Method for preparing 4-chloro-3-nitroanisole compound by using microreactor
By performing the diazotization reaction of raw materials in a micro reactor and performing the chlorination reaction in a batch kettle reactor, the problem that traditional batch kettle reactors cannot accurately control the temperature is solved, and efficient preparation and safe production of 4-chloro-3-nitroanisole is achieved, which improves yield and reduces the risk of equipment corrosion.
Patent Information
- Application Number
- CN202510502533.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-22
- Publication Date
- 2025-08-05
AI Technical Summary
Traditional batch kettle reactors cannot accurately control the reaction temperature when preparing 4-chloro-3-nitroanisole, and there is serious remixture phenomenon and heat accumulation, resulting in increased side reactions, reduced yields, and risk of explosion.
After the raw material diazotization reaction is carried out by using a micro reactor, the chlorination reaction is carried out in the batch kettle reactor. The efficient heat and mass transfer ability and unique flow behavior of the micro reactor are used to accurately control the reaction temperature and time, reduce side reactions, and improve yield.
It has achieved a significant shortening of reaction time, improved the yield and safety of 4-chloro-3-nitroanisole, reduced the operation difficulty and equipment corrosion risk, and has high efficiency heat and mass transfer performance and environmentally friendly characteristics.
Smart Images
Figure CN120423958A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing a 4-chloro-3-nitroanisole compound, in particular to a method for preparing the 4-chloro-3-nitroanisole compound by utilizing a microreactor. Background Art
[0002] 4-Chloro-3-nitroanisole is an important chemical intermediate. It serves as one of the starting materials for the rheumatoid arthritis drug iguratimod, can also be used to synthesize the anti-tumor drug metoclopramide, and is also an important intermediate for dyes. Traditional batch reactors are unable to precisely control the reaction temperature and suffer from severe back-mixing, leading to side reactions and reduced yields in the diazotization reaction. Furthermore, the diazotization reaction is highly exothermic, and the diazonium salt intermediate is thermally unstable. Low mass and heat transfer efficiencies in batch reactors can lead to heat accumulation, causing rapid decomposition of the diazonium salt, creating an explosion hazard.
[0003] The traditional batch reactor preparation route for preparing 4-chloro-3-nitrobenzene methyl ether consists of two steps: 2-methoxy-4-nitroaniline and 31% dilute hydrochloric acid are added dropwise to an aqueous sodium nitrite solution at -5-3°C to obtain an aqueous solution of 2-methoxy-4-nitrobenzene diazonium hydrochloride. The diazonium salt solution is then added dropwise to a dilute hydrochloric acid solution of cuprous chloride at the same temperature to obtain a crude product. Finally, the product is dissolved in an organic solvent and washed with water to obtain a dark yellow crystalline product of 4-chloro-3-nitrobenzene methyl ether with a content of 97%-98% and a yield of 68%-73%. Summary of the Invention
[0004] The object of the invention is to provide a method for preparing 4-chloro-3-nitroanisole using a microreactor. The method uses a microreactor to perform a diazotization reaction on the raw materials, followed by a chlorination reaction in an intermittent reactor. 2-methoxy-4-nitroaniline is used as the raw material, and sodium nitrite and cuprous chloride are used to prepare the 4-chloro-3-nitroanisole compound. The method reduces byproducts of the diazotization reaction, improves the reaction yield and content, reduces operational difficulty, effectively eliminates safety issues such as strong heat release and easy material impact in the diazotization reaction, and improves operational safety.
[0005] The technical solution adopted in the present invention is as follows: A method for preparing a 4-chloro-3-nitroanisole compound using a microreactor, wherein the method uses a microreactor to perform a diazotization reaction on a raw material and then performs a chlorination reaction in an intermittent reactor reactor, comprising the following steps: (1) o-Nitro-p-anisidine, aqueous hydrochloric acid solution and water are mixed to obtain a homogeneous solution A; (2) Dissolve sodium nitrite in water to obtain a homogeneous solution B; (3) The homogeneous solution A prepared in step (1) and the homogeneous solution B prepared in step (2) are simultaneously pumped into the microreactor, precooled through a precooling pipe, and then pumped into the micromixer in the microreactor. After being fully mixed, they are pumped into the microreactor in the microreactor for reaction. After the reaction is completed, a diazo solution is obtained. After mixing cuprous chloride, aqueous hydrochloric acid solution and cyclohexane, a homogeneous solution C is obtained; (5) The diazo solution prepared in step (3) is slowly added dropwise to the homogeneous solution C prepared in step (4), and the mixture is heated after continuous stirring. The mixture is allowed to stand for separation, and the organic layer is washed with water after the water layer is removed. The mixture is cooled, crystallized, and filtered to obtain the finished product 4-chloro-3-nitroanisole.
