Continuous flow synthesis method of amantadine hydrochloride

Abstract

The invention belongs to the field of compound synthesis, and particularly relates to a continuous flow synthesis method of amantadine hydrochloride. According to the method, 1-bromoadamantane and urea are taken as raw materials and react in a high-temperature melting impinging stream reactor, so that continuous synthesis of amantadine hydrochloride is realized. By applying the continuous high-temperature melting impinging stream reactor, the problems of thermal runaway and pressure accumulation in the traditional intermittent amantadine hydrochloride synthesis process are solved, and an intrinsically safe technical scheme is provided. High-efficiency mixing and heat transfer of solid raw materials are realized by adopting a high-temperature melting impinging stream reactor, and the temperature runaway and overpressure risks are effectively avoided and the hidden danger of local overheating or gas retention is eliminated by accurately controlling the retention time and the feeding speed of the materials and dynamically balancing the thermodynamic state of a reaction system.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a continuous flow synthesis method for adamantaneamine hydrochloride. Background Technology

[0002] Amantadine, a high-value organic compound with a three-dimensional cage-like structure, is widely used in antiviral drugs and the treatment of Parkinson's disease. Its hydrochloride form, amantadine hydrochloride, has become a key drug for the treatment of influenza viruses and the intervention of neurodegenerative diseases due to its combination of broad-spectrum antiviral activity and neuroprotective function.

[0003] In industrial production, the synthesis of adamantaneamine mainly relies on two technical routes: one is the nitration of adamantane to produce 1-adamantyl nitrate (Moiseev et al., 1976; Sasaki et al., 1968), and the other is the preparation of intermediates via the bromination reaction of 1-bromoadamantane. Among these, 1-bromoadamantane is widely used due to its higher synthesis efficiency, with a typical process including a three-step method (He et al., 2013): using acetamide as an amination reagent to generate 1-acetamidoadamantane, followed by hydrolysis and hydrochloric acid salt formation to obtain the target product. In addition, Vu et al. (2017) developed a two-step Ritter reaction system using adamantane, acetonitrile, and sulfuric acid aqueous solution as raw materials, simplifying the process through sodium hydroxide hydrolysis and hydrochloric acid salt formation.

[0004] However, the above techniques have significant drawbacks: 1) Although the two-step method shortens the synthesis route, it relies on non-environmentally friendly solvents such as dichloromethane and energy-intensive vacuum evaporation operations (Vu et al., 2017); 2) Multi-stage extraction and purification steps lead to process redundancy, and the solvent toxicity problem has not been fundamentally solved; 3) The direct amination of urea or formamide-mediated pathways attempted by Phan (2019), Pham (2020), and Phan Thi (2022), although optimizing the choice of raw materials, have not overcome the limitations of solvent toxicity, energy consumption, and step complexity. Using urea as an amination reagent has the advantages of readily available raw materials and low cost, but the instantaneous reaction between urea and adamantane during the reaction process releases a large amount of heat and gas, leading to a sudden increase in local temperature of the reaction system accompanied by the risk of overpressure.

[0005] Therefore, the current synthesis process of adamantaneamine hydrochloride has the following problems: the use of batch reactors can easily lead to safety hazards such as thermal runaway and pressure accumulation, as well as the risk of sudden temperature rise and overpressure due to the large instantaneous heat release and high gas production during the reaction. Therefore, it is necessary to study a safe continuous synthesis method for adamantaneamine hydrochloride. Summary of the Invention

[0006] The purpose of this invention is to provide a continuous flow synthesis method for adamantane hydrochloride, which achieves safe and controllable reaction process and suppression of side reactions by optimizing the thermodynamic balance control and gas emission management of the reaction system.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A continuous flow synthesis method for adamantane hydrochloride is disclosed, which uses 1-bromoadamantane and urea as raw materials and reacts them in a high-temperature molten impingement reactor to achieve the continuous synthesis of adamantane hydrochloride.

