A method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor

Abstract

The present invention belongs to the technical field of organic synthesis processes, and particularly relates to a method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor. In the present invention, o-methoxyacetanilide is used as a substrate, and a mixed acid prepared by mixing concentrated sulfuric acid and concentrated nitric acid is used as a nitrating reagent. They are respectively pumped into the reaction zone of a continuous flow microchannel reactor through metering pumps for mixing and residence reaction to synthesize 2-methoxy-4-nitroacetanilide. It has a high nitration conversion rate and high reaction selectivity, can realize the continuous, safe, efficient and stable production of this product, significantly reduce the consumption of nitric acid and the discharge of three wastes, and has a low production cost.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis processes, and relates to a method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor. Background Art

[0002] 2-Methoxy-4-nitroacetanilide is an important dye intermediate and is also widely used in fields such as medicine and pesticides, with extremely high added value.

[0003] In recent years, due to its small volume, large specific surface area, easy scale-up, continuous process, good rapid mixing effect, good heat transfer effect, high temperature and high pressure resistance and other characteristics, continuous flow reactors have been successively developed for nitration reactions to improve the safety of nitration reactions.

[0004] Patent CN113582867 discloses a continuous synthesis method of 2-acetamido-5-nitrophenyl ether. After o-anisidine is acylated in an acetic acid solution, the obtained o-methoxyacetanilide reacts with 98% nitric acid in an acetic acid system, the nitration temperature is 30 - 90°C, and the residence time is 1 - 3 min. This reaction uses acetic acid as a solvent. In the actual production process, a large amount of acetic acid is not easily recovered, and the treatment of acidic wastewater is difficult, thus increasing the production cost.

[0005] Patent CN113185417 discloses the reaction of a 30% acetic acid solution of o-methoxyacetanilide with concentrated nitric acid. The molar ratio of concentrated nitric acid / o-methoxyacetanilide is 1.3:1, the temperature is 80°C, the residence time is 60 s, and the pressure is 5.5 bar. This reaction has a high temperature and is carried out under pressure conditions, increasing the equipment cost.

[0006] Patent CN113527128 discloses preparing an o-methoxyacetanilide solution with dichloroethane, preparing a nitrating reagent with nitric acid and sodium metabisulfite, mixing in a T-shaped mixer and then reacting. The nitration reaction temperature is 45 - 60°C, and the time is 0.5 - 1.5 min. Among them, the amount of nitric acid used is large, and the acidified wastewater generated by the unreacted nitric acid solution is also difficult to treat, thus increasing the production cost.

[0007] The existing production processes still have certain defects in terms of production cost, process reliability, etc., and it is necessary to develop a safe method for continuously producing 2-methoxy-4-nitroacetanilide by nitration with relatively high yield and purity. Summary of the Invention

[0008] The purpose of the present invention is to provide a method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor. The specific method includes:

[0009] (1) At room temperature, dissolve the substrate o-methoxyacetanilide in an organic solvent;

[0010] (2) Mix concentrated sulfuric acid and concentrated nitric acid to prepare a mixed acid; wherein, the mass ratio of concentrated sulfuric acid to concentrated nitric acid is 1:0.2 - 1:0.7, the mass concentration of concentrated sulfuric acid is 50% - 60%, and the mass concentration of concentrated nitric acid is 98%.

[0011] (3) Pump the organic solution containing the substrate o - methoxyacetanilide prepared in step (1) and the mixed acid in step (2) into the reaction zone of a continuous - flow microchannel reactor through metering pumps respectively, mix and stay for reaction to synthesize 2 - methoxy - 4 - nitroacetanilide.

[0012] Preferably, in step (1), the organic solvent is selected from dichloromethane, dichloroethane or chloroform, and more preferably dichloromethane or dichloroethane.

[0013] Preferably, the mass ratio of the organic solvent to the substrate o - methoxyacetanilide in step (1) is 2:1 - 10:1, and preferably 3:1 - 4:1.

