Method for synthesizing oxolinic acid and intermediate thereof by using microchannel reactor

Abstract

The invention discloses a method for synthesizing oxolinic acid and an intermediate thereof by using a micro-channel reactor, and belongs to the technical field of quinolone medicine synthesis in organic synthesis. According to the method, oxolinic acid is synthesized from N-ethyl piperonamine in a solvent-free end-to-end mode in the microchannel reactor, carbonization of reactants and products is avoided through continuous flowing, and the risk that experimenters make direct contact with concentrated sulfuric acid is avoided. According to the invention, the ultrasonic-assisted micro-channel reactor is utilized to synthesize the intermediate nitrobenzodioxole of oxolinic acid, and mixing of water and oil phases is greatly increased through a micro-scale effect; meanwhile, due to the mechanical effect and the cavitation effect brought by ultrasonic assistance, the pipeline is prevented from being blocked by solids, the reaction time is greatly shortened, and the total time is only 31 min. According to the microchannel reaction technology, the green solvent is adopted as a medium, the reaction time can be effectively shortened, the potential safety hazard of production is greatly reduced, and the method is suitable for synthesizing oxolinic acid and intermediates thereof.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and specifically to a method for synthesizing oxaquinic acid and its intermediates using a microchannel reactor. Background Technology

[0002] Oxolinic acid (OA), also known as oxolinic acid, has the chemical name 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinolinecarboxylic acid. Its molecular formula is C2. 13 H 11 NO5 has the following chemical structural formula:

[0003] Oxaquinic acid belongs to the first-generation quinolone bactericide class and has a wide range of applications. Oxaquinic acid targets bacterial deoxynucleotides (DNA), inhibiting DNA gyrase and causing irreversible damage to chromosomes, thus preventing bacterial cell division and achieving its antibacterial effect. Oxaquinic acid exhibits good antibacterial activity against common fish pathogens, such as *Vibrio scutellariae*, *Aeromonas hydrophila*, *Edwards*, *Aeromonas salmonii*, and *Pseudomonas aeruginosa*. It is commonly used to treat bacterial diseases in fish and shrimp. Its MIC (microinhibition concentration) against common aquatic animal pathogens is 3.8–5.6 μg / mL, making it one of the best drugs for treating aquatic animal diseases. It is widely used in the EU, the US, South America, East Asia, and Southeast Asia.

[0004] The literature reports that the methods for synthesizing oxaquinic acid can be mainly divided into three categories: Route (1)

[0005] This synthetic route has few steps, bromination is easy to carry out, and ammonolysis does not produce N-dimethyl substituted or unsubstituted impurities, making separation relatively simple. However, the bromination reaction results in unavailable starting materials, easily corroded equipment, significant HBr contamination, and complicated post-processing. Furthermore, ammonolysis is difficult to perform, requiring high temperatures and pressures, demanding sophisticated equipment, and resulting in a low yield of 74%.

[0006] Route (2)

[0007] This synthetic route employs a hydrogenation reduction method, which minimizes environmental pollution and yields high purity of piperidine. However, when acetaldehyde is used as the alkylating agent, it requires reduction followed by dropwise addition under pressure, making it difficult to control during production, resulting in numerous side reactions and low yields. Therefore, it lacks practical significance for industrial production.

[0008] Route (3)

[0009] The reaction route is long, and the method is complex, wherein many dangerous reactions and harsh conditions are involved. Among them, the nitration reaction belongs to a dangerous reaction process, which has the characteristics of fast reaction speed and large amount of heat release. In industrial mass production, it is easy to have a temperature runaway phenomenon, resulting in uneven reaction, and even serious safety hazards such as explosion. The method using high temperature and high pressure catalytic hydrogenation uses cheap hydrogen as a reducing agent and uses a metal catalyst. Since the catalytic hydrogenation reaction belongs to a typical gas-liquid-solid three-phase reaction, the low mixing and exchange efficiency between the three phases determines that the reaction must be carried out at high temperature and high pressure to ensure the complete conversion of the raw materials. The flammable and explosive properties of hydrogen make it possible to have a large production safety accident if the reaction is dangerous, and the operation requirements are extremely high, and the equipment safety approval is very difficult. In addition, this path also needs to react under the condition of high temperature of diphenyl ether, and the reaction condition is harsh, the reaction temperature is not easy to control, and the energy consumption is great, which is not suitable for industrial production.

