CN116178163A - Continuous flow preparation process of nitroacetate compound - Google Patents
Continuous flow preparation process of nitroacetate compound Download PDFInfo
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- CN116178163A CN116178163A CN202211595703.4A CN202211595703A CN116178163A CN 116178163 A CN116178163 A CN 116178163A CN 202211595703 A CN202211595703 A CN 202211595703A CN 116178163 A CN116178163 A CN 116178163A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
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Abstract
The invention provides a continuous flow preparation process of nitroacetate compounds, and belongs to the field of chemical medicine preparation. The process for preparing the nitroacetate compound by continuous flow avoids the use of dichromate and does not produce heavy metal pollution; the use of nitric acid is avoided, and high-risk nitration is not involved; realizes automatic control, reduces the risk and cost of manual operation, and realizes safe, environment-friendly and efficient green chemical production.
Description
Technical Field
The invention belongs to the field of chemical medicine preparation, and in particular relates to a continuous flow preparation process of nitroacetate compounds.
Background
Nitroacetate compounds are important raw material compounds in organic synthesis. For example, chinese patent application No. CN114133393a reports that ethyl nitroacetate is an important intermediate for the synthesis of antiviral drugs for the treatment of covd-19 coronavirus infection.
At present, most of the methods for synthesizing nitroacetate compounds take acetoacetate compounds as starting materials and ethyl nitroacetate as an example, and the main synthesis methods at present are as follows (the synthetic route is shown as follows): the ethyl acetoacetate reacts with sodium nitrite to obtain an alpha-oximido ethyl acetoacetate compound, and sodium dichromate is oxidized to generate ethyl nitroacetate. However, on one hand, heavy metal pollution can be generated by dichromate used in the method, inconvenience is brought to three-waste treatment, and serious pollution can be caused to the environment; on the other hand, the method adopts a traditional kettle reactor, and the conventional stirring mass transfer and heat transfer efficiency is relatively low, so that local overheating of the reaction can occur, and the reaction is dangerous.
In order to overcome the defects of local overheat, low yield, poor safety, heavy metal pollution, difficulty in large-scale amplification and the like in the existing preparation of nitroacetate compounds by adopting a traditional kettle-type reactor, the Chinese patent application with publication number of CN107304165A discloses a process for preparing nitroacetate by utilizing a microchannel reactor, which comprises the following two steps (the synthetic route is shown as follows): (1) Respectively feeding ethyl acetoacetate and an activated nitric acid reagent into a micro-channel reactor from different pipelines to perform nitration reaction to obtain 2-nitroethyl acetoacetate; (2) And (3) reacting the ethyl 2-nitroacetoacetate prepared in the step (1) with ethanol to obtain ethyl nitroacetate. However, the nitration reaction adopted in the process is an important supervisory reaction, is an exothermic reaction, has high exothermic reaction speed, can cause explosion when being poorly controlled, has high risk, and is not suitable for large-scale production.
In order to overcome the problems, the process for preparing the nitroacetate compound, which is safe, nontoxic, green, pollution-free and suitable for large-scale amplification, has important significance.
Disclosure of Invention
The invention aims to provide a novel continuous flow preparation process of nitroacetate compounds.
The invention provides a continuous flow preparation process of nitroacetate compounds, which is carried out in a continuous flow reactor, wherein a mixed solution of a compound I and a solvent is connected to a metering pump 1, and the metering pump 1 is connected to a continuous flow preheater 1; the sodium nitrite aqueous solution enters a metering pump 2, and the metering pump 2 is connected into a continuous flow preheater 2; the continuous flow preheater 1 and the continuous flow preheater 2 are both connected to the continuous flow mixer 1, and the continuous flow mixer 1 is connected to the continuous flow reactor 1; h 2 O 2 The aqueous solution is connected to a metering pump 3, and the metering pump 3 is connected to a continuous flow preheater 3; the continuous flow preheater 3 and the continuous flow reactor 1 are both connected to the continuous flow mixer 2, and the continuous flow mixer 2 is connected to the continuous flow reactor 2; the quenching liquid is connected into a metering pump 4, the metering pump 4 and the continuous flow reactor 2 are connected into a continuous flow mixer 3, and the continuous flow mixer 3 is connected into a continuous flow cooling module;
the reaction route of the process is as follows:
r is C 1-8 An alkyl group;
the process comprises the following steps: firstly, a metering pump 1 and a metering pump 2 are started, then a metering pump 3 is started, finally, a metering pump 4 is started, after the reaction is finished, a reaction liquid is collected in a continuous flow cooling module, and the compound III, namely the nitroacetate compound, is obtained through purification.
