Continuous deuteration preparation method of deuterated aniline
Through the fully automated synthesis control equipment, a catalyst is used to catalyze the hydrogen-deuterium exchange reaction between aniline and heavy water, and the problems of mildness, simplicity, deuteratedness and yield of deuterated aniline synthesis in the prior art are solved, and efficient and economical preparation of deuterated aniline is achieved.
Patent Information
- Application Number
- CN202510299489.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-13
- Publication Date
- 2025-06-13
AI Technical Summary
In the synthesis of deuterated aniline in the prior art, the reaction conditions are mild and easy to operate, and the deuterated degree and yield are also low, making it difficult to achieve large-scale industrial production.
Using fully automated synthesis control equipment, the hydrogen-deuterium exchange reaction between aniline and heavy water is catalyzed by a catalyst through continuous fluid pipeline reaction, deuterium water is supplemented multiple times to increase the deuterated degree, and high-purity deuterated aniline is obtained through distillation.
The preparation of deuterated aniline with mild reaction conditions, simple operation, high deuteratedness and high product yield is achieved, and the use of precious metal catalysts and high temperature and high pressure conditions is avoided, and the potential for large-scale industrial production is provided.
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Figure CN120136710A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of chemical synthesis, and more specifically, it relates to a continuous deuteration preparation method of deuterated aniline. Background Art
[0002] Aniline is an extremely important chemical raw material in the pharmaceutical, pesticide, rubber, and dye manufacturing industries. Aniline is an important raw material for the production of sulfonamide pharmaceuticals; in the pesticide industry, it can be used as a raw material for the production of many insecticides, fungicides, and herbicides; in the rubber industry, aniline is an important raw material for rubber auxiliaries, used to manufacture antioxidant A, antioxidant D, antioxidant RD, antioxidant 4010, accelerator M, 808, D, and CA, etc.; in the printing and dyeing industry, it can be used for the dye aniline black. In addition, aniline is also an intermediate for the production of spices, plastics, varnishes, films, etc., and can be used as a stabilizer in explosives, an antiknock agent in gasoline, and as a solvent.
[0003] Due to their high stability, good tracer effects, and lack of radioactivity, deuterated compounds play an increasingly important role in the biological and pharmaceutical fields. For example, in pharmacokinetic studies, introducing deuterated fragments into drug molecules can well track the metabolic pathways of drugs in the body. In organic chemical reactions, due to the high reactivity of aniline, it is often used to achieve group conversion of amino groups. If we want to study its reaction mechanism, we can use deuterated aniline to trace the reaction process, so as to better infer the specific course of the reaction. Similarly, deuterated aniline can be used as a raw material to synthesize other important deuterated drug molecules. Therefore, developing a synthesis method of deuterated aniline has important practical significance.
[0004] Using aniline as the starting material, activating the C-H bond on the benzene ring through a catalyst to achieve direct hydrogen-deuterium exchange is still an effective means for synthesizing deuterated aniline. In 2008, Nobuhiro Ito et al. reported in Bulletin of the Chemical Society of Japan, 81(2):278-286 that using carbon-supported noble metal platinum as a catalyst, the hydrogen on the benzene ring of aniline undergoes hydrogen-deuterium exchange with heavy water under a hydrogen atmosphere by heating. The reaction conditions are relatively mild, and the deuteration degree reaches 98%, but the yield is only 66%. This method requires the use of noble metals and the yield is not high. In 2016, Mark C. Bagley et al. reported in Synlett, 27(17):2467-2472 that using heavy water and DCl as deuterium sources, hydrogen-deuterium exchange occurs with aniline under microwave conditions at 190°C. The deuteration degree of the product is low and the yield is not high. Neither of the above two methods has the possibility of realizing industrial large-scale production.
[0005] Therefore, developing a preparation method of deuterated aniline with relatively mild reaction conditions, simple operation, high deuteration degree and good economic benefits has broad application prospects. Summary of the Invention
[0006] The purpose of the present invention is to provide a continuous deuteration preparation method of deuterated aniline to achieve the advantages of relatively mild reaction conditions, simple operation, high deuteration degree, high product yield, etc.
