CN115591495A - System and method for continuously preparing medical intermediate 2-hydroxy-5-nitropyridine by using microreactor - Google Patents

System and method for continuously preparing medical intermediate 2-hydroxy-5-nitropyridine by using microreactor Download PDF

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CN115591495A
CN115591495A CN202211236968.5A CN202211236968A CN115591495A CN 115591495 A CN115591495 A CN 115591495A CN 202211236968 A CN202211236968 A CN 202211236968A CN 115591495 A CN115591495 A CN 115591495A
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microreactor
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陈光文
陈戴欣
廉应江
韩梅
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Dalian Institute of Chemical Physics of CAS
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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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • B01J19/0013—Controlling the temperature of the process
    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0053—Details of the reactor
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • 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
    • B01J2219/00004—Scale aspects
    • B01J2219/00011—Laboratory-scale plants
    • B01J2219/00013—Miniplants

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  • Pyridine Compounds (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

The invention belongs to the technical field of chemical industry, and particularly relates to a system and a method for continuously preparing a medical intermediate 2-hydroxy-5-nitropyridine by using a micro-reaction, wherein the method specifically comprises the following steps: the concentrated sulfuric acid solution of 2-aminopyridine and the mixed acid of nitric acid and sulfuric acid are mixed in a microreactor to generate 2-amino-5-nitropyridine through nitration reaction, and then the concentrated sulfuric acid solution and the mixed acid of nitric acid and sulfuric acid are mixed with the aqueous solution of sodium nitrite in the microreactor to generate diazotization and hydrolysis reaction to generate the 2-hydroxy-5-nitropyridine. The system comprises six microreactors, wherein the microreactors are connected in series, and the last microreactor is connected with a stirring kettle through a pipeline. The invention adopts the microreactor to realize the continuous preparation of the 2-hydroxy-5-nitropyridine, simplifies the process flow, has short reaction period, is easy to control the reaction and high in product selectivity, improves the safety of the preparation process, and can be used for commercially producing the medical intermediate 2-hydroxy-5-nitropyridine.

Description

System and method for continuously preparing medical intermediate 2-hydroxy-5-nitropyridine by using microreactor
Technical Field
The invention belongs to the technical field of chemical production, and particularly relates to equipment for preparing 2-hydroxy-5-nitropyridine and a using method thereof.
Background
The 2-hydroxy-5-nitropyridine can be used as an intermediate of medicines, pesticides and dyes and is used for synthesizing various pyridine compounds. The currently reported synthesis method of 2-hydroxy-5-nitropyridine is mainly characterized in that 2-aminopyridine is used as a raw material, 2-aminopyridine is added into concentrated sulfuric acid at a lower temperature in an intermittent kettle and stirred to be dissolved, then mixed acid of nitric acid and sulfuric acid is slowly dripped at a temperature lower than 30 ℃, then the temperature is raised, the mixture is stirred and reacted for 5 hours at a temperature of about 50 ℃, then sodium nitrite aqueous solution is dripped at a temperature of 0-10 ℃ at a low temperature, and the 2-hydroxy-5-nitropyridine is obtained through crystallization and separation. The above process has long reaction time and low yield.
The nitration reaction is a strong exothermic process, and the traditional batch preparation process is often accompanied by 'hot spots', on one hand, the problem of safety is caused; on the other hand, because the local temperature is too high, side reaction is easy to occur, so that the conversion rate of raw materials is low; meanwhile, the process is complex, the flow is long, the efficiency is low and the production cost is high.
Compared with a conventional batch kettle, the microreactor has the advantages of high heat and mass transfer coefficients, good mixing performance, easy temperature control, safe and controllable process and the like. The micro-reactor has excellent heat transfer and mass transfer capacity, and can realize the uniform mixing of materials and the high-efficiency transfer of reaction heat. The efficient mass and heat transfer characteristics of the microreactor are utilized to realize the nitration of 2-aminopyridine into 2-amino-5-nitropyridine, so that the 2-aminopyridine and sodium nitrite are subjected to diazotization reaction and the heat in the hydrolysis reaction process is rapidly transferred, the occurrence of side reactions is reduced, and the process safety and selectivity are improved. The microreactor is adopted to prepare the 2-hydroxy-5-nitropyridine, and a new method and means are provided for solving the problems existing in the preparation process of the batch still.