[0014] In step (2) of the present invention, the mass ratio of concentrated sulfuric acid to concentrated nitric acid has a great influence on the product purity and yield. Preferably, the mass ratio of concentrated sulfuric acid to concentrated nitric acid in step (2) is 1:0.25 - 1:0.5, and more preferably 1:0.5.

[0015] Preferably, the mass concentration of concentrated sulfuric acid in step (2) is preferably 60%.

[0016] Preferably, the molar ratio of the substrate o - methoxyacetanilide to nitric acid in the reaction zone is 1:1.1 - 1:1.4, and more preferably 1:1.3.

[0017] Preferably, the mixing and reaction residence time in step (3) is 4 min - 6.5 min, and more preferably 5.9 min.

[0018] Preferably, the mixing and residence reaction temperature in step (3) is 25 - 35 °C, and more preferably 30 °C.

[0019] Further, step (3) is to pump the substrate organic solution in step (1) and the mixed acid of concentrated sulfuric acid and concentrated nitric acid in step (2) into different pre - heating zones respectively, pre - heat to the reaction temperature and then pump them into the reaction zone of the continuous - flow reactor for mixing reaction; the pre - heating temperature is controlled by an external heat - exchange device, and the heat - exchange medium includes but is not limited to heat - conducting oil, steam, etc.

[0020] Furthermore, the method for preparing 2 - methoxy - 4 - nitroacetanilide of the present invention further includes: cooling, washing with water, collecting and drying the reaction product 2 - methoxy - 4 - nitroacetanilide. Preferably based on this step, the purity of the obtained product is usually above 90%.

[0021] Among them, the cooling process includes but is not limited to cooling the reaction product in an ice-water bath of the cooling coil of a continuous flow microchannel reactor, or the product can also be cooled at room temperature or in an ice-water bath after collection; the collection includes but is not limited to concentrating and / or filtering the reaction product.

[0022] The continuous reactor module described in the present invention, the reactor module is optionally any reactor capable of realizing a continuous flow process, and is selected from any one or more of a microreactor, a tandem loop reactor, and a tubular reactor. The microreactor, also known as a microstructured reactor or a microchannel reactor, is a device in which a chemical reaction occurs in a limited area with a general lateral dimension of 1 mm or less. The most typical form of such a limited area is a micro-sized channel. The tandem loop reactor is a reactor formed by connecting coil reactors in series with pipes, where the coil reactor is in the form of a coil made of a tubular reactor. The tubular reactor is a continuous operation reactor that emerged in the middle of the last century and is in the shape of a tube with a large length-to-diameter ratio. This reactor can be very long, can be a single tube or multiple tubes in parallel; it can be an empty tube or a packed tube. It can be a mass transfer-enhanced structure and / or a straight channel structure, where the mass transfer-enhanced module microstructures include but are not limited to a diamond structure, a heart structure, a triangular structure, and a circular structure, and the straight channel module microstructures include but are not limited to a cylindrical structure and a rectangular structure.

[0023] The method for synthesizing 2-methoxy-4-nitroacetanilide by the continuous flow reactor of the present invention has incomparable advantages over the traditional batch production method, and can realize the continuous, safe, efficient, and stable production of this product. Compared with the existing process, this process has greatly reduced the consumption of nitric acid and the emission of three wastes, and produces in a continuous and safe manner, with a high nitration conversion rate and a high reaction selectivity. The yield of 2-methoxy-4-nitroacetanilide synthesized by the method of the present invention can reach more than 90%. In a preferred embodiment of the present invention, the yield of the product reaches 96% and the purity reaches 99%, and it can be directly used for subsequent industrial production, greatly reducing the production cost. Description of the Drawings

[0024] Figure 1 It is a process flow chart of one of the synthesis processes of 2-methoxy-4-nitroacetanilide of the present invention;

[0025] Figure 2 It is another process flow chart of the synthesis process of 2-methoxy-4-nitroacetanilide of the present invention. Detailed Embodiments

[0026] The present invention will be described in detail below in conjunction with embodiments. However, the following embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, should be covered by the protection scope of the present invention.

