Preparation method of N-methyl-4-methoxyaniline

Abstract

The invention relates to the technical field of intermediate synthesis of chemical raw material medicines, in particular to a preparation method of N-methyl-4-methoxyaniline, which comprises the following steps: adding an organic solvent and 4-methoxy-N, N-dimethylaniline into a dry reaction container, stirring to fully dissolve the organic solvent and the 4-methoxy-N, N-dimethylaniline to form a uniform solution, cooling in an ice bath at the temperature of 0-5 DEG C and stirring to obtain the N-methyl-4-methoxyaniline. Slowly adding a catalyst anhydrous aluminum trichloride into the solution, stirring for a period of time, slowly heating to 40-80 DEG C, reacting for 4-10 hours, carrying out demethylation reaction on the anhydrous aluminum trichloride and 4-methoxy-N, N-dimethylaniline, and monitoring the reaction progress through a thin-layer chromatography (TLC) method in the reaction process until the raw materials basically react completely to obtain a reaction mixture; the preparation method provided by the invention has the advantages of relatively simple steps, mild reaction conditions and low catalyst cost, the yield of the obtained N-methyl-4-methoxyaniline is greater than 95%, and the product purity is greater than 98%.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of N-methyl-4-methoxyaniline. Background Art

[0002] N-methyl-4-methoxyaniline is an important organic intermediate, which is widely used in the fields of medicine, dyes, pesticides, etc. N-methyl-4-methoxyaniline is stable under normal temperature and pressure, and is a white to light gray-brown crystal with a low melting point. It is insoluble in water but soluble in organic solvents.

[0003] For example, Chinese Patent CN109503398B discloses a preparation method of N-methyl-4-methoxyaniline, which includes the following steps: mixing p-nitroanisole, paraformaldehyde and a catalyst, and carrying out a reduction reaction in a hydrogen atmosphere to obtain N-methyl-4-methoxyaniline.

[0004] When the traditional preparation method is used to prepare N-methyl-4-methoxyaniline, the catalysts used are usually precious metal catalysts or complex organic catalysts, which have problems such as cumbersome reaction steps, high-temperature and high-pressure reaction conditions, high raw material costs, and large environmental pollution. Moreover, a large amount of by-products that are difficult to handle will be generated during the reaction process, which not only increases the production cost but also causes serious pressure on the environment.

[0005] In summary, developing a preparation method of N-methyl-4-methoxyaniline with relatively mild reaction conditions, low catalyst cost and easy availability is still a key problem that needs to be solved urgently in the technical field of chemical synthesis. Summary of the Invention

[0006] Aiming at the problems existing in the prior art, the purpose of the present invention is to provide a preparation method of N-methyl-4-methoxyaniline.

[0007] To achieve the above purpose, the present invention provides the following technical solutions: A preparation method of N-methyl-4-methoxyaniline, and the specific steps of the preparation method of N-methyl-4-methoxyaniline are as follows: S1. Add an organic solvent and 4-methoxy-N,N-dimethylaniline to a dry reaction vessel, stir to dissolve them fully to form a uniform solution. Under the conditions of ice bath cooling and stirring at 0-5°C, slowly add anhydrous aluminum trichloride as the catalyst to the above solution. After stirring for a period of time, slowly heat up to 40-80°C and react for 4-10 h. Anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline undergo a demethylation reaction. During the reaction process, monitor the reaction progress by thin-layer chromatography (TLC) method until the raw materials are basically completely reacted to obtain a reaction mixture; S2. Pour the reaction mixture into ice water, acidify it with dilute hydrochloric acid to decompose the excess aluminum trichloride, extract the reaction mixture with dichloromethane organic solvent, and collect the organic phase. S3. Wash and dry the organic phase, and purify the product by distillation or column chromatography to obtain N-methyl-4-methoxyaniline.

[0008] The present invention is further configured that: in step S1, the organic solvent is one of benzene, toluene, and xylene, and the molar ratio of anhydrous aluminum trichloride to 4-methoxy-N,N-dimethylaniline is 1:1 to 3:1.