Disclosure of Invention
In order to solve the problems of more side reactions, long reaction time, easy formation of hot spots in the process, temperature runaway and safety in industrial production of 2-hydroxy-5-nitropyridine by using an intermittent kettle. The mass transfer and heat transfer efficiency of the micro-reactor is 1 to 3 orders of magnitude higher than that of a kettle type reactor, and the heat generated by the reaction can be rapidly taken away, so that the probability of accidents is reduced. Aiming at the problems in the process of preparing 2-hydroxy-5-nitropyridine by using the batch still, the invention provides a system for continuously preparing 2-hydroxy-5-nitropyridine by using the microreactor, which can enhance the mass and heat transfer process of the reaction by using the high-efficiency mixing capability and excellent mass and heat transfer performance of the microreactor, and meanwhile, the combination of the microreactor and the stirred tank improves the production efficiency, remarkably reduces the volume and reaction time of the reactor, improves the reaction selectivity and process safety, and reduces the occurrence of side reactions. Compared with the traditional batch preparation, the method can realize the continuous production of the 2-hydroxy-5-nitropyridine, has high conversion rate of raw materials, less side reactions and product yield of more than 53 percent (preferably 65 percent), and has important commercial value.
In one aspect, the invention provides a system for continuously preparing a medical intermediate 2-hydroxy-5-nitropyridine by using a sleeve-type microreactor, which comprises six sleeve-type microreactors, wherein the six sleeve-type microreactors are connected in series through a pipeline, each sleeve-type microreactor is internally provided with a heat exchanger, and the last sleeve-type microreactor is connected with a stirred tank (collection tank).
The six sleeve-type microreactors are a first-stage microreactor, a second-stage microreactor, a third-stage microreactor, a fourth-stage microreactor, a fifth-stage microreactor and a sixth-stage microreactor in sequence along the flow direction of a material, and the sixth-stage microreactor is connected with the stirred tank;
the micro-reactor is a sleeve type micro-channel reactor.
Preferably, the first-stage microreactor, the second-stage microreactor and the fifth-stage microreactor are sleeve-type microreactors with the inner diameter of 4-6 mm, the length of a tube of 50-60 cm and the volume of an inner tube of 6.5-8.5 ml, and the inner parts of the sleeve-type microreactors are filled with fillers with the porosity of 85-97 percent, and the actual reaction volume is 6-7.5 ml; the third-stage micro-reactor, the fourth-stage micro-reactor and the sixth-stage micro-reactor are sleeve type micro-reactors with the inner diameter of 4-6 mm, the length of a tube of 60-75 cm and the volume of an inner tube of 8-11 ml, the inner parts of the sleeve type micro-reactors are filled with fillers with the porosity of 85-97 percent, and the actual reaction volume is 8-10 ml.
Preferably, the packing is a wire mesh packing, such as a stainless steel mesh packing.
Preferably, the inner tube of the double-tube microreactor is a reaction tube, and the outer tube of the double-tube microreactor is a heat exchanger.
Preferably, the different-stage sleeve-type microreactors are connected through a pipeline with the inner diameter of 2-4 mm and the length of each pipeline of 10-50 cm.
Preferably, the collection kettle is a general jacketed glass kettle or a stainless steel kettle, and the temperature in the kettle is controlled by an external refrigerant.
On the other hand, the invention provides a method for preparing 2-hydroxy-5-nitropyridine by using the system, wherein a concentrated sulfuric acid solution of 2-aminopyridine is mixed with mixed nitric-sulfuric acid in a first-stage microreactor to carry out nitration reaction, reaction liquid is formed and then is continuously mixed in a second-stage microreactor, a third-stage microreactor, a fourth-stage microreactor and a fifth-stage microreactor to carry out nitration reaction to generate 2-amino-5-nitropyridine, after the nitration reaction is completed, the reaction liquid is mixed with a sodium nitrite aqueous solution in a sixth-stage microreactor to carry out diazotization and hydrolysis reaction to generate 2-hydroxy-5-nitropyridine, finally the completely reacted material enters a stirring kettle, is further cooled, neutralized and crystallized by ammonia water, and is filtered to obtain the product 2-hydroxy-5-nitropyridine.
