CN113813895B - Continuous reaction device and continuous preparation method of 5-nitropyridine-3-formic acid - Google Patents
Continuous reaction device and continuous preparation method of 5-nitropyridine-3-formic acid Download PDFInfo
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- B01J19/0013—Controlling the temperature of the process
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0053—Details of the reactor
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2204/00—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices
- B01J2204/002—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices the feeding side being of particular interest
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00027—Process aspects
- B01J2219/00033—Continuous processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00051—Controlling the temperature
- B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
- B01J2219/00087—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor
- B01J2219/00092—Tubes
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Abstract
A continuous reaction device comprises a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container; the continuous reactor is provided with a first inlet, a second inlet and an outlet, and the first feeder, the second feeder and the product container are all polytetrafluoroethylene containers; the first and second feeders were located in a nitrogen atmosphere. Also disclosed is a method for synthesizing 5-nitropyridine-3-carboxylic acid, which comprises using the continuous reaction apparatus.
Description
Technical Field
The invention relates to the technical field of preparation of drug intermediates, in particular to a continuous reaction device and a continuous preparation method of 5-nitropyridine-3-formic acid.
Background
5-bromoisoquinoline and derivatives thereof are important compounds, have stronger biological activity, and are widely applied to the fields of medicines, pesticides and the like, and the 5-nitropyridine-3-formic acid mentioned in the application rarely appears as a medical intermediate or is disclosed by documents or data. Due to the characteristics of the molecule, a unique synthetic route and a unique higher yield problem, the method cannot be popularized to the synthesis of other similar structures.
Due to the nature of the molecule, this method cannot be generalized to the synthesis of other similar structures. This is determined by the originality of the preparation, the higher yields and the irreproducibility of the shorter reaction times obtained in numerous trials, other routes having substantially no higher yields or acceptable reaction times. In particular, no practical problem of the production risk of the present application is noted, and no improvement in the apparatus is made by the same or similar method as that of the present application.
In addition, the prior art has the problem that 5-nitropyridine-3-carboxylic acid is not stable, is easy to decompose and even explode after being gathered in a certain amount, and the substance is usually used with a small amount, but cannot meet the requirement of a large amount of raw materials. Moreover, the raw material 5-aminopyridine-3-formic acid is required to be oxidized to prepare a product, which is very dangerous, and through repeated comparison tests, by using a batch reactor, such as a reaction kettle, a four-mouth bottle and the like, even though the nitrogen protection is carried out in the whole process, when reactants and products are gathered to a certain amount, the danger is still high, and the explosion condition is generated. Therefore, it is very dangerous to carry out this reaction batchwise. Even with a strict nitrogen protection, the risk is not significantly reduced.
Disclosure of Invention
The first purpose of the invention is to solve two specific problems in the prior art, namely, the problem that 5-aminopyridine-3-formic acid is directly oxidized to obtain 5-nitropyridine-3-formic acid from 5-aminopyridine-3-formic acid, the reaction process is very dangerous, and the problem cannot be obviously solved even under the protection of nitrogen is solved through a continuous reactor, and the problem that the product 5-nitropyridine-3-formic acid is very dangerous and even cannot be exposed in the air at normal temperature is solved through the continuous reactor.
The invention claims a continuous reaction device, which is characterized in that: comprises a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container; the continuous reactor is provided with a first inlet, a second inlet and a reactor outlet, and the volume of a coil pipe in the continuous reactor is not less than 30ml; a liquid inlet pipe connected with an inlet of a first pump is inserted into the first feeder, and a liquid outlet pipe connected with an outlet of the first pump is connected with a first inlet; a liquid inlet pipe connected with an inlet of a second pump is inserted into the second feeder, and a liquid outlet pipe connected with an outlet of the second pump is connected with a second inlet; the outlet pipe of the reactor outlet is inserted into the product container.
The first feeder, the second feeder and the product container are all polytetrafluoroethylene containers; the first feeder and the second feeder are positioned in a nitrogen atmosphere; the product container has not less than 1000ml of ice-water mixture.