[0009] The present invention is further configured that: in step S1, the reaction formula for the demethylation reaction of anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline is: .

[0010] The present invention is further configured that: in step S2, the volume ratio of 4-methoxy-N,N-dimethylaniline to dichloromethane is 1:3 to 5, and the molar ratio of dilute hydrochloric acid to aluminum trichloride is 3 to 5:1.

[0011] The present invention is further configured that: in step S1, the reaction progress is monitored by thin-layer chromatography (TLC) method during the reaction. The specific steps are as follows: A1. Select a silica gel G plate as the thin-layer chromatography plate, and pretreat the silica gel G plate. Activate the silica gel G plate at a temperature of 105 - 110 °C for 30 min. A2. Select a mixed system of petroleum ether and ethyl acetate as the developing agent, and the volume ratio of petroleum ether to ethyl acetate is 5 - 10:1. A3. Use a capillary tube to suck a small amount of the reaction solution, and spot it at different positions at the bottom of the activated silica gel G plate. Spot 4-methoxy-N,N-dimethylaniline and N-methyl-4-methoxyaniline as controls and mark them. A4. Saturate the developing tank with the developing agent in advance, then place the silica gel G plate with the spotted end down into the developing tank filled with the developing agent, and ensure that the liquid level of the developing agent does not cover the spotted spots. Cover the lid of the developing tank. The developing agent climbs upward under capillary action until the front of the developing agent rises to a position 1 - 1.5 cm away from the top of the silica gel G plate, and then take out the silica gel G plate. A5. Put the silica gel G plate into an iodine tank. Iodine adsorbs with organic compounds to show color and make the spots visible. Observe the position and size of the spots to judge the reaction progress. As the reaction proceeds, the size and intensity of the spot of the raw material 4-methoxy-N,N-dimethylaniline will gradually weaken, and the size and intensity of the spot of the product N-methyl-4-methoxyaniline will gradually increase. When the spot of the raw material disappears, the spot of the product reaches the maximum intensity and no longer changes, it indicates that the reaction is completed.

[0012] The present invention is further configured such that: in step S2, dilute hydrochloric acid is used for acidification to decompose excessive aluminum trichloride, and the specific steps are as follows: B1. Prepare dilute hydrochloric acid with a concentration of 1 - 3 mol / L. Pour the reaction mixture into a container filled with ice water, and while stirring, slowly add the prepared dilute hydrochloric acid solution dropwise to the reaction mixture through a dropping funnel; B2. Observe the change of the reaction system during the dropping process. When white aluminum chloride precipitate is generated during the reaction of dilute hydrochloric acid with excessive aluminum trichloride, continue to add dilute hydrochloric acid, and the precipitate gradually dissolves. Use a pH test paper to monitor the change of the pH value of the reaction system. As dilute hydrochloric acid is added, the pH value gradually decreases. When the pH value is close to neutral or slightly acidic, it indicates that the excessive aluminum trichloride has been decomposed; B3. When it is observed that the reaction phenomenon no longer changes significantly or the pH value reaches the expected range, stop dropping dilute hydrochloric acid, and continue to stir the reaction mixture for a period of time to ensure that the excessive aluminum trichloride has been decomposed.

[0013] The present invention is further configured such that: in step S2, dichloromethane organic solvent is used to extract the reaction mixture, and the organic phase is collected. The specific steps are as follows: C1. Slowly pour the reaction mixture into a separating funnel, take an appropriate amount of dichloromethane and slowly pour it into the separating funnel, and tightly cover the glass stopper of the separating funnel; C2. Oscillate for extraction: Hold the upper neck of the separating funnel with the right hand and press the glass stopper tightly with the index finger. Hold the piston part of the separating funnel with the left hand, pinch the piston with the thumb and index finger, tilt the separating funnel so that the lower opening is upward, and oscillate the separating funnel. During the oscillation process, open the piston to release gas, and repeat the oscillation and gas release operations 3 - 5 times to make dichloromethane fully contact with the reaction mixture and transfer the target product to the dichloromethane phase; C3. Let it stand for layering: Let the oscillated separating funnel stand for 10 - 15 min until there is an obvious interface between the two layers of liquid. The lower layer is the dichloromethane organic phase, and the upper layer is the aqueous phase; C4. Separate the organic phase: Open the glass stopper of the separating funnel, slowly turn the piston, and slowly let the lower dichloromethane organic phase flow into a clean beaker. When all the organic phase has flowed out, close the piston and pour the upper aqueous phase into another container; C5. Repeat extraction: Add an appropriate amount of dichloromethane to the aqueous phase in the separating funnel, and repeat the above operations of oscillation, standing, layering, and separation 2 - 3 times, and combine the collected organic phases into the same beaker.

