Preparation method of hydrobromic acid vortioxetine intermediate based on continuous flow hydrogenation

Abstract

The invention provides a preparation method of a hydrobromic acid vortioxetine intermediate based on continuous flow hydrogenation, and belongs to the technical field of chemical synthesis. The method provided by the invention comprises the following steps: introducing a reducing gas and a (2, 4-dimethylphenyl) (2-nitrophenyl) sulfane solution into a reaction column of a continuous flow hydrogenation reaction device, and carrying out a reduction reaction to obtain a hydrobromic acid vortioxetine intermediate; a reaction column of the continuous flow hydrogenation reaction device is filled with a nitro reduction catalyst. According to the method, nitryl of (2, 4-dimethylphenyl) (2-nitrophenyl) sulfanyl is reduced through continuous flow hydrogenation equipment, the hydrobromic acid intermediate 2-[(2, 4-dimethylphenyl) sulfanyl] aniline is obtained, the continuous flow equipment is adopted for reduction, the use amount of reducing gas can be reduced, and high safety is achieved; moreover, the product obtained by the method is high in yield and purity, the post-treatment steps are simple, and the method is more beneficial to industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a method for preparing an intermediate of vilazodone hydrobromide based on continuous flow hydrogenation. Background Art

[0002] The chemical name of vilazodone hydrobromide is: 1-[2-(2,4-dimethyl-phenylthio)-phenyl]-piperazine hydrobromide, and its molecular formula is: C 18 H 22 N 2 S·HBr, and its structural formula is as follows:

[0003]

[0004] Vilazodone hydrobromide can inhibit serotonin reuptake, and has the effects of being a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, and antagonists of 5-HT3, 5-HT1D, and 5-HT7 receptors. It is the first antidepressant drug with multiple pharmacodynamic activities.

[0005] One of the preparation methods of vilazodone hydrobromide is to cyclize 2-[(2,4-dimethylphenyl)thio]aniline with 2-(chloroethyl)amine to obtain vilazodone. Its synthetic route is as follows:

[0006]

[0007] And 2-[(2,4-dimethylphenyl)thio]aniline, as a key intermediate, is mainly prepared by nitro reduction. Its synthetic route is as follows:

[0008]

[0009] Currently, common methods for preparing 2-[(2,4-dimethylphenyl)thio]aniline by nitro reduction include traditional batch reactions using Raney nickel or palladium as a catalyst and hydrogen reduction, or using hydrazine hydrate for nitro reduction. However, hydrazine hydrate is an easily explosive chemical with great safety hazards. Moreover, traditional batch reactions have problems such as high temperature and pressure in the process, long time consumption, low conversion rate, many impurities, and high industrial production costs.

[0010] Therefore, there is an urgent need to provide a method for preparing an intermediate of vilazodone hydrobromide with good safety, high product conversion rate, high yield, and being more suitable for industrial production. Summary of the Invention

[0011] The purpose of the present invention is to provide a method for preparing an intermediate of vilazodone hydrobromide based on continuous flow hydrogenation. The method provided by the present invention has good safety, high product conversion rate, high yield, and is more suitable for industrial production.

[0012] To achieve the above-mentioned invention object, the present invention provides the following technical solutions:

[0013] The present invention provides a preparation method of a hydrogen bromide vortioxetine intermediate based on continuous flow hydrogenation, including:

[0014] Introduce a reducing gas and a solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane into the reaction column of a continuous flow hydrogenation reaction device for a reduction reaction to obtain a hydrogen bromide vortioxetine intermediate; a nitro reduction catalyst is filled in the reaction column of the continuous flow hydrogenation reaction device.

[0015] Preferably, the reducing gas is hydrogen.

[0016] Preferably, the flow rate of the reducing gas is 40 - 90 mL / min.

[0017] Preferably, the mass concentration of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution is 30 - 70%.

[0018] Preferably, the solvent of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution is anhydrous ethanol, 95% ethanol or tetrahydrofuran.

[0019] Preferably, the flow rate of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution is 0.2 - 0.5 mL / min.

[0020] Preferably, the temperature of the reduction reaction is 40 - 90 °C.

[0021] Preferably, the back pressure of the reduction reaction is 1 - 3 MPa.

