Preparation method of 4, 5-dimethyl-2-nitroacetanilide

Abstract

The invention relates to a preparation method of 4, 5-dimethyl-2-nitroacetanilide, in particular to a method for continuously preparing 4, 5-dimethyl-2-nitroacetanilide in a microchannel reactor, which comprises the following steps: (1) adding 3, 4-dimethylacetanilide into a solvent selected from dichloromethane, dichloroethane, chloroform or a combination thereof to provide a mixture; (2) mixing the nitric acid aqueous solution with the sulfuric acid aqueous solution to provide mixed acid; and (3) contacting the mixture with a mixed acid in a microchannel reactor, and reacting to form the 4, 5-dimethyl-2-nitroacetanilide. The method provided by the invention can effectively prevent generation of over-nitrification by-products, and improves the reaction yield to about 96%.

Description

Technical Field

[0001] The invention relates to a method for preparing 4,5-dimethyl-2-nitroacetanilide, and in particular to a method for continuously synthesizing 4,5-dimethyl-2-nitroacetanilide in a microchannel reactor. Background Art

[0002] 4,5-dimethyl-2-nitroacetanilide is a high value-added fine chemical and pharmaceutical intermediate, and its growing demand will bring rich economic returns. In the existing technology, 4,5-dimethyl-2-nitroacetanilide is acetylated by 3,4-dimethylaniline to generate 3,4-dimethylacetanilide, which is then nitrated to generate 4,5-dimethyl-2-nitroacetanilide, and finally refined.

[0003] CN114591180A discloses that the most important step in the preparation method of 4,5-dimethyl-2-nitroacetanilide is nitration reaction, and its autoclave process is: using 1000 ml of acetic acid as solvent, 196.5 grams of 3,4-dimethylacetanilide (purity 98.5%) is added to acetic acid; the mixed solution is cooled to 0-5°C, 82.9g of nitric acid and 108.3g of sulfuric acid (purity 98%) are added dropwise, after the addition is completed, the reaction is kept warm for 0.5 hours, and then continued to heat to room temperature, kept warm for 1 hour, the reaction solution is poured into water, stirred, and filtered to obtain 238.4g of product 4,5-dimethyl-2-nitroacetanilide (purity 89.3%), and the product yield is 86.2%. The operation process of the entire reaction process is very slow and inefficient, a large amount of acetic acid is used as a solvent, and the recovery and reuse of acetic acid after quenching with post-treatment water becomes very difficult. In addition, the nitration reaction is a high-risk batch or semi-batch reaction, which brings more uncertainty to the reaction safety and easily produces over-nitration by-products, affecting the yield.

[0004] Therefore, there is an urgent need for a new method for preparing 4,5-dimethyl-2-nitroacetanilide, which can continuously synthesize 4,5-dimethyl-2-nitroacetanilide and effectively prevent the generation of over-nitration by-products, thereby improving the yield. Summary of the invention

[0005] In order to solve the above technical problems, the inventors found that the continuous flow process in the microchannel reactor can well replace the intermittent or semi-batch kettle reaction. At the same time, the combined use of specific reaction solvents can improve the mass transfer and heat transfer efficiency, better intensify the reaction, thereby shortening the reaction time and greatly reducing the operational risk of the reaction.

[0006] In one aspect, the present invention provides a method for continuously preparing 4,5-dimethyl-2-nitroacetanilide in a microchannel reactor, comprising:

[0007] (1) adding 3,4-dimethylacetanilide to a halogenated alkane solvent to provide a mixture;

[0008] (2) mixing an aqueous nitric acid solution with an aqueous sulfuric acid solution to provide a mixed acid; and

[0009] (3) contacting the mixture with a mixed acid in a microchannel reactor to react and form 4,5-dimethyl-2-nitroacetanilide.

[0010] In some embodiments of the present invention, the halogenated alkane solvent is selected from dichloromethane, dichloroethane, chloroform or a combination thereof.

[0011] In some embodiments of the present invention, the concentration of the 3,4-dimethylacetanilide is 5-50% by weight, based on the weight of the mixture.

