Co., Ltd., CAS number 7647-01-0; the remaining raw materials were commercially available products.

[0034] Comparative Example 1: The difference from Example 1 is that in step S3, the solvent tetrahydrofuran was replaced with N,N-dimethylformamide, while the other steps remained unchanged, to prepare the ivabradine intermediate compound.

[0035] Comparative Example 2: The difference from Example 1 is that in step S3, the solvent tetrahydrofuran is replaced with dimethyl sulfoxide, while the other steps remain unchanged, to prepare the ivabradine intermediate compound.

[0036] The ivabradine intermediates obtained in Examples 1-3 and Comparative Examples 1-2 were subjected to high-performance liquid chromatography (HPLC) to determine their chemical purity and gas chromatography (GC) to determine the residual key solvents, respectively, in accordance with the general rules of the Chinese Pharmacopoeia or relevant enterprise standards. The total molar yield of the process was calculated, and the results are shown in Table 1. Table 1 Performance test results of ivabradine intermediate compounds As can be seen from Table 1, the ivabradine intermediate compounds prepared in Examples 1-3 show advantages in terms of product purity, production safety, and process efficiency compared to the process routes using traditional high-boiling-point and highly toxic solvents in Comparative Examples 1-2.

[0037] In Comparative Example 1, the chemical purity and overall yield of the final product decreased significantly, and high levels of residual N,N-dimethylformamide were detected. This may be because the mild and highly selective reduction system of the "sodium borohydride / boron trifluoride-tetrahydrofuran complex" in tetrahydrofuran in step S3 was replaced with the high-boiling-point polar solvent N,N-dimethylformamide. N,N-dimethylformamide may decompose under the action of the strong Lewis acid boron trifluoride, or due to its strong solubility and alkalinity, it may promote the racemization, over-reduction, or amide bond cleavage of the key chiral intermediate, introducing structurally similar impurities, which directly reduces the chemical purity of the product. In addition, its high boiling point makes it difficult to completely remove the solvent by conventional drying in post-processing. The large amount of residual N,N-dimethylformamide not only lowers the purity detection value as an impurity, but also poses a safety risk.

[0038] Comparative Example 2 showed the worst chemical purity and overall yield of the final product, with an extremely high residual dimethyl sulfoxide content. This is likely due to the replacement of the solvent with dimethyl sulfoxide. Dimethyl sulfoxide itself possesses certain oxidizing and strong reducing properties, and the Lewis acid system is thermodynamically incompatible. This could trigger side reactions within the solvent itself, ineffectively consuming the reducing agent, and potentially interfere with or even disrupt the crucial chiral reduction process, leading to product oxidation or structural rearrangement and the generation of a large amount of complex byproduct mixtures. Furthermore, dimethyl sulfoxide has an extremely high boiling point, strong polarity, and similar solubility to the product, hindering the effective precipitation and purification of the target product during crystallization. Its high boiling point also makes it almost impossible to remove from the solid product using conventional processes, resulting in solvent residue. Ultimately, it exhibited the worst results in terms of purity, safety, and efficiency.

[0039] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A method for synthesizing an intermediate compound of ivabradine, characterized in that, Includes the following steps: Step 1: First, IVBB-2 is mixed with water, concentrated hydrochloric acid and chloroform for extraction. After washing the organic phase, DMF catalyst and thionyl chloride are added and refluxed to obtain IVBB-2 chloroform solution. After cooling, monomethylamine is introduced to react, quench and extract. The organic phase is washed, pulped and crystallized, and centrifuged and dried to obtain intermediate IVBB-3. Step 2: The intermediate IVBB-3 was dissolved in tetrahydrofuran and then reduced with sodium borohydride and boron trifluoride tetrahydrofuran complex. The reaction was quenched with dilute hydrochloric acid, and the free amine was precipitated by adding alkali. After extraction with dichloromethane, it was salted with isopropanol hydrochloride solution, crystallized, centrifuged and dried to obtain the ivabradine intermediate compound. The general structural formula of the ivabradine intermediate compound is shown in Formula 1: Formula 1.