[0022] Preferably, the nitro reduction catalyst includes a Raney nickel catalyst or a palladium-carbon catalyst.

[0023] Preferably, the nitro reduction catalyst is amorphous, spherical or quasi-spherical, and the particle size of the nitro reduction catalyst is 1 - 3 mm.

[0024] The present invention provides a method for preparing an intermediate of vilazodone hydrobromide based on continuous flow hydrogenation, comprising: introducing a reducing gas and a solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane into a reaction column of a continuous flow hydrogenation reaction device to carry out a reduction reaction to obtain an intermediate of vilazodone hydrobromide; a nitro reduction catalyst is filled in the reaction column of the continuous flow hydrogenation reaction device. The present invention reduces the nitro group of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane through a continuous flow hydrogenation device to obtain the intermediate of vilazodone hydrobromide, 2-[(2,4-dimethylphenyl)thio]aniline. This method uses a continuous flow device for reduction, which can reduce the amount of reducing gas used and has high safety; moreover, the product obtained by this method has a high yield and purity, making the post-treatment steps simple and more conducive to industrial production. The results of the examples show that the intermediate of vilazodone hydrobromide prepared by the present invention has a high yield (≥99%) and good quality (purity ≥99%), and industrial production can be easily achieved by directly scaling up the equipment. Description of the Drawings

[0025] Figure 1 It is the chromatogram of 2-[(2,4-dimethylphenyl)thio]aniline prepared in Example 1 of the present invention. Detailed Embodiments

[0026] The present invention provides a method for preparing an intermediate of vilazodone hydrobromide based on continuous flow hydrogenation, comprising: introducing a reducing gas and a solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane into a reaction column of a continuous flow hydrogenation reaction device to carry out a reduction reaction to obtain an intermediate of vilazodone hydrobromide; a nitro reduction catalyst is filled in the reaction column of the continuous flow hydrogenation reaction device.

[0027] In the present invention, the reducing gas is preferably hydrogen. By using the above reducing gas, the nitro group of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane can be reduced under the action of a catalyst.

[0028] In the present invention, the flow rate of the reducing gas is preferably 40 - 90 mL / min, more preferably 50 - 80 mL / min, and further preferably 60 - 70 mL / min. By controlling the flow rate of the reducing gas within the above range in the present invention, it is more conducive to fully react with the solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane and reduce the amount of reducing gas used. In the present invention, the flow rate of the reducing gas is preferably adjusted through a European-style continuous hydrogenation reactor. In the examples of the present invention, the model of the European-style continuous hydrogenation reactor can be European-style H-FLOW-S10.

[0029] In the present invention, the mass concentration of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution is preferably 30-70%. As an embodiment of the present invention, the mass concentration of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution can be 30%, 40%, 50%, 60% or 70%. The present invention controls the mass concentration of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution within the above range, which is more conducive to improving the reaction efficiency.

[0030] In the present invention, the solvent of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution is preferably anhydrous ethanol, 95% ethanol or tetrahydrofuran, and more preferably 95% ethanol. The present invention uses the above solvents to have good solubility for (2,4-dimethylphenyl)(2-nitrophenyl)sulfane.

[0031] In the present invention, the flow rate of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution is preferably 0.2-0.5 mL / min. As an embodiment of the present invention, the flow rate of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution can be 0.2 mL / min, 0.3 mL / min, 0.4 mL / min or 0.5 mL / min. The present invention controls the flow rate of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution within the above range, which is more conducive to fully reacting with the reducing gas, improving the yield and purity of the product, and reducing the amount of the reducing gas used.

[0032] The present invention has no special limitation on the model of the continuous flow hydrogenation reaction device, and any conventional continuous flow hydrogenation reaction device can be used. In the examples of the present invention, the model of the continuous flow hydrogenation reaction device can be European Sheng H-FLOW-S10.