[0006] The method for preparing 4-chloro-3-nitroanisole compound using a microreactor, in step (1), the concentration of the solute o-nitro-p-methoxyaniline in the homogeneous solution A is 0.001-0.1 mol / mL.
[0007] In the method for preparing 4-chloro-3-nitroanisole compound using a microreactor, the concentration of the solute sodium nitrite in the homogeneous solution B in step (2) is 0.008-1 mol / mL.
[0008] The method for preparing a 4-chloro-3-nitroanisole compound using a microreactor, wherein the flow rate of the homogeneous solution A prepared in step (1) in the microreactor is 0.05-3 mL / min, and the flow rate of the homogeneous solution B prepared in step (2) in the microreactor is 0.05-3 mL / min.
[0009] In the method for preparing 4-chloro-3-nitroanisole compound using a microreactor, the precooling temperature of the precooling pipe in step (3) is -10~5°C.
[0010] In the method for preparing 4-chloro-3-nitroanisole compound using a microreactor, the reaction temperature of the microreactor in step (3) is -7 to 5°C, and the residence time is 1 to 10 minutes.
[0011] Technical effects of the present invention: This reaction utilizes continuous flow synthesis technology to precisely control the reaction temperature. The entire process has a short reaction time, low toxicity and pollution, high safety, few side reactions, and better selectivity than conventional processes. The yield of 4-chloro-3-nitroanisole can reach 80-85%.
[0012] Compared with the prior art, the present invention has the following technical advantages: 1. Large specific surface area, excellent heat and mass transfer performance per unit specific surface area, reaction time is shortened from several hours to tens of seconds or minutes, reaction efficiency is significantly improved, with efficient heat and mass transfer performance, can achieve rapid mixing of materials, and ensure the efficiency of the reaction process; 2. Unique flow behavior, excellent mixing effect between different raw materials in the microchannel, which can make the reaction process, 3. Good anti-corrosion performance, the microchannel in the reactor can be modified by Hastelloy, and the metering pump material is PTFE and titanium feed, which avoids the serious corrosion problem of equipment in conventional reactors; 4. Reduce operational exposure, reduce "three wastes", alleviate workers' chemical exposure problems in industrial production, reduce waste gas pollution and transfer leakage, avoid the need for additional equipment in conventional batch reactions, and have the advantages of low energy consumption and environmental friendliness; 5. The process is safe because it has extremely high heat and mass transfer capabilities and the characteristics of precise and controllable reaction time and short reaction time. High-risk compounds can be obtained through precise control of the reaction and can be quenched in time, reducing the risk of high-risk reactions. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Figure 1 Schematic diagram of the structure of the micro-reactor used in the diazotization reaction of the present invention. DETAILED DESCRIPTION
[0014] The present invention will be described in detail below with reference to the embodiments shown in the accompanying drawings.
[0015] A method for preparing 4-chloro-3-nitroanisole using a microreactor comprises the following steps: (1) At -7~5°C, o-nitro-p-anisidine, aqueous hydrochloric acid solution and water are mixed to obtain a homogeneous solution A; (2) Dissolve sodium nitrite in water at 0-20°C to obtain a homogeneous solution B; (3) The homogeneous solution A prepared in step (1) and the homogeneous solution B prepared in step (2) are simultaneously pumped into the microreactor, precooled through a precooling pipe, and then pumped into the micromixer in the microreactor. After being fully mixed, they are pumped into the microreactor in the microreactor for reaction. After the reaction is completed, a diazo solution is obtained.
