A continuous preparation process of 3-amino-1-adamantanol and a special tubular reaction device

Abstract

The application discloses a continuous preparation process and a special tubular reaction device of 3-amino-1-adamantanol, and the process comprises the following steps: respectively conveying a sulfuric acid solution A of adamantylamine sulfate or hydrochloride and a nitric acid solution B into a tubular reactor R1 to perform a nitration reaction, then respectively conveying the nitration reaction liquid and a water solution C of a reducing agent into a tubular reactor R2 to perform a hydrolysis reaction, conveying the obtained 3-amino-1-adamantanol acid solution and a lye D into a tubular reactor R3 to perform a neutralization reaction, and finally performing extraction, cooling crystallization, suction filtration and drying in sequence to obtain the product 3-amino-1-adamantanol. The tubular continuous process is used for synthesizing 3-amino-1-adamantanol, the reaction time is greatly shortened, the reaction selectivity is good, the product yield reaches more than 96%, the process automation level is obviously improved, and the process process essential safety is enhanced. The tubular reactor used in the application can be based on the capacity demand, and is more suitable for large-scale production and application.

Description

Technical Field

[0001] The present invention relates to a continuous preparation process of 3-amino-1-adamantanol and a special tubular reaction device. Background Art

[0002] 3-Amino-1-adamantanol (CAS#: 702-82-9), a white or light yellow crystalline powder solid with a melting point of 265-268°C, is a key intermediate in the synthesis of the hypoglycemic drug vildagliptin.

[0003] The routes for synthesizing 3-amino-1-adamantanol reported in domestic and foreign literature mainly include the following four kettle processes:

[0004] (1) 3-Bromo-1-adamantanecarboxylic acid route: 3-Bromo-1-adamantanecarboxylic acid is subjected to azidation and Curtius rearrangement with sodium azide, followed by reflux hydrolysis with 10% hydrobromic acid solution to obtain 3-amino-1-adamantanol. This route involves complex synthesis steps, the sodium azide used in this method is explosive and has a low safety factor, and ethyl chloroformate is a highly toxic substance. The total yield is 80% to 85% (Donetti A, Bellora E, et al. Synthesis of 1-Amino-3-Hydroxy-Adamantane[J]. Synthetic Communications, 1973).

[0005]

[0006] (2) Nitration of amantadine hydrochloride: Using amantadine hydrochloride as the raw material, it is nitrated in the presence of sulfuric acid and nitric acid, followed by alkaline hydrolysis with potassium hydroxide to produce 3-amino-1-adamantanol. The raw materials required for this route are readily available and low-cost, making this method a common method for industrial production. However, the traditional autoclave nitration process carries significant production risks, long reaction times, and low production efficiency, with yields of only 62% to 84% (Klimova NV, et al. Hydroxyadamantanes and Their Biological Activity [J]. Chemistry Information, 1986).

[0007]

[0008] (3) Selective oxidation of adamantane: First, tetrafluoroboric acid is used to form a salt with adamantane to protect the amino group. Then, trifluoroacetone is used at low temperature to selectively oxidize the CH on the adamantane bridge to obtain 3-amino-1-adamantanol. The oxidant trifluoroacetone used in this route is highly toxic, has a low boiling point, is unstable, and cannot be recycled, resulting in a high synthesis cost (Asensio G, et al. Regioselective Oxyfunctionalization of Unactivated Tertiary and Secondary CH Bonds of Alkylamines by Methyl(trifluoromethyl)dioxirane in Acid Medium[J]. American Chemical Society, 1993).

[0009]

[0010] (4) Selective hydroxylation of adamantane: Using adamantane as a raw material, bromochloroform as a solvent, and hexamethylmolybdenum as a catalyst, adamantane was selectively hydroxylated at 150°C to obtain 3-amino-1-adamantanol with a yield of 80%. However, the high cost of hexamethylmolybdenum and the environmental damage and toxicity of bromochloroform make it unsuitable for industrial production (Khusnutdinov RI, et al. Selective Hydroxylation of Adamantane and Its Derivatives [J]. Russian Journal of Organic Chemistry, 2009).