Further, the first pump and the second pump are continuous flow reactor pumps, and the flow path can be detached; the first feeder and the second feeder have a solvent of not less than 1L and a product container volume of not less than 5L; the continuous reactor is provided with constant temperature control, and the shell of the continuous reactor is made of stainless steel.
A continuous preparation method of 5-nitropyridine-3-formic acid, which is carried out by using the continuous reaction device, is characterized by comprising the following steps.
(1) The preparation method comprises the following steps: the control system is that 5-aminopyridine-3-formic acid is added and dissolved in concentrated sulfuric acid at the speed of less than 0.5g/min at the temperature of 15-25 ℃, every 10g of 5-aminopyridine-3-formic acid is matched with 25ml of concentrated sulfuric acid to obtain a first raw material, and the first raw material is placed in a first feeder under the condition of keeping nitrogen atmosphere. Every 10g of 5-aminopyridine-3-formic acid is matched with 60ml of hydrogen peroxide and 120ml of fuming sulfuric acid, the system is controlled between 15 ℃ and 25 ℃, the hydrogen peroxide is dripped into the fuming sulfuric acid at the speed of less than 0.5ml/min to obtain a second raw material, and the second raw material is placed into a second feeder under the condition of keeping nitrogen atmosphere.
(2) The reaction steps are as follows: connecting pipelines of a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container, pumping nitrogen into the continuous reactor for a plurality of times, keeping the temperature of the continuous reactor at 24-26 ℃, enabling a first raw material to flow into the continuous reactor from a first inlet at a flow rate of 1.2-1.3mL/min through the first pump, enabling a second raw material to flow into the reactor from a second inlet at a flow rate of 8.5-9.5mL/min through the second pump, and enabling reaction liquid to stay in the continuous reactor for 2.5-3.5mins; the effluent from the effluent line at the outlet of the continuous reactor flowed directly into the ice-water mixture in the product vessel.
(3) Post-treatment: after all the reaction liquid flows into the product container, moving the product container to the nitrogen protective atmosphere, adjusting the pH value to 0.8-1.2 by using 25% of sodium hydroxide solution with mass fraction, extracting for three times by using ethyl acetate, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, combining ethyl acetate phases, and concentrating to obtain a crude product; for every 10g of 5-aminopyridine-3-carboxylic acid, 300ml of ethyl acetate and 20g of anhydrous sodium sulfate are used for matching extraction.
(4) And (3) crude product treatment: dissolving the crude product in 10 mass percent NaOH solution, filtering to remove insoluble impurities, extracting impurities from the water phase by using ethyl acetate, removing the organic phase, adjusting the pH value of the water phase to 1.5-2.5 by using 25 mass percent hydrochloric acid, and filtering to obtain a pure 5-nitropyridine-3-formic acid product; 10% of NaOH solution 100ml and ethyl acetate 300ml for extraction per 10g of 5-aminopyridine-3-carboxylic acid for matching dissolution.
Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water.
Compared with the prior art, the invention has the advantages that: 1. the device is improved in the aspect of device, the device perfectly solves the problem that two reaction raw materials are not easy to prepare and can be stored, two raw materials which are enough to be applied can be prepared by slowly dripping at a proper temperature, according to practical experience, the two raw materials are not controlled in temperature during preparation, the adding speed is not slow enough, the two raw materials cannot be used, the explosion risk exists, the raw materials are further protected by configuring nitrogen atmosphere for the two feeders, and through tests, the raw materials which are not protected by the nitrogen atmosphere can be mutated or exploded, cannot be stored for a long time, and the oxygen threatens the raw materials greatly; tests prove that the nitrogen protection is significant, the yield can easily reach about 79% under the condition of relatively easy addition at present, if the raw materials are not protected by nitrogen, the reaction is incomplete, the reaction yield is insufficient, the yield is 51.2%,43%,54% and the like, even a meaningful amount of the product in the step four cannot be obtained at all, and the reaction cannot be carried out because a large amount of raw materials are oxidized by air. Secondly, the product 5-nitropyridine-3-formic acid is very active, a large amount of the product is very dangerous when existing at normal temperature, the problem cannot be solved by a batch reactor, the problem is solved by a continuous reactor, and the aggregated product can directly enter a large amount of ice-water mixture, so that the aggregation risk is also reduced to the minimum. Third, the preparation of the two feed addition rates, the feed rate ratio of the continuous reactor, and the residence time of the subject application are the result of well-studied experiments and are well-chosen by thorough experimentation and are not available without inventive effort, the setting of these values being non-obvious to those skilled in the art. Component B the oxidation of component A is not a reaction with exact stoichiometric ratios, and such practically effective ratios must be obtained by the applicant's targeted experiments, which could not have been expected beforehand.