[0010] In order to overcome the above difficulties, the synthesis of oxolinic acid is completed by using micro-channel or micro-reactor technology, and the synthesis method has not been reported in the literature so far. SUMMARY

[0011] In order to solve the problems of great harm of reagent, troublesome post-treatment, harsh reaction conditions and easy occurrence of severe explosion in traditional synthesis reaction, the application provides a method for synthesizing oxolinic acid and intermediates thereof by using a micro-channel reactor. The synthesis method provided by the application is intrinsically safe and green. The method uses micro-channel synthesis technology throughout the process, which significantly shortens the reaction time, improves the reaction rate and product purity, and avoids the use of non-green and difficult-to-handle solvents, thereby reducing waste generation.

[0012] In a first aspect, the application provides a method for synthesizing oxolinic acid by using a micro-channel reactor, comprising:

[0013] N-ethyl piperamine (formula 1) and ethoxymethylene malonic acid diethyl ester (formula 2) are pumped into a first micro-channel reactor for mixing reaction to obtain a first reaction liquid; The first reaction liquid and acetic anhydride are pumped into a T-shaped mixer for sufficient mixing, and then pumped into a first reaction device, and concentrated sulfuric acid is pumped in at the same time. After sufficient mixing, a three-phase mixed liquid is obtained, which is pumped into a second micro-channel reactor for complete reaction to obtain a second reaction liquid; The second reaction liquid is directly pumped into a second reaction device containing water for heat preservation reaction, and oxolinic acid (formula 5) is obtained after post-treatment.

[0014] Further, the flow rate of N-ethylpiperamine is 0.2 mL / min~2 mL / min, preferably 0.24 mL / min, 0.3 mL / min, 0.4 mL / min, 0.5 mL / min, 0.8 mL / min, 1 mL / min, 1.5 mL / min, 2 mL / min.

[0015] Further, the flow rate of ethoxymethyl methyl ester is 0.2 mL / min~2 mL / min, preferably 0.24 mL / min, 0.3 mL / min, 0.4 mL / min, 0.5 mL / min, 0.8 mL / min, 1 mL / min, 1.5 mL / min, 2 mL / min.

[0016] Further, the molar ratio of N-ethylpiperamine and ethoxymethylidene malonic acid diethyl ester is 1: (1.05~1.5), preferably 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.

[0017] Further, the residence time of the mixing reaction in the first micro-channel reactor is 5 min~20 min, preferably 5 min, 10 min, 14 min, 15 min, 16 min, 18 min, 20 min.

[0018] Further, the temperature of the mixing reaction in the first micro-channel reactor is 90 °C~130 °C, preferably 90 °C, 100 °C, 110 °C, 120 °C, 130 °C.

[0019] Further, the back pressure valve pressure of the mixing reaction in the first micro-channel reactor is 0.5 MPa~2 MPa; preferably 0.5 MPa~1.5 MPa; preferably 0.5 MPa, 0.8 MPa, 1 MPa, 1.5 MPa, 2 MPa.

[0020] Further, the molar ratio of the first reaction solution: acetic anhydride: concentrated sulfuric acid is 1: (1.5~2.5): (0.75~1.5), preferably 1:1.5:0.73, 1:1.79:0.93, 1:2:1, 2.5:1.5, wherein the molar ratio of the first reaction solution is the molar amount of N-ethylpiperamine input; the feeding ratio of concentrated sulfuric acid is calculated based on the content of H2SO4. The mass fraction of concentrated sulfuric acid used in the present application is 98%.

[0021] Further, the flow rate of the first reaction liquid is 0.04 mL / min~4 mL / min, preferably 0.05 mL / min, 0.1 mL / min, 0.2 mL / min, 0.287 mL / min, 0.3 mL / min, 0.5 mL / min, 1 mL / min, 1.5 mL / min, 2 mL / min, 2.5 mL / min, 3 mL / min, 3.5 mL / min, 4 mL / min.