Further, R is methyl or ethyl.
Further, the solvent is an organic solvent; the mass volume ratio of the compound I to the solvent is 1: (0.8-1.2) g/ml; compound I, sodium nitrite and H 2 O 2 The equivalent ratio of (2) is 1: (0.7-1.3): (1.2-1.8); the mass ratio of the compound I to the quenching liquid is 1: (4-10).
Further, the organic solvent is acetic acid, and the quenching liquid is water; the mass volume ratio of the compound I to the solvent is 1:1g/ml; compound I, sodium nitrite and H 2 O 2 The equivalent ratio of (2) is 1:1.02:1.5; the mass ratio of the compound I to the quenching liquid is 1:6.
further, the mass concentration of the sodium nitrite aqueous solution is 20% -40%, preferably 30%, and the H is 2 O 2 The mass concentration of the aqueous solution is 20-40%, preferably 27%.
Further, the temperatures 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 are set to be-10-5 ℃, preferably-5-0 ℃;
the temperature of the continuous flow cooling module is set to be 0-10 ℃.
Further, the ratio of flow rates of the metering pump 1, the metering pump 2, the metering pump 3 and the 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.
further, the flow rate of the metering pump 1 is 70.0ml/min, the flow rate of the metering pump 2 is 71.5ml/min, the flow rate of the metering pump 3 is 58ml/min, and the flow rate of the metering pump 4 is 58.5ml/min.
Further, the opening time of the metering pump 3 is 80-100s after the metering pump 1 and the metering pump 2 are opened, the opening time of the metering pump 4 is 125-145s after the metering pump 3 is opened, and the time for collecting the reaction liquid is 170-190s after the metering pump 4 is opened.
Further, the opening time of the metering pump 3 is 90s after the metering pump 1 and the metering pump 2 are opened, the opening time of the metering pump 4 is 135s after the metering pump 3 is opened, and the time for collecting the reaction liquid is 180s after the metering pump 4 is opened.
Further, the purification mode is as follows: collecting the reaction solution, concentrating to remove solvent, extracting with dichloromethane, concentrating, and rectifying.
Compared with the prior art, the process for continuously preparing the nitroacetate compound has the following beneficial effects:
1) The dichromate is avoided, and heavy metal pollution is avoided;
2) The use of nitric acid is avoided, and high-risk nitration is not involved;
3) The oximation reaction condition adopted by the invention is mild and easy to control;
3) The hydrogen peroxide is used as the oxidant, and the byproduct is water, so that the method is environment-friendly;
4) In the continuous flow reactor of the invention, the whole process is a continuous process, so that other problems encountered in the traditional kettle type reaction are avoided, such as: the invention realizes automatic control, reduces the danger and cost of manual operation, and realizes safe, environment-friendly and efficient green chemical production.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a schematic diagram showing the structure and reaction scheme of a continuous flow reaction apparatus used in the examples.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The structure of the continuous flow reaction apparatus used in the following examples is prior art and a schematic diagram is shown in FIG. 1.
The 30% sodium nitrite aqueous solution refers to a sodium nitrite aqueous solution with a mass concentration of 30%.
The 27% hydrogen peroxide solution refers to a hydrogen peroxide aqueous solution with a mass concentration of 27%.