[0027] The embodiments of the present invention use commercially available high-throughput microchannel reactors and pipeline modules. As Figure 1 or Figure 2 shown in the way of sample injection.

[0028] Example 1

[0029] o-Methoxyacetanilide and dichloromethane were mixed and dissolved in a mass ratio of 1:3 and placed in storage tank A. 60% concentrated sulfuric acid and 98% concentrated nitric acid were mixed in a mass ratio of 1:0.5 and placed in storage tank B. The two streams of materials were respectively injected into the reaction zone of the reactor through a pump for mixing reaction. At this time, the molar ratio of concentrated nitric acid to the substrate was controlled at 1.3:1, the temperature was controlled at 30 °C, and the residence time was 5.9 min. The reaction solution was quantitatively collected, and after ice-water bath, water washing, filtration, and drying, 2-methoxy-4-nitroacetanilide was obtained. The HPLC content analysis (normalization) was 99%, and the yield was 96%.

[0030] Example 2

[0031] o-Methoxyacetanilide and dichloromethane were mixed and dissolved in a mass-volume ratio of 1:3 and placed in storage tank A. 60% concentrated sulfuric acid and 98% concentrated nitric acid were mixed in a mass ratio of 1:0.25 and placed in storage tank B. The two streams of materials were respectively injected into the reaction zone of the reactor through a pump for mixing reaction. At this time, the molar ratio of concentrated nitric acid to the substrate was controlled at 1.3:1, the temperature was controlled at 30 °C, and the residence time was 5.9 min. The reaction solution was quantitatively collected, and after ice-water bath, water washing, filtration, and drying, 2-methoxy-4-nitroacetanilide was obtained. The HPLC content analysis (normalization) was 96%, and the yield was 96%.

[0032] Example 3

[0033] o-Methoxyacetanilide and dichloromethane were mixed and dissolved in a mass-volume ratio of 1:4 and placed in storage tank A. 60% concentrated sulfuric acid and 98% concentrated nitric acid were mixed in a mass ratio of 1:0.2 and placed in storage tank B. The two streams of materials were respectively injected into the reaction zone of the reactor through a pump for mixing reaction. At this time, the molar ratio of concentrated nitric acid to the substrate was controlled at 1.3:1, the temperature was controlled at 30 °C, and the residence time was 5.9 min. The reaction solution was quantitatively collected, and after ice-water bath, water washing, filtration, and drying, 2-methoxy-4-nitroacetanilide was obtained. The HPLC content analysis (normalization) was 94%, and the yield was 94%.

[0034] Example 4

[0035] Mix and dissolve o - methoxyacetanilide and dichloromethane in a mass - to - volume ratio of 1:4 and place it in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid in a mass ratio of 1:0.7 and place it in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.3:1, control the temperature at 30 °C, and the residence time at 5.9 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, 2 - methoxy - 4 - nitroacetanilide is obtained. The HPLC content analysis (normalization) is 94%, and the yield is 93%.

[0036] Example 5

[0037] Mix and dissolve o - methoxyacetanilide and dichloromethane in a mass - to - volume ratio of 1:3 and place it in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid in a mass ratio of 1:0.5 and place it in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.1:1, control the temperature at 30 °C, and the residence time at 5.9 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, 2 - methoxy - 4 - nitroacetanilide is obtained. The HPLC content analysis (normalization) is 95%, and the yield is 92%.

[0038] Example 6

[0039] Mix and dissolve o - methoxyacetanilide and dichloromethane in a mass - to - volume ratio of 1:3 and place it in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid in a mass ratio of 1:0.5 and place it in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through metering pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.4:1, control the temperature at 30 °C, and the residence time at 5.9 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, 2 - methoxy - 4 - nitroacetanilide is obtained. The HPLC content analysis (normalization) is 97%, and the yield is 96%.