[0011]

[0012] Chinese patent CN 109824524 A reports a process for preparing 3-amino-1-adamantanol by nitration using a microchannel reactor. However, the exothermic reactions, such as hydrolysis and neutralization, are performed batchwise. The maximum yield of this method is only 82%, with a purity of 99%, which is not ideal. Furthermore, the patent does not describe the content of key impurities such as dihydroxy and ketone in the product, making it impossible to meet the control requirements for pharmaceutical intermediate production.

[0013]

[0014] In addition, the detailed dimensions, specifications, shapes, materials and other key parameters of the microchannel equipment have not been made public, making it impossible to verify whether the process meets the relevant requirements for pharmaceutical production. Microchannel reactors also have certain limitations, including: (1) The flow channel of the microchannel reactor is between microns and millimeters. Such narrow channels will block the microchannels when the fluid has high viscosity, solid materials with large particles, or when large solid particles settle during the reaction, resulting in the inability to carry out continuous production, and the blockage is difficult to clean; (2) The processing cost of micro-equipment is expensive, and in many process conditions, its processing capacity still cannot meet the actual industrial production needs; (3) The increase in the number of microreactors greatly increases the complexity of monitoring and control, and the actual production cost is relatively high.

[0015] The sulfuric acid solution A of sulfuric acid or amantadine hydrochloride involved in the present invention has a large viscosity (80-100mPa.s) at room temperature and reaction temperature, and there is a risk of clogging the pipeline. In addition, in order to achieve a higher output, it is necessary to increase the feed rate of the material, which will make the resistance drop of the entire microchannel reaction pipeline very large, which is not conducive to equipment selection and poses a challenge to the automated control of the entire production process. In order to increase the mass transfer and heat transfer effects, shorten the residence time, and improve production efficiency, the present invention is filled with a twisted mixing element in the tubular reactor R1, which mainly enhances the lateral and longitudinal movement of the reaction solution through a cutting effect. For the forced convection heat transfer process, the boundary layer determines the thermal resistance of the entire heat transfer process. The mixing element can force the fluid in the boundary layer to flow toward the center of the tube, avoid the temperature difference between the center of the tube and the tube wall, and improve the reaction selectivity. Summary of the Invention

[0016] In response to the above-mentioned technical problems existing in the prior art, the object of the present invention is to provide a continuous preparation process for 3-amino-1-adamantanol and a dedicated tubular reaction apparatus. A tubular reactor suitable for the process of the present invention is designed based on reaction kinetics, mass transfer, and heat transfer calculations to achieve a full-process continuous tubular nitration, hydrolysis, and neutralization reaction.

[0017] The object of the present invention is achieved through the following technical solutions:

[0018] A continuous preparation process for 3-amino-1-adamantanol comprises: delivering sulfuric acid or a sulfuric acid solution A of amantadine hydrochloride and a nitric acid solution B to a tubular reactor R1 via metering pumps P1 and P2, respectively, for nitration reaction to obtain a nitration reaction liquid of 3-nitro-1-adamantanamine; hydrolyzing the nitration reaction liquid with a reducing agent solution C delivered by a metering pump P3 in a tubular reactor R2 to obtain a 3-amino-1-adamantanol acid solution; neutralizing the 3-amino-1-adamantanol acid solution with an alkaline solution D delivered by a metering pump P4 in a tubular reactor R3 to make the pH of the reaction liquid alkaline to obtain an alkaline solution containing 3-amino-1-adamantanol; and extracting the alkaline solution of 3-amino-1-adamantanol, cooling and crystallizing it, filtering it with suction, and drying it to obtain the product 3-amino-1-adamantanol. The reaction formula is as follows:

[0019]

[0020] Furthermore, the sulfuric acid solution A of sulfuric acid or amantadine hydrochloride is prepared by dissolving sulfuric acid or amantadine hydrochloride in a sulfuric acid solution, wherein the concentration of the sulfuric acid solution is 80-114.6%, preferably 92-105%; and the molar ratio of sulfuric acid to sulfuric acid or amantadine hydrochloride is 4-10:1.

[0021] Furthermore, the nitric acid solution B has a nitric acid mass concentration of 80-98%, preferably 95-98%, and a feed molar flow ratio of nitric acid to sulfuric acid or amantadine hydrochloride is 2-5:1.