Preferably, the reaction temperature of the microreactor is controlled to be 10-80 ℃.
Preferably, firstly, preparing raw material liquid, including preparing concentrated sulfuric acid solution, mixed nitric acid and sulfuric acid and sodium nitrite aqueous solution, wherein the mass concentration of the concentrated sulfuric acid solution of 2-aminopyridine is 5-20 wt%, preferably 10wt%; in the nitric-sulfuric mixed acid solution, the molar ratio of fuming nitric acid to concentrated sulfuric acid is 1-5, and the molar ratio of nitric acid to sulfuric acid is preferably 1; the concentration of the sodium nitrite aqueous solution is 10wt% -40 wt%, preferably 25%; the molar ratio of the 2-aminopyridine to the sodium nitrite is 1.05-1.25, and the preferred molar ratio is 1.
Preferably, the flow rate of the concentrated sulfuric acid solution of the 2-aminopyridine is 4.5-5.5 ml/min, and the flow rate of the mixed acid of the nitric acid and the sulfuric acid is 1.2-1.6 ml/min; the flow rate of the sodium nitrite water solution is 2.4-3.2 ml/min.
Preferably, the concentrated sulfuric acid solution of the 2-aminopyridine and the mixed acid are mixed and reacted in the first-stage reactor and the second-stage reactor, and the molar ratio of the 2-aminopyridine to the nitric acid is 1.0-1.15; the temperature of the first-stage reactor and the second-stage reactor is 10-60 ℃, and the preferable reaction temperature is 30 ℃.
Preferably, the medium-mixing reaction liquid is rearranged and reacted in the third-stage microreactor and the fourth-stage microreactor 4, the reaction temperature is 50-80 ℃, and the reaction temperature is preferably 60 ℃.
Mixing and reacting a sodium nitrite aqueous solution and a reaction solution in a sixth-stage microreactor, wherein the molar ratio of 2-aminopyridine to sodium nitrite is 1.05-1.25, and the preferred molar ratio is 1.15; the temperature of the fifth-stage reactor and the sixth-stage reactor is 20-50 ℃, and the preferable reaction temperature is 40 ℃.
Preferably, the total residence time of the reaction mass in the microreactor is 4-8 min, preferably 6min.
Preferably, the collection kettle is adjusted to pH 5-6 with ammonia water, the crystallization temperature is 0-15 ℃, and the crystallization temperature is preferably 5 ℃.
The method for continuously preparing the 2-hydroxy-5-nitropyridine by using the microreactor specifically comprises the following steps:
(1) Preparation of concentrated sulfuric acid solution of 2-aminopyridine: slowly adding a certain amount of 2-aminopyridine into concentrated sulfuric acid at room temperature, and stirring to completely dissolve the 2-aminopyridine to form a concentrated sulfuric acid solution of the 2-aminopyridine as a raw material A; wherein the mass concentration of the concentrated sulfuric acid solution of the 2-aminopyridine is 5 to 20 weight percent;
(2) Preparing a mixed acid solution of nitric acid and sulfuric acid: slowly adding a certain amount of fuming nitric acid into concentrated sulfuric acid at room temperature to form a nitric-sulfuric acid mixed acid solution serving as a raw material B, wherein the molar ratio of the nitric acid to the sulfuric acid is 1;
(3) Preparing a sodium nitrite aqueous solution: at room temperature, adding a certain amount of sodium nitrite into water, stirring and dissolving to form a sodium nitrite aqueous solution as a raw material C, wherein the mass concentration of the sodium nitrite aqueous solution is 10-40 wt%;
(4) Two materials A (concentrated sulfuric acid solution of 2-aminopyridine) and B (nitric-sulfuric acid mixed solution) are input into the micro-reactor through two continuous conveying devices, are mixed in the first-stage reactor and the second-stage micro-reactor to carry out nitration reaction, and the reaction temperature of the section is controlled to be 10-40 ℃ through a heat exchanger arranged in the micro-reactor; and the reacted materials enter a third-stage micro reactor and a fourth-stage micro reactor.