[0022] Further, the flow rate of the acetic anhydride is 0.1 mL / min~0.5 mL / min, preferably 0.1 mL / min, 0.2 mL / min, 0.25 mL / min, 0.287 mL / min, 0.3 mL / min, 0.35 mL / min, 0.4 mL / min, 0.5 mL / min.

[0023] Further, the flow rate of the concentrated sulfuric acid is 0.06 mL / min~0.2 mL / min, preferably 0.06 mL / min, 0.07 mL / min, 0.08 mL / min, 0.085 mL / min, 0.09 mL / min, 0.1 mL / min, 0.15 mL / min, 0.2 mL / min.

[0024] Further, the flow rate of the second reaction liquid is 0.2 mL / min~2 mL / min, preferably 0.2 mL / min, 0.5 mL / min, 0.8 mL / min, 1 mL / min, 1.5 mL / min, 2 mL / min.

[0025] Further, the reaction temperature in the second micro-channel reactor is 70 °C~150 °C, preferably 70 °C, 80 °C, 90 °C, 100 °C, 110 °C, 120 °C, 130 °C, 140 °C, 150 °C.

[0026] Further, the reaction residence time in the second micro-channel reactor is 3 min~10 min, preferably 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min.

[0027] Further, the reaction pressure in the second micro-channel reactor is 0.5 MPa~1.5 MPa; preferably 0.5 MPa, 0.8 MPa, 1 MPa, 1.2 MPa, 1.5 MPa.

[0028] Further, the volume of the water is 1-5 times of the volume of the second reaction liquid, preferably 1 times, 2 times, 3 times, 4 times, or 5 times.

[0029] Further, the temperature of the heat preservation is 60-100 °C, preferably 70 °C, 80 °C, 90 °C, or 100 °C.

[0030] Further, the heat preservation time is 2-8 h, preferably 2 h, 4 h, 6 h, or 8 h.

[0031] Further, after the heat preservation reaction is completed, the post-treatment process is as follows: the reaction liquid is subjected to suction filtration, washed with water and ethanol, and the filter cake is placed in a forced air drying oven for drying to obtain a solid. Preferably, the drying refers to drying at 60-100 °C for 2-8 h, and further preferably, drying at 80 °C for 8 h.

[0032] Further, the first micro-channel reactor, the T-shaped mixer, and the second micro-channel reactor can be connected or not connected to each other in any combination; in some embodiments, the micro-channel reaction system is selected from one of the following modes: Mode i, the first micro-channel reactor, the T-shaped mixer, and the second micro-channel reactor are not connected to each other; Mode ii, the first micro-channel reactor, the T-shaped mixer, and the second micro-channel reactor are directly connected to each other, and the T-shaped mixer and the second micro-channel reactor are not connected to each other; Mode iii, the first micro-channel reactor and the T-shaped mixer are not connected to each other, and the T-shaped mixer and the second micro-channel reactor are directly connected in series to form an integral whole; Mode iv, the first micro-channel reactor, the T-shaped mixer, and the second micro-channel reactor are directly connected in series to form an integral whole.

[0033] Compared with the traditional synthesis method, the synthesis process of the inventive oxiquinac does not need a reaction solvent, and the reaction is directly performed by the reactants, which greatly reduces the production cost, avoids the direct contact between the experimental personnel and concentrated sulfuric acid in the experimental process, is intrinsically safe, improves the space-time yield, and reduces the risk of carbonization of the reactants. In addition, the entire process is an end-to-end synthesis performed by N-ethyl-3,4-methylenedioxyaniline, which simplifies the operation process, and the reaction time of the ester hydrolysis step is only 19 min, the reaction efficiency is high, the purity of the obtained product is high, and the space-time yield is 23.2 g / h.

[0034] In a second aspect, the application provides a method for synthesizing N-ethyl piperamine by using a micro-channel reactor, comprising: The mixture of nitro-piperonyl ring and acetaldehyde in organic solvent is mixed, preheated, and then the mixture is respectively delivered into the fixed bed reaction module of the third micro-channel reactor, and the mixture is mixed and reacted under the action of the catalyst to obtain N-ethyl piperonylamine.