[0022] Furthermore, the reducing agent solution C is one of urea solution, ammonia water, Na2SO3 solution, and NaHSO3 solution, or a mixed solution of two or more thereof, and its solute mass concentration is 3 to 20%, preferably 5 to 10%; the feed molar flow ratio of the reducing agent to sulfuric acid or adamantane hydrochloride is 1 to 1.5:1.

[0023] Furthermore, the alkali solution D is a sodium hydroxide or potassium hydroxide aqueous solution with a mass concentration of 20-50%; the feed molar flow ratio of the alkali to sulfuric acid or amantadine hydrochloride is 10-30:1.

[0024] Furthermore, the extraction solvent is one of n-hexane, ethyl acetate, dichloromethane, toluene, chlorobenzene, and xylene, or a mixture of any two of them.

[0025] Furthermore, the solvent used in the cooling crystallization is one of n-hexane, ethyl acetate, dichloromethane, toluene, chlorobenzene, and xylene, or a mixture of any two of them, and the crystallization temperature is -15°C to 0°C.

[0026] Furthermore, the tubular reactor R1 is composed of a tube with an inner diameter of 1.7 mm to 21 mm, and is made of a material such as 316L, Hastelloy, tantalum, silicon carbide, etc. that is corrosion-resistant and has good thermal conductivity. The tubular reactor R1 is filled with a mixing element, the reaction temperature of the tubular reactor R1 is 30 to 80°C, and the material residence time in the tubular reactor R1 is 2 to 60 minutes.

[0027] Furthermore, the tubular reactor R2 is composed of a tube with an inner diameter of 1.7 mm to 14 mm, and is made of a corrosion-resistant and thermally conductive material such as Hastelloy, 2205 stainless steel, Hastelloy, tantalum, silicon carbide, etc. The reaction temperature of the tubular reactor R2 is 40 to 90°C, and the material residence time in the tubular reactor R2 is 10 to 30 minutes.

[0028] Furthermore, the tubular reactor R3 is composed of a tube with an inner diameter of 1.7 mm to 12 mm, and is made of corrosion-resistant and thermally conductive materials such as Hastelloy, 316L, 2205 stainless steel, tantalum, and silicon carbide. The reaction temperature of the tubular reactor R3 is 65 to 100°C, and the material residence time in the tubular reactor R3 is 1 to 5 minutes.

[0029] The present invention also provides a special tubular reaction device for a continuous preparation process of 3-amino-1-adamantanol, comprising a tubular reactor R1, a tubular reactor R2, and a tubular reactor R3. The inlet of the tubular reactor R1 is divided into two routes, one of which is connected to a metering pump P1 for conveying sulfuric acid or a sulfuric acid solution A of amantadine hydrochloride by a pipeline, and the other is connected to a metering pump P2 for conveying a nitric acid solution B by a pipeline; the inlet of the tubular reactor R2 is divided into two routes, one of which is connected to the outlet of the tubular reactor R1 by a pipeline, and the other is connected to a metering pump P3 for conveying a reducing agent aqueous solution C by a pipeline; the inlet of the tubular reactor R3 is divided into two routes, one of which is connected to the outlet of the tubular reactor R2 by a pipeline, and the other is connected to a metering pump P4 for conveying an alkali solution D by a pipeline. The outlet of the tubular reactor R3 discharges the reaction liquid after the neutralization reaction.

[0030] By adopting the above method, compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] (1) The present invention realizes the continuous preparation of 3-amino-1-adamantanol through the entire process of nitration, hydrolysis, and neutralization for the first time. The reaction process is continuous, pipelined, and closed, which significantly improves the level of process automation and enhances the inherent safety of the process. Compared with previously reported kettle reactions and semi-continuous flow processes, the quality is improved while the reaction time is greatly shortened.

[0032] (2) The production device consists of a three-stage tubular reactor. Compared with the microchannel reactor, the tubular reactor used in the present invention can be designed with a suitable size according to the production capacity requirements and combined with mass transfer and heat transfer calculations. It has high production capacity and low cost, and is more suitable for large-scale production and application.