(5) The material reacted by the second-stage micro-reactor enters a third-stage micro-reactor and a fourth-stage micro-reactor, the reaction temperature of the reactors is controlled to be 50-80 ℃ through a heat exchanger arranged in the micro-reactor, and the material enters a fifth-stage micro-reactor and a sixth-stage micro-reactor after the reaction is finished.
(6) And the materials reacted by the fourth-stage microreactor enter a fifth-stage microreactor and a sixth-stage microreactor, the materials are continuously mixed in the fifth-stage microreactor until the reaction is complete, the materials are mixed with the raw material C in the sixth-stage microreactor, the reaction temperature of the fifth-stage microreactor and the reaction temperature of the sixth-stage microreactor are controlled to be 20-50 ℃ through a heat exchanger arranged in the microreactors, and the materials enter a collection kettle after the reaction is finished.
(7) And (3) feeding the completely reacted materials into a collection kettle, cooling to 0-15 ℃, neutralizing with ammonia water, adjusting the pH value to 5-6, crystallizing, and performing suction filtration to obtain the product 2-hydroxy-5-nitropyridine.
The invention has the beneficial effects that: (1) The invention adopts the microreactor to realize the continuous preparation of the microreactor for the 2-hydroxy-5-nitropyridine; (2) The micro-reactor has small volume, simplifies the process flow and is easy to amplify; (3) Compared with an intermittent reaction kettle, the preparation method adopts a micro-reactor for continuous preparation, and has the advantages of high mixing efficiency, high mass and heat transfer rate, controllable temperature in the reaction process, high product yield and the like; (4) The reaction liquid can flow out of the reactor after being mixed and reacted in the reactor quickly, so that the retention time of the reaction liquid in the reactor is shortened, side reactions caused by 'hot spots' are avoided, and the selectivity of the product is improved; (5) The high-efficiency mass and heat transfer characteristics of the microreactor ensure that the production process is high in safety, and the safety risk caused by 'hot spots' in the reaction process is reduced; (6) The liquid holdup in the micro-reactor is low, and compared with the traditional kettle type reactor, the severity of accidents caused by a large amount of materials is avoided.
The characteristic advantages of the invention are apparent from the description of the following examples of embodiment
Drawings
FIG. 1 is a flow chart of the continuous preparation of 2-hydroxy-5-nitropyridine according to the present invention.
In the figure: the device comprises a first-stage microreactor 1, a second-stage microreactor 2, a third-stage microreactor 3, a fourth-stage microreactor 4, a fifth-stage microreactor 5, a sixth-stage microreactor 6, a delivery pump 7 and a stirring kettle 8.
Detailed Description
In order that those skilled in the art will better understand the present invention, the following examples are provided to further illustrate the present invention, but the scope of the present invention is not limited by these examples. The reagents used in the examples are commercially available reagents, and the technical means used in the examples are conventional means known to those skilled in the art.
EXAMPLE 1 continuous preparation of 2-hydroxy-5-nitropyridine in microreactor
As shown in figure 1, a system for continuously preparing a medical intermediate 2-amino-5-nitropyridine by using sleeve-type microreactors comprises six sleeve-type microreactors, wherein the six sleeve-type microreactors are connected in series through a pipeline, each sleeve-type microreactor is internally provided with a micro-heat exchanger, and the last reactor is connected with a stirred tank; the six sleeve-type microreactors are a first-stage microreactor 1, a second-stage microreactor 2, a third-stage microreactor 3, a fourth-stage microreactor 4, a fifth-stage microreactor 5 and a sixth-stage microreactor 6 in sequence along the flow direction of materials, the sixth-stage microreactor 6 is connected with a stirred tank 8, the first-stage microreactor 1 is connected with two material conveying pumps 7, the sixth-stage microreactor 6 is connected with one material conveying pump 7, and the three material conveying pumps 7 are all advection pumps; and the six microreactors are all sleeve-type microchannel reactors. The first-stage microreactor 1, the second-stage microreactor 2 and the fifth-stage microreactor 5 are sleeve-type microreactors with the inner diameter of 4mm, the length of a pipe of 55cm and the volume of an inner pipe of 6.9ml, 316 stainless steel wire mesh fillers are filled in the sleeve-type microreactors, the porosity is 95 percent, and the actual reaction volume is 6.5ml; the third-stage microreactor 3, the fourth-stage microreactor 4 and the sixth-stage microreactor 6 are sleeve-type microreactors with the inner diameter of 4mm, the length of a tube of 70cm and the volume of an inner tube of 8.8ml, and wire mesh packing, the porosity of 95 percent and the actual reaction volume of 8.4ml are filled in the sleeve-type microreactors. The inner pipe of the double-pipe micro-reactor is a reaction pipe, and the outer pipe of the double-pipe micro-reactor is a heat exchanger. The different stages of micro reactors are connected through plastic hoses with the inner diameter of 2mm, and the length of the plastic hoses is 25cm. The stirring kettle 6 is a general jacket type glass kettle, and the temperature in the kettle is controlled by an external coolant.