[0007] To achieve the present invention, the synthetic route of deuterated aniline is as follows:
[0008]
[0009] A fully automated synthesis control device provided by the present application specifically adopts the following scheme:
[0010] A fully automated synthesis control device includes:
[0011] Sampler;
[0012] A circulating heating device, connected to the pipeline reactor, includes a heater and a circulating pump for heating the reaction;
[0013] A pipeline reactor, connected to the sampler, includes 10 pipeline reaction units connected in series. The front end of the catalyst unit of the 2nd to the last one of the continuous pipeline reaction units is connected to the deuterium source replenishment pipeline, and the reaction liquid outflow end of each catalyst unit in the continuous pipeline reaction unit is connected to the low-concentration deuterium source recovery end.
[0014] A continuous deuteration preparation method of deuterated aniline provided by the present application includes the following steps:
[0015] Using aniline and deuterium source as raw materials, reacting under the catalytic conditions of a solvent and a catalyst, collecting the outflowing reaction liquid, and rectifying to obtain deuterated aniline. The reaction route is as follows:
[0016]
[0017] Further optionally, the method specifically includes the following steps:
[0018] Load the metal catalyst into the reactor, turn on the circulating heating, and preheat the reactor to the reaction temperature;
[0019] Mix aniline, deuterium source and solvent evenly, pump them into the preheated reactor at a certain flow rate for reaction, and slowly supplement and pump deuterium source into the reaction system at the same time;
[0020] Collect the reaction liquid, and obtain deuterated aniline through rectification.
[0021] Optionally, the catalyst is any one or two of iron, cobalt, nickel and copper, or a nano-alloy of any two of them, or any one or two of the halide salts of iron, cobalt, nickel and copper supported on a carrier.
[0022] Optionally, the reaction temperature is 110 - 280 °C, preferably 130 - 200 °C.
[0023] Optionally, the initial mixing ratio (molar ratio) of aniline, deuterium source and solvent is 1:(5 - 25):(1 - 15).
[0024] Optionally, the organic solvent is selected from any one or more of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
[0025] Optionally, the reaction flow rate is 0.1 - 10 mL / min, preferably 0.5 - 2 mL / min.
[0026] Optionally, the flow rate of the supplementary deuterium source pumped in is 0.1 - 5 mL / min, preferably 0.2 - 1.5 mL / min.
[0027] Optionally, the deuterium source reagent is selected from one or two of heavy water, deuterated methanol, deuterated ethanol, deuterated isopropanol.
[0028] In summary, the present application has the following beneficial effects:
[0029] Through the continuous fluid pipeline reaction catalyzed by the catalyst, using aniline as the raw material and through hydrogen-deuterium exchange with heavy water, the present invention solves the problems of high production cost and complex process in the synthesis of deuterated aniline. Moreover, the reaction conditions are mild. By continuously supplementing deuterium water for multiple times during the reaction process for continuous deuteration, the deuteration degree is improved, and high-purity deuterated aniline is obtained in high yield. The whole process does not require expensive noble metal catalysts, nor high-temperature and high-pressure conditions, and the operation is relatively simple, which is conducive to realizing industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 : Schematic diagram of the reaction process and device of the embodiment of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0031] The following further elaborates in detail the structure and effects of the present application in combination with embodiments. It can be understood that the specific embodiments described herein are only used to explain the present invention, rather than limiting the present invention. Additionally, it should be noted that for the sake of description, only parts related to the present invention are shown in the drawings, rather than all the structures.
[0032] Example 1
[0033] This embodiment discloses a fully automated synthesis control device. Refer to Figure 1 , the fully automated synthesis control device includes:
[0034] A sampler;
[0035] A circulating heating device, connected to the pipeline reactor, including a heater and a circulating pump, for heating the reaction;
[0036] A pipeline reactor, connected to the sampler, includes 10 pipeline reaction units connected in series. The front end of the catalyst unit of the 2nd to the last one of the continuous pipeline reaction units is connected to the deuterium source supplement pipeline, and the reaction liquid outflow end of each catalyst unit in the continuous pipeline reaction unit is connected to the low-concentration deuterium source recovery end.