[0033] (3) The present invention rationally controls the matching relationship between the reaction process and the mass and heat transfer processes, resulting in high production efficiency and a reaction yield of over 96%, which is 6% to 10% higher than traditional kettle-type and semi-continuous flow processes. The product purity reaches over 99.8%, which is significantly improved. The content of key impurities such as dihydroxy and ketone is less than 0.1%, and the selectivity of the target product is 3% to 6% higher, which is a significant increase compared with existing methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The present invention is a schematic diagram of the reaction process for continuously preparing 3-amino-1-adamantanol. DETAILED DESCRIPTION

[0035] The present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

[0036] Example 1

[0037] like Figure 1As shown, amantadine sulfate (1.0 eq) and sulfuric acid (concentration 98%, 6.0 eq) are formulated into material A, nitric acid (mass concentration 95%, 3.0 eq) is used as material B, urea solution (mass concentration 5%, 1.5 eq) is used as material C, and aqueous sodium hydroxide solution (mass concentration 40%, 20.0 eq) is used as material D. Material A and material B are respectively conveyed into a tubular reactor R1 (inner diameter 1.7 mm) by metering pumps P1 and P2. A mixing element is installed in the tubular reactor R1. The temperature of the tubular reactor R1 is controlled to 30° C. by a water bath. The residence time of the material in the tubular reactor R1 is controlled to 60 min by setting the pump flow rate. A nitration reaction is carried out in the tubular reactor R1 to obtain a nitrated solution. Material C, delivered by metering pump P3, was mixed and the temperature of tubular reactor R2 (inner diameter 1.7 mm) was controlled at 70°C via a water bath. The material residence time in tubular reactor R2 was controlled to 15 minutes by setting the pump flow rate. A hydrolysis reaction was carried out in tubular reactor R2. The hydrolyzed liquid and material D, delivered by metering pump P4, were introduced into tubular reactor R3 (inner diameter 1.7 mm) together. The temperature of tubular reactor R3 was controlled at 65°C via a water bath. Neutralization was carried out after a residence time of 5 minutes. The flow rate was controlled by metering pumps to achieve a molar flow ratio of amantadine sulfate, sulfuric acid, nitric acid, urea, and alkali of 1.0:6.0:3.0:1.5:20.0. The delivery rate of material A was 36.5 mL / min. The reaction solution was extracted with xylene, separated, and subjected to rotary evaporation to obtain a crude product. The crude product was recrystallized from xylene and crystallized by cooling to -10°C. After filtration and drying, a white solid powder was obtained with a molar yield of 96.3% and a purity of 99.7%.

[0038] Example 2

[0039] like Figure 1As shown, amantadine hydrochloride (1.0 eq) and sulfuric acid (concentration 98%, 10.0 eq) are formulated as material A, nitric acid (mass concentration 95%, 5.0 eq) is used as material B, urea solution (mass concentration 5%, 1.5 eq) is used as material C, and sodium hydroxide aqueous solution (mass concentration 20%, 30.0 eq) is used as material D. Material A and material B are respectively conveyed into a tubular reactor R1 (inner diameter 8.0 mm) by metering pumps P1 and P2. A mixing element is installed in the tubular reactor R1. The temperature of the tubular reactor R1 is controlled to 60° C. by a water bath. The residence time of the material in the tubular reactor R1 is controlled to 20 min by setting the pump flow rate. A nitration reaction is carried out in the tubular reactor R1 to obtain a nitrated solution and a mixture of the obtained nitrated solution and the obtained solution. Material C, delivered by metering pump P3, was mixed and the temperature of tubular reactor R2 (internal diameter 8.0 mm) was controlled at 40°C by a water bath. The residence time of the material in tubular reactor R2 was controlled to 30 minutes by setting the pump flow rate. A hydrolysis reaction was carried out in tubular reactor R2. The hydrolyzed liquid after the reaction entered tubular reactor R3 (internal diameter 8.0 mm) together with material D delivered by metering pump P4. The temperature of tubular reactor R3 was controlled at 100°C by a water bath. After a residence time of 1 minute, a neutralization reaction was carried out. The flow rate was controlled by metering pumps to adjust the feed molar flow ratio of amantadine hydrochloride, sulfuric acid, nitric acid, urea, and alkali to 1.0:10.0:5.0:1.5:30.0. The delivery rate of material A was 74.1 mL / min. The reaction solution was extracted with dichloromethane, separated, and rotary evaporated to obtain a crude product. The crude product was recrystallized from xylene and crystallized by cooling at -10°C. After filtration and drying, a white solid powder was obtained with a molar yield of 97.3% and a purity of 99.3%.