Example 1 continuous flow Process for preparing methyl nitroacetate
A mixed solution of methyl acetoacetate ((500 g,4.3 mol) and acetic acid (500 ml, 1V) was prepared and connected to a metering pump 1, a 30% aqueous sodium nitrite solution (1011.2 g,4.39mol,1.02 eq) was weighed and connected to a metering pump 2, a 27% aqueous hydrogen peroxide solution (836 g,6.45mol,1.5 eq) was connected to a metering pump 3, and a quenching liquid was water (3000 g) and connected to a metering pump 4.
Setting the circulation temperature of the continuous flow preheater 1, the continuous flow preheater 2 and the continuous flow preheater 3 to be-5-0 ℃ and stabilizing;
setting the circulation temperature of the continuous flow mixer 1, the continuous flow mixer 2 and the continuous flow mixer 3 to be-5-0 ℃ and stabilizing;
setting the circulation temperature of the continuous flow reactor 1 and the continuous flow reactor 2 to be-5-0 ℃ and stabilizing;
setting the circulation temperature of the continuous flow cooling module to be 0-10 ℃ and stabilizing;
the flow rate of the metering pump 1 is set to be 70.0ml/min, the flow rate of the metering pump 2 is set to be 71.5ml/min, the flow rate of the metering pump 3 is set to be 58ml/min, and the flow rate of the metering pump 4 is set to be 58.5ml/min.
Simultaneously starting a metering pump 1 and a metering pump 2, starting a metering pump 3 after 90s of operation, starting a metering pump 4 after 135s of operation, collecting reaction liquid after 180s of operation, concentrating to remove acetic acid, extracting a product with dichloromethane, concentrating to obtain a crude product, and rectifying to obtain a pure product of methyl nitroacetate. The GC purity of the pure methyl nitroacetate product was 97% and the yield was 90%.
Example 2 continuous flow Process for preparing ethyl nitroacetate
A mixed solution of ethyl acetoacetate ((500 g,3.8 mol) and acetic acid (500 ml, 1V) was prepared, and was connected to a metering pump 1, a 30% aqueous sodium nitrite solution (902.7 g,3.91mol,1.02 eq) was weighed, and was connected to a metering pump 2, a 27% aqueous hydrogen peroxide solution (738.8 g,5.7mol,1.5 eq) was connected to a metering pump 3, and a quenching liquid was water (3000 g), and was connected to a metering pump 4.
Setting the circulation temperature of the continuous flow preheater 1, the continuous flow preheater 2 and the continuous flow preheater 3 to be-5-0 ℃ and stabilizing;
setting the circulation temperature of the continuous flow mixer 1, the continuous flow mixer 2 and the continuous flow mixer 3 to be-5-0 ℃ and stabilizing;
setting the circulation temperature of the continuous flow reactor 1 and the continuous flow reactor 2 to be-5-0 ℃ and stabilizing;
setting the circulation temperature of the continuous flow cooling module to be 0-10 ℃ and stabilizing;
the flow rate of the metering pump 1 is set to be 70.0ml/min, the flow rate of the metering pump 2 is set to be 71.5ml/min, the flow rate of the metering pump 3 is set to be 58ml/min, and the flow rate of the metering pump 4 is set to be 58.5ml/min.
Simultaneously starting a metering pump 1 and a metering pump 2, starting a metering pump 3 after 90s of operation, starting a metering pump 4 after 135s of operation, collecting reaction liquid after 180s of operation, concentrating to remove acetic acid, extracting a product by using dichloromethane, concentrating to obtain a crude product, and rectifying to obtain a pure ethyl nitroacetate product. The GC purity of the pure ethyl nitroacetate product was 98% and the yield was 91%.
In summary, the invention provides a continuous flow preparation process of nitroacetate compounds, which avoids the use of dichromate and does not produce heavy metal pollution; the use of nitric acid is avoided, and high-risk nitration is not involved; realizes automatic control, reduces the risk and cost of manual operation, and realizes safe, environment-friendly and efficient green chemical production.