[0035] Further, the concentration of nitro-piperonyl ring in the organic solvent is 0.02 mol / L-0.3 mol / L; preferably 0.05 mol / L-0.2 mol / L, preferably 0.05 mol / L-0.3 mol / L; preferably 0.024 mol / L, 0.03 mol / L, 0.06 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L.

[0036] Further, the concentration of acetaldehyde in the organic solvent is 0.05 mol / L-0.45 mol / L; preferably 0.05 mol / L, 0.06 mol / L, 0.07 mol / L, 0.072 mol / L, 0.08 mol / L, 0.09 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L.

[0037] Further, the organic solvent is at least one selected from ethanol, acetonitrile or toluene; preferably acetonitrile or ethanol.

[0038] Further, the molar ratio of nitro-piperonyl ring and acetaldehyde is 1:(1.2-2.5); preferably 1:1.2, 1:1.4, 1:1.5, 1:2, 1:2.5.

[0039] Further, the preheating temperature is 30-50°C, preferably 35°C, 40°C, 45°C, 50°C.

[0040] Further, the pump-in speed of the mixed solution is 0.1-1 mL / min, preferably 0.1 mL / min, 0.2 mL / min, 0.25 mL / min, 0.3 mL / min, 0.4 mL / min, 0.5 mL / min, 0.6 mL / min, 0.7 mL / min, 0.8 mL / min, 1 mL / min.

[0041] Further, the mixed solution is preheated in the preheating module.

[0042] Further, the flow rate of hydrogen is 10-40 mL / min; preferably 10 mL / min, 20 mL / min, 30 mL / min, 40 mL / min.

[0043] Further, the temperature of the mixing reaction is 30-50℃; preferably 30℃, 40℃, 50℃.

[0044] Further, the residence time of the mixing reaction is 1-10 min; preferably 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 10 min.

[0045] Further, the pressure of the mixing reaction is 0.5-2 MPa; preferably 0.5 MPa, 0.6 MPa, 0.8 MPa, 1 MPa, 1.5 MPa, 1.7 MPa, 1.9 MPa, 2 MPa.

[0046] Further, the mass ratio of the nitro-piperonyl ring to the catalyst is 1:(0.01-0.1); preferably 1:0.01, 1:0.02, 1:0.04, 1:0.05, 1:0.06, 1:0.08, 1:0.1.

[0047] Further, the catalyst is at least one selected from palladium-carbon or Pt / C, wherein the mass ratio of the noble metal to the total mass of the catalyst is 1%-10%; preferably 5% Pt / C. In the experiment, the relative mass fraction of the Pt / C (5 w / w% loading) to the raw material is 5.9-11.8% according to the concentration of the nitro-piperonyl ring of 0.06 mol / L and the flow rate of 0.5 mL / min for 48 hours of continuous operation. At the beginning of the experiment, the amount of the catalyst to be fed can be selected from one of the following: the amount of the platinum-carbon is 1-2 g; preferably 1.7 g.

[0048] Further, the catalyst is placed in a fixed-bed reaction module.

[0049] The present application provides a method for synthesizing N-ethyl piperonylamine by using a micro-channel reactor, which realizes the simultaneous completion of two reactions in one step through the simultaneous occurrence of nitro reduction and reductive amination in the micro-channel reactor. Compared with the traditional reaction which needs to separate the two steps, the method of the present application significantly simplifies the reaction synthesis steps, increases the reaction efficiency, reduces the production cost, and the total time is only 6 min, the reaction efficiency is high, the product purity is 99%, and the cost is reduced and the efficiency is increased.

[0050] The method has small environmental pollution, high purity of the obtained product, and the reactants can be pumped at normal pressure, and the production process is simple and efficient, which has the significance of industrial production.

[0051] In a third aspect, the present application provides a method for synthesizing nitro-piperonyl ring by using a micro-channel reactor, comprising: The pepper ring and dilute nitric acid are pumped into the fourth micro-channel reactor for mixing reaction, and the product is obtained after post-treatment.