[0040] Example 3

[0041] like Figure 1As shown, amantadine sulfate (1.0 eq) and sulfuric acid (concentration 105%, 4.0 eq) are formulated into material A, nitric acid (mass concentration 98%, 2.0 eq) is used as material B, NaHSO3 solution (mass concentration 10%, 1 eq) is used as material C, and aqueous sodium hydroxide solution (mass concentration 50%, 10.0 eq) is used as material D. Material A and material B are respectively conveyed into a tubular reactor R1 (inner diameter 14 mm) by metering pumps P1 and P2. A mixing element is installed in the tubular reactor R1. The temperature of the tubular reactor R1 is controlled to 80° C. by a water bath. The residence time of the material in the tubular reactor R1 is controlled to 2 min by setting the pump flow rate. A nitration reaction is carried out in the tubular reactor R1 to obtain a nitrated solution. Material C delivered by metering pump P3 is mixed, and the temperature of tubular reactor R2 (inner diameter 14mm) is controlled to 90°C by water bath. The material residence time in tubular reactor R2 is controlled to 10min by setting the pump flow rate. Hydrolysis reaction is carried out in tubular reactor R2. The hydrolyzed liquid after reaction enters tubular reactor R3 (inner diameter 12mm) together with material D delivered by metering pump P4. The temperature of tubular reactor R3 is controlled to 65°C by water bath. After 5min residence time, neutralization reaction is carried out. The flow rate is controlled by metering pump so that the feed molar flow ratio of amantadine sulfate, sulfuric acid, nitric acid, NaHSO3, and alkali is 1.0:4.0:2.0:1:10.0, wherein the delivery flow rate of material A is 108.5mL / min. The reaction solution is extracted with chlorobenzene, separated, and rotary evaporation to obtain a crude product. The crude product is recrystallized from xylene and crystallized by cooling at -10°C. After filtration and drying, a white solid powder was obtained with a molar yield of 96.5% and a purity of 99.5%.

[0042] Example 4

[0043] Experimental process is with embodiment 1, and difference is that material C is changed into Na2SO3 solution (mass concentration 10%, 1.0eq), and material D is changed into potassium hydroxide aqueous solution (mass concentration 30%, 10.0eq).Amantadine sulfate, sulfuric acid, nitric acid, Na2SO3, the feed molar flow ratio of alkali is 1.0:6.0:3.0:1.0:10.0, and the flow of metering pump P1 is 36.5mL / min.Control tubular reactor R1, R2, R3 temperature by water-bath and be respectively 40 ℃, 40 ℃, 80 ℃, and the material residence time in tubular reactor R1, R2, R3 is respectively 50min, 30min, 3min.Other conditions are identical with embodiment 1, and finally obtain molar yield 96.3%, purity 99.7%.

[0044] Example 5

[0045] Experimental process is with embodiment 2, and difference is that material C is changed into NaHSO solution (mass concentration 5%, 1.5eq), and material D is changed into potassium hydroxide aqueous solution (mass concentration 40%, 20.0eq).Amantadine hydrochloride, sulfuric acid, nitric acid, NaHSO , the feed molar flow ratio of alkali is 1.0:10.0:5.0:1.5:20.0, and the flow of metering pump P1 is 74.1mL / min.It is 80 ℃ by water-bath control tubular reactor R1 temperature, and changing the material residence time in tubular reactor R1 is 3min.Other conditions are identical with embodiment 1, and finally obtain molar yield 97.6%, purity 99.2%.

[0046] Example 6

[0047] The experimental procedure was the same as in Example 1, except that no mixing element was installed in tubular reactor R1. Other conditions were the same as in Example 1, resulting in a final molar yield of 87.4% and a purity of 98.2%. Due to the high viscosity of the reaction solution, uniform dispersion of the reaction solution was difficult, resulting in poor mass transfer and a relatively low reaction conversion rate. Local hot spots were easily generated, leading to an increase in byproducts and reduced selectivity.

[0048] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be considered as being limited to the specific forms described in the embodiments.