[0012] In some embodiments of the present invention, the concentration of the nitric acid aqueous solution is 20 wt %-68 wt %.

[0013] In some embodiments of the present invention, the concentration of the aqueous sulfuric acid solution is 50 wt %-98 wt %.

[0014] In some embodiments of the present invention, the amount of HNO3 in the mixed acid is 1.0 to 10 molar equivalents.

[0015] In some embodiments of the present invention, the residence time of the reaction in the microchannel reactor is 5 seconds to 2 minutes.

[0016] In some embodiments of the present invention, the temperature of the microchannel reactor is -5°C-200°C.

[0017] In some embodiments of the present invention, the back pressure value of the microchannel reactor is 0.5 bar-5 bar.

[0018] In some embodiments of the present invention, the feed ratio of the mixture to the mixed acid is 1-5 by volume.

[0019] In some embodiments of the present invention, the flow rate of the mixture entering the microchannel reactor is 20-120 ml / min, and the flow rate of the mixed acid entering the microchannel reactor is 20-120 ml / min.

[0020] Compared with the prior art, the present invention performs the reaction in a microchannel reactor and uses a specific reaction solvent to pretreat the reaction raw materials, thereby effectively preventing the generation of over-nitration byproducts and improving the reaction yield. Preferably, the yield is increased to about 96%. The present invention utilizes the advantages of the microchannel reactor in mass transfer and heat transfer, greatly shortening the reaction time. The residence time in the microchannel reactor is only 5 seconds to 2 minutes. Moreover, preferably, by controlling the concentration of the aqueous sulfuric acid solution in the range of 50-98 weight %, the conversion rate of the reaction raw materials can be improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a schematic diagram of a microchannel reactor 10 for synthesizing 4,5-dimethyl-2-nitroacetanilide in one embodiment of the present invention. The first material enters the reactor module 11 from the feed port 12, the second material enters the reactor module 11 from the feed port 13, and the final product is collected at the outlet 14 of the reactor. The reactor 10 includes 5 reaction modules 11. BPR represents a back pressure regulating valve, which is used to adjust the pressure and bubbles of the liquid circuit; IPC (In-process-control) represents intermediate control. DETAILED DESCRIPTION

[0022] The technical solution of the present invention is now described in conjunction with specific embodiments. It should be understood that the following embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0023] In the present invention, the reaction equation for synthesizing 4,5-dimethyl-2-nitroacetanilide is:

[0024]

[0025] As used herein, the term "microchannel reactor" refers to a microreactor whose internal structure is mainly composed of micrometer-sized (usually 10-300 μm) channels.

[0026] As used herein, the term "(LC) analysis" refers to liquid chromatography (LC) analysis.

[0027] Herein, reaction residence time = total volume flow rate of reaction raw materials (ml / min) / reactor internal volume (ml). The reactor internal volume can be provided by the supplier of commercially available microchannel reactors.

[0028] The conversion rate described herein = (initial amount of reactants - remaining amount of reactants) / initial amount of reactants.

[0029] Selectivity as described herein = amount of target product / (starting amount of reactants x conversion rate).

[0030] The separation yield described herein = the (actual) production amount of the target product / theoretical production amount of the target product×100%.

[0031] The purity of the products described herein was calculated by area normalization of the final product in LC analysis.

[0032] The temperature described herein refers to degrees Celsius. If necessary, the concentration / content / amount / number of portions described herein may be measured by weight.

[0033] In the present invention, the microchannel reactor can refer to the content described in CN102325589A of Corning Incorporated. In the present invention, the term "microchannel reactor" refers to a microreactor whose internal structure is mainly composed of micron-level (usually 10-300μm) channels. The microchannel reactor includes but is not limited to Corning G1-glass reactor, Corning G5-SiC reactor, etc.

[0034] The reaction temperature of the microchannel reactor can be accurately controlled by a heat exchanger, and the mixture and the mixed acid enter the reactor through an injection device, which includes but is not limited to injection by pump, extrusion, osmosis, injection, etc. In some embodiments, the mixture and the mixed acid can be pumped from their respective material reservoirs by plunger pumps, and enter the microchannel reactor through a feed frame for reaction.