[0040] Example 7

[0041] Mix and dissolve o - methoxyacetanilide and dichloromethane in a mass - to - volume ratio of 1:3 and place it in storage tank A. Mix 50% concentrated sulfuric acid and 98% concentrated nitric acid in a mass ratio of 1:0.5 and place it in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.3:1, control the temperature at 30 °C, and the residence time at 5.9 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, 2 - methoxy - 4 - nitroacetanilide is obtained. The HPLC content analysis (normalization) is 97%, and the yield is 96%.

[0042] Example 8

[0043] Mix and dissolve o - methoxyacetanilide and dichloromethane at a mass - to - volume ratio of 1:3, and place them in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid at a mass ratio of 1:0.5, and place them in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.3:1, control the temperature at 30°C, and the residence time at 4 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, obtain 2 - methoxy - 4 - nitroacetanilide. The HPLC content analysis (normalization) is 95%, and the yield is 93%.

[0044] Example 9

[0045] Mix and dissolve o - methoxyacetanilide and dichloromethane at a mass - to - volume ratio of 1:3, and place them in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid at a mass ratio of 1:0.5, and place them in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.3:1, control the temperature at 30°C, and the residence time at 6.5 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, obtain 2 - methoxy - 4 - nitroacetanilide. The HPLC content analysis (normalization) is 96%, and the yield is 93%.

[0046] Example 10

[0047] Mix and dissolve o - methoxyacetanilide and dichloromethane at a mass - to - volume ratio of 1:3, and place them in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid at a mass ratio of 1:0.25, and place them in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.3:1, control the temperature at 40°C, and the residence time at 5.9 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, obtain 2 - methoxy - 4 - nitroacetanilide. The HPLC content analysis (normalization) is 99%, and the yield is 96%.

[0048] Example 11

[0049] o-Methoxyacetanilide and dichloromethane were mixed and dissolved at a mass-to-volume ratio of 1:3 and placed in storage tank A. 60% concentrated sulfuric acid and 98% concentrated nitric acid were mixed at a mass ratio of 1:0.25 and placed in storage tank B. The two streams of materials were respectively pumped into the reaction zone of the reactor for mixing reaction. At this time, the molar ratio of concentrated nitric acid to the substrate was controlled at 1.3:1, the temperature was controlled at 25 °C, and the residence time was 5.9 min. The reaction solution was quantitatively collected, and after ice-water bath, water washing, filtration, and drying, 2-methoxy-4-nitroacetanilide was obtained. The HPLC content analysis (normalization) was 98%, and the yield was 95%.

[0050] Comparative Example 1

[0051] o-Methoxyacetanilide and dichloromethane were mixed and dissolved at a mass-to-volume ratio of 1:3 and placed in storage tank A. 60% concentrated sulfuric acid and 98% concentrated nitric acid were mixed at a mass ratio of 1:0.75 and placed in storage tank B. The two streams of materials were respectively pumped into the reaction zone of the reactor for mixing reaction. At this time, the molar ratio of concentrated nitric acid to the substrate was controlled at 1.3:1, the temperature was controlled at 30 °C, and the residence time was 5.9 min. The reaction solution was quantitatively collected, and after ice-water bath, water washing, filtration, and drying, 2-methoxy-4-nitroacetanilide was obtained. The HPLC content analysis (normalization) was 70%, and the yield was 70%.

