A continuous flow preparation process for nitroacetic acid ester compounds

Abstract

The present invention provides a continuous flow process for preparing nitroacetic acid ester compounds, belonging to the field of chemical pharmaceutical preparation. This process avoids the use of dichromate, thus preventing heavy metal pollution; avoids the use of nitric acid, thus avoiding the highly dangerous nitration reaction; and implements automated control, reducing the risks and costs of manual operation, thereby achieving safe, environmentally friendly, and efficient green chemical production.

Description

Technical Field

[0001] The invention belongs to the field of chemical drug preparation, and particularly relates to a continuous flow preparation process for nitroacetate compounds. Background Art

[0002] Nitroacetic acid esters are important raw materials in organic synthesis. For example, Chinese patent application number CN114133393A reports that ethyl nitroacetate is an important intermediate in the synthesis of antiviral drugs for treating COVID-19 coronavirus infection.

[0003] Currently, most methods for synthesizing nitroacetic acid esters use acetoacetic acid esters as starting materials. Taking ethyl nitroacetate as an example, the main synthesis method is as follows (the synthetic route is shown below): ethyl acetoacetate is first reacted with sodium nitrite to produce α-oximino ethyl acetoacetate, which is then oxidized with sodium dichromate to produce ethyl nitroacetate. However, the dichromate used in this method generates heavy metal pollution, which inconveniences waste treatment and poses serious environmental pollution. Furthermore, this method utilizes a traditional kettle reactor, which, due to the relatively low mass and heat transfer efficiency of conventional stirring, can lead to localized overheating in the reaction, posing a risk to the reaction.

[0004]

[0005] In order to overcome the shortcomings of the conventional use of a traditional kettle reactor for preparing nitroacetic acid ester compounds, such as local overheating during the reaction, temperature fluctuations, low yield, poor safety, heavy metal contamination, and difficulty in scale-up, a Chinese patent application with publication number CN107304165A discloses a process for preparing ethyl nitroacetate using a microchannel reactor, comprising the following two steps (the synthesis route is shown below): (1) introducing ethyl acetoacetate and an activated nitric acid reagent into a microchannel reactor through different pipes for nitration to obtain ethyl 2-nitroacetoacetate; (2) reacting the ethyl 2-nitroacetoacetate prepared in step (1) with ethanol to obtain ethyl nitroacetate. However, the nitration reaction used in this process is a key regulated reaction. It is an exothermic reaction, and the exothermic reaction speed is fast. If not properly controlled, it may cause explosion, which is highly dangerous and not suitable for large-scale production.

[0006]

[0007] In order to overcome the above problems, it is of great significance to develop a process for preparing nitroacetic acid ester compounds that is safe, non-toxic, green, pollution-free, and suitable for large-scale expansion. Summary of the Invention

[0008] The object of the present invention is to provide a new continuous flow preparation process for nitroacetic acid ester compounds.

[0009] The present invention provides a continuous flow preparation process for nitroacetic acid ester compounds. The process is carried out in a continuous flow reactor. In the continuous flow reactor, a mixed solution of compound 1 and a solvent is connected to a metering pump 1, which is connected to a continuous flow preheater 1; a sodium nitrite aqueous solution is connected to a metering pump 2, which is connected to the continuous flow preheater 2; the continuous flow preheater 1 and the continuous flow preheater 2 are both connected to a continuous flow mixer 1, which is connected to the continuous flow reactor 1; an H2O2 aqueous solution is connected to a metering pump 3, which is connected to the continuous flow preheater 3; the continuous flow preheater 3 and the continuous flow reactor 1 are both connected to the continuous flow mixer 2, which is connected to the continuous flow mixer 2; a quenching liquid is connected to a metering pump 4, which is connected to the continuous flow mixer 3 and the continuous flow reactor 2; the continuous flow mixer 3 is connected to a continuous flow cooling module;

[0010] The reaction route of the process is:

[0011]

[0012] R is C 1-8 alkyl;

[0013] The process includes the following steps: first starting metering pump 1 and metering pump 2, then starting metering pump 3, and finally starting metering pump 4. After the reaction is completed, the reaction liquid is collected in a continuous flow cooling module and purified to obtain compound III, i.e., a nitroacetic acid ester compound.

[0014] Furthermore, R is a methyl group or an ethyl group.

