Method for preparing 4-chloro-3-nitroanisole by using micro-channel reactor to chloridize diazonium hydrochloride
The precise control of the diazo chloride hydrochloride reaction through the microchannel reactor solves the problems of large area, low production capacity and low yield in traditional processes, and achieves efficient and safe preparation of 4-chloro-3-nitroanisole to meet the high-end market demand.
Patent Information
- Application Number
- CN202510502584.0
- 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
The traditional 4-chloro-3-nitroanisole synthesis process has problems such as large equipment footprint, low production capacity, difficult product yield, high energy consumption and poor safety, and cannot meet the demand of the high-end market.
4-chloro-3-nitrobenzyl ether was prepared by using a micro-channel reactor to prepare diazo hydrochloride. By precisely controlling the reaction conditions, including the molar ratio, flow rate and temperature of cuprous chloride and hydrochloric acid, instantaneous mixing and efficient reaction were achieved.
It significantly improves product yield and safety, shortens reaction time, reduces energy consumption, and improves the consistency of production efficiency and product quality.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing 4-chloro-3-nitroanisole, in particular to a method for preparing 4-chloro-3-nitroanisole by using diazonium chloride hydrochloride in a microchannel reactor. Background Art
[0002] 4-Chloro-3-nitroanisole, a key intermediate in the synthesis of various pharmaceuticals and pesticides, has a wide range of applications. It plays an essential role in the synthesis of drugs such as iguratimod and metoclopramide. Iguratimod, a potent drug developed by Toyama Chemical Co., Ltd. in Japan for rheumatoid arthritis and osteoarthritis, continues to see growing market demand.
[0003] Current synthesis technology for 4-chloro-3-nitroanisole suffers from numerous drawbacks. Traditional synthesis methods rely on stirred-tank reactors, which require large equipment footprints and have low space utilization, increasing production site costs. Furthermore, production capacity is low, making it difficult to meet the growing demand for large-scale production. Furthermore, traditional processes encounter bottlenecks in improving product yield and content, making it difficult to increase yield and achieve higher quality standards, thus failing to meet the demands of the high-end market.
[0004] The current production process uses o-nitro-p-anisidine as the starting material. After diazotization with sodium nitrite in dilute hydrochloric acid, it is then reacted with acidic cuprous chloride in a "one-pot" reaction. Ethyl acetate or chloroform is added for extraction, concentration is achieved, and the product is then distilled under reduced pressure. Finally, it is crystallized from ethanol to obtain pale yellow crystals with a yield of approximately 66%. The product has a high boiling point of 293.2°C at atmospheric pressure. The reduced pressure distillation step requires high vacuum conditions, which not only places extremely high demands on the vacuum performance of the equipment but also consumes a large amount of energy resources. More importantly, the process struggles to increase product yield and content, failing to meet the growing market demand for high-quality, high-purity 4-chloro-3-nitroanisole. These factors collectively increase the difficulty of industrial production and severely hinder the efficient advancement of continuous and large-scale production. An innovative synthetic process is urgently needed to address these issues. Summary of the Invention
[0005] The present invention aims to provide a method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride in a microchannel reactor. The method adopts a microchannel reactor mode for synthesis, effectively overcoming the difficulty in controlling the chlorination reaction in the prior art that is too violent, and significantly improving the intrinsic safety of the process.
[0006] The purpose of the present invention is achieved through the following technical solutions: A method for preparing 4-chloro-3-nitrobenzene methyl ether from diazonium chloride hydrochloride in a microchannel reactor, wherein 2-methoxy-4-nitrobenzene diazonium hydrochloride is used as a raw material to synthesize 4-chloro-3-nitrobenzene methyl ether in a microchannel reactor; The specific steps are as follows: In an ice-water bath, cuprous chloride and 31% hydrochloric acid are mixed to obtain a reaction solution, wherein the molar ratio of cuprous chloride to hydrochloric acid is 1.0:3.5~5.5; diazonium hydrochloride is fed into a pre-cooling module by a horizontal flow pump and pre-cooled at 0°C. After that, the two liquids enter the reaction module of the microchannel continuous flow reactor at a constant flow rate, instantaneously mix and contact and react, and the molar ratio of diazonium hydrochloride to cuprous chloride is controlled to be 1.0:1.2~1.9. The reaction time is set to 6 minutes; after the reaction is completed, the reaction solution flows into a collection tank, and the reaction solution in the collection tank is extracted with cyclohexane. The aqueous layer material is adjusted to neutral and post-treated. The cyclohexane layer material is washed with water until neutral and then reduced to -10~-5°C for crystallization. The product is rinsed twice with cyclohexane solvent and dried to obtain light yellow to off-white 4-chloro-3-nitroanisole crystals: .