[0035] The microchannel reactor usually has more than three reactor modules, and those skilled in the art can select them according to the mass transfer / heat transfer efficiency requirements and the required residence time of the reaction being carried out.

[0036] In the present invention, the mixture and the mixed acid can be introduced into a microchannel reactor for reaction, specifically including: allowing the mixture and the mixed acid to contact, mix, and react in the channel of the microchannel reactor, and realizing plug flow along the channel so that the reaction liquid can achieve the effect of enhanced mass transfer.

[0037] Figure 1 Corning G1-glass microchannel reactor 10 used in some specific embodiments of the present invention includes 5 microchannel reactor modules 11, a heat exchanger device (not marked in the figure) and an injection device (not marked in the figure). The heat exchange device includes a heat exchange passage adjacent to the reaction passage of the microchannel reactor module, which is connected to other liquid or gaseous media, and a control device located outside that can keep the medium in the heat exchange passage circulating and control its temperature. The injection device includes a plunger pump and a matching injection frame, which can pump the reactants into the microchannel reactor module. The mixture is passed into the microchannel reactor module 11 from the feed port 12, and the mixed acid is passed into the microchannel reactor module 11 from the feed port 13. After the reaction is completed, the reaction product flows out of the reactor from the discharge port 14.

[0038] In the present invention, the method for continuously preparing 4,5-dimethyl-2-nitroacetanilide in a microchannel reactor comprises or consists of the following steps:

[0039] (1) adding 3,4-dimethylacetanilide to a halogenated alkane solvent to provide a mixture; in a preferred embodiment, the mixture may be premixed, for example, in a material reservoir, before the mixture is fed into a microchannel reactor;

[0040] (2) mixing an aqueous nitric acid solution with an aqueous sulfuric acid solution to provide a mixed acid; in a preferred embodiment, the aqueous nitric acid solution and the aqueous sulfuric acid solution are mixed at a mass fraction of 5-50%; and

[0041] (3) contacting the mixture with a mixed acid in a microchannel reactor to react and form 4,5-dimethyl-2-nitroacetanilide; in a preferred embodiment, the mixture and the mixed acid are pumped into the microchannel reactor simultaneously.

[0042] A solvent selected from dichloromethane, dichloroethane, chloroform or a combination thereof

[0043] In an embodiment of the present invention, based on the weight of the mixture, the concentration of the 3,4-dimethylaniline is 5-50 wt%, 5-40 wt%, 5-30 wt%, 5-20 wt%, 5-10 wt% or any combination of the above ranges.

[0044] In an embodiment of the present invention, the concentration of the nitric acid aqueous solution is 20 wt %-68 wt %, 20 wt %-58 wt %, 20 wt %-48 wt %, 20 wt %-38 wt %, 20 wt %-28 wt %, or a range formed by any combination of the endpoints of the above ranges.

[0045] In some embodiments of the present invention, the concentration of the aqueous sulfuric acid solution is 50% by weight-98% by weight, 50% by weight-88% by weight, 50% by weight-78% by weight, 50% by weight-68% by weight, 50% by weight-58% by weight, or any combination of the above-mentioned range endpoints. In the present invention, the concentration of the aqueous sulfuric acid solution can affect the conversion efficiency of the raw material. When the concentration of sulfuric acid is too low, it is easy to cause 3,4-dimethylacetanilide to be unable to be fully converted. But when the concentration of sulfuric acid is too high, it is easy to cause 3,4-dimethylacetanilide to generate a dinitro by-product.

[0046] In some embodiments of the present invention, the amount of HNO3 in the mixed acid is 1.0 to 10 molar equivalents, 1.0 to 8 molar equivalents, 1.0 to 6 molar equivalents, 1.0 to 4 molar equivalents, 1.0 to 2 molar equivalents, or a range formed by any combination of the endpoints of the above ranges.