[0052] Further, the reaction temperature is 40-70°C, preferably 40, 50, 55, 60, 65, 70°C. Further, the molar ratio of the pepper ring to the dilute nitric acid, based on the content of nitric acid in the dilute nitric acid, is 1: (2-5), preferably 1:2, 1:3, 1:3.5, 1:4, 1:4.2, 1:4.5, 1:5.

[0053] Further, the reaction time is 3-15 min, preferably 5-10 min, preferably 3, 5, 6, 8, 10, 12, 15 min.

[0054] Further, the feeding speed of the pepper ring is 0.5-1.5 mL / min, preferably 0.5, 0.8, 1, 1.2, 1.5 mL / min.

[0055] Further, the feeding speed of the dilute nitric acid is 5-15 mL / min, preferably 5, 8, 10, 12, 15 mL / min.

[0056] Further, the dilute nitric acid is diluted from 68% nitric acid to obtain a dilute nitric acid with a mass concentration of 15-30%, preferably a mass concentration of 22%, and preferably the solvent is at least one of water, acetonitrile, ethanol, ethyl acetate, preferably water.

[0057] Further, the mixing reaction is carried out under ultrasonic conditions.

[0058] Further, the frequency of the ultrasonic vibration is 10-100 kHz, preferably 10, 20, 30, 40, 50, 60, 80, 90, 100 kHz.

[0059] Further, the post-treatment process is to adjust the pH to 7-8 with NaOH solution, suction filtration, washing the filter cake with water, and drying the washed filter cake.

[0060] The present application synthesizes nitro-piperonyl ring (i.e., 1,2-methylenedioxy-4-nitrobenzene) by using an ultrasonic-assisted micro-channel reactor, greatly increases the mixing of water and oil two phases through micro-scale effect. Meanwhile, the mechanical effect and cavitation effect brought by ultrasonic assistance avoids solid blockage of pipeline and greatly accelerates the reaction time, and the total reaction time is only 6 minutes, the purity is more than 99%, and the space-time yield is 95 g / h.

[0061] The method does not need a bromination step, is relatively environmentally friendly, has simple post-treatment operation, mild reaction, short reaction time, and high yield.

[0062] In a fourth aspect, the present application provides a method for synthesizing oxolinic acid by using a micro-channel reactor, comprising: Step one: synthesizing nitro-piperonyl ring: synthesizing nitro-piperonyl ring according to the method of the third aspect; Step two: synthesizing N-ethyl-piperonylamine: synthesizing N-ethyl-piperonylamine according to the method of the second aspect; Step three: synthesizing oxolinic acid: synthesizing oxolinic acid according to the method of the first aspect.

[0063] The remaining reaction conditions are described in the first aspect to the third aspect of the present application.

[0064] The method of the present application uses 1,2-methylenedioxybenzene as a starting material, and adopts micro-channel synthesis technology throughout the process. Oxolinic acid is synthesized by nitration reaction, catalytic hydrogenation, reductive amination, condensation reaction, cyclization reaction and ester hydrolysis reaction in a micro-channel reactor. The intermediate 1,2-methylenedioxy-4-nitrobenzene is synthesized by an ultrasonic-assisted method, which only takes 6 minutes, greatly reduces the safety hazards caused by a large amount of heat release in the nitration reaction, greatly reduces the reaction time and avoids solid blockage, and the purity is more than 99%. In addition, the intermediate N-ethyl-piperonylamine is synthesized by adding a metal catalyst 5% Pt / C, which realizes one-pot synthesis, significantly simplifies the operation process, takes only 6 minutes, and has a purity of more than 99%. Finally, N-ethyl-piperonylamine is synthesized into oxolinic acid in a micro-channel reactor without solvent, continuous flow avoids carbonization of reactants and products, avoids the risk of direct contact of experimenters with concentrated sulfuric acid, realizes a purity of more than 99%, and has a space-time yield of 23.2 g / h. The total reaction time of each step before ester hydrolysis is only 31 minutes, and the reaction efficiency is high. The micro-channel reaction technology of the present application uses green solvent as a medium, which can effectively shorten the reaction time, greatly reduce the safety hazards of production, and is suitable for synthesizing oxolinic acid and its intermediates.