The method for continuously preparing the 2-hydroxyl-5-nitropyridine by utilizing the microreactor comprises the following specific steps:
(1) Slowly adding 2-aminopyridine (0.903 mol, 85g) into 765g concentrated sulfuric acid (98 wt%) in batches at room temperature, and stirring to completely dissolve the 2-aminopyridine to obtain a concentrated sulfuric acid solution of the 2-aminopyridine as a raw material phase A; wherein the mass concentration of the 2-aminopyridine is 10wt%.
(2) At room temperature, 64.3g (1.0 mol, 98wt%) of nitric acid was slowly added to 200g (2.0 mol, 98wt%) of concentrated sulfuric acid, and stirred to form a nitric-sulfuric mixed acid solution having a molar ratio of nitric acid to sulfuric acid of 1.
(3) Slowly adding sodium nitrite (0.725mol, 50g) into 150g of water at room temperature, stirring and completely dissolving to obtain a sodium nitrite aqueous solution serving as a raw material phase C; wherein the mass concentration of the sodium nitrite is 25wt%.
(4) Three raw material phases A (5.5 ml/min), B (1.5 ml/min) and C (2.8 ml/min) are input into the microchannel reactor through three advection pumps, the reactor is controlled through an external circulation water bath, and two materials A and B are intensively mixed and reacted in the first-stage microreactor 1 and the second-stage microreactor 2. The reaction materials further enter a third-stage microreactor 3 and a fourth-stage microreactor 4 to be mixed and react; the reaction materials further enter a fifth-stage microreactor 5 and a sixth-stage microreactor 6, and the reaction materials C are intensively mixed and reacted in the sixth-stage microreactor 6; meanwhile, the reaction temperature of the first-stage microreactor 1 and the second-stage microreactor 2 is controlled to be 30 ℃, the reaction temperature of the third-stage microreactor 3 and the reaction temperature of the fourth-stage microreactor 4 are controlled to be 60 ℃, and the reaction temperature of the fifth-stage microreactor 5 and the reaction temperature of the sixth-stage microreactor 6 are controlled to be 40 ℃. The total residence time of the material in the microreactor was 6min. And (3) after the reaction is completed, allowing the product to enter a collection kettle, cooling to 5 ℃, stirring, dropwise adding ammonia water to adjust the pH to 5-6, allowing a large amount of light yellow precipitate to appear, and performing suction filtration to obtain the product 2-hydroxy-5-nitropyridine. Analysis by HPLC: the conversion rate of the raw material is 99.5 percent, and the product yield is 80.2 percent.
Examples 2-6 continuous preparation of 2-hydroxy-5-nitropyridine in a microreactor
The same system and method for continuously preparing 2-hydroxy-5-nitropyridine as in example 1 was used. In the reaction process, concentrated sulfuric acid solution (5.5 ml/min) of 2-aminopyridine, mixed acid (1.5 ml/min), sodium nitrite aqueous solution (2.7 ml/min), total retention time is 6min, the molar ratio of 2-aminopyridine to nitric acid is 1, 1.10, the molar ratio of 2-aminopyridine to sodium nitrite is 1.