[0037] Example 2
[0038] This embodiment discloses a continuous deuteration preparation method of deuterated aniline. Using aniline and deuterium source as raw materials, under the catalytic conditions of a solvent and a catalyst, a reaction occurs. The flowing reaction liquid is collected and rectified to obtain deuterated aniline. The reaction route is as follows:
[0039]
[0040] The method specifically includes the following steps:
[0041] Fill iron(III) chloride supported on alumina into the catalyst unit of the pipeline reactor, start the circulating heating device, and preheat the pipeline to 150 °C. During the preheating and temperature rising period, stir and mix aniline (30.0 g, 0.322 mol, 1 equivalent), heavy water (64.5 g, 32.2 mol, 10 equivalents) and N-methylpyrrolidone (76.1 g, 0.768 mol, 2 equivalents) evenly. After the set temperature of the pipeline is reached, pump the reaction materials into the continuous pipeline reactor through the sampler at a flow rate of 0.8 mL / min, and at the same time supplement heavy water into the pipeline system at a flow rate of 0.3 mL / min. Collect the flowing reaction liquid at the outlet of the end of the continuous reactor. The reaction liquid can obtain 28.5 g of deuterated aniline through the rectification device, and low-purity heavy water can be collected through the recovery ports of each reaction unit. The yield of deuterated aniline is 90.0%, and the deuteration degree is 99.11%.
[0042] Example 3
[0043] This embodiment discloses a continuous deuteration preparation method of deuterated aniline. Using aniline and deuterium source as raw materials, under the catalytic conditions of a solvent and a catalyst, a reaction occurs. The flowing reaction liquid is collected and rectified to obtain deuterated aniline. The reaction route is as follows:
[0044]
[0045] The method specifically includes the following steps:
[0046] Fill the iron(III) chloride supported on alumina into the catalyst unit of the tubular reactor, start the circulating heating device, and preheat the tube to 110 °C. During the preheating and temperature rising period, stir and mix aniline (30.0 g, 0.322 mol, 1 equivalent), heavy water (32.3 g, 16.1 mol, 5 equivalents) and N-methylpyrrolidone (38.0 g, 0.384 mol, 1 equivalent) evenly. After the set temperature of the tube is reached, pump the reaction material into the continuous tubular reactor through the injector at a flow rate of 0.1 mL / min, and at the same time supplement heavy water and pump it into the tube system at a flow rate of 0.1 mL / min. Collect the outflowing reaction liquid at the outlet of the end of the continuous reactor. The reaction liquid can obtain 28.2 g of deuterated aniline through the rectification device, and the low-purity heavy water can be collected through the recovery port of each reaction unit. The yield of deuterated aniline is 89.1%, and the deuteration degree is 99.0%.
[0047] Example 4
[0048] This example discloses a continuous deuteration preparation method of deuterated aniline. This method uses aniline and a deuterium source as raw materials, reacts under the catalytic conditions of a solvent and a catalyst, collects the outflowing reaction liquid, and rectifies it to obtain deuterated aniline. The reaction route is as follows:
[0049]
[0050] The method specifically includes the following steps:
[0051] Fill the iron(III) chloride supported on alumina into the catalyst unit of the tubular reactor, start the circulating heating device, and preheat the tube to 280 °C. During the preheating and temperature rising period, stir and mix aniline (30.0 g, 0.322 mol, 1 equivalent), heavy water (161.5 g, 80.5 mol, 25 equivalents) and N-methylpyrrolidone (570.0 g, 5.76 mol, 15 equivalents) evenly. After the set temperature of the tube is reached, pump the reaction material into the continuous tubular reactor through the injector at a flow rate of 10 mL / min, and at the same time supplement heavy water and pump it into the tube system at a flow rate of 5 mL / min. Collect the outflowing reaction liquid at the outlet of the end of the continuous reactor. The reaction liquid can obtain 26.3 g of deuterated aniline through the rectification device, and the low-purity heavy water can be collected through the recovery port of each reaction unit. The yield of deuterated aniline is 83.3%, and the deuteration degree is 98.12%.