[0065] In a fifth aspect, the present application provides a system for synthesizing oxolinic acid, comprising a condensation reaction unit, a cyclization reaction unit and an ester hydrolysis reaction unit, wherein, condensation reaction unit: comprising N-ethyl piperamine feeding device, ethoxymethylene malonic acid diethyl ester feeding device, first double injection pump, first micro-channel reactor; the N-ethyl piperamine feeding device and the ethoxymethylene malonic acid diethyl ester feeding device are connected with the first double injection pump, the first double injection pump is connected with the first micro-channel reactor; the first micro-channel reactor comprises a first pumping module, a first mixing module and a first reaction module connected in sequence, and a first pressure adjusting module; the first reaction module is connected in series by a plurality of reaction module units; cycloaddition reaction unit: comprising acetic anhydride feeding device, second double injection pump, T-type mixer, first reaction device, concentrated sulfuric acid feeding device, third double injection pump, second micro-channel reactor; the second micro-channel reactor comprises a second pumping module and a second reaction module connected in sequence; the second reaction module is connected in series by a plurality of reaction module units; the acetic anhydride feeding device and the reaction module of the condensation reaction unit are connected with the second double injection pump; the second double injection pump is connected with the T-type mixer and the first reaction device in sequence, and the concentrated sulfuric acid feeding device is connected with the first reaction device through the third double injection pump; the first reaction device is connected with the second pumping module of the second micro-channel reactor; ester hydrolysis reaction unit: comprising a second reaction device, and the second reaction module of the second micro-channel reactor is connected with the second reaction device through a fourth double injection pump.

[0066] Further, the system further comprises a nitro reduction-reduction amination reaction unit.

[0067] Further, the nitro reduction-reduction amination reaction unit comprises a nitro piperine ring feeding device, an acetaldehyde feeding device, a first mixing device, a seventh double injection pump, a fourth preheating device, a third hydrogen feeding device, and a third micro-channel reactor; the third micro-channel reactor comprises a third pumping module, a third fixed bed reaction module and a third gas-liquid separation module connected in sequence; the nitro piperine ring feeding device and the acetaldehyde feeding device are connected with the first mixing device, and the first mixing device is connected with the third preheating device through the seventh double injection pump; the third preheating device and the third hydrogen feeding device are connected with the third pumping module; the third fixed bed reaction module is connected in series by a plurality of third fixed bed reaction module units.

[0068] Further, the system further comprises a nitro reaction unit.

[0069] Further, the nitro reaction unit comprises a 1,2-methylenedioxybenzene feeding device, a dilute nitric acid feeding device, an eighth double injection pump, a second T-shaped mixer, and a fourth micro-channel reactor; the 1,2-methylenedioxybenzene feeding device and the dilute nitric acid feeding device are connected to the T-shaped mixer through the eighth double injection pump; the fourth micro-channel reactor comprises a fifth pumping module, an ultrasonic module, a third reaction module, and a receiving module; the second T-shaped mixer is connected to the fifth pumping module; the fifth pumping module is sequentially connected to the third reaction module and the receiving module.

[0070] In some embodiments, the condensation reaction unit, the ring-closing reaction unit, and the ester hydrolysis reaction unit are sequentially connected or exist separately.

[0071] In some embodiments, the nitro reduction-reductive amination reaction unit and the condensation reaction unit are sequentially connected or exist separately.

[0072] In some embodiments, the nitro reaction unit, the nitro reduction-reductive amination reaction unit, the condensation reaction unit, the ring-closing reaction unit, and the ester hydrolysis reaction unit are sequentially connected or exist separately.

[0073] In the present application, the inner diameter of all micro-channel reactors is 0.5 mm-15 mm; preferably, the inner diameter is 0.5 mm-5 mm, preferably 1.6 mm, 2.5 mm, 4.8 mm, 10 mm, 15 mm, etc.

[0074] Advantages: The method of the present application adopts micro-channel synthesis technology, compared with traditional kettle synthesis, avoids the safety problems (such as nitration reaction) caused by a large amount of heat release, is intrinsically safe during the whole synthesis process, reduces waste generation by using green solvents, greatly shortens the reaction time, and avoids some non-green and difficult-to-handle solvents.