At present, no report of the preparation of the product exists in the prior art, compared with the preparation method of the same substance, the method is exquisite, the utilization rate of raw materials is very high, the industrial production is realized with great value, the method of the invention is exquisite in design, the synthesis is effectively realized, the yield is higher, the average is more than 78%, the method has certain industrial production value and great economic value, the invention embodies strong invention conception and creativity, the good preparation effect is obtained, no similar public information can be used for reference in the prior art, and the scheme of the invention has originality. The method is repeated for more than one hundred times without any explosion or similar effect, and meaningful yield values are obtained, so that the method is a safe and effective 5-nitropyridine-3-formic acid production method, and no clear technical suggestion exists in the prior art.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a schematic view of the device.
Fig. 2 is a schematic structural view of main components of the device.
FIG. 3 is a nuclear magnetic map of the final product.
Reference numerals: 1. a first feeder, 2, a second feeder, 3, a continuous reactor, 4, a first pump, 5, a second pump, 6, a product container, 31, a first inlet, 32, a second inlet, 33, a reactor outlet, 34, a coil, 41, a first pump inlet, 42, a first pump outlet, 51, a second pump inlet, 52, a second pump outlet.
Detailed Description
The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, and the scope of the present invention will be more clearly and clearly defined.
Example 1
The system comprises a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container; the continuous reactor is provided with a first inlet, a second inlet and a reactor outlet, and the volume of a coil pipe in the continuous reactor is not less than 30ml; a liquid inlet pipe connected with an inlet of a first pump is inserted into the first feeder, and a liquid outlet pipe connected with an outlet of the first pump is connected with a first inlet; a liquid inlet pipe connected with an inlet of a second pump is inserted into the second feeder, and a liquid outlet pipe connected with an outlet of the second pump is connected with a second inlet; the effluent pipe at the outlet of the reactor is inserted into a product container. The first and second filling means are for example containers with a narrow outlet, which may for example be sealed by a sealing plug inserted into the outlet duct. The continuous reactor can be self-made or commercially available or customized, and the parts of the interior contacting with the liquid are all made of anti-corrosion coatings or anti-corrosion materials and do not react with common acid and alkali chemically. The pump is a commercially available product purchased and its flow rate can be adjusted within a desired range, for example, the speed can cover 0.1ml/min to 30ml/min.
The first feeder, the second feeder and the product container are all polytetrafluoroethylene containers; the first feeder and the second feeder are positioned in a nitrogen atmosphere; the product container has not less than 1000ml of ice-water mixture.
Further, the first pump and the second pump are continuous flow reactor pumps, and the flow path can be detached; the first feeder and the second feeder have a solvent of not less than 1L and a product container volume of not less than 5L; the continuous reactor is provided with constant temperature control, and the shell of the continuous reactor is made of stainless steel. The thermostatic control is, for example, a device that is externally sleeved on the coil, such as a thermostatic water blanket.
Example 2
A preparation method of 5-nitropyridine-3-formic acid is characterized by comprising the following steps:
(1) The preparation method comprises the following steps: the control system is that 5-aminopyridine-3-formic acid is added and dissolved in concentrated sulfuric acid at the speed of 0.4g/min at the temperature of 20 ℃, every 10g of 5-aminopyridine-3-formic acid is matched with 25ml of concentrated sulfuric acid to obtain a first raw material, and the first raw material is placed in a first feeder under the condition of keeping nitrogen atmosphere.