Claims (10)
1. A continuous flow preparation process of nitroacetate compounds is characterized in that: the process is carried out in a continuous flow reactor, wherein a mixed solution of a compound I and a solvent is connected to a metering pump 1, and the metering pump 1 is connected to a continuous flow preheater 1; the sodium nitrite aqueous solution enters a metering pump 2, and the metering pump 2 is connected into a continuous flow preheater 2; the continuous flow preheater 1 and the continuous flow preheater 2 are both connected to the continuous flow mixer 1, and the continuous flow mixer 1 is connected to the continuous flow reactor 1; h 2 O 2 The aqueous solution is connected to a metering pump 3, and the metering pump 3 is connected to a continuous flow preheater 3; the continuous flow preheater 3 and the continuous flow reactor 1 are both connected to the continuous flow mixer 2, and the continuous flow mixer 2 is connected to the continuous flow reactor 2; the quenching liquid is connected into a metering pump 4, the metering pump 4 and the continuous flow reactor 2 are connected into a continuous flow mixer 3, and the continuous flow mixer 3 is connected into a continuous flow cooling module;
the reaction route of the process is as follows:
r is C 1-8 An alkyl group;
the process comprises the following steps: firstly, a metering pump 1 and a metering pump 2 are started, then a metering pump 3 is started, finally, a metering pump 4 is started, after the reaction is finished, a reaction liquid is collected in a continuous flow cooling module, and the compound III, namely the nitroacetate compound, is obtained through purification.
2. The continuous flow preparation process of claim 1, wherein: the solvent is an organic solvent; the mass volume ratio of the compound I to the solvent is 1: (0.8-1.2) g/ml; compound I, sodium nitrite and H 2 O 2 The equivalent ratio of (2) is 1: (0.7-1.3): (1.2-1.8); the mass ratio of the compound I to the quenching liquid is 1: (4-10).
3. The continuous flow preparation process of claim 2, wherein: the organic solvent is acetic acid, and the quenching liquid is water; the mass volume ratio of the compound I to the solvent is 1:1g/ml; compound I, sodium nitrite and H 2 O 2 The equivalent ratio of (2) is 1:1.02:1.5; the mass ratio of the compound I to the quenching liquid is 1:6.
4. the continuous flow preparation process of claim 1, wherein: the mass concentration of the sodium nitrite aqueous solution is 20% -40%, preferably 30%, and the H is 2 O 2 The mass concentration of the aqueous solution is 20-40%, preferably 27%.
5. The continuous flow preparation process of claim 1, wherein: the temperatures 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 are set to be-10-5 ℃, preferably-5-0 ℃;
the temperature of the continuous flow cooling module is set to be 0-10 ℃.
6. The continuous flow preparation process of claim 1, wherein: the ratio of the flow rates of the metering pump 1, the metering pump 2, the metering pump 3 and the 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.
7. the continuous flow preparation process of claim 6, wherein: the flow rate of the metering pump 1 is 70.0ml/min, the flow rate of the metering pump 2 is 71.5ml/min, the flow rate of the metering pump 3 is 58ml/min, and the flow rate of the metering pump 4 is 58.5ml/min.
8. The continuous flow preparation process of claim 1, wherein: the opening time of the metering pump 3 is 80-100s after the metering pump 1 and the metering pump 2 are started, the opening time of the metering pump 4 is 125-145s after the metering pump 3 is started, and the time for collecting the reaction liquid is 170-190s after the metering pump 4 is started.
9. The continuous flow preparation process of claim 8, wherein: the opening time of the metering pump 3 is 90s after the metering pump 1 and the metering pump 2 are started, the opening time of the metering pump 4 is 135s after the metering pump 3 is started, and the time for collecting the reaction liquid is 180s after the metering pump 4 is started.
10. The continuous flow preparation process according to any one of claims 1-9, characterized in that: the purification mode is as follows: collecting the reaction solution, concentrating to remove solvent, extracting with dichloromethane, concentrating, and rectifying.
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| CN202211595703.4A CN116178163A (en) | 2022-12-13 | 2022-12-13 | Continuous flow preparation process of nitroacetate compound |
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| CN202211595703.4A CN116178163A (en) | 2022-12-13 | 2022-12-13 | Continuous flow preparation process of nitroacetate compound |
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