CN-122010742-A - 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. 1-bromoadamantane and urea are used as raw materials to react in a high-temperature melting impinging stream reactor, so that continuous synthesis of the amantadine hydrochloride is realized. The invention solves the problems of thermal runaway and pressure accumulation in the traditional intermittent synthesis process of the amantadine hydrochloride by using the continuous high-temperature melting impinging stream reactor, and provides an intrinsically safe technical scheme. The high-temperature melting impinging stream reactor is adopted to realize high-efficiency mixing and heat transfer of solid raw materials, and the thermodynamic state of the reaction system is dynamically balanced by precisely controlling the material residence time and the feeding speed, so that the risks of temperature runaway and overpressure are effectively avoided, and the hidden danger of local overheating or gas retention is eliminated.

Inventors

• Xing Tiehan
• LIU SHIHAO
• YAN SHIJIE
• WEI WEI
• ZHANG JIANJUN
• LI SHULONG
• LIU DONG

Assignees

• 沈阳化工研究院有限公司

Dates

Publication Date

20260512

Application Date

20260225

Claims (6)

1. 1. A continuous flow synthesis method of amantadine hydrochloride is characterized in that 1-bromoadamantane and urea are used as raw materials to react in a high-temperature melting impinging stream reactor, so as to realize continuous synthesis of the amantadine hydrochloride.
2. 2. The continuous flow synthesis method of amantadine hydrochloride according to claim 1, wherein 1-bromoadamantane and urea are heated to molten states respectively, the molten materials are sprayed into a cavity of an impinging stream reactor in opposite directions through a high-pressure spray nozzle respectively, amination reaction is carried out under the synergistic effect of a high-temperature environment and a high-strength impinging flow field, the obtained amination reaction products are collected and then are uniformly transferred into a distillation kettle, alkali liquor is added to adjust the pH of the system to be strong alkaline, then target product amantadine is separated through steam distillation, the amantadine is subjected to salt formation reaction, and high-purity amantadine hydrochloride products are obtained after solid-liquid separation, washing and drying.
3. 3. The continuous flow synthesis process of amantadine hydrochloride according to claim 2, comprising the steps of: (1) Heating 1-bromoadamantane and urea to 180-240 ℃ respectively to reach a molten state; (2) Respectively spraying the molten materials into a cavity of a high-temperature melting impinging stream reactor in opposite directions through a high-pressure spray nozzle, and carrying out amination reaction under the actions of 160-240 ℃ and an impinging flow field to obtain amination reaction products; (3) Collecting the amination reaction product obtained in the step (2) through a cyclone separator, transferring the amination reaction product to a distillation kettle, adding sodium hydroxide solution to adjust the pH value of the system to 14, and performing steam distillation until no amantadine is distilled out; (4) Transferring the amantadine obtained by distillation to an acidification kettle, adding dilute hydrochloric acid for salifying reaction, and then crystallizing, filtering and drying to obtain an amantadine hydrochloride product.
4. 4. A continuous flow synthesis process of amantadine hydrochloride according to claim 3, wherein the molar ratio of 1-bromoadamantane to urea is 1:1.0-2.0.
5. 5. The continuous flow synthesis process of amantadine hydrochloride according to claim 3, wherein the high temperature melt impingement flow reactor has a cavity with a radial length of 0.1-0.5 m and an axial length of 0.2-1.0 m.
6. 6. A continuous flow synthesis of amantadine hydrochloride according to claim 3, wherein the pH at the salt formation reaction in step (4) is 3-4.

Description

Continuous flow synthesis method of amantadine hydrochloride Technical Field The invention belongs to the field of compound synthesis, and particularly relates to a continuous flow synthesis method of amantadine hydrochloride. Background Amantadine (AMANTADINE) is widely used in the fields of antiviral drugs and parkinson's disease treatment as a high-added-value organic compound having a three-dimensional cage structure. The hydrochloride form, amantadine hydrochloride (AMANTADINE HYDROCHLORIDE), has been a key drug for anti-influenza virus therapy and neurodegenerative disease intervention because of its broad-spectrum antiviral activity and neuroprotection. In industrial production, the synthesis of amantadine mainly relies on two technical routes, one of which is the nitration of amantadine to 1-adamantyl nitrate (Moiseev et al., 1976;Sasaki et al, 1968), and the other of which is the preparation of an intermediate by bromination of 1-bromoadamantane. Among them, 1-bromoadamantane is widely used because of its high synthesis efficiency, and typical process includes three steps (He et al, 2013) of generating 1-acetamido adamantane with acetamide as amination reagent, hydrolyzing and salifying with hydrochloric acid to obtain the target product. In addition, the two-step Ritter reaction system developed by Vu et al (2017) takes adamantane, acetonitrile and sulfuric acid aqueous solution as raw materials, and realizes process simplification through sodium hydroxide hydrolysis and hydrochloride formation. However, the above technology has significant drawbacks of 1) shortening the synthesis path by a two-step method, but relying on non-environment friendly solvents such as methylene dichloride and high energy consumption for reduced pressure evaporation operation (Vu et al, 2017), 2) causing process redundancy by multistage extraction and purification steps, and not fundamentally solving the problem of solvent toxicity, and 3) optimizing the direct amination of urea or formamide-mediated paths tried by Phan (2019), phan (2020) and Phan Thi (2022), but not breaking through the limitations of solvent toxicity, energy consumption and step complexity. The urea is used as an amination reagent, so that the method has the advantages of easily available raw materials and low cost, but a great amount of heat and gas can be released by the instantaneous reaction of the urea and the bromoadamantane in the reaction process, so that the local temperature of a reaction system is increased suddenly and the risk of overpressure is caused. Therefore, the existing synthesis process of the amantadine hydrochloride has the problems that the intermittent reaction kettle is easy to cause potential safety hazards of thermal runaway and pressure accumulation, and the temperature rise and overpressure risks caused by high instantaneous heat release and high gas yield in the reaction process. Thus, it is necessary to investigate a safe continuous synthesis process of amantadine hydrochloride. Disclosure of Invention The invention aims to provide a continuous flow synthesis method of amantadine hydrochloride, which realizes the safety and controllability of the reaction process and the inhibition of side reactions by optimizing the thermodynamic equilibrium control and the gas emission management of a reaction system. In order to achieve the above purpose, the invention adopts the following technical scheme: A continuous flow synthesis method of amantadine hydrochloride takes 1-bromoadamantane and urea as raw materials, and the raw materials react in a high-temperature melting impinging stream reactor to realize continuous synthesis of the amantadine hydrochloride. Further, respectively heating 1-bromoadamantane and urea to a molten state, respectively jetting the molten materials into a impinging stream reactor cavity in opposite directions through a high-pressure nozzle, carrying out amination reaction under the synergistic effect of a high-temperature environment and a high-strength impinging stream field, collecting the obtained amination reaction products, uniformly transferring the amination reaction products into a distillation kettle, adding alkali liquor to adjust the pH of the system to be strong alkaline, then separating target product amantadine through steam distillation, carrying out salt formation reaction on the amantadine, and carrying out solid-liquid separation, washing and drying to obtain a high-purity amantadine hydrochloride product. Specifically, the method comprises the following steps: (1) Heating 1-bromoadamantane and urea to 180-240 ℃ respectively to reach a molten state; (2) Respectively spraying the molten materials into a cavity of a high-temperature melting impinging stream reactor in opposite directions through a high-pressure spray nozzle, and carrying out amination reaction under the actions of 180-240 ℃ and an impinging flow field to obtain amination reaction products; (3) Collecting the amination