[0052] Example 5
[0053] This example discloses a continuous deuteration preparation method of deuterated aniline. This method uses aniline and a deuterium source as raw materials, reacts under the catalytic conditions of a solvent and a catalyst, collects the outflowing reaction liquid, and rectifies it to obtain deuterated aniline. The reaction route is as follows:
[0054]
[0055] The method specifically includes the following steps:
[0056] Fill the iron(III) chloride supported on alumina into the catalyst unit of the tubular reactor, start the circulating heating device, and preheat the pipeline to 130 °C. During the preheating and temperature rising period, stir and mix aniline (30.0 g, 0.322 mol, 1 equivalent), heavy water (64.5 g, 32.2 mol, 10 equivalents) and N-methylpyrrolidone (76.1 g, 0.768 mol, 2 equivalents) evenly. After the set temperature of the pipeline is reached, pump the reaction materials into the continuous tubular reactor through an injector at a flow rate of 0.5 mL / min, and at the same time supplement heavy water and pump it into the pipeline system at a flow rate of 0.2 mL / min. Collect the outflowing reaction liquid at the outlet of the end of the continuous reactor. The reaction liquid can obtain 28.8 g of deuterated aniline through the rectification device, and the low-purity heavy water can be collected through the recovery port of each reaction unit. The yield of deuterated aniline is 91.1%, and the deuteration degree is 99.1%.
[0057] Example 6
[0058] This example discloses a continuous deuteration preparation method of deuterated aniline. This method uses aniline and a deuterium source as raw materials, reacts under the catalytic conditions of a solvent and a catalyst, collects the outflowing reaction liquid, and rectifies to obtain deuterated aniline. The reaction route is as follows:
[0059]
[0060] The method specifically includes the following steps:
[0061] Fill the iron(III) chloride supported on alumina into the catalyst unit of the tubular reactor, start the circulating heating device, and preheat the pipeline to 200 °C. During the preheating and temperature rising period, stir and mix aniline (30.0 g, 0.322 mol, 1 equivalent), heavy water (64.5 g, 32.2 mol, 10 equivalents) and N-methylpyrrolidone (76.1 g, 0.768 mol, 2 equivalents) evenly. After the set temperature of the pipeline is reached, pump the reaction materials into the continuous tubular reactor through an injector at a flow rate of 2 mL / min, and at the same time supplement heavy water and pump it into the pipeline system at a flow rate of 1.5 mL / min. Collect the outflowing reaction liquid at the outlet of the end of the continuous reactor. The reaction liquid can obtain 28.4 g of deuterated aniline through the rectification device, and the low-purity heavy water can be collected through the recovery port of each reaction unit. The yield of deuterated aniline is 90.0%, and the deuteration degree is 99.2%.
[0062] This specific embodiment is only an interpretation of the present application and does not limit the present application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.
Claims
1. A method for preparing deuterated aniline by continuous deuteration, characterized in that: The following steps are involved: Aniline and a deuterium source are used as raw materials, and a reaction occurs under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected and distilled to obtain deuterated aniline. The reaction route is as follows:
2. The method for preparing deuterated aniline by continuous deuteration according to claim 1, characterized in that: The method specifically comprises the following steps: Load the metal catalyst into the reactor, start the circulating heating, and preheat the reactor to the reaction temperature; Aniline, deuterium source and solvent are mixed evenly, and pumped into a preheated reactor at a certain flow rate for reaction, and deuterium source is slowly pumped into the reaction system at the same time; The reaction solution is collected and distilled to obtain deuterated aniline.
3. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The catalyst is any one or two of iron, cobalt, nickel and copper, or a nano alloy of any two of them, or any one or two of halide salts of iron, cobalt, nickel and copper supported by a carrier.
4. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The reaction temperature is 110-280°C, preferably 130-200°C.
5. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The initial mixing ratio (molar ratio) of the aniline, the deuterium source and the solvent is 1:(5-25):(1-15).
6. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The organic solvent is selected from any one or more of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.
7. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The reaction flow rate is 0.1-10 mL / min, preferably 0.5-2 mL / min.
8. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The flow rate of the supplementary heavy water pump is 0.1-5 mL / min, preferably 0.2-1.5 mL / min.
9. The method for preparing deuterated aniline by continuous deuteration according to claim 2, characterized in that: The deuterium source reagent is selected from one or two of heavy water, deuterated methanol, deuterated ethanol, and deuterated isopropanol.