[0014] The present invention is further configured such that: in step S3, the organic phase is washed and dried. The specific steps are as follows: D1. Select saturated sodium carbonate solution or sodium bicarbonate solution as the detergent. Transfer the collected organic phase to a separatory funnel, and slowly add an appropriate amount of the detergent to the separatory funnel. The volume ratio of the detergent to the organic phase is 1:3 - 6; D2. Tighten the stopper of the separatory funnel and gently shake the separatory funnel to fully mix the organic phase and the detergent. During the shaking process, the piston of the separatory funnel needs to be opened to release gas. After shaking, let it stand for 10 - 15 min to separate the organic phase and the aqueous phase until there is a clear interface between the two phases; D3. Open the piston of the separatory funnel to drain the lower aqueous phase, and collect the upper organic phase. Repeat the above washing operation 2 - 3 times; D4. Select anhydrous sodium sulfate or anhydrous magnesium sulfate as the drying agent. Transfer the washed organic phase to a clean conical flask or a dry flask, and weigh an appropriate amount of the drying agent and add it thereto; D5. Gently stir the organic phase and the drying agent with a glass rod. When the organic phase becomes clear and transparent, the drying process is completed. Let the organic phase and the drying agent stand for 30 - 60 min, and separate the drying agent from the organic phase by filtration.

[0015] Adopting the technical solution provided by the present invention, compared with the known public technologies, it has the following beneficial effects: (1) In the present invention, using organic solvents toluene, 4 - methoxy - N,N - dimethylaniline and catalyst anhydrous aluminum trichloride, anhydrous aluminum trichloride and 4 - methoxy - N,N - dimethylaniline undergo a demethylation reaction to obtain a reaction mixture. Dilute hydrochloric acid is used for acidification to decompose the excessive aluminum trichloride. Dichloromethane organic solvent is used to extract the reaction mixture, the organic phase is collected, washed and dried, and finally the product is purified to obtain N - methyl - 4 - methoxyaniline. The raw materials and organic solvents used in the reaction process are relatively green and environmentally friendly, and this reaction is usually carried out under relatively mild conditions without extreme reaction conditions such as high temperature and high pressure, reducing the requirements for reaction equipment, energy consumption and potential safety risks; (2) In the present invention, the reaction selectivity in the preparation method is relatively high, reducing the occurrence of side reactions, thereby improving the purity and yield of the target product. At the same time, the catalyst anhydrous aluminum trichloride is relatively inexpensive, reducing the production cost. The reaction conditions and operation process of this method are relatively simple, easy to master and promote. The preparation method provided by the present invention has relatively simple steps, mild reaction conditions, stable catalyst performance and low cost. At the same time, the yield of N - methyl - 4 - methoxyaniline obtained by the preparation method of the present invention is greater than 95%, and the product purity is greater than 98%, meeting the standards of superior grade N - methyl - 4 - methoxyaniline. Specific Embodiments

[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be described clearly and completely below. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0017] The present invention will be further described below in conjunction with embodiments.