[0033] In the present invention, a nitro reduction catalyst is filled in the reaction column of the continuous flow hydrogenation reaction device. In the present invention, the nitro reduction catalyst preferably includes a Raney nickel catalyst or a palladium-carbon catalyst, and more preferably a Raney nickel catalyst. The present invention has no special limitation on the source of the Raney nickel catalyst or the palladium-carbon catalyst, and any conventional commercially available product can be used. In the examples of the present invention, the source of the Raney nickel catalyst or the palladium-carbon catalyst can be European Sheng (Beijing) Technology Co., Ltd. The present invention can catalyze the reduction of the nitro group in (2,4-dimethylphenyl)(2-nitrophenyl)sulfane by filling a nitro reduction catalyst in the reaction column of the continuous flow hydrogenation reaction device. The present invention has no special limitation on the filling amount of the nitro reduction catalyst, and it can be adjusted according to the size of the reaction column of the continuous flow hydrogenation reaction device so that the reaction column is filled with the nitro reduction catalyst.

[0034] In the present invention, the nitro reduction catalyst is preferably amorphous, spherical or quasi-spherical, more preferably spherical; the particle size of the nitro reduction catalyst is preferably 1 to 3 mm, more preferably 1 to 2 mm. The use of the nitro reduction catalyst with the above morphology in the present invention is more conducive to improving the catalytic effect.

[0035] In the present invention, the method for introducing the reducing gas and the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution into the reaction column of the continuous flow hydrogenation reaction device is preferably as follows: first introduce the reducing gas into the reaction column of the continuous flow hydrogenation reaction device, and then perform a preheating treatment on the reaction column of the continuous flow hydrogenation reaction device to obtain a preheated reaction column; introduce the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution into the preheated reaction column.

[0036] In the present invention, it is preferred that after the reducing gas is introduced into the reaction column of the continuous flow hydrogenation reaction device, the back pressure in the reaction column is first adjusted, and then the reaction column of the continuous flow hydrogenation reaction device is preheated. By adjusting the back pressure in the reaction column in the present invention, it is beneficial to improve the reaction efficiency after the subsequent introduction of the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution. In the present invention, the back pressure is preferably 1 to 3 MPa.

[0037] The present invention has no special limitation on the method of the preheating treatment. By using a conventional preheating method, the temperature of the preheated reaction column can reach the temperature of the reduction reaction. By performing a preheating treatment on the reaction column of the continuous flow hydrogenation reaction device in the present invention, it is possible to directly perform a reduction reaction after hydrogen and the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution are introduced into the preheated reaction column, thereby improving the yield and purity of the product.

[0038] In the present invention, the temperature of the preheating treatment is preferably 40 to 90 °C, more preferably 60 to 70 °C. By controlling the temperature of the preheating treatment within the above range in the present invention, the temperature of the preheated reaction column can reach the reduction reaction temperature of 40 to 90 °C.

[0039] In the present invention, the temperature of the reduction reaction is preferably 40 to 90 °C. As an example of the present invention, the temperature of the reduction reaction can be 40 °C, 50 °C, 60 °C, 70 °C, 80 °C or 90 °C. Performing the reduction reaction at the above temperature in the present invention can improve the reaction efficiency.

[0040] The present invention has no special limitation on the time of the reduction reaction, and it can be adjusted according to the amount of the product to be obtained. The method provided by the present invention is carried out in a continuous flow hydrogenation reaction device and is a continuous reaction. Therefore, by continuously introducing the reducing gas and the (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution, the reduction reaction can be carried out to obtain the product. Therefore, the reaction time can be adjusted according to the amount of the product to be obtained.

[0041] In the present invention, the back pressure of the reduction reaction is preferably 1 to 3 MPa, more preferably 1 to 2 MPa. Reacting under the above back pressure in the present invention can promote the reduction reaction to be more complete.

[0042] The present invention preferably concentrates and solidifies the product obtained from the reduction reaction in sequence to obtain 2-[(2,4-dimethylphenyl)thio]aniline, which is the intermediate of vilazodone hydrobromide.

[0043] The present invention has no special limitation on the methods of the concentration and solidification, and conventional methods of concentration and solidification can be adopted. The present invention removes the solvent and unreacted raw materials by concentration, and obtains the solid of 2-[(2,4-dimethylphenyl)thio]aniline by solidification. The present invention has no special limitation on the method of the solidification, as long as it can solidify the concentrated substance.