[0007] In the method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride in a microchannel reactor, the molar ratio of cuprous chloride to 31% hydrochloric acid is 1.0:3.5-5.5, and the molar ratio of diazonium hydrochloride to cuprous chloride is 1.0:1.2-1.9.
[0008] In the method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride using a microchannel reactor, the cuprous chloride hydrochloric acid solution is transported by a horizontal flow pump with precise flow control, and the flow rate is controlled at 0.6-1.0 ml / min.
[0009] In the method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride in a microchannel reactor, the diazonium hydrochloride is transported via a horizontal flow pump with precise flow control, and the flow rate is controlled at 1.0-1.4 ml / min.
[0010] The method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride in a microchannel reactor has a reaction temperature of -5 to 7°C.
[0011] The method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride in a microchannel reactor has a reaction retention time of 6 minutes.
[0012] The advantages and effects of the present invention are: The present invention utilizes a microchannel continuous flow reactor to chlorinate 2-methoxy-4-nitrobenzene diazonium hydrochloride, effectively avoiding the local overheating phenomenon that is prone to occur in conventional kettle reactors. The microchannel reactor can accurately control the reaction process, greatly improving the inherent safety of the process. In the microchannel reactor, the materials can be mixed instantly, greatly shortening the reaction time. Compared with the traditional process that requires several hours of reaction time, the reaction time of the present invention can be greatly reduced to a few minutes. This efficient reaction mode significantly improves the conversion rate, and thus the product yield is also improved, bringing higher economic benefits to industrial production. The microchannel reactor has good heat dissipation performance, which can timely conduct away the reaction heat and effectively eliminate local overheating. This not only further improves the safety of the reaction process, but also reduces the possibility of side reactions caused by uneven temperature, ensures the stability of the reaction and the consistency of product quality, reduces the probability of safety accidents caused by improper operation, and provides reliable protection for the production process. DETAILED DESCRIPTION
[0013] The present invention is described in detail below with reference to the embodiments. Example
[0014] Preparation of diazonium hydrochloride: Add o-nitro-p-anisidine, 31% hydrochloric acid, and deionized water to a 500mL three-necked flask (at a molar ratio of 1:4). Freeze and cool to -5°C to 2°C and stir for half an hour. Add a pre-prepared solution of sodium nitrite and deionized water (molar ratio 1:1.6) dropwise while stirring. Control the addition rate to maintain a -5°C to 2°C reaction temperature. The starch potassium iodide test paper should indicate a blue color with no reddish-brown gas production. Complete the addition over approximately 3 hours. After the addition is complete, keep the reaction at -5°C to 2°C for 3 hours. Filter the diazo solution and keep the filtrate refrigerated below 2°C.
[0015] Synthesis and purification of products: In a 1000mL three-necked flask, add cuprous chloride and concentrated hydrochloric acid in a molar ratio of 1:4, and add 0.2ml of tributyl phosphate. Freeze and cool to -5℃~2℃. Slowly add the above-mentioned cold diazo solution dropwise, and the reaction temperature is controlled at -5℃~2℃. The addition time is about 3~4 hours. After the addition is complete, continue to maintain -5℃~2℃ for 1 hour. Then remove the freezing equipment, allow the reaction solution to warm up naturally, and continue stirring overnight. After the reaction is completed, separate the solid product by filtration, and use about 1000ml of deionized water to rinse the filter cake until the pH value of the washed filtrate is neutral to obtain a crude product.
[0016] The crude 4-chloro-3-nitroanisole and ethanol were placed in a 500 mL three-necked flask, heated to reflux, then cooled to about 40°C and filtered. The filtrate was distilled to remove about 130 g of ethanol. The filtrate was cooled to -5~0°C and stirred to precipitate, filtered, and washed with chilled ethanol to obtain a light yellow solid. The product content was calculated to be about 98.7% and the yield was 67.2%.