[0052] Comparative Example 2

[0053] o-Methoxyacetanilide and dichloromethane were mixed and dissolved at a mass-to-volume ratio of 1:4 and placed in storage tank A. 60% concentrated sulfuric acid and 98% concentrated nitric acid were mixed at a mass ratio of 1:0.18 and placed in storage tank B. The two streams of materials were respectively pumped into the reaction zone of the reactor for mixing reaction. At this time, the molar ratio of concentrated nitric acid to the substrate was controlled at 1.3:1, the temperature was controlled at 30 °C, and the residence time was 5.9 min. The reaction solution was quantitatively collected, and after ice-water bath, water washing, filtration, and drying, 2-methoxy-4-nitroacetanilide was obtained. The HPLC content analysis (normalization) was 70%, and the yield was 60%.

[0054] Comparative Example 3

[0055] According to the method of Example 1 above, the concentrated sulfuric acid concentration was changed for research. The results showed that when the sulfuric acid concentration exceeded 60% or was lower than 50%, the reaction was prone to wall sticking, resulting in pipeline blockage and a decrease in product purity.

[0056] Ratio of mixed acid Whether solid precipitates in the reactor HPLC content analysis (normalization) 98% nitric acid / 70% sulfuric acid = 0.25 Wall sticking 80％ 98% nitric acid / 65% sulfuric acid = 0.5 Wall sticking 83％ 98% nitric acid / 45% sulfuric acid = 0.67 Wall sticking 80％

[0057] Comparative Example 4

[0058] Mix and dissolve o - methoxyacetanilide and dichloromethane at a mass - to - volume ratio of 1:5 and place them in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid at a mass ratio of 1:0.75 and place them in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.45:1, control the temperature at 45 °C, and the residence time at 1 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, obtain 2 - methoxy - 4 - nitroacetanilide. The HPLC content analysis (normalization) is 60%, and the yield is 50%.

[0059] Comparative Example 5

[0060] Mix and dissolve o - methoxyacetanilide and dichloromethane at a mass - to - volume ratio of 1:5 and place them in storage tank A. Mix 60% concentrated sulfuric acid and 98% concentrated nitric acid at a mass ratio of 1:0.8 and place them in storage tank B. Inject the two streams of materials into the reaction zone of the reactor through pumps respectively for mixing reaction. At this time, control the molar ratio of concentrated nitric acid to the substrate to be 1.4:1, control the temperature at 25 °C, and the residence time at 10 min. Quantitatively collect the reaction solution, and after ice - water bath, water washing, filtration, and drying, obtain 2 - methoxy - 4 - nitroacetanilide. The HPLC content analysis (normalization) is 60%, and the yield is 50%.

Claims

1. A method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor, characterized in that, The method described includes: (1) At room temperature, dissolve the substrate o - methoxyacetanilide in an organic solvent; the organic solvent is one of dichloromethane, dichloroethane or chloroform; (2) Mix concentrated sulfuric acid and concentrated nitric acid to prepare a mixed acid; (3) Pump the organic solution containing the substrate o - methoxyacetanilide prepared in step (1) and the mixed acid in step (2) into the reaction zone of a continuous - flow microchannel reactor through metering pumps respectively for mixing and residence reaction to synthesize 2 - methoxy - 4 - nitroacetanilide; the molar ratio of the substrate o - methoxyacetanilide to nitric acid in the reaction zone is 1:1.3; the mixing and residence time is 5.9 min; The mass ratio of the concentrated sulfuric acid to the concentrated nitric acid is 1:0.5, the mass concentration of the concentrated sulfuric acid is 50% - 60%, and the mass concentration of the concentrated nitric acid is 98%.

2. The method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor according to claim 1, characterized in that, In step (1), the mass ratio of the organic solvent to the substrate o - methoxyacetanilide is 2:1 - 10:

1.

3. The method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor according to claim 1, characterized in that, The temperature of the mixing and residence reaction in step (3) is 25 - 35 °C.

4. The method for synthesizing 2-methoxy-4-nitroacetanilide in a continuous flow reactor according to claim 1, characterized in that, The continuous - flow reactor is selected from any one or any combination of a micro - reactor, a series of coiled - tube reactors, and a tubular reactor.

Images