Every 10g of 5-aminopyridine-3-formic acid is matched with 60ml of hydrogen peroxide and 120ml of fuming sulfuric acid, the system is controlled at 20 ℃, the hydrogen peroxide is dripped into the fuming sulfuric acid at the speed of 0.4ml/min to obtain a second raw material, and the second raw material is placed into a second feeder under the condition of keeping nitrogen atmosphere; in the first step, through a plurality of tests, if a nitrogen atmosphere is not applied, the yield is greatly reduced, other changes of raw materials can occur, and when an effective product can be produced, the yield is reduced by 5-15%.
(2) The reaction steps are as follows: connecting pipelines of a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container, pumping nitrogen into the continuous reactor for a plurality of times, keeping the temperature of the continuous reactor at 25 ℃, enabling a first raw material to flow into the continuous reactor from a first inlet at a flow rate of 1.25mL/min through the first pump, enabling a second raw material to flow into the reactor from a second inlet at a flow rate of 9.0mL/min through the second pump, and enabling the residence time of a reaction liquid in the continuous reactor to be 3mins; the effluent liquid of the liquid outlet pipe at the outlet of the continuous reactor directly flows into the ice-water mixture of the product container;
(3) And (3) post-treatment: after all the reaction liquid flows into the product container, moving the product container to a nitrogen protective atmosphere, adjusting the pH value to 1 by using a sodium hydroxide solution with the mass fraction of 25%, extracting for three times by using ethyl acetate, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, combining ethyl acetate phases, and concentrating to obtain a crude product; every 10g of 5-aminopyridine-3-formic acid is extracted by 300ml of ethyl acetate and 20g of anhydrous sodium sulfate;
(4) And (3) crude product treatment: dissolving the crude product in 10 mass percent NaOH solution, filtering to remove insoluble impurities, extracting impurities from the water phase by using ethyl acetate, removing the organic phase, adjusting the pH value of the water phase to 2 by using 25 mass percent hydrochloric acid, and filtering to obtain a pure 5-nitropyridine-3-formic acid product; 10% of NaOH solution (100 ml) and ethyl acetate (300 ml) for extraction were added per 10g of 5-aminopyridine-3-carboxylic acid for dissolution. 9.5 product, yield 79.2%.
Example 3
A preparation method of 5-nitropyridine-3-formic acid is characterized by comprising the following steps:
(1) The preparation method comprises the following steps: controlling a system to add and dissolve 5-aminopyridine-3-formic acid into concentrated sulfuric acid at the speed of 0.45g/min at the temperature of 21 ℃, wherein each 10g of 5-aminopyridine-3-formic acid is matched with 26ml of concentrated sulfuric acid to obtain a first raw material, and the first raw material is placed into a first feeder under the condition of keeping a nitrogen atmosphere;
every 10g of 5-aminopyridine-3-formic acid is matched with 63ml of hydrogen peroxide and 122ml of oleum, the system is controlled at 20 ℃, the hydrogen peroxide is dripped into the oleum at the speed of 0.45ml/min to obtain a second raw material, and the second raw material is placed into a second feeder under the condition of keeping nitrogen atmosphere;
(2) The reaction steps are as follows: connecting pipelines of a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container, pumping nitrogen into the continuous reactor for a plurality of times, keeping the temperature of the continuous reactor at 26 ℃, enabling a first raw material to flow into the continuous reactor from a first inlet at a flow rate of 1.27mL/min through the first pump, enabling a second raw material to flow into the reactor from a second inlet at a flow rate of 9.2mL/min through the second pump, and enabling the retention time of a reaction liquid in the continuous reactor to be 3.5mins; the effluent liquid of the liquid outlet pipe at the outlet of the continuous reactor directly flows into the ice-water mixture of the product container;
(3) And (3) post-treatment: after all the reaction liquid flows into the product container, moving the product container to the nitrogen protective atmosphere, adjusting the pH value to 1 by using a sodium hydroxide solution with the mass fraction of 23%, extracting for three times by using ethyl acetate, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, combining ethyl acetate phases, and concentrating to obtain a crude product; every 10g of 5-aminopyridine-3-formic acid is extracted by matching with 350ml of ethyl acetate and 25g of anhydrous sodium sulfate;
(4) And (3) crude product treatment: dissolving the crude product in a 10 mass percent NaOH solution, filtering to remove insoluble impurities, extracting impurities from a water phase by using ethyl acetate, removing an organic phase, adjusting the pH value of the water phase to 2 by using 23 mass percent hydrochloric acid, and filtering to obtain a pure 5-nitropyridine-3-formic acid product; 10% of NaOH solution (100 ml) and ethyl acetate (300 ml) for extraction were added per 10g of 5-aminopyridine-3-carboxylic acid for dissolution. 9.4g of product are obtained in 78.37% yield.
Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water. The preparation dropping speed of the two raw materials, the feeding speed ratio of the continuous reactor and the residence time are the results of specially-researched tests, are better values selected by full tests and can not be obtained without creative labor, and the values are set by a person skilled in the art. Component B oxidizing component A is not a reaction with an exact stoichiometric ratio, and such a practically effective ratio must be obtained by the applicant's targeted experiments, which could not be expected beforehand.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that are not thought of through the inventive work should be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.
Claims (2)
1. A continuous preparation method of 5-nitropyridine-3-formic acid is implemented by using a continuous reaction device, and is characterized in that:
the continuous reaction device comprises a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container;
the continuous reactor is provided with a first inlet, a second inlet and a reactor outlet, and the volume of a coil pipe in the continuous reactor is not less than 30ml;
a liquid inlet pipe connected with an inlet of a first pump is inserted into the first feeder, and a liquid outlet pipe connected with an outlet of the first pump is connected with a first inlet; a liquid inlet pipe connected with an inlet of a second pump is inserted into the second feeder, and a liquid outlet pipe connected with an outlet of the second pump is connected with a second inlet; a liquid outlet pipe at the outlet of the reactor is inserted into the product container;
the first feeder, the second feeder and the product container are all polytetrafluoroethylene containers;
the first feeder and the second feeder are positioned in a nitrogen atmosphere;
the product container has not less than 1000ml of ice-water mixture;
the first pump and the second pump are continuous flow reactor pumps, and the flow path can be detached;
the first feeder and the second feeder have a solvent of not less than 1L and a product container volume of not less than 5L; the continuous reactor is provided with constant temperature control, and the shell of the continuous reactor is made of stainless steel;
the continuous preparation method of the 5-nitropyridine-3-formic acid comprises the following steps:
(1) The preparation method comprises the following steps: controlling a system to be between 15 and 25 ℃, adding and dissolving 5-aminopyridine-3-formic acid into concentrated sulfuric acid at a speed of below 0.5g/min, wherein every 10g of 5-aminopyridine-3-formic acid is matched with 25ml of concentrated sulfuric acid to obtain a first raw material, and putting the first raw material into a first feeder under the condition of keeping a nitrogen atmosphere;
every 10g of 5-aminopyridine-3-formic acid is matched with 60ml of hydrogen peroxide and 120ml of fuming sulfuric acid, the system is controlled between 15 ℃ and 25 ℃, the hydrogen peroxide is dripped into the fuming sulfuric acid at the speed of less than 0.5ml/min to obtain a second raw material, and the second raw material is placed into a second feeder under the condition of keeping nitrogen atmosphere;
(2) The reaction steps are as follows: connecting pipelines of a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container, pumping nitrogen into the continuous reactor for a plurality of times, keeping the temperature of the continuous reactor at 24-26 ℃, enabling a first raw material to flow into the continuous reactor from a first inlet at a flow rate of 1.2-1.3mL/min through the first pump, enabling a second raw material to flow into the reactor from a second inlet at a flow rate of 8.5-9.5mL/min through the second pump, and enabling the residence time of a reaction liquid in the continuous reactor to be 2.5-3.5mins; the effluent liquid of the liquid outlet pipe at the outlet of the continuous reactor directly flows into the ice-water mixture of the product container;