[0017] Examples 2 to 6: Under ice-water bath, cuprous chloride and 31% hydrochloric acid are mixed to obtain reaction solution, wherein, the molar ratio of cuprous chloride to hydrochloric acid is 1:3.5~5.5. Set external heat exchanger temperature to 5 DEG C, so that system circulation temperature reaches equilibrium. Homemade diazonium hydrochloride (synthesized by embodiment 1 method) is passed through pre-cooling module by horizontal flow pump and pre-cooled, and pre-cooling temperature is 0 DEG C, and then enters the reaction module of microchannel continuous flow reactor. Regulate cuprous chloride flow rate 0.8ml / min, regulate diazonium liquid flow rate 1.2ml / min, make the molar ratio of diazonium hydrochloride to cuprous chloride 1:1.2~1.9, control the residence time of reactant in reactor to be 6 minutes, make reaction product flow into collecting tank, this example continuously collects reactant for 2 hours, preserves at room temperature, adds cyclohexane solvent extraction, and stands for 1 hour. The aqueous layer was adjusted to a pH value close to neutral and then treated. The cyclohexane layer was washed with water until neutral, and then cooled to -10~-5°C for precipitation for 8~10 hours. The mixture was filtered, rinsed with cyclohexane, and dried to obtain a light yellow to off-white crystalline powder.
[0018] Table 1 Example 2 3 4 5 6 Molar ratio of cuprous chloride to hydrochloric acid 1.0:3.5 1.0:4.0 1.0:4.5 1.0:5.0 1.0:5.5 Molar ratio of diazonium hydrochloride to cuprous chloride 1:1.2 1:1.4 1:1.5 1:1.7 1:1.9 Reaction temperature (℃) 5.0 5.0 5.0 5.0 5.0 Flow rate of hydrochloric acid reaction solution (ml / min) 0.8 0.8 0.8 0.8 0.8 Diazonium salt flow rate (ml / min) 1.2 1.2 1.2 1.2 1.2 purity(%) 98.2 98.9 99.1 99.3 99.2 Yield (%) 74.3 75.1 76.5 77.3 75.3 Implementation 7~10: Under ice-water bath, cuprous chloride and 31% hydrochloric acid are mixed to obtain reaction solution, wherein, the mol ratio of cuprous chloride to hydrochloric acid is 1.0: 5.0. External heat exchanger temperature is set to -5 ~ 7 DEG C, so that system circulation temperature reaches equilibrium. Homemade diazonium hydrochloride (Synthesis by Example 1 Method) is passed through a horizontal flow pump and precooled in a precooling module, and the precooling temperature is -5 ~ 7 DEG C, and then enters the reaction module of microchannel continuous flow reactor. Regulate cuprous chloride flow rate 1.0ml / min, regulate diazonium hydrochloride liquid flow rate 1.2ml / min, make the mol ratio of diazonium hydrochloride to cuprous chloride 1.0: 1.7, control the residence time of reactant in reactor to be 6 minutes, make reaction product flow into collecting tank, this example continuously collects reactant of 2 hours, preserves at room temperature, adds cyclohexane solvent extraction, and stands for 1 hour. The aqueous layer was adjusted to a pH value close to neutral and then treated. The cyclohexane layer was washed with water until neutral, and then cooled to -10~-5°C for precipitation for 8~10 hours. The mixture was filtered, rinsed with cyclohexane, and dried to obtain a light yellow to off-white crystalline powder.
[0019] Table 2 Example 7 8 9 10 Molar ratio of cuprous chloride to hydrochloric acid 1.0:5.0 1.0:5.0 1.0:5.0 1.0:5.0 Molar ratio of diazonium salt to cuprous chloride 1:1.7 1:1.7 1:1.7 1:1.7 Reaction temperature (℃) -5.0 0 5.0 7.0 Flow rate of hydrochloric acid reaction solution (ml / min) 0.9 0.9 0.9 0.9 Diazonium salt flow rate (ml / min) 1.2 1.2 1.2 1.2 purity(%) 98.9 99.1 99.4 98.4 Yield (%) 74.5 75.1 78.3 77.0 Examples 11 to 15: Under ice-water bath, cuprous chloride and 31% hydrochloric acid are mixed to obtain a reaction solution, wherein the molar ratio of cuprous chloride to hydrochloric acid is 1.0: 5.0. The external heat exchanger temperature is set to 5 ° C so that the system circulation temperature reaches equilibrium. Diazo hydrochloride (synthesized by the method of embodiment 1) is passed through a tetrafluoro advection pump into a pre-cooling module for pre-cooling, and the pre-cooling temperature is 0 ° C, and then enters the reaction module of the microchannel continuous flow reactor. Regulate the cuprous chloride flow rate 0.6 ~ 1.0 ml / min, regulate the diazonium liquid flow rate 1.7 ml / min, make the molar ratio of diazonium salt to cuprous chloride 1.0: 1.5 ~ 1.9, control the residence time of the reactant in the reactor to 6 minutes, make the reaction product flow into the collection tank, this example continuously collects the reactant for 2 hours, stores at room temperature, adds cyclohexane solvent extraction, and stands for 1 hour. The aqueous layer was adjusted to a pH value close to neutral and then treated. The cyclohexane layer was washed with water until neutral, and then cooled to -10~-5°C for precipitation for 8~10 hours. The mixture was filtered, rinsed with cyclohexane, and dried to obtain a light yellow to off-white crystalline powder.