[0015] Furthermore, the solvent is an organic solvent; the mass volume ratio of compound I and the solvent is 1:(0.8-1.2) g / ml; the equivalent ratio of compound I, sodium nitrite and H2O2 is 1:(0.7-1.3):(1.2-1.8); the mass ratio of compound I and the quenching solution is 1:(4-10).

[0016] Furthermore, the organic solvent is acetic acid, the quenching liquid is water; the mass volume ratio of compound I and the solvent is 1:1 g / ml; the equivalent ratio of compound I, sodium nitrite and H2O2 is 1:1.02:1.5; the mass ratio of compound I and the quenching liquid is 1:6.

[0017] Furthermore, the mass concentration of the sodium nitrite aqueous solution is 20%-40%, preferably 30%, and the mass concentration of the H2O2 aqueous solution is 20-40%, preferably 27%.

[0018] Furthermore, the temperature of the continuous flow preheater 1, the continuous flow preheater 2, the continuous flow preheater 3, the continuous flow mixer 1, the continuous flow mixer 2, the continuous flow mixer 3, the continuous flow reactor 1 and the continuous flow reactor 2 is set to -10 to 5°C, preferably -5 to 0°C;

[0019] The temperature of the continuous flow cooling module is set at 0-10°C.

[0020] Furthermore, the ratio of the flow rates of the metering pump 1, metering pump 2, metering pump 3 and metering pump 4 is 1:(0.90-1.10):(0.75-0.95):(0.75-0.95), preferably 1:1.02:0.83:0.84.

[0021] Furthermore, the flow rate of the metering pump 1 is 70.0 ml / min, the flow rate of the metering pump 2 is 71.5 ml / min, the flow rate of the metering pump 3 is 58 ml / min, and the flow rate of the metering pump 4 is 58.5 ml / min.

[0022] Furthermore, the metering pump 3 is started 80-100 seconds after the metering pump 1 and the metering pump 2 are started, the metering pump 4 is started 125-145 seconds after the metering pump 3 is started, and the reaction liquid is collected 170-190 seconds after the metering pump 4 is started.

[0023] Furthermore, the metering pump 3 is started 90 seconds after the metering pump 1 and the metering pump 2 are started, the metering pump 4 is started 135 seconds after the metering pump 3 is started, and the reaction liquid is collected 180 seconds after the metering pump 4 is started.

[0024] Furthermore, the purification method is: taking the reaction solution, concentrating to remove the solvent, extracting with dichloromethane, concentrating, and distilling.

[0025] Compared with the prior art, the continuous flow process for preparing nitroacetic acid ester compounds of the present invention has the following beneficial effects:

[0026] 1) Avoid the use of dichromate and will not produce heavy metal pollution;

[0027] 2) Avoid the use of nitric acid and do not involve highly dangerous nitration reactions;

[0028] 3) The oximation reaction conditions used in the present invention are mild and easy to control;

[0029] 3) The present invention uses hydrogen peroxide as an oxidant, and the by-product is water, which is green and environmentally friendly;

[0030] 4) In the continuous flow reactor of the present invention, the entire process is a continuous process, avoiding other problems encountered in traditional batch reactions, such as: local overheating and temperature runaway, low yield, poor safety, heavy metal contamination, and difficulty in large-scale expansion. The present invention realizes automated control, reduces the risks and costs of manual operation, and thus realizes safe, environmentally friendly, and efficient green chemical production.

[0031] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0032] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Schematic diagram of the structure and reaction flow of the continuous flow reaction device used in the examples. DETAILED DESCRIPTION

[0034] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0035] The structure of the continuous flow reaction device used in the following examples is the prior art, as shown in the schematic diagram. Figure 1 shown.

[0036] 30% sodium nitrite aqueous solution refers to a sodium nitrite aqueous solution with a mass concentration of 30%.

[0037] 27% hydrogen peroxide solution refers to a hydrogen peroxide solution with a mass concentration of 27%.

[0038] Example 1: Continuous Flow Process for Preparing Methyl Nitroacetate

[0039]

[0040] Prepare a mixed solution of methyl acetoacetate (500 g, 4.3 mol) and acetic acid (500 ml, 1 V) and connect it to metering pump 1; weigh 30% sodium nitrite aqueous solution (1011.2 g, 4.39 mol, 1.02 eq) and connect it to metering pump 2; connect 27% hydrogen peroxide aqueous solution (836 g, 6.45 mol, 1.5 eq) to metering pump 3; and connect water (3000 g) as the quenching liquid to metering pump 4.