[0047] In some embodiments of the present invention, the residence time of the reaction in the microchannel reactor is 5 seconds to 2 minutes, 5 seconds to 1 minute, 5 seconds to 0.5 minutes, 5 seconds to 20 seconds, 5 seconds to 10 seconds, or a range formed by any combination of the endpoints of the above ranges.

[0048] In some embodiments of the present invention, the temperature of the microchannel reactor is -5°C-200°C, -5°C-150°C, -5°C-100°C, -5°C-50°C, -5°C-20°C, -5°C-0°C, or a range formed by any combination of the endpoints of the above ranges.

[0049] In some embodiments of the present invention, the back pressure value of the microchannel reactor is 0.5 bar-5 bar, 0.5 bar-4 bar, 0.5 bar-3 bar, 0.5 bar-2 bar, 0.5 bar-1 bar, or a range formed by any combination of the endpoints of the above ranges.

[0050] In some embodiments of the present invention, the feed ratio of the mixture to the mixed acid is 1-5, 1-4, 1-3, 1-2, or any combination of the endpoints of the above ranges, by volume.

[0051] In some embodiments of the present invention, the flow rate of the mixture entering the microchannel reactor is 20-120 ml / min, 20-100 ml / min, 20-80 ml / min, 20-60 ml / min, 20-40 ml / min, or a range formed by any combination of the endpoints of the above ranges; the flow rate of the mixed acid entering the microchannel reactor is 20-120 ml / min, 20-100 ml / min, 20-80 ml / min, 20-60 ml / min, 20-40 ml / min, or a range formed by any combination of the endpoints of the above ranges.

[0052] Example

[0053] Unless otherwise specified, the raw materials used in the present invention are all industrial grade raw materials.

[0054] In the embodiment, the raw material 3,4-dimethylacetanilide can be purchased from Beijing Bailingwei Technology Co., Ltd., with a purity of >99.5%; nitric acid can be purchased from Nanjing Chemical Reagent Co., Ltd., wherein the nitric acid content can reach 98%; and sulfuric acid can be purchased from Jiangsu Yongfeng Chemical Reagent Co., Ltd., wherein the sulfuric acid content can reach 98%. Dichloromethane can be purchased from Shanghai MacLean Biochemical Technology Co., Ltd., with a purity of >99.5%; dichloroethane can be purchased from Aike Reagent, with a purity of >99.5%; and chloroform can be purchased from Runjing Chemical, with a purity of >97%.

[0055] Example 1

[0056] 100 g of 3,4-dimethylacetanilide (purity: 98%) was dissolved in 1850 g of dichloromethane (wherein the concentration of 3,4-dimethylacetanilide was 5 wt%) to obtain a feed A solution. A nitric acid aqueous solution (100 g HNO3 and 400 g water, 20 wt%) was prepared, and then a sulfuric acid aqueous solution (980 g H2SO4 and 20 g water, 98 wt%) was prepared, and the two aqueous solutions were stirred and mixed to form a feed B.

[0057] Among them, the pump of feed A is set to 10 ml / min, the pump of feed B is set to 20 ml / min, HNO3 is 9.6 equivalents; the temperature zone is set to -5°C.

[0058] After the system stabilized (about 88 seconds), sample collection began. LC analysis showed that the conversion rate of the starting material was 99%. Quantitative analysis of the reaction solution showed that the selectivity of 4,5-dimethyl-2-nitroacetanilide was 99%. The separation yield was 95% and the product purity was 99.7%.

[0059] Example 2

[0060] 100 g of 3,4-dimethylacetanilide (purity: 98%) was dissolved in 480 g of dichloromethane (wherein the concentration of 3,4-dimethylacetanilide was 16.9 wt %) to obtain a feed A solution. A nitric acid aqueous solution (100 g HNO3 and 150 g water, 40 wt %) was prepared, and then a sulfuric acid aqueous solution (700 g H2SO4 and 300 g water, 70 wt %) was prepared, and the two aqueous solutions were stirred and mixed to form a feed B.

[0061] Among them, the pump of feed A is set to 30 ml / min, the pump of feed B is set to 80 ml / min, HNO3 is 3.3 equivalents; the temperature zone is set to 100°C.