[0075] The reaction route of the method of the present application is short, and all kinds of dangerous reactions and harsh conditions are carried out in the micro-channel reactor, avoiding the safety hazards existing in nitration reaction, the use of concentrated sulfuric acid, and hydrogenation reaction, the reaction time is short, and the flying temperature phenomenon does not occur, and the reaction flow pump-in mode can effectively control the reaction uniformity, the operation is safe, the temperature is easy to control, and the energy consumption is low.

[0076] Explanation of terms Certain embodiments of the application are now described in detail by reference to the accompanying figures and the following description. The application is intended to encompass all alternatives, modifications and equivalents thereof which are included within the scope of the application as defined by the claims. One skilled in the art will recognize that many methods and materials equivalent to those described herein can be used in the practice of the application. The present application is not limited to the methods and materials described herein. In the event of a conflict between the incorporated documents, patents and similar materials and the present application, including but not limited to defined terms, term application, described techniques, and the like, the present application controls.

[0077] It should be further recognized that certain features of the application, described in detail herein, are described in the context of multiple separate embodiments for clarity but can also be provided in combination in a single embodiment. Conversely, various features of the application, described in the context of a single embodiment for brevity, can also be provided separately or in any appropriate subcombination.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0079] In the description of the specification, the description using the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that a specific feature, structure, material or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present application. Descriptive terms of the above-mentioned terms in the specification do not necessarily refer to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in one or more embodiments or examples. In addition, the person skilled in the art can combine and combine the different embodiments or examples described in the specification and the features of the different embodiments or examples, without contradiction.

[0080] In the following, all numbers disclosed herein are approximations. Each numerical value, herein disclosed, can be varied in some percentage, e.g. 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, in either direction (i.e. higher or lower) of the value. Whenever a numerical range is disclosed, any number within the range (i.e. N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8%, N + / - 10%, N + / - 15%, or N + / - 20%) is also disclosed, wherein " + / - " means plus or minus. BRIEF DESCRIPTION OF DRAWINGS

[0081] Figure 1Microchannel synthesis flow chart for nitro-piperonyl ring.

[0082] Figure 2 Microchannel synthesis flow chart for two-step one-pot synthesis of N-ethyl-piperamine.

[0083] Figure 3 Three-step combined microchannel synthesis flow chart for oxolinic acid.

[0084] Figure 4 Microchannel synthesis flow chart for oxolinic acid.

[0085] Figure 5 Microchannel synthesis flow chart for oxolinic acid. 1 HNMR chart. DETAILED DESCRIPTION

[0086] In order to make the purpose, technical solutions and advantages of the present application more clear, the present application is further described in detail below with examples. The specific examples described herein are only used to explain the present application and do not constitute any limitation to the present application. In addition, in the following description, the description of well-known structures and techniques is omitted to avoid unnecessary confusion of the concept of the present disclosure. Such structures and techniques are also described in many publications.

[0087] The reagents used in the present application can be purchased from the market or can be prepared by the methods described in the present application.

[0088] I. Nitro-piperonyl ring (also known as: 1,2-methylenedioxy-4-nitrobenzene): Pumping module: double injection pump. Mixing module: sixteenth inch T-shaped mixer.

[0089] The microchannel reactor includes: (1) reaction module: quarter inch polytetrafluoroethylene tube; inner diameter 0.5 mm~15mm; preferably inner diameter 0.5 mm~5 mm, further preferably 4.8 mm. (2) ultrasonic module + heating module: ultrasonic oscillator rod + ultrasonic cleaner.

[0090] The microchannel synthesis flow chart for nitro-piperonyl ring is shown in Figure 1 as follows: Phase A: 1,2-methylenedioxybenzene; Phase B: dilute nitric acid (mass fraction concentration 22%) The A phase in the 1,2-methylenedioxybenzene feeding device and the B phase in the dilute nitric acid feeding device are respectively pumped into a T-shaped mixer by double injection pumps, enter the micro-channel reactor through the pumping module, react in the reaction module of the micro-channel reactor under the action of the ultrasonic module, the frequency of ultrasonic vibration is 80 kHZ, and the receiving module collects the reaction liquid. The reaction liquid is neutralized with NaOH solution, the neutralization pH is 7-8, the reaction liquid is suction filtered, the filter cake is washed with water, the filter cake is placed in a blast drying oven and dried at 80 ℃ for 8 h, and the obtained yellow solid is nitro-piperonyl ring.