[0016] (4) Mixing cuprous chloride, aqueous hydrochloric acid solution, and cyclohexane to obtain a homogeneous solution C; (5) The diazo solution prepared in step (3) is slowly added dropwise to the homogeneous solution C prepared in step (4), and the mixture is heated after continuous stirring. The mixture is allowed to stand for separation, and the organic layer is washed with water after the water layer is removed. The mixture is cooled, crystallized, and filtered to obtain the finished product 4-chloro-3-nitroanisole.
[0017] In step (1), the concentration of the aqueous hydrochloric acid solution is not less than 31 wt %. In the obtained homogeneous solution A, the concentration of the solute hydrochloric acid is preferably 0.005 to 1 mol / mL.
[0018] In step (2), the concentration of the solute sodium nitrite in the homogeneous solution B is 0.008-0.01 mol / mL, preferably 0.008-0.009 mol / mL.
[0019] The molar ratio of the solute hydrochloric acid and sodium nitrite in the o-nitro-p-anisidine and hydrochloric acid aqueous solution is 1:4.1:1.1.
[0020] In step (3), the flow rate of the homogeneous solution A prepared in step (1) in the microreactor is 1-8 mL / min, and the flow rate of the homogeneous solution B prepared in step (2) in the microreactor is 1-8 mL / min.
[0021] In step (3), in the precooling pipe, the precooling temperature is -10~5°C, preferably -10~0°C; in the microreactor, the reaction temperature is -7~5°C, preferably -5~3°C, and the residence time is 1~8 min.
[0022] The micro-reactor comprises a micro-mixer and a micro-reactor connected by a connecting pipe; wherein the feed port of the micro-mixer is connected to two pre-cooling pipes, and the feed ports of the pre-cooling pipes are respectively connected to a material inlet.
[0023] Among them, the inner diameter of the pre-cooling pipe is 0.1~5mm, and the volume is 0.1~2mL; In the microreactor, the inner diameter of the reaction channel is 0.1~5mm and the volume is 2~50mL.
[0024] Among them, the micro mixer is preferably a T-type mixing valve.
[0025] Reaction formula of the present invention is as follows:
[0026] The hydrochloric acid used in the following examples is all 31 wt % hydrochloric acid aqueous solution.
[0027] The structure of the micro-reactor used in the following examples is shown in Figure 1 ; Among them, the micro mixer is a T-type mixing valve. Example
[0028] In the microchannel reaction device, the connecting pipe diameter is 2.1 mm, the liquid inlet pipe is 15 cm long, the connecting pipe between the T-valve and the microchannel reactor is 25 cm long, and the connecting pipe between the microreactor and the outlet is 20 cm long.
[0029] In container A, add 1.6g of 2-methoxy-4-nitroaniline, 4.6g of hydrochloric acid, and 4.0g of water to prepare a reaction mixture. In container B, dissolve 0.7g of sodium nitrite in 1.2g of water to prepare an aqueous solution. Precool these two solutions to -2°C and pump them simultaneously through a T-type mixing valve into the microchannel reactor. The reaction temperature is -2°C and the reaction time is 2 minutes. This yields a diazo solution.
[0030] To container C, add 1.2g of cuprous chloride, 7.6g of hydrochloric acid, and 3.0g of cyclohexane, stirring and cooling to -7-5°C. Slowly add the diazo solution dropwise at this temperature. After complete addition, maintain the temperature and stir for 3 hours. Add 2.8g of cyclohexane and raise the temperature to 55-60°C. Allow to stand and separate, remove the acidic aqueous layer, and wash the organic layer with water. Cool, crystallize, and filter to obtain the finished product, 4-chloro-3-nitroanisole, with a content of 99.2% and a yield of 85.0%.
[0031] The steps of Examples 2 to 10 are the same as those of Example 1, wherein the specific parameters are shown in the table below: Example Dropping rate mL / min Reaction temperature ℃ Reaction time min Finished product content% Finished product yield% Finished product appearance 1 4 -2 2 99.2 85.0 light yellow 2 2 -2 4 99.8 85.3 Off-white 3 1 -2 8 99.7 83.2 Off-white 4 8 -2 1 99.4 84.9 light yellow 5 2 -5 4 99.3 82.0 light yellow 6 2 1 4 99.3 81.7 light yellow 7 2 3 4 99.2 81.5 light yellow Example 11: Since the diazotization reaction is an exothermic reaction, when an industrial batch reactor is used to react, the yield is often sharply reduced due to severe local heat release. Therefore, microchannel reaction is selected to carry out the reaction. Due to the extremely large specific surface area and excellent heat and mass transfer capacity of the microchannel reactor, it is very friendly to the reaction that will produce local heat release. By accurately controlling the residence time of the reactants in the channel, the reaction time is shortened, and a large amount of heat release is avoided. In order to prove the advantage of the microchannel reactor, the present invention carries out a comparative test.