[0008] Furthermore, 1-bromoadamantane and urea are heated to a molten state, and the molten materials are sprayed into the impinging flow reactor chamber through high-pressure nozzles. Under the synergistic effect of high temperature environment and high intensity impinging flow field, an amination reaction occurs. The resulting amination reaction products are collected and transferred to a distillation kettle. Alkali solution is added to adjust the pH of the system to strong alkalinity. Subsequently, the target product adamantane is separated by steam distillation. The adamantane is then subjected to a salt formation reaction. After solid-liquid separation, washing and drying, a high-purity adamantane hydrochloride product is obtained.

[0009] Specifically, it includes the following steps: (1) Heat 1-bromoadamantane and urea to 180-240℃ respectively until they reach a molten state; (2) Molten materials are sprayed into the cavity of a high-temperature molten impingement flow reactor through high-pressure nozzles and subjected to amination reaction at 180-240℃ under the action of the impingement flow field to obtain amination reaction products. (3) The amination reaction product obtained in step (2) is collected by a cyclone separator and transferred to a distillation kettle. Sodium hydroxide solution is added to adjust the pH of the system to 14, and steam distillation is carried out until no adamantane is distilled off. (4) The distilled adamantane is transferred to an acidification vessel, and dilute hydrochloric acid is added to carry out a salt formation reaction. Then, after crystallization, filtration and drying, adamantane hydrochloride product is obtained.

[0010] The molar ratio of 1-bromoadamantane to urea is 1:1.0-2.0.

[0011] The radial length of the cavity of the high-temperature molten impingement flow reactor is 0.1-0.5m, and the axial length is 0.2-1.0m.

[0012] The pH during the salt formation reaction in step (4) is 3-4.

[0013] The high-temperature molten impingement reactor includes a reaction module and a separation module. The reaction module includes a cylindrical reaction chamber 1 with a heat exchange component (circulating oil bath heat exchange component) and two adjustable nozzles 2 (the included angle between the two nozzles is controlled from 60° to 180°). The separation module is a cyclone separator. The separation module and the reaction module are connected by a metal pipe 3. Solid products are collected by the bottom exhaust pipe 5 of the cyclone separator. The top is the reaction tail gas discharge channel 6, and the side is equipped with a blower pipe 4 to provide airflow power.

[0014] The working principle of the high-temperature molten impingement flow reactor is based on the formation of a highly turbulent impact zone by opposing high-speed jets, achieving micro-mixing. High-temperature molten material is injected at high speed through adjustable-angle nozzles, creating an impact zone at the center of the reaction chamber. The collision of the two jets generates intense turbulence, rapidly mixing the material at a microscale, significantly shortening the reaction time and improving reaction efficiency. The resulting mixture enters a cyclone separator through a metal pipe, where gas-solid separation is achieved under centrifugal force. Solid products are collected through a bottom exhaust pipe, effectively separated and collected at the bottom, while gaseous exhaust gases are discharged from the top. The airflow provided by the side blower pipes maintains the efficient operation of the cyclone separator, ensuring complete recovery of solid products, ultimately achieving an integrated process of high-temperature molten reaction and product separation.

[0015] The advantages of this invention are: This invention solves the problems of thermal runaway and pressure accumulation in the traditional batch synthesis process of adamantaneamine hydrochloride by applying a continuous high-temperature molten impingement reactor, providing an inherently safe technical solution. The high-temperature molten impingement reactor achieves efficient mixing and heat transfer of solid raw materials. By precisely controlling the material residence time and feeding rate, the thermodynamic state of the reaction system is dynamically balanced, effectively avoiding the risks of temperature runaway and overpressure, and eliminating the hidden dangers of local overheating or gas stagnation. This method maintains the reaction system within the optimal condition range, with a stable product yield of 92%-97%, significantly improving process controllability. It is suitable for the large-scale production of solid products from liquid-liquid reactions, and with the addition of a gas-liquid separation device, the orderly emission of waste gas is achieved, combining industrial adaptability with green chemical requirements. Attached Figure Description

[0016] Figure 1 This is a three-dimensional schematic diagram of the device according to an embodiment of the present invention, wherein 1-reaction chamber, 2-nozzle, 3-metal pipe, 4-blowing pipe, 5-bottom exhaust pipe of cyclone separator, and 6-reaction tail gas discharge channel.