Claims

1. A continuous preparation process for 3-amino-1-adamantanol, characterized in that The process comprises: transporting sulfuric acid or a sulfuric acid solution A of amantadine hydrochloride and a nitric acid solution B to a tubular reactor R1 for a nitration reaction to obtain a nitration reaction liquid of 3-nitro-1-adamantanamine; transporting the nitration reaction liquid and a reducing agent aqueous solution C to a tubular reactor R2 for a hydrolysis reaction to obtain a 3-amino-1-adamantanol acid solution; transporting the 3-amino-1-adamantanol acid solution and an alkaline solution D to a tubular reactor R3 for a neutralization reaction, during which the pH of the reaction liquid becomes alkaline to obtain an alkaline solution containing 3-amino-1-adamantanol; and finally extracting, cooling and crystallizing, filtering, and drying to obtain the product 3-amino-1-adamantanol. The sulfuric acid solution A of sulfuric acid or amantadine hydrochloride is prepared by dissolving sulfuric acid or amantadine hydrochloride in a sulfuric acid solution, wherein the concentration of the sulfuric acid solution is 80-114.6%, and the molar ratio of sulfuric acid to sulfuric acid or amantadine hydrochloride is 4-10:1; The nitric acid solution B has a nitric acid mass concentration of 80-98%, and a feed molar flow ratio of nitric acid to sulfuric acid or amantadine hydrochloride of 2-5:1; The reducing agent solution C is one of urea solution, Na2SO3 solution, and NaHSO3 solution, or a mixed solution of two or more thereof, wherein the solute mass concentration is 3-20%, and the feed molar flow ratio of the reducing agent to sulfuric acid or amantadine hydrochloride is 1-1.5:1; The material residence time in the tubular reactor R1 is 2 to 60 min, and the reaction temperature is 30 to 80 °C; The material residence time in the tubular reactor R2 is 10-30 min, and the reaction temperature is 40-90°C; The material residence time in the tubular reactor R3 is 1 to 5 minutes, and the reaction temperature is 65 to 100°C.

2. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The concentration of sulfuric acid solution is 92-105%.

3. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The mass concentration of nitric acid is 95-98%.

4. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The solute mass concentration of the reducing agent solution C is 5-10%.

5. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The alkali solution D is a sodium hydroxide or potassium hydroxide aqueous solution with a mass concentration of 20-50%. The feed molar flow ratio of the alkali to sulfuric acid or amantadine hydrochloride is 10-30:

1.

6. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The extraction solvent is one of n-hexane, ethyl acetate, dichloromethane, toluene, chlorobenzene, and xylene, or a mixture of any two of them.

7. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The solvent used for cooling crystallization is one of n-hexane, ethyl acetate, dichloromethane, toluene, chlorobenzene, and xylene, or a mixture of any two thereof, and the crystallization temperature is -15°C to 0°C.

8. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The inner diameter of the tubular reactor R1 is 1.7 mm to 21 mm, the inner diameter of the tubular reactor R2 is 1.7 mm to 14 mm, and the inner diameter of the tubular reactor R3 is 1.7 mm to 12 mm.

9. A continuous preparation process for 3-amino-1-adamantanol as claimed in claim 1, characterized in that The tubular reactor R1, tubular reactor R2 or tubular reactor R3 is made of a corrosion-resistant material with good thermal conductivity, and the corrosion-resistant material with good thermal conductivity is selected from Hastelloy, 316L, 2205 stainless steel, tantalum or silicon carbide; wherein the tubular reactor R1 is filled with a mixing element.

10. The dedicated tubular reaction device for the continuous preparation process of 3-amino-1-adamantanol according to claim 1, characterized in that The invention comprises a tubular reactor R1, a tubular reactor R2 and a tubular reactor R3. The inlet of the tubular reactor R1 is divided into two routes, one of which is connected to a metering pump P1 for conveying sulfuric acid or sulfuric acid solution A of amantadine hydrochloride by a pipeline, and the other is connected to a metering pump P2 for conveying nitric acid solution B by a pipeline; the inlet of the tubular reactor R2 is divided into two routes, one of which is connected to the outlet of the tubular reactor R1 by a pipeline, and the other is connected to a metering pump P3 for conveying a reducing agent aqueous solution C by a pipeline; the inlet of the tubular reactor R3 is divided into two routes, one of which is connected to the outlet of the tubular reactor R2 by a pipeline, and the other is connected to a metering pump P4 for conveying an alkali solution D by a pipeline. The outlet of the tubular reactor R3 discharges the reaction liquid after the neutralization reaction.

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