TABLE 1 influence of different temperatures of the microchannel reactor on the reaction
Figure BDA0003883454450000061
Examples 7-9 continuous preparation of 2-hydroxy-5-nitropyridine in microreactor
The same system and method for continuously preparing 2-hydroxy-5-nitropyridine as in example 1 was used. In the reaction process, concentrated sulfuric acid solution (5.5 ml/min) of 2-aminopyridine, mixed acid (1.5 ml/min), sodium nitrite aqueous solution (2.7 ml/min), total residence time is 6min, the molar ratio of 2-aminopyridine to nitric acid is 1.10, the molar ratio of 2-aminopyridine to sodium nitrite is 1.12, the reaction temperature of the third-stage microreactor 3 and the fourth-stage microreactor 4 is 60 ℃, the reaction temperature of the fifth-stage microreactor 5 and the sixth-stage microreactor 6 is 40 ℃, the temperature of the sleeve-type microreactors 1 and 2 is different, and the specific results are respectively shown in table 2.
TABLE 2 influence of different temperatures of the microchannel reactor on the reaction
Figure BDA0003883454450000071
Examples 10-12 continuous preparation of 2-hydroxy-5-nitropyridine in a microreactor
The same system and method for continuously preparing 2-hydroxy-5-nitropyridine as in example 1 was used. In the reaction process, the temperature of the sleeve type microreactor 1 and the sleeve type microreactor 2 is 45 ℃, the temperature of the sleeve type microreactor 3 and the temperature of the sleeve type microreactor 4 are 60 ℃, the temperature of the sleeve type microreactor 5 and the temperature of the sleeve type microreactor 6 are 40 ℃, the concentrated sulfuric acid solution (5.5 ml/min) of 2-aminopyridine and the mixed acid of nitric acid and sulfuric acid (1.5 ml/min) are adopted. The molar ratio of the 2-aminopyridine to the nitric acid is 1.10, the different molar ratios of the 2-aminopyridine and the sodium nitrite are controlled by adjusting the sample amount of the sodium nitrite aqueous solution, and the specific results are respectively shown in table 3.
TABLE 3 influence of different molar ratios of 2-hydroxy-5-nitropyridine and nitric acid on the reaction
Figure BDA0003883454450000072
The system for continuously preparing the 2-hydroxy-5-nitropyridine by the microreactor utilizes the high-efficiency mass and heat transfer characteristics of the microreactor, effectively solves the production safety problem caused by 'hot spots' in the existing method, improves the selectivity of the product, reduces the occurrence of side reactions, realizes the continuous production of the 2-hydroxy-5-nitropyridine microreactor, and has high commercial development value.
It will be understood by those skilled in the art that various modifications and changes may be made to the present invention. Such modifications and adaptations are intended to be within the scope of the present invention as defined in the following claims.

Claims (10)

1. A system for continuously preparing a medical intermediate 2-hydroxy-5-nitropyridine in a sleeve-type microreactor is characterized by comprising: six sleeve-type microreactors are connected in series through a pipeline, each sleeve-type microreactor is provided with a heat exchanger, and the last sleeve-type microreactor is connected with a stirring kettle through a pipeline;
the six sleeve-type microreactors are a first-stage microreactor, a second-stage microreactor, a third-stage microreactor, a fourth-stage microreactor, a fifth-stage microreactor and a sixth-stage microreactor in sequence along the flow direction of materials.
2. The system of claim 1, wherein the first-stage microreactor and the second-stage reactor are sleeve-type microreactors with the inner diameter of 4-6 mm and the tube length of 50-60 cm, the first-stage microreactor and the second-stage reactor are internally filled with fillers, and the porosity is 85-97%; the third-stage microreactor and the fourth-stage reactor are sleeve-type microreactors with the inner diameter of 4-6 mm and the tube length of 60-75 cm, the third-stage microreactor and the fourth-stage reactor are internally filled with fillers, and the porosity is 85-97%; the inner pipe of the double-pipe micro-reactor is a reaction pipe, and the outer pipe of the double-pipe micro-reactor is a heat exchanger; the different stages of micro reactors are connected through a pipeline with the inner diameter of 2-4 mm and the length of 10-50 cm; the stirring kettle is a jacketed glass kettle or a stainless steel kettle.