[0044] The method provided by the present invention reduces the nitro group of (2,4-dimethylphenyl)(2-nitrophenyl) sulfide through a continuous flow hydrogenation device to obtain the intermediate of vilazodone hydrobromide, 2-[(2,4-dimethylphenyl)thio]aniline. Reducing by using a continuous flow device in this method can reduce the consumption of reducing gas and has high safety; moreover, the product obtained by this method has high yield and purity, making the post-treatment steps simple and more conducive to industrial production.

[0045] Next, the technical solutions in the present invention will be described clearly and completely in combination with the embodiments in the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0046] Example 1

[0047] A preparation method of the intermediate of vilazodone hydrobromide based on continuous flow hydrogenation:

[0048] Dissolve 100 g of (2,4-dimethylphenyl)(2-nitrophenyl) sulfide in 200 g of 95% ethanol to obtain a (2,4-dimethylphenyl)(2-nitrophenyl) sulfide solution with a mass concentration of 33%.

[0049] The reaction column was filled with Raney nickel catalyst using continuous flow and installed on the European-style Sheng H-FLOW-S10 equipment. The European-style Sheng continuous hydrogenation reactor (European-style Sheng H-FLOW-S10) was opened, the hydrogen gas flow rate was adjusted to 60 mL / min, the back pressure was set to 2.0 MPa. After the system back pressure reached 2.0 MPa, the preheater temperature was set to 38 °C, and after the temperature of the reaction column reached 40 °C, a solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane was introduced, the injection rate was set to 0.5 mL / min, and the product was collected at the end of the equipment. The product was concentrated to obtain a colorless oily liquid, which solidified into a solid at low temperature, namely 2-[(2,4-dimethylphenyl)thio]aniline. After detection, the yield of 2-[(2,4-dimethylphenyl)thio]aniline was 99%, and the purity was 100.000% (ignoring the limit of 0.015%) ESI.(pos.ion) m / z = 229.19 [M+H] + 。

[0050] The chromatogram of 2-[(2,4-dimethylphenyl)thio]aniline prepared in this example is as Figure 1 shown. The peak results are shown in Table 1:

[0051] Table 1 Peak results of the chromatogram of 2-[(2,4-dimethylphenyl)thio]aniline prepared in this example

[0052] Retention time (min) Area (μV·s) % Area Height (μV) Tailing factor 25.087 30860783.695 100.000 2662338 1.05

[0053] Example 2

[0054] A preparation method of a hydrogen bromide vilazodone intermediate based on continuous flow hydrogenation:

[0055] 20 g of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane was dissolved in 20 g of absolute ethanol to obtain a 50% by mass concentration solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane;

[0056] Fill a reaction column with Raney nickel catalyst for continuous flow and install it on the European-style Sheng H-FLOW-S10 equipment. Open the European-style Sheng continuous hydrogenation reactor (European-style Sheng H-FLOW-S10), adjust the hydrogen gas flow rate to 60 mL / min, set the back pressure to 2.0 MPa. After the system back pressure reaches 2.0 MPa, set the preheater temperature to 38 °C. When the temperature of the reaction column reaches 70 °C, start to introduce the solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane, set the injection rate to 0.4 mL / min, and collect the product at the end of the equipment. After concentration, the product is obtained as a colorless oily liquid, which solidifies into a solid at low temperature, namely 2-[(2,4-dimethylphenyl)thio]aniline. The yield is 99%, the purity is 100.000% (ignoring the limit of 0.015%) ESI.(pos.ion) m / z = 229.19 [M+H] + 。

[0057] Example 3

[0058] A preparation method of an intermediate of vilazodone hydrobromide based on continuous flow hydrogenation:

[0059] Dissolve 20 g of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane in 20 g of tetrahydrofuran to obtain a (2,4-dimethylphenyl)(2-nitrophenyl)sulfane solution with a mass concentration of (50)%;