[0017] Figure 2 for Figure 1 Front view of the device.

[0018] Figure 3 for Figure 1 Left view of the device.

[0019] Figure 4 for Figure 1 Top view of the device.

[0020] Figure 5 This is a process flow diagram of the present invention. Detailed Implementation

[0021] High-temperature molten impingement reactor Figures 1-4 The high-temperature molten impingement flow reactor shown includes a reaction module and a separation module. The reaction module includes a cylindrical reaction chamber (1) with an inner diameter of 20 cm and a height of 30 cm, and is equipped with a circulating oil bath heat exchange assembly; two adjustable nozzles 2, with the included angle of the two nozzles controlled at 180°; the separation module is a cyclone separator, and the separation module is connected to the reaction module through a metal pipe 3. Solid products are collected by the bottom exhaust pipe 5 of the cyclone separator, the top is the reaction tail gas discharge channel 6, and the side is equipped with a blower pipe 4 to provide airflow power.

[0022] The working principle of the high-temperature molten impingement flow reactor is based on the formation of a highly turbulent impact zone by opposing high-speed jets, achieving micro-mixing. High-temperature molten material is injected at high speed through adjustable-angle nozzles, creating an impact zone at the center of the reaction chamber. The collision of the two jets generates intense turbulence, rapidly mixing the material at a microscale, significantly shortening the reaction time and improving reaction efficiency. The resulting mixture enters a cyclone separator through a metal pipe, where gas-solid separation is achieved under centrifugal force. Solid products are collected through a bottom exhaust pipe, effectively separated and collected at the bottom, while gaseous exhaust gases are discharged from the top. The airflow provided by the side blower pipes maintains the efficient operation of the cyclone separator, ensuring complete recovery of solid products, ultimately achieving an integrated process of high-temperature molten reaction and product separation.

[0023] Example 1 (1) According to Figure 5 The process involves heating 1-bromoadamantane and urea to 160°C to a molten state via independent heating channels, and then conveying them to the preheating pipeline via a heatable or heat-insulating horizontal flow pump, so that the materials reach the predetermined reaction temperature of 160°C before entering the reactor. (2) Molten 1-bromoadamantane and urea are transported to the reaction system at rates of 115.4 g / min and 50.5 g / min (molar ratio 1.0:1.6) respectively through a material conveying pipeline. The materials are heated to 200°C before entering the atomizing nozzle. The molten materials are simultaneously injected into the reaction chamber through the nozzle to achieve thorough mixing, complete the amination reaction, and obtain the amination reaction product. (3) The amination reaction product obtained in step (2) is separated into gas and solid by a cyclone separation module. After the system stabilizes, the separated material is transferred to a distillation unit, the pH of the system is adjusted to 14 and then steam distillation is performed to separate the target product adamantane until no adamantane is distilled off. The fraction containing adamantane is collected. (4) After cooling and filtering the fraction containing adamantane to obtain crude product, it is transferred to an acidification reactor for salt formation reaction. Hydrochloric acid is added to adjust the pH of the system to 3, and the temperature is raised to 80°C and stirred continuously for 1 hour. After filtration, adamantane hydrochloride can be finally obtained. The adamantane product of step (2) per unit time is taken, and after acidification alone, the purity of the product is 96.7%, and the total yield based on the raw material 1-bromoadamantane is 85.7%.