[0020] Table 3
[0021] Examples 16-20: Under ice-water bath, cuprous chloride and 31% hydrochloric acid are mixed to obtain reaction solution, wherein, the mol ratio of cuprous chloride to hydrochloric acid is 1.0: 5.0. External heat exchanger temperature is set to 5 DEG C so that system circulation temperature reaches equilibrium. Homemade diazo liquid (Synthesis by Example 1 method) is passed through a horizontal flow pump into a pre-cooling module for pre-cooling, and the pre-cooling temperature is 0 DEG C, and then enters the reaction module of microchannel continuous flow reactor. Regulate cuprous chloride flow rate 0.8ml / min, regulate diazo liquid flow rate 1.0~1.4ml / min, make the mol ratio of diazonium salt to cuprous chloride 1.0: 1.35~1.10, control the residence time of reactant in reactor to be 6 minutes, make reaction product flow into collecting tank, this example continuously collects reactant for 2 hours, preserves at room temperature, adds cyclohexane solvent extraction, and stands for 1 hour. The aqueous layer was adjusted to a pH value close to neutral and then treated. The cyclohexane layer was washed with water until neutral, and then cooled to -10~-5°C for precipitation for 8~10 hours. The mixture was filtered, rinsed with cyclohexane, and dried to obtain a light yellow to off-white crystalline powder.
[0022] Table 4
[0023] The above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents to achieve the same technical effects; as long as the use requirements are met, they are within the scope of protection of the present invention.
Claims
1. A method for preparing 4-chloro-3-nitroanisole from diazonium chloride hydrochloride using a microchannel reactor, characterized in that: The method uses 2-methoxy-4-nitrobenzene diazonium hydrochloride as a raw material to synthesize 4-chloro-3-nitroanisole in a microchannel reactor; The specific steps are as follows: In an ice-water bath, cuprous chloride and 31% hydrochloric acid are mixed to obtain a reaction solution, wherein the molar ratio of cuprous chloride to hydrochloric acid is 1.0:3.5~5.5; diazonium hydrochloride is fed into a pre-cooling module by a horizontal flow pump and pre-cooled at 0°C. After that, the two liquids enter the reaction module of the microchannel continuous flow reactor at a constant flow rate, instantaneously mix and contact and react, and the molar ratio of diazonium hydrochloride to cuprous chloride is controlled to be 1.0:1.2~1.
9. The reaction time is set to 6 minutes; after the reaction is completed, the reaction solution flows into a collection tank, and the reaction solution in the collection tank is extracted with cyclohexane. The aqueous layer material is adjusted to neutral and post-treated. The cyclohexane layer material is washed with water until neutral and then cooled to -10~-5°C for crystallization. The product is rinsed twice with cyclohexane solvent and dried to obtain light yellow to off-white 4-chloro-3-nitroanisole crystals: 。 2. a kind of micro passage reactor diazonium chloride hydrochloride according to claim 1 prepares 4-chloro-3-nitroanisole method, it is characterized in that, The molar ratio of the cuprous chloride to 31% hydrochloric acid is 1.0:3.5-5.5, and the molar ratio of diazonium hydrochloride to cuprous chloride is 1.0:1.2-1.
9.
3. a kind of micro passage reactor diazonium chloride hydrochloride according to claim 1 prepares 4-chloro-3-nitroanisole method, it is characterized in that, The cuprous chloride hydrochloric acid solution is delivered by a horizontal flow pump with precise flow control, and the flow rate is controlled at 0.6-1.0 ml / min.
4. a kind of micro passage reactor diazonium chloride hydrochloride according to claim 1 prepares 4-chloro-3-nitroanisole method, it is characterized in that, The diazonium hydrochloride is delivered via a horizontal flow pump with precise flow control, and the flow rate is controlled at 1.0-1.4 ml / min.
5. a kind of micro passage reactor diazonium chloride hydrochloride according to claim 1 prepares 4-chloro-3-nitroanisole method, it is characterized in that, The reaction temperature is -5~7°C.
6. a kind of micro passage reactor diazonium chloride hydrochloride according to claim 1 prepares 4-chloro-3-nitroanisole method, it is characterized in that, The reaction retention time is 6 min.