[0041] The circulation temperature of continuous flow preheater 1, continuous flow preheater 2 and continuous flow preheater 3 is set to -5 to 0°C and reaches stability;

[0042] The circulation temperature of the continuous flow mixer 1, the continuous flow mixer 2 and the continuous flow mixer 3 is set to -5 to 0°C and reaches stability;

[0043] The circulation temperature of the continuous flow reactor 1 and the continuous flow reactor 2 is set to -5 to 0°C and reaches stability;

[0044] Set the cycle temperature of the continuous flow cooling module to 0-10°C and reach stability;

[0045] Set the flow rate of metering pump 1 to 70.0 ml / min, set the flow rate of metering pump 2 to 71.5 ml / min, set the flow rate of metering pump 3 to 58 ml / min, and set the flow rate of metering pump 4 to 58.5 ml / min.

[0046] Metering pumps 1 and 2 were simultaneously started and operated for 90 seconds. Metering pump 3 was then started and operated for 135 seconds. Metering pump 4 was then started and operated for 180 seconds. The reaction solution was collected and concentrated to remove acetic acid. The product was extracted with dichloromethane and concentrated to obtain a crude product. Purified methyl nitroacetate was obtained by distillation. The GC purity of the purified methyl nitroacetate was 97%, and the yield was 90%.

[0047] Example 2: Continuous Flow Process for Preparing Ethyl Nitroacetate

[0048]

[0049] Prepare a mixed solution of ethyl acetoacetate (500 g, 3.8 mol) and acetic acid (500 ml, 1 V) and connect it to metering pump 1; weigh 30% sodium nitrite aqueous solution (902.7 g, 3.91 mol, 1.02 eq) and connect it to metering pump 2; connect 27% hydrogen peroxide aqueous solution (738.8 g, 5.7 mol, 1.5 eq) to metering pump 3; and connect water (3000 g) as the quenching liquid to metering pump 4.

[0050] The circulation temperature of continuous flow preheater 1, continuous flow preheater 2 and continuous flow preheater 3 is set to -5 to 0°C and reaches stability;

[0051] The circulation temperature of the continuous flow mixer 1, the continuous flow mixer 2 and the continuous flow mixer 3 is set to -5 to 0°C and reaches stability;

[0052] The circulation temperature of the continuous flow reactor 1 and the continuous flow reactor 2 is set to -5 to 0°C and reaches stability;

[0053] Set the cycle temperature of the continuous flow cooling module to 0-10°C and reach stability;

[0054] Set the flow rate of metering pump 1 to 70.0 ml / min, set the flow rate of metering pump 2 to 71.5 ml / min, set the flow rate of metering pump 3 to 58 ml / min, and set the flow rate of metering pump 4 to 58.5 ml / min.

[0055] Metering pumps 1 and 2 were simultaneously started and operated for 90 seconds. Metering pump 3 was then started and operated for 135 seconds. Metering pump 4 was then started and operated for 180 seconds. The reaction solution was collected and concentrated to remove acetic acid. The product was extracted with dichloromethane and concentrated to obtain a crude product. This was then distilled to obtain pure ethyl nitroacetate. The GC purity of the pure ethyl nitroacetate was 98%, and the yield was 91%.

[0056] In summary, the present invention provides a continuous flow preparation process for nitroacetic acid ester compounds. This process avoids the use of dichromate and does not produce heavy metal pollution; avoids the use of nitric acid and does not involve highly dangerous nitration reactions; and achieves automated control, reducing the risks and costs of manual operation, thereby realizing safe, environmentally friendly, and efficient green chemical production.