3. The system of claim 1, wherein the filler is a wire mesh filler.
4. A method for preparing 2-hydroxy-5-nitropyridine using the system of any of claims 1 to 3, wherein: mixing a concentrated sulfuric acid solution of 2-aminopyridine and a mixed acid of nitric acid and sulfuric acid in the first-stage microreactor to initiate a reaction, and continuously mixing the formed reaction liquid in the second-stage microreactor, the third-stage microreactor, the fourth-stage microreactor and the fifth-stage microreactor for reaction until the nitration reaction is complete; and then mixing the reaction liquid with a sodium nitrite aqueous solution in a sixth-stage microreactor to perform diazotization and hydrolysis reaction, then feeding the mixture into a stirring kettle, cooling the mixture in the stirring kettle, neutralizing the mixture with ammonia water, crystallizing, and filtering to obtain the 2-hydroxy-5-nitropyridine.
5. The method of claim 4, wherein: the method comprises the following steps:
(1) Respectively preparing a concentrated sulfuric acid solution and a mixed acid solution of nitric acid and sulfuric acid of 2-aminopyridine and a sodium nitrite aqueous solution;
(2) Conveying the concentrated sulfuric acid solution of the 2-aminopyridine and the mixed acid of the nitric acid and the sulfuric acid respectively to a first-stage microreactor for mixing and reaction by two continuous conveying devices, and controlling the temperature of the first-stage microreactor by a heat exchanger;
(3) The material reacted by the first-stage microreactor enters a second-stage microreactor, a third-stage microreactor, a fourth-stage microreactor and a fifth-stage microreactor to be continuously mixed until the reaction is complete, and the temperature of the second-stage microreactor, the third-stage microreactor, the fourth-stage microreactor and the fifth-stage microreactor is controlled by a heat exchanger;
(4) The material reacted by the fifth-stage microreactor enters a sixth-stage microreactor to be mixed with the sodium nitrite aqueous solution, the reaction is complete, and the temperature of a system of the sixth-stage microreactor is controlled through a heat exchanger;
(5) And (3) cooling the material after the reaction is completed in a stirring kettle, neutralizing with ammonia water, crystallizing, and filtering to obtain the product 2-hydroxy-5-nitropyridine.
6. The method according to claim 4 or 5, wherein the mass concentration of the sulfuric acid solution of the 2-aminopyridine is 5-20 wt%; the molar ratio of nitric acid to concentrated sulfuric acid in the nitric-sulfuric mixed acid solution is 1.0-1.15; the molar ratio of the 2-aminopyridine to the nitric acid is 1.0-1.15; the concentration of the sodium nitrite aqueous solution is 10wt% -40 wt%; the molar ratio of the 2-aminopyridine to the sodium nitrite is 1.05-1.25.
7. The method of claim 4 or 5, wherein the microreactor reaction temperature is controlled to be between 10 ℃ and 80 ℃; wherein the reaction temperature of the first-stage reactor and the second-stage reactor is preferably 10-40 ℃; the reaction temperature of the third-stage reactor and the fourth-stage reactor is preferably 50-80 ℃; the reaction temperature of the fifth-stage reactor and the sixth-stage reactor is preferably 20-50 ℃.
8. The process for preparing 2-hydroxy-5-nitropyridine according to claim 4 or 5, characterized in that the total residence time of the reaction mass in the microreactor is comprised between 4 and 8min.
9. The process for producing 2-hydroxy-5-nitropyridine according to claim 4 or 5, wherein the pH in the stirred tank is adjusted to 5 to 6 with ammonia and the crystallization temperature is 0 to 15 ℃.
10. The method for preparing 2-hydroxy-5-nitropyridine according to claim 4 or 5, characterized in that the flow rate of the concentrated sulfuric acid solution of 2-aminopyridine is 4.5 to 5.5ml/min, and the flow rate of the mixed nitric and sulfuric acid is 1.2 to 1.6ml/min; the flow rate of the sodium nitrite water solution is 2.4-3.2 ml/min.
CN202211236968.5A 2022-10-10 2022-10-10 System and method for continuously preparing medical intermediate 2-hydroxy-5-nitropyridine by using microreactor Pending CN115591495A (en)

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