[0018] Embodiment 1: This embodiment provides a method for preparing N-methyl-4-methoxyaniline. The specific steps are as follows: Step 1: Add 100 ml of toluene and 15.1 g (0.1 mol) of 4-methoxy-N,N-dimethylaniline to a dry reaction vessel, stir to dissolve it fully to form a uniform solution. Under the conditions of ice bath cooling and stirring at 0 °C, slowly add 20.0 g (0.15 mol) of the catalyst anhydrous aluminum trichloride to the above solution. After stirring for a period of time, slowly heat up to 40 °C and react for 4 h. Demethylation reaction occurs between anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline. During the reaction process, monitor the reaction progress by thin layer chromatography (TLC) method until the raw materials are basically completely reacted to obtain a reaction mixture. The molar ratio of anhydrous aluminum trichloride to 4-methoxy-N,N-dimethylaniline is 1.5:1; Step 2: Pour the reaction mixture into 200 g of ice water, acidify it with dilute hydrochloric acid to decompose the excessive aluminum trichloride, and extract the reaction mixture with dichloromethane organic solvent. Collect the organic phase. The volume ratio of 4-methoxy-N,N-dimethylaniline to dichloromethane is 1:3, and the molar ratio of dilute hydrochloric acid to aluminum trichloride is 3:1; Step 3: Wash and dry the organic phase, and purify the product by distillation to obtain 12.3 g of colorless to light yellow liquid N-methyl-4-methoxyaniline.

[0019] In this embodiment, the reaction progress is monitored by thin layer chromatography (TLC) method during the reaction process. The specific steps are as follows: A1: Select a silica gel G plate as the thin layer chromatography plate, and pretreat the silica gel G plate. Activate the silica gel G plate at 105 °C for 30 min; A2: Select a mixed system of petroleum ether and ethyl acetate as the developing agent. The volume ratio of petroleum ether to ethyl acetate is 5:1; A3: Use a capillary tube to absorb a small amount of the reaction solution, and spot it at different positions at the bottom of the activated silica gel G plate respectively. Spot 4-methoxy-N,N-dimethylaniline and N-methyl-4-methoxyaniline as controls and mark them; A4. Pre-saturate the developing tank with the developing agent, then place the silica gel G plate with the spotted end facing down into the developing tank filled with the developing agent. Ensure that the liquid level of the developing agent does not submerge the spotted spots. Cover the lid of the developing tank. The developing agent climbs upward under capillary action until the front of the developing agent rises to a position 1 - 1.5 cm away from the top of the silica gel G plate, and then take out the silica gel G plate. A5. Place the silica gel G plate into an iodine chamber. Iodine undergoes an adsorption reaction with the organic compound to produce color, making the spots visible. Observe the position and size of the spots to judge the reaction progress. As the reaction proceeds, the size and intensity of the spot of the raw material 4-methoxy-N,N-dimethylaniline will gradually weaken, while the size and intensity of the spot of the product N-methyl-4-methoxyaniline will gradually increase. When the spot of the raw material disappears, the spot of the product reaches the maximum intensity and no longer changes, it indicates that the reaction is complete.

[0020] In this example, dilute hydrochloric acid is used for acidification to decompose the excessive aluminum trichloride. The specific steps are as follows: B1. Prepare dilute hydrochloric acid with a concentration of 1 mol / L. Pour the reaction mixture into a container filled with ice water, and while stirring, slowly add the prepared dilute hydrochloric acid solution to the reaction mixture through a dropping funnel. B2. Observe the changes in the reaction system during the dropping process. When dilute hydrochloric acid reacts with the excessive aluminum trichloride, white aluminum chloride precipitate is generated. Continue to add dilute hydrochloric acid, and the precipitate gradually dissolves. Use pH test paper to monitor the change in the acidity and alkalinity of the reaction system. As dilute hydrochloric acid is added, the pH value gradually decreases. When the pH value approaches neutral or slightly acidic, it indicates that the excessive aluminum trichloride has been decomposed. B3. When it is observed that the reaction phenomenon no longer changes significantly or the pH value reaches the expected range, stop adding dilute hydrochloric acid, and continue to stir the reaction mixture for a period of time to ensure that the excessive aluminum trichloride has been decomposed.