Claims

1. A continuous flow preparation process for nitroacetic acid ester compounds, characterized in that: The process is carried out in a continuous flow reactor, in which a mixed solution of compound I and a solvent is connected to a metering pump 1, which is connected to a continuous flow preheater 1; a sodium nitrite aqueous solution is connected to a metering pump 2, which is connected to a continuous flow preheater 2; the continuous flow preheater 1 and the continuous flow preheater 2 are both connected to a continuous flow mixer 1, which is connected to a continuous flow reactor 1; an H2O2 aqueous solution is connected to a metering pump 3, which is connected to a continuous flow preheater 3; the continuous flow preheater 3 and the continuous flow reactor 1 are both connected to a continuous flow mixer 2, which is connected to a continuous flow mixer 2; a quenching liquid is connected to a metering pump 4, which is connected to a continuous flow mixer 3 and a continuous flow reactor 2; and the continuous flow mixer 3 is connected to a continuous flow cooling module. The reaction route of the process is: R is C 1-8 alkyl; The process includes the following steps: first starting metering pump 1 and metering pump 2, then starting metering pump 3, and finally starting metering pump 4. After the reaction is completed, the reaction liquid is collected in a continuous flow cooling module and purified to obtain compound III, i.e., a nitroacetic acid ester compound.

2. The continuous flow preparation process according to claim 1, characterized in that: The solvent is an organic solvent; the mass volume ratio of compound I and the solvent is 1:(0.8-1.2) g / ml; the equivalent ratio of compound I, sodium nitrite and H2O2 is 1:(0.7-1.3):(1.2-1.8); the mass ratio of compound I and the quenching solution is 1:(4-10).

3. The continuous flow preparation process according to claim 2, characterized in that: The organic solvent is acetic acid, and the quenching liquid is water; the mass volume ratio of compound I and the solvent is 1:1 g / ml; the equivalent ratio of compound I, sodium nitrite and H2O2 is 1:1.02:1.5; and the mass ratio of compound I and the quenching liquid is 1:

6.

4. The continuous flow preparation process according to claim 1, characterized in that: The mass concentration of the sodium nitrite aqueous solution is 20%-40%, and the mass concentration of the H2O2 aqueous solution is 20-40%.

5. The continuous flow preparation process according to claim 4, characterized in that: The mass concentration of the sodium nitrite aqueous solution is 30%, and the mass concentration of the H2O2 aqueous solution is 27%.

6. The continuous flow preparation process according to claim 1, characterized in that: The temperature of the continuous flow preheater 1, the continuous flow preheater 2, the continuous flow preheater 3, the continuous flow mixer 1, the continuous flow mixer 2, the continuous flow mixer 3, the continuous flow reactor 1 and the continuous flow reactor 2 is set to -10 to 5°C; The temperature of the continuous flow cooling module is set at 0-10°C.

7. The continuous flow preparation process according to claim 6, characterized in that: The temperatures of the continuous flow preheater 1, continuous flow preheater 2, continuous flow preheater 3, continuous flow mixer 1, continuous flow mixer 2, continuous flow mixer 3, continuous flow reactor 1 and continuous flow reactor 2 are set to -5 to 0°C.

8. The continuous flow preparation process according to claim 1, characterized in that: The flow rate ratio of the metering pump 1, metering pump 2, metering pump 3 and metering pump 4 is 1: (0.90-1.10): (0.75-0.95): (0.75-0.95).

9. The continuous flow preparation process according to claim 8, characterized in that: The flow rate ratio of the metering pump 1, metering pump 2, metering pump 3 and metering pump 4 is 1:1.02:0.83:0.

84.

10. The continuous flow preparation process according to claim 8, characterized in that: The flow rate of the metering pump 1 is 70.0 ml / min, the flow rate of the metering pump 2 is 71.5 ml / min, the flow rate of the metering pump 3 is 58 ml / min, and the flow rate of the metering pump 4 is 58.5 ml / min.

11. The continuous flow preparation process according to claim 1, characterized in that: The metering pump 3 is started 80-100 seconds after the metering pump 1 and the metering pump 2 are started, the metering pump 4 is started 125-145 seconds after the metering pump 3 is started, and the reaction liquid is collected 170-190 seconds after the metering pump 4 is started.

12. The continuous flow preparation process according to claim 11, characterized in that: The metering pump 3 is started 90 seconds after the metering pumps 1 and 2 are started, the metering pump 4 is started 135 seconds after the metering pump 3 is started, and the reaction liquid is collected 180 seconds after the metering pump 4 is started.

13. The continuous flow preparation process according to any one of claims 1 to 12, characterized in that: The purification method is: taking the reaction solution, concentrating to remove the solvent, extracting with dichloromethane, concentrating, and distilling.

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