[0062] After the system stabilized (about 26 seconds), sample collection began. LC analysis showed that the conversion rate of the starting material was 99%. Quantitative analysis of the reaction solution showed that the selectivity of 4,5-dimethyl-2-nitroacetanilide was 99%. The separation yield was 95% and the product purity was 99.7%.

[0063] Example 3

[0064] 100 g of 3,4-dimethylacetanilide (purity: 98%) was dissolved in 100 g of dichloromethane (wherein the concentration of 3,4-dimethylacetanilide was 49 wt%) to obtain a feed A solution. A nitric acid aqueous solution (100 g of HNO3 and 53.8 g of water, 65 wt%) was prepared, and then a sulfuric acid aqueous solution (70 g of H2SO4 and 70 g of water, 50 wt%) was prepared, and the two aqueous solutions were stirred and mixed to form a feed B.

[0065] Among them, the pump of feed A is set to 100 ml / min, the pump of feed B is set to 100 ml / min, HNO3 is 1.1 equivalents; the temperature zone is set to 150°C.

[0066] After the system stabilized (about 14.6 seconds), samples were collected. LC analysis showed that the conversion rate of the starting material was 99%. Quantitative analysis of the reaction solution showed that the selectivity of 4,5-dimethyl-2-nitroacetanilide was 99%. The separation yield was 96% and the product purity was 99.7%.

[0067] Example 4

[0068] 100 g of 3,4-dimethylacetanilide (purity: 98%) was dissolved in 100 g of ethylene dichloride (wherein the concentration of 3,4-dimethylacetanilide was 49 wt%) to obtain a feed A solution. A nitric acid aqueous solution (100 g of HNO3 and 53.8 g of water, 65 wt%) was prepared, and then a sulfuric acid aqueous solution (70 g of H2SO4 and 70 g of water, 50 wt%) was prepared, and the two aqueous solutions were stirred and mixed to form a feed B.

[0069] Among them, the pump of feed A is set to 100 ml / min, the pump of feed B is set to 100 ml / min, HNO3 is 1.1 equivalents; the temperature zone is set to 150°C.

[0070] After the system stabilized (about 14.6 seconds), samples were collected. LC analysis showed that the conversion rate of the starting material was 99%. Quantitative analysis of the reaction solution showed that the selectivity of 4,5-dimethyl-2-nitroacetanilide was 99%. The separation yield was 96% and the product purity was 99.7%.

[0071] Example 5

[0072] 100 g of 3,4-dimethylacetanilide (purity: 98%) was dissolved in 100 g of chloroform (wherein the concentration of 3,4-dimethylacetanilide was 49 wt%) to obtain a feed A solution. A nitric acid aqueous solution (100 g of HNO3 and 53.8 g of water, 65 wt%) was prepared, and then a sulfuric acid aqueous solution (70 g of H2SO4 and 70 g of water, 50 wt%) was prepared, and the two aqueous solutions were stirred and mixed to form a feed B.

[0073] Among them, the pump of feed A is set to 100 ml / min, the pump of feed B is set to 100 ml / min, HNO3 is 1.1 equivalents; the temperature zone is set to 150°C.

[0074] After the system stabilized (about 14.6 seconds), samples were collected. LC analysis showed that the conversion rate of the starting material was 99%. Quantitative analysis of the reaction solution showed that the selectivity of 4,5-dimethyl-2-nitroacetanilide was 99%. The separation yield was 96% and the product purity was 99.7%.

[0075] Comparative Example 1

[0076] With 500 ml of dichloromethane as solvent, 196.5 g of N-(3,4-dimethylphenyl)acetamide (purity 98.5%) was added to a reactor containing dichloromethane. The mixed solution was cooled to 0-5°C, and 82.9 g of nitric acid and 108.3 g of sulfuric acid (purity 98%) were added dropwise for 2 hours, and then the temperature was continued to rise to room temperature and kept warm for 3 hours. The reaction solution was poured into water, stirred, and filtered to obtain 243.2 g of the product N-(4,5-dimethyl-2-nitrophenyl)acetamide (purity 91.1%), and the product yield was 87.9%.