[0024] Example 2 (1) According to Figure 5 The process involves heating 1-bromoadamantane and urea to a molten state through independent heating channels, and then transporting them to the preheating pipeline via a heatable or heat-insulating horizontal flow pump, so that the materials reach the predetermined reaction temperature of 160°C before entering the reactor. (2) Molten 1-bromoadamantane and urea are transported to the reaction system at rates of 115.4 g / min and 50.5 g / min (molar ratio 1.0:1.6) respectively through a material conveying pipeline. The materials are heated to 220°C before entering the atomizing nozzle. The molten materials are simultaneously injected into the reaction chamber through the nozzle to achieve thorough mixing, complete the amination reaction, and obtain the amination reaction product. (3) The amination reaction product obtained in step (2) is separated into gas and solid by a cyclone separation module. After the system stabilizes, the separated material is transferred to a distillation unit, the pH of the system is adjusted to 14 and then steam distillation is performed to separate the target product adamantane until no adamantane is distilled off. The fraction containing adamantane is collected. (4) After cooling and filtering the fraction containing adamantane to obtain crude product, it is transferred to an acidification reactor for salt formation reaction. Hydrochloric acid is added to adjust the pH of the system to 3, and the temperature is raised to 80°C and stirred continuously for 1 hour. After filtration, adamantane hydrochloride can be finally obtained. The adamantane product of step (2) per unit time is taken, and after acidification alone, the purity of the product is 97.3%, and the total yield based on the raw material 1-bromoadamantane is 91.7%.

[0025] Example 3 (1) According to Figure 5 The process involves heating 1-bromoadamantane and urea to a molten state through independent heating channels, and then transporting them to the preheating pipeline via a heatable or heat-insulating horizontal flow pump, so that the materials reach the predetermined reaction temperature of 160°C before entering the reactor. (2) Molten 1-bromoadamantane and urea are transported to the reaction system at rates of 173.1 and 75.8 g / min (molar ratio 1.0:1.6) respectively through a material conveying pipeline. The materials are heated to 220°C before entering the atomizing nozzle. The molten materials are simultaneously injected into the reaction chamber through the nozzle to achieve thorough mixing, complete the amination reaction, and obtain the amination reaction product. (3) The amination reaction product obtained in step (2) is separated into gas and solid by a cyclone separation module. After the system stabilizes, the separated material is transferred to a distillation unit, the pH of the system is adjusted to 14 and then steam distillation is performed to separate the target product adamantane until no adamantane is distilled off. The fraction containing adamantane is collected. (4) After cooling and filtering the fraction containing adamantane to obtain crude product, transfer it to an acidification reactor, add hydrochloric acid to adjust the pH of the system to 3, heat to 80℃ and stir continuously for 1 hour, and finally obtain adamantane hydrochloride after filtration. The adamantane product of step (2) per unit time was acidified separately and the product purity was 98.0%, and the total yield based on the raw material 1-bromoadamantane was 94.7%.

[0026] Comparative Example 1 (1) 1-Bromoadamantane and urea are heated to the molten state through independent heating channels and then transported to the preheating pipeline by a heatable or heat-insulating horizontal flow pump so that the materials reach the predetermined reaction temperature of 160°C before entering the reactor. (2) Molten 1-bromoadamantane and urea are transported to the reaction system at rates of 115.4 g / min and 25.3 g / min (molar ratio 1.0:0.8) respectively through a material conveying pipeline. The materials are heated to 220°C before entering the atomizing nozzle. The molten materials are simultaneously injected into the reaction chamber through the atomizing nozzle assembly to complete the amination reaction and obtain the amination reaction product. (3) The amination reaction product obtained in step (2) is separated into gas and solid by a cyclone separation module. The separated material is transferred to a distillation unit, the pH of the system is adjusted to 14 and then steam distilled until no more adamantane is distilled off, and the fraction containing adamantane is collected; (4) After cooling and filtering the fraction containing adamantane to obtain crude product, transfer it to an acidification reactor, add hydrochloric acid to adjust the pH of the system to 3, heat to 80℃ and stir continuously for 1 hour, and finally obtain adamantane hydrochloride after filtration. The adamantane product of step (2) per unit time was acidified separately and the product purity was 55.0%, and the total yield based on the raw material 1-bromoadamantane was 43.5%.