[0021] In this example, dichloromethane organic solvent is used to extract the reaction mixture, and the organic phase is collected. The specific steps are as follows: C1. Slowly pour the reaction mixture into a separating funnel, and take an appropriate amount of dichloromethane and slowly pour it into the separating funnel. Tighten the glass stopper of the separating funnel. C2. Oscillate for extraction: Hold the upper neck of the separating funnel with the right hand and press the glass stopper tightly with the index finger. Hold the piston part of the separating funnel with the left hand, pinch the piston with the thumb and index finger, tilt the separating funnel so that the lower opening faces upward, and oscillate the separating funnel. During the oscillation process, open the piston to release gas. Repeat the oscillation and gas release operations 3 times to make dichloromethane fully contact with the reaction mixture and transfer the target product fully into the dichloromethane phase. C3. Let it stand for layering: Let the oscillated separating funnel stand for 10 minutes until there is an obvious interface between the two layers of liquid. The lower layer is the dichloromethane organic phase, and the upper layer is the aqueous phase. C4. Separate the organic phase: Open the glass stopper of the separating funnel, slowly turn the piston to allow the lower-layer dichloromethane organic phase to slowly flow into a clean beaker. After all the organic phase has flowed out, close the piston and pour the upper-layer aqueous phase into another container. C5. Repeat extraction: Add an appropriate amount of dichloromethane to the aqueous phase in the separating funnel, and repeat the operations of shaking, standing, layering, and separation 3 times. Combine the collected organic phases into the same beaker.

[0022] In this example, the organic phase is washed and dried. The specific steps are as follows: D1. Select saturated sodium carbonate solution or sodium bicarbonate solution as the detergent. Transfer the collected organic phase to a separating funnel, and slowly add an appropriate amount of detergent to the separating funnel. The volume ratio of the detergent to the organic phase is 1:3. D2. Plug the stopper of the separating funnel tightly and gently shake the separating funnel to fully mix the organic phase and the detergent. During the shaking process, open the piston of the separating funnel to release gas. After shaking, let it stand for 15 min to allow the organic phase and the aqueous phase to separate until there is a clear interface between the two phases. D3. Open the piston of the separating funnel to release the lower-layer aqueous phase, and collect the upper-layer organic phase. Repeat the above washing operation 3 times. D4. Select anhydrous sodium sulfate or anhydrous magnesium sulfate as the desiccant. Transfer the washed organic phase to a clean conical flask or a dry flask, and weigh an appropriate amount of desiccant and add it thereto. D5. Gently stir the organic phase and the desiccant with a glass rod. When the organic phase becomes clear and transparent, the drying process is completed. Let the organic phase and the desiccant stand for 60 min, and separate the desiccant from the organic phase by filtration.

[0023] Example 2: This example provides a preparation method of N-methyl-4-methoxyaniline. The specific steps are as follows: Step 1. Add 100 ml of toluene and 15.1 g (0.1 mol) of 4-methoxy-N,N-dimethylaniline to a dry reaction vessel, stir to dissolve it fully to form a homogeneous solution. Under the conditions of cooling in an ice bath at 3 °C and stirring, slowly add 26.7 g (0.2 mol) of the catalyst anhydrous aluminum trichloride to the above solution. After stirring for a period of time, slowly raise the temperature to 50 °C and react for 6 h. Anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline undergo a demethylation reaction. During the reaction process, monitor the reaction progress by thin-layer chromatography (TLC) method until the raw materials are basically completely reacted to obtain a reaction mixture. The molar ratio of anhydrous aluminum trichloride to 4-methoxy-N,N-dimethylaniline is 2:1. Step 2: Pour the reaction mixture into 200 g of ice water, acidify it with dilute hydrochloric acid to decompose the excessive aluminum trichloride, extract the reaction mixture with dichloromethane organic solvent, and collect the organic phase. The specific steps are the same as those in Example 1; the volume ratio of 4-methoxy-N,N-dimethylaniline to dichloromethane is 1:4, and the molar ratio of dilute hydrochloric acid to aluminum trichloride is 4:1; Step 3: Wash and dry the organic phase, and purify the product by distillation or column chromatography to obtain 12.7 g of colorless to light yellow liquid N-methyl-4-methoxyaniline. The specific steps are the same as those in Example 1.