2. The method for synthesizing an ivabradine intermediate compound according to claim 1, characterized in that, The specific preparation steps of the IVBB-2 chloroform solution are as follows: IVBB-2 and water were added to a reaction vessel and stirred for 20 minutes. Concentrated hydrochloric acid and chloroform were slowly added, and the mixture was stirred thoroughly before extraction. The mixture was allowed to stand and separate into layers. The lower aqueous phase was removed, and the organic phase was retained. The organic phase was washed with water 3-5 times. N,N-dimethylformamide was then added as a catalyst. Thionyl chloride was slowly added dropwise while stirring at room temperature. After the addition was complete, the temperature was raised to 60-65°C and refluxed. The reaction was maintained at this temperature until the reaction was complete, yielding an IVBB-2 chloroform solution.

3. The method for synthesizing an ivabradine intermediate compound according to claim 2, characterized in that, The mass ratio of IVBB-2, water, concentrated hydrochloric acid, chloroform, N,N-dimethylformamide and thionyl chloride is 44-46:198-202:23-25:297-303:0.6-0.8:26-28.

4. The method for synthesizing an ivabradine intermediate compound according to claim 1, characterized in that, The specific preparation steps for the intermediate IVBB-3 are as follows: Cool the IVBB-2 chloroform solution to 0-10℃, slowly introduce monomethylamine while stirring, and stir until the reaction is complete. Add water to quench excess amine, perform supplementary extraction with chloroform, combine all organic phases, wash with water, and then slurry and crystallize the washed organic phase with isopropanol and methyl tert-butyl ether. Centrifuge and separate to obtain a wet cake. Wash the wet cake 3-5 times with methyl tert-butyl ether, vacuum dry, and pulverize to obtain intermediate IVBB-3.

5. The method for synthesizing an ivabradine intermediate compound according to claim 4, characterized in that, The mass ratio of the IVBB-2 chloroform solution, monomethylamine, water, isopropanol, and methyl tert-butyl ether is 340-350:40-42:89-91:26-28:98-100.

6. The method for synthesizing an ivabradine intermediate compound according to claim 1, characterized in that, The specific preparation steps of the ivabradine intermediate compound are as follows: The reduction reaction mixture was cooled to 0°C, and dilute hydrochloric acid was slowly added for quenching. After quenching, the mixture was stirred for 20 min, and 32% liquid alkali was slowly added dropwise to adjust the pH value to >10, so that the target product precipitated in the form of free amine. Dichloromethane was then added for extraction, and the mixture was stirred thoroughly and allowed to stand for separation. The lower organic phase (containing free amine) was separated, and the aqueous phase was extracted a second time with dichloromethane. The organic phases were combined and transferred to a salting vessel. Isopropanol was added, and a solution of isopropanol hydrochloride was slowly added dropwise while stirring. The addition of isopropanol promoted crystallization. The mixture was centrifuged, washed with isopropanol, and dried under vacuum to obtain the ivabradine intermediate compound.

7. The method for synthesizing an ivabradine intermediate compound according to claim 6, characterized in that, The mass ratio of the reduction reaction mixture, dilute hydrochloric acid, 32% liquid alkali, dichloromethane, isopropanol, and isopropanol hydrochloride solution is 22:73-77:181-185:347-353:127-134:17.3-17.

7.

8. The method for synthesizing an ivabradine intermediate compound according to claim 7, characterized in that, The specific preparation steps of the reduction reaction mixture are as follows: Intermediate IVBB-3 and tetrahydrofuran were added to a reaction vessel and stirred until completely dissolved. Sodium borohydride was slowly added while stirring for 20 minutes. The mixture was then cooled to 0-10°C, and the boron trifluoride tetrahydrofuran complex was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 50-60°C and the reaction was maintained until complete to obtain the reduction reaction mixture.

9. The method for synthesizing an ivabradine intermediate compound according to claim 8, characterized in that, The mass ratio of the intermediate IVBB-3, tetrahydrofuran, sodium borohydride, and the boron trifluoride tetrahydrofuran complex is 24-26:257-263:21-23:90-92.

Images