[0027] Comparative Example 2 (1) The high-temperature molten impingement reactor and reactant preheating pipeline are preheated by a heat transfer oil circulation system, and the temperature is set to 160℃. 1-Bromoadamantane and urea are heated to the molten state through independent heating channels; (2) Molten 1-bromoadamantane and urea are transported to the reaction system at rates of 173.1 and 75.8 g / min (molar ratio 1.0:1.6) respectively through a material conveying pipeline. The materials are heated to 160°C before entering the atomizing nozzle. The molten materials are simultaneously injected into the reaction chamber through the atomizing nozzle assembly to complete the amination reaction and obtain the amination reaction product. (3) The amination reaction product obtained in step (2) is separated into gas and solid by a cyclone separation module. The separated material is transferred to a distillation unit, the pH of the system is adjusted to 14 and then steam distilled until no more adamantane is distilled off, and the fraction containing adamantane is collected; (4) After cooling and filtering the fraction containing adamantane to obtain crude product, the crude product is transferred to an acidification reactor. Hydrochloric acid is added to adjust the pH of the system to 3, and the temperature is raised to 80°C and stirred continuously for 1 hour. After filtration, adamantane hydrochloride can be obtained. The adamantane product of step (2) per unit time is taken, and after acidification alone, the purity of the product is 77.8%, and the total yield based on the raw material 1-bromoadamantane is 70.7%.

[0028] As shown in Comparative Example 1, when the molar ratio of 1-bromoadamantane to urea is 1.0:0.8, the stoichiometry of urea is insufficient, leading to incomplete conversion of the raw materials and a significant decrease in product yield. As shown in Comparative Example 2, when the heating temperature of 1-bromoadamantane and urea is 160℃, which is lower than the optimal process temperature for this reaction, the apparent chemical reaction rate decreases. The reaction proceeds to the post-processing stage before complete conversion, and unreacted raw materials are carried into the separation process, ultimately resulting in a low product yield.

Claims

1. A continuous flow synthesis method for adamantaneamine hydrochloride, characterized in that, The continuous synthesis of adamantane hydrochloride was achieved by reacting 1-bromoadamantane and urea in a high-temperature molten impingement reactor.

2. The continuous flow synthesis method of adamantaneamine hydrochloride according to claim 1, characterized in that, 1-Bromoadamantane and urea were heated to a molten state, and the molten materials were sprayed into the impinging flow reactor chamber through high-pressure nozzles. Under the synergistic effect of high temperature and high-intensity impinging flow field, an amination reaction occurred. The amination reaction products were collected and transferred to a distillation vessel. Alkali solution was added to adjust the pH of the system to strong alkalinity. Subsequently, the target product adamantane was separated by steam distillation. The adamantane was then subjected to a salt formation reaction. After solid-liquid separation, washing and drying, a high-purity adamantane hydrochloride product was obtained.

3. The continuous flow synthesis method of adamantane hydrochloride according to claim 2, characterized in that, Includes the following steps: (1) Heat 1-bromoadamantane and urea to 180-240℃ respectively until they reach a molten state; (2) Molten materials are sprayed into the cavity of a high-temperature molten impingement flow reactor through high-pressure nozzles and subjected to amination reaction at 160-240℃ under the action of the impingement flow field to obtain amination reaction products. (3) The amination reaction product obtained in step (2) is collected by a cyclone separator and transferred to a distillation kettle. Sodium hydroxide solution is added to adjust the pH of the system to 14, and steam distillation is carried out until no more adamantane is distilled off. (4) The distilled adamantane is transferred to an acidification vessel, and dilute hydrochloric acid is added to carry out a salt formation reaction. Then, after crystallization, filtration and drying, adamantane hydrochloride product is obtained.

4. The continuous flow synthesis method of adamantaneamine hydrochloride according to claim 3, characterized in that, The molar ratio of 1-bromoadamantane to urea is 1:1.0-2.

0.

5. The continuous flow synthesis method of adamantaneamine hydrochloride according to claim 3, characterized in that, The high-temperature molten impingement flow reactor has a cavity radial length of 0.1-0.5 m and an axial length of 0.2-1.0 m.

6. The continuous flow synthesis method of adamantane hydrochloride according to claim 3, characterized in that, The pH during the salt formation reaction in step (4) is 3-4.

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