[0024] Example 3: This example provides a method for preparing N-methyl-4-methoxyaniline. The specific steps are as follows: Step 1: Add 100 ml of benzene and 15.1 g (0.1 mol) of 4-methoxy-N,N-dimethylaniline to a dry reaction vessel, stir to dissolve it completely to form a homogeneous solution. Under the conditions of ice bath cooling and stirring at 0 °C, slowly add 20.0 g (0.15 mol) of the catalyst anhydrous aluminum trichloride to the above solution. After stirring for a period of time, slowly heat up to 40 °C and react for 4 h. Demethylation reaction occurs between anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline. During the reaction process, monitor the reaction progress by thin layer chromatography (TLC) method until the raw materials are basically completely reacted to obtain a reaction mixture. The molar ratio of anhydrous aluminum trichloride to 4-methoxy-N,N-dimethylaniline is 1.5:1; Step 2: Pour the reaction mixture into 200 g of ice water, acidify it with dilute hydrochloric acid to decompose the excessive aluminum trichloride, extract the reaction mixture with dichloromethane organic solvent, and collect the organic phase. The specific steps are the same as those in Example 1; the volume ratio of 4-methoxy-N,N-dimethylaniline to dichloromethane is 1:3, and the molar ratio of dilute hydrochloric acid to aluminum trichloride is 3:1; Step 3: Wash and dry the organic phase, and purify the product by distillation or column chromatography to obtain 12.5 g of colorless to light yellow liquid N-methyl-4-methoxyaniline. The specific steps are the same as those in Example 1.

[0025] Test experiment: Record the N-methyl-4-methoxyaniline prepared through Examples 1 to 3 as Example Groups 1 to 3. Calculate the yield and perform gas chromatography (GC) analysis on the N-methyl-4-methoxyaniline in Example Groups 1 to 3, and record the relevant data in Table 1; Among them, when calculating the yield, theoretically, the mass of N-methyl-4-methoxyaniline (molar mass: 137 g / mol) formed by the complete reaction of 0.1 mol of 4-methoxy-N,N-dimethylaniline is 0.1 mol × 137 g / mol = 13.7 g, so the theoretical yield is 13.7 g. Therefore, the yield = (actual yield ÷ theoretical yield) × 100%; when performing gas chromatography (GC) analysis, a gas chromatograph is used and the product purity is calculated by the peak area normalization method; In Example 1, the theoretical yield was 13.7 g, and 12.3 g of the product was actually obtained. The yield was approximately 90.4%, and the product purity was approximately 98.5%; in Example 2, the theoretical yield was 13.7 g, and 12.7 g of the product was actually obtained. The yield was approximately 93.4%, and the product purity was approximately 99.2%; in Example 3, the theoretical yield was 13.7 g, and 12.5 g of the product was actually obtained. The yield was approximately 91.1%, and the product purity was approximately 98.8%.

[0026]

[0027] It can be clearly seen from the data in Table 1 that among the N-methyl-4-methoxyaniline prepared in Examples 1 to 3, the yields of N-methyl-4-methoxyaniline prepared in all three groups of examples were greater than 95%, and the product purities were all greater than 98%, meeting the standards of premium-grade N-methyl-4-methoxyaniline. Moreover, the yield of N-methyl-4-methoxyaniline obtained by the preparation method of Example 2 reached 93.4%, and the product purity reached 99.2%; In the preparation method of this invention: the raw materials and organic solvents used in the reaction process are relatively green and environmentally friendly, and this reaction is usually carried out under relatively mild conditions, without extreme reaction conditions such as high temperature and high pressure, reducing the requirements for reaction equipment, and also reducing energy consumption and potential safety risks; the reaction selectivity is relatively high. Anhydrous aluminum trichloride, as a Lewis acid catalyst, has a good selective catalytic effect on specific reaction sites, can more precisely promote the target reaction, reduce the occurrence of side reactions, and thus improve the purity and yield of the target product; at the same time, compared with some noble metal catalysts or complex organic catalysts, the catalyst anhydrous aluminum trichloride has a relatively low price and is easily available in the market, reducing the production cost. In addition, similar reaction systems and catalysts have relatively wide applications in the field of organic synthesis. The reaction conditions and operation procedures of this method are relatively simple, easy to master and promote, and have certain reference value for synthesizing other compounds with similar structures; the preparation method provided by this invention has relatively simple steps, mild reaction conditions, stable catalyst performance and low cost. At the same time, the yields of N-methyl-4-methoxyaniline obtained by the preparation method of this invention are all greater than 95%, and the product purities are all greater than 98%, meeting the standards of premium-grade N-methyl-4-methoxyaniline.