[0060] Fill a reaction column with Raney nickel catalyst for continuous flow and install it on the European-style Sheng H-FLOW-S10 equipment. Open the European-style Sheng continuous hydrogenation reactor European-style Sheng H-FLOW-S10, adjust the hydrogen gas flow rate to 60 mL / min, set the back pressure to 2.0 MPa. After the system back pressure reaches 2.0 MPa, set the preheater temperature to 38 °C. When the temperature of the reaction column reaches 50 °C, start to introduce the solution of (2,4-dimethylphenyl)(2-nitrophenyl)sulfane, set the injection rate to 0.3 mL / min, and collect the product at the end of the equipment. After concentration, the product is obtained as a colorless oily liquid, which solidifies into a solid at low temperature, namely 2-[(2,4-dimethylphenyl)thio]aniline. The yield is 98%, the purity is 100.000% (ignoring the limit of 0.015%) ESI.(pos.ion) m / z = 229.19 [M+H] + 。

[0061] Comparative Example 1

[0062] A preparation method of an intermediate of vilazodone hydrobromide:

[0063] In a 30 L reactor, 2-(2,4-dimethylphenylthio) nitrobenzene (1.83 kg, 7.06 mol), activated carbon (0.18 kg, 15.00 mol), ferric chloride hexahydrate (0.38 kg, 1.42 mol), and absolute ethanol (7.14 kg, 111.44 mol) were added. The temperature was raised to an internal temperature of 55 °C, and 80% hydrazine hydrate (1.76 kg, 28.24 mol) was added dropwise. After the addition was complete, the mixture was kept warm for 1 h, and then the temperature was raised to an internal temperature of 80 °C and reacted for 4 h. When the content of the compound detected by in-process control was ≤5%, the reaction was considered complete and the reaction was stopped. The mixture was filtered, the filtrate was collected and concentrated to obtain the crude product of 2-(2,4-dimethylphenylthio) aniline. Ethyl acetate (8.24 kg, 93.46 mol) was added to the crude product, and it was extracted three times with purified water (9.83 kg, 508.33 mol). The organic phase was collected, anhydrous magnesium sulfate (0.92 kg, 7.64 mol) was added to the organic phase for drying, the filtrate was collected by filtration and concentrated to obtain 1.60 kg of 2-(2,4-dimethylphenylthio) aniline as a pale yellow viscous liquid, with a yield of 98.86% and HPLC: 99.924%.

[0064] As can be seen from the above results, compared with the traditional batch reaction method described in the comparative example, the method provided by the present invention has a high yield (≥99%) and good quality (purity ≥99%) for the intermediate of vilazodone hydrobromide; the post-treatment method of the prepared crude product is simple, and the equipment can be directly scaled up and industrial production can be easily realized.

[0065] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a vortioxetine hydrobromide intermediate based on continuous flow hydrogenation, comprising: A reducing gas and a (2,4-dimethylphenyl) (2-nitrophenyl) sulfane solution are introduced into a reaction column of a continuous flow hydrogenation reaction device to carry out a reduction reaction to obtain a vortioxetine hydrobromide intermediate; and a nitro reduction catalyst is filled in the reaction column of the continuous flow hydrogenation reaction device.

2. The preparation method according to claim 1, characterized in that: The reducing gas is hydrogen.

3. The preparation method according to claim 1, characterized in that: The flow rate of the reducing gas is 40 to 90 mL / min.

4. The preparation method according to claim 1, characterized in that: The mass concentration of the (2,4-dimethylphenyl) (2-nitrophenyl) sulfane solution is 30-70%.

5. The preparation method according to claim 1 or 4, characterized in that: The solvent of the (2,4-dimethylphenyl) (2-nitrophenyl) sulfane solution is anhydrous ethanol, 95 ethanol or tetrahydrofuran.

6. The preparation method according to claim 1 or 4, characterized in that: The flow rate of the (2,4-dimethylphenyl) (2-nitrophenyl) sulfane solution is 0.2 to 0.5 mL / min.

7. The preparation method according to claim 1, characterized in that: The temperature of the reduction reaction is 40-90°C.

8. The preparation method according to claim 1 or 7, characterized in that: The back pressure of the reduction reaction is 1-3 MPa.

9. The preparation method according to claim 1, characterized in that: The nitro reduction catalyst includes a Raney nickel catalyst or a palladium carbon catalyst.

10. The preparation method according to claim 1 or 9, characterized in that: The nitro reduction catalyst is amorphous, spherical or quasi-spherical, and the particle size of the nitro reduction catalyst is 1 to 3 mm.

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