[0077] Comparative Example 2

[0078] According to CN 114591180A, 196.5 g of 3,4-dimethylacetanilide (purity 98.5%) is added to acetic acid with 1000 ml of acetic acid as solvent; the mixed solution is cooled to 0-5°C, 82.9 g of nitric acid and 108.3 g of sulfuric acid (purity 98%) are added dropwise, and after the addition is completed, the mixture is kept warm for 0.5 hour, and then the mixture is heated to room temperature and kept warm for 1 hour. The reaction solution is poured into water, stirred, and filtered to obtain 238.4 g of the product 4,5-dimethyl-2-nitroacetanilide (purity 89.3%), with a product yield of 86.2%.

[0079] In Comparative Example 1, the autoclave process uses dichloromethane as a solvent, and its reaction system is a liquid-liquid two-phase, with poor mixing effect, low reaction efficiency, and prolonged time, which is not conducive to the enlarged production of the autoclave. In Comparative Example 1, the reaction of 100 grams takes 5 hours to complete. Therefore, when the reactants are enlarged to the tonnage level, the reaction time will be longer. In Comparative Example 2, acetic acid is used as a solvent, which can turn the reaction system into a homogeneous phase, avoiding the disadvantage that autoclave stirring cannot mix uniformly for heterogeneous reactions. However, the acetic acid solvent will reduce the nitration ability of nitric acid and sulfuric acid. In addition, the use of a large amount of acetic acid as a solvent in production will inevitably increase the complexity and investment cost of acetic acid recovery.

[0080] In Examples 1-5 of the present invention, the G1 microchannel reactor can take advantage of strong mixing for liquid-liquid heterogeneous reactions. By using halogenated alkanes such as dichloromethane as solvents instead of acetic acid in the kettle process of the prior art, the strong mixing of the G1 microchannel reactor can be used to increase the reaction rate and shorten the reaction time to seconds while ensuring that the nitration system is not weakened.

[0081] The present invention has been described in detail above in conjunction with specific implementation methods and exemplary examples, but these descriptions cannot be understood as limiting the present invention. Those skilled in the art will appreciate that, without departing from the spirit and scope of the present invention, various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its implementation methods, all of which fall within the scope of the present invention.

Claims

1. A method for continuously preparing 4,5-dimethyl-2-nitroacetanilide in a microchannel reactor, comprising: (1) adding 3,4-dimethylacetanilide to a halogenated alkane solvent to provide a mixture; (2) mixing an aqueous nitric acid solution with an aqueous sulfuric acid solution to provide a mixed acid; as well as (3) contacting the mixture with a mixed acid in a microchannel reactor to react and form 4,5-dimethyl-2-nitroacetanilide.

2. The method according to claim 1, wherein: The halogenated alkane solvent is selected from dichloromethane, dichloroethane, chloroform or a combination thereof.

3. The method according to claim 1, wherein: The concentration of the 3,4-dimethylaniline is 5-50 wt % based on the weight of the mixture.

4. The method according to claim 1, wherein: The concentration of the nitric acid aqueous solution is 20 wt %-68 wt %.

5. The method according to claim 1, wherein: The concentration of the aqueous sulfuric acid solution is 50 wt % to 98 wt %.

6. The method according to claim 1, wherein: The amount of HNO3 in the mixed acid is 1.0 to 10 molar equivalents.

7. The method according to claim 1, wherein: The residence time of the reaction in the microchannel reactor is 5 seconds to 2 minutes.

8. The method according to claim 1, wherein: The temperature of the microchannel reactor is -5°C to 200°C.

9. The method according to claim 1, wherein: The back pressure value of the microchannel reactor is 0.5 bar to 5 bar.

10. The method according to claim 1, wherein: The feed ratio of the mixture to the mixed acid is 1-5 by volume.

11. The method according to claim 1, wherein: The flow rate of the mixture entering the microchannel reactor is 20-120 ml / min, and the flow rate of the mixed acid entering the microchannel reactor is 20-120 ml / min.

Images