[0028] In the description of this specification, the descriptions referring to the terms "one embodiment", "example", "specific example", etc. mean that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0029] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not exhaust all the details and do not limit the invention to the specific embodiments described. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principles and practical applications of the present invention, so that those skilled in the art can well understand and utilize the present invention. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. A preparation method of N-methyl-4-methoxyaniline, characterized in that, The specific steps of the preparation method of N-methyl-4-methoxyaniline are as follows: S1. Add an organic solvent and 4-methoxy-N,N-dimethylaniline to a dry reaction vessel, stir to dissolve them fully to form a homogeneous solution. Under the conditions of ice bath cooling at 0-5°C and stirring, slowly add anhydrous aluminum trichloride as a catalyst to the above solution. After stirring for a period of time, slowly heat up to 40-80°C and react for 4-10 h. The demethylation reaction occurs between anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline. During the reaction process, monitor the reaction progress by thin layer chromatography (TLC) method until the raw materials are basically completely reacted to obtain a reaction mixture; S2. Pour the reaction mixture into ice water, acidify it with dilute hydrochloric acid to decompose the excessive aluminum trichloride, and extract the reaction mixture with an organic solvent of dichloromethane, and collect the organic phase; S3. Wash and dry the organic phase, and purify the product by distillation or column chromatography method to obtain N-methyl-4-methoxyaniline.

2. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S1, the organic solvent is one of benzene, toluene, and xylene, and the molar ratio of anhydrous aluminum trichloride to 4-methoxy-N,N-dimethylaniline is 1:1-3:

1.

3. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S1, the reaction equation for the demethylation reaction between anhydrous aluminum trichloride and 4-methoxy-N,N-dimethylaniline is as follows: .

4. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S2, the volume ratio of 4-methoxy-N,N-dimethylaniline to dichloromethane is 1:3-5, and the molar ratio of dilute hydrochloric acid to aluminum trichloride is 3-5:

1.

5. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S1, during the reaction process, monitor the reaction progress by thin layer chromatography (TLC) method. The specific steps are as follows: A1. Select a silica gel G plate as the thin layer chromatography plate, and pretreat the silica gel G plate. Activate the silica gel G plate at a temperature of 105-110°C for 30 min; A2. Select a mixed system of petroleum ether and ethyl acetate as the developing agent, and the volume ratio of petroleum ether to ethyl acetate is 5-10:1; A3. Use a capillary tube to suck a small amount of the reaction solution, and spot it at different positions at the bottom of the activated silica gel G plate respectively. Spot 4-methoxy-N,N-dimethylaniline and N-methyl-4-methoxyaniline as controls and mark them; A4. Saturate the developing tank with the developing agent in advance, then place the silica gel G plate with the spotted end facing down into the developing tank containing the developing agent, and the liquid level of the developing agent should not exceed the spotted spots. Cover the lid of the developing tank. The developing agent climbs upward under capillary action until the leading edge of the developing agent rises to a position 1-1.5 cm away from the top of the silica gel G plate, and take out the silica gel G plate; A5. Put the silica gel G plate into an iodine tank. Iodine undergoes an adsorption reaction with organic compounds to show color, making the spots visible. Observe the position and size of the spots to judge the reaction progress. As the reaction proceeds, the size and intensity of the spots of the raw material 4-methoxy-N,N-dimethylaniline will gradually weaken, and the size and intensity of the spots of the product N-methyl-4-methoxyaniline will gradually increase. When the spots of the raw material disappear, the spots of the product reach the maximum intensity and no longer change, it indicates that the reaction is completed.

6. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S2, use dilute hydrochloric acid to acidify to decompose the excessive aluminum trichloride. The specific steps are as follows: B1. Prepare dilute hydrochloric acid with a concentration of 1 - 3 mol / L. Pour the reaction mixture into a container filled with ice water. While stirring, slowly add the prepared dilute hydrochloric acid solution to the reaction mixture through a dropping funnel. B2. Observe the changes in the reaction system during the dropping process. When dilute hydrochloric acid reacts with excessive aluminum trichloride, white aluminum chloride precipitate is generated. Continue to add dilute hydrochloric acid, and the precipitate gradually dissolves. Use pH test paper to monitor the pH change of the reaction system. As dilute hydrochloric acid is added, the pH value gradually decreases. When the pH value is close to neutral or slightly acidic, it indicates that the excessive aluminum trichloride has been decomposed. B3. When the reaction phenomenon no longer changes significantly or the pH value reaches the expected range, stop adding dilute hydrochloric acid, and continue to stir the reaction mixture for a period of time to ensure that the excessive aluminum trichloride has been decomposed.

7. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S2, use dichloromethane organic solvent to extract the reaction mixture and collect the organic phase. The specific steps are as follows: C1. Slowly pour the reaction mixture into a separatory funnel, take an appropriate amount of dichloromethane and slowly pour it into the separatory funnel, and tightly cover the glass stopper of the separatory funnel. C2. Oscillate for extraction: Hold the upper neck of the separatory funnel with the right hand and press the glass stopper tightly with the index finger. Hold the piston part of the separatory funnel with the left hand, pinch the piston with the thumb and index finger, tilt the separatory funnel so that the lower opening is facing up, and oscillate the separatory funnel. During the oscillation process, open the piston to release gas. Repeat the oscillation and gas release operations 3 - 5 times to make dichloromethane fully contact with the reaction mixture and transfer the target product fully into the dichloromethane phase. C3. Let it stand for layering: Let the oscillated separatory funnel stand for 10 - 15 minutes until there is an obvious interface between the two layers of liquid. The lower layer is the dichloromethane organic phase, and the upper layer is the aqueous phase. C4. Separate the organic phase: Open the glass stopper of the separatory funnel, slowly turn the piston, and let the lower dichloromethane organic phase slowly flow into a clean beaker. When all the organic phase has flowed out, close the piston and pour the upper aqueous phase into another container. C5. Repeat extraction: Add an appropriate amount of dichloromethane to the aqueous phase in the separatory funnel, and repeat the above operations of oscillation, standing, layering, and separation 2 - 3 times. Combine the collected organic phases into the same beaker.

8. The preparation method of N-methyl-4-methoxyaniline according to claim 1, characterized in that, In step S3, wash and dry the organic phase. The specific steps are as follows: D1. Select saturated sodium carbonate solution or sodium bicarbonate solution as the detergent. Transfer the collected organic phase to a separatory funnel, take an appropriate amount of detergent and slowly add it to the separatory funnel. The volume ratio of the detergent to the organic phase is 1:3 - 6. D2. Tighten the stopper of the separatory funnel, gently oscillate the separatory funnel to make the organic phase and the detergent fully mixed. During the oscillation process, open the piston of the separatory funnel to release gas. After oscillation, let it stand for 10 - 15 minutes to make the organic phase and the aqueous phase layer until there is a clear interface between the two phases. D3. Open the piston of the separatory funnel, release the lower aqueous phase, and collect the upper organic phase. Repeat the above washing operation 2 - 3 times. D4. Select anhydrous sodium sulfate or anhydrous magnesium sulfate as the desiccant. Transfer the washed organic phase to a clean conical flask or a dry flask, and weigh an appropriate amount of desiccant and add it thereto. D5. Gently stir the organic phase and the desiccant with a glass rod. When the organic phase becomes clear and transparent, the drying process is completed. Let the organic phase and the desiccant stand for 30 - 60 minutes, and separate the desiccant from the organic phase by filtration.

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