(3) And (3) post-treatment: after all the reaction liquid flows into the product container, moving the product container to the nitrogen protective atmosphere, adjusting the pH value to 0.8-1.2 by using 25% of sodium hydroxide solution with mass fraction, extracting for three times by using ethyl acetate, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, combining ethyl acetate phases, and concentrating to obtain a crude product; every 10g of 5-aminopyridine-3-formic acid is extracted by 300ml of ethyl acetate and 20g of anhydrous sodium sulfate;
(4) And (3) crude product treatment: dissolving the crude product in 10 mass percent NaOH solution, filtering to remove insoluble impurities, extracting impurities from the water phase by using ethyl acetate, removing the organic phase, adjusting the pH value of the water phase to 1.5-2.5 by using 25 mass percent hydrochloric acid, and filtering to obtain a pure 5-nitropyridine-3-formic acid product; 10% of NaOH solution 100ml and ethyl acetate 300ml for extraction per 10g of 5-aminopyridine-3-carboxylic acid for matching dissolution.
2. The method for preparing 5-nitropyridine-3-carboxylic acid as in claim 1, comprising the steps of:
(1) The preparation method comprises the following steps: controlling a system to be 18-22 ℃, adding and dissolving 5-aminopyridine-3-formic acid into concentrated sulfuric acid at a speed of 0.4g/min, wherein every 10g of 5-aminopyridine-3-formic acid is matched with 25ml of concentrated sulfuric acid to obtain a first raw material, and putting the first raw material into a first feeder under the condition of keeping a nitrogen atmosphere;
every 10g of 5-aminopyridine-3-formic acid is matched with 60ml of hydrogen peroxide and 120ml of fuming sulfuric acid, the system is controlled between 18 ℃ and 22 ℃, the hydrogen peroxide is dripped into the fuming sulfuric acid at the speed of 0.4ml/min to obtain a second raw material, and the second raw material is placed into a second feeder under the condition of keeping a nitrogen atmosphere;
(2) The reaction steps are as follows: connecting pipelines of a first feeder, a second feeder, a continuous reactor, a first pump, a second pump and a product container, pumping nitrogen into the continuous reactor for a plurality of times, keeping the temperature of the continuous reactor at 25 ℃, enabling a first raw material to flow into the continuous reactor from a first inlet at a flow rate of 1.25mL/min through the first pump, enabling a second raw material to flow into the reactor from a second inlet at a flow rate of 9.0mL/min through the second pump, and enabling the residence time of a reaction liquid in the continuous reactor to be 3mins; the effluent liquid of the liquid outlet pipe at the outlet of the continuous reactor directly flows into the ice-water mixture of the product container;
(3) And (3) post-treatment: after all the reaction liquid flows into the product container, moving the product container to a nitrogen protective atmosphere, adjusting the pH value to 1 by using a sodium hydroxide solution with the mass fraction of 25%, extracting for three times by using ethyl acetate, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, combining ethyl acetate phases, and concentrating to obtain a crude product; every 10g of 5-aminopyridine-3-formic acid is extracted by 300ml of ethyl acetate and 20g of anhydrous sodium sulfate;
(4) And (3) crude product treatment: dissolving the crude product in 10 mass percent NaOH solution, filtering to remove insoluble impurities, extracting impurities from the water phase by using ethyl acetate, removing the organic phase, adjusting the pH value of the water phase to 2 by using 25 mass percent hydrochloric acid, and filtering to obtain a pure 5-nitropyridine-3-formic acid product; 10% of NaOH solution (100 ml) and ethyl acetate (300 ml) for extraction were added per 10g of 5-aminopyridine-3-carboxylic acid for dissolution.
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