[0032] Experiments were conducted using a microchannel reactor, see Examples 1 to 10.
[0033] Using kettle reaction: Add 16g of 2-methoxy-4-nitroaniline and 46g of hydrochloric acid to a reaction kettle, followed by 40g of water. Cool to -7-5°C while mechanically stirring. Add 19g of a 37.9% sodium nitrite aqueous solution dropwise to the kettle. Stir at this temperature for 3 hours to obtain a diazo solution, which is then stored at low temperature.
[0034] Add 12g of cuprous chloride, 76g of hydrochloric acid, and 30g of cyclohexane to a reactor, stirring and cooling to -7-5°C. Slowly add the diazo solution dropwise at this temperature, maintaining the temperature with stirring for 3 hours. Add 28g of cyclohexane and heat to 55-60°C. Allow to stand and separate, remove the acidic and aqueous layer, and wash the organic layer with water. Cool, crystallize, and filter to obtain the finished product, 4-chloro-3-nitroanisole, with a 97.2% content and a 71.5% yield.
[0035] Compared with the above embodiments, it can be seen that when a microchannel reactor is used for reaction, the reaction efficiency and reaction yield are improved, and the large amount of local heat release during the autoclave reaction is avoided, thereby ensuring the safety of the experiment.
Claims
1. A method for preparing 4-chloro-3-nitroanisole compound using a microreactor, characterized in that: The method uses a microreactor to carry out a diazotization reaction of the raw material and then carries out a chlorination reaction in an intermittent tank reactor, comprising the following steps: (1) o-Nitro-p-anisidine, aqueous hydrochloric acid solution and water are mixed to obtain a homogeneous solution A; (2) Dissolve sodium nitrite in water to obtain a homogeneous solution B; (3) The homogeneous solution A prepared in step (1) and the homogeneous solution B prepared in step (2) are simultaneously pumped into the microreactor, precooled through a precooling pipe, and then pumped into the micromixer in the microreactor. After being fully mixed, they are pumped into the microreactor in the microreactor for reaction. After the reaction is completed, a diazo solution is obtained. After mixing cuprous chloride, aqueous hydrochloric acid solution and cyclohexane, a homogeneous solution C is obtained; (5) The diazo solution prepared in step (3) is slowly added dropwise to the homogeneous solution C prepared in step (4), and the mixture is heated after continuous stirring. The mixture is allowed to stand for separation, and the organic layer is washed with water after the water layer is removed. The mixture is cooled, crystallized, and filtered to obtain the finished product 4-chloro-3-nitroanisole.
2. A method for preparing 4-chloro-3-nitroanisole compound by utilizing a microreactor according to claim 1, characterized in that, In the step (1), the concentration of the solute o-nitro-p-methoxyaniline in the homogeneous solution A is 0.001-0.1 mol / mL.
3. A method for preparing 4-chloro-3-nitroanisole compound by utilizing a microreactor according to claim 1, characterized in that, The concentration of the solute sodium nitrite in the homogeneous solution B in step (2) is 0.008-1 mol / mL.
4. A method for preparing 4-chloro-3-nitroanisole compound by utilizing a microreactor according to claim 1, characterized in that, The flow rate of the homogeneous solution A prepared in step (1) in the microreactor is 0.05-3 mL / min, and the flow rate of the homogeneous solution B prepared in step (2) in the microreactor is 0.05-3 mL / min.
5. A method for preparing 4-chloro-3-nitroanisole compound by utilizing a microreactor according to claim 1, characterized in that, The pre-cooling temperature of the pre-cooling pipe in step (3) is -10~5°C.
6. A method for preparing 4-chloro-3-nitroanisole compound by utilizing a microreactor according to claim 1, characterized in that, The reaction temperature of the microreactor in step (3) is -7~5°C, and the residence time is 1~10 minutes.