[0091] The dilute nitric acid is obtained by diluting 68% nitric acid with water to obtain a dilute nitric acid with a mass concentration of 15%-30%, preferably a mass concentration of 22%.

[0092] The feeding speed of the A phase is 0.1 mL / min-2 mL / min, preferably 0.5 mL / min-1.5 mL / min, and preferably 1 mL / min.

[0093] The feeding speed of the B phase is 1 mL / min-20 mL / min, preferably 5 mL / min-15 mL / min, and preferably 10 mL / min.

[0094] The reaction time is 5 min-10 min, preferably 6 min.

[0095] The reaction temperature is 40 ℃-70 ℃, preferably 55 ℃.

[0096] The molar ratio of the piperonyl ring to the dilute nitric acid is 1: (2-5), preferably 1:4.2.

[0097] The frequency of ultrasonic vibration is 10 kHZ-100 kHZ, preferably 80 kHZ.

[0098] II. Synthesis of N-ethyl-3,4-methylenedioxyaniline: two-step combined reaction Synthesis of N-ethyl-3,4-methylenedioxyaniline The micro-channel synthesis flow chart of two-step one-pot synthesis of N-ethyl piperonylamine is as shown in Figure 2 The specific description is as follows: Method 1: The nitro-piperonyl ring feeding device and the acetaldehyde feeding device feed the nitro-piperonyl ring and acetaldehyde into the organic solvent in the mixing device to obtain a mixed solution; the catalyst is added into the fixed bed reaction module; the mixed solution is pumped into the preheating device through the double injection pump for preheating, and the preheated material and hydrogen are pumped into the fixed bed reaction module of the micro-channel reactor through the pumping module for mixing reaction, and then the reaction liquid flowing out of the gas-liquid separator module is collected, and post-treatment is performed to obtain N-ethyl-piperonylamine.

[0099] The flow rate of the hydrogen is 10 mL / min to 40 mL / min, preferably 20 mL / min.

[0100] The flow rate of the reaction liquid (1,2-methylenedioxy-4-nitrobenzene and acetaldehyde mixed solution) is 0.1 mL / min to 1 mL / min, preferably 0.5 mL / min.

[0101] The mass ratio of the nitro-piperonyl ring to the catalyst is 1:(0.01 to 0.1); the catalyst is at least one selected from activated carbon or Pt / C, wherein the mass ratio of the noble metal is 1% to 10% of the total mass of the catalyst. Preferably, it is 5% Pt / C. The platinum carbon dosage is 1.7 g; according to the concentration of the nitro-piperonyl ring 0.06 mol / L, the flow rate 0.5 mL / min, and continuous operation for 48 hours, the relative raw material mass fraction of the Pt / C (5 w / w% loading) is 11.8%.

[0102] The concentration of the nitro-piperonyl ring (1,2-methylenedioxy-4-nitrobenzene) is 0.02 mol / L to 0.3 mol / L; preferably 0.05 mol / L to 0.2 mol / L, preferably 0.05 mol / L to 0.3 mol / L; preferably 0.06 mol / L.

[0103] The concentration of the acetaldehyde is 0.05 mol / L to 0.45 mol / L; preferably 0.05 mol / L to 0.2 mol / L, preferably 0.09 mol / L.

[0104] The temperature of the reaction is 30 ℃ to 50 ℃, preferably 40 ℃.

[0105] The solvent of the reaction is at least one selected from ethanol, acetonitrile, and toluene, preferably acetonitrile.

[0106] The reaction time is 1 min to 10 min, preferably 6 min.

[0107] The pressure of the mixing reaction is 0.5 MPa to 2 MPa; preferably 1.7 MPa.

[0108] III. Synthesis of Oxyquinoline Acid: Three-step tandem reaction Pumping module: double injection pump. T-type mixer: sixteenth inch T-type mixer.

[0109] The microchannel reactor is selected from at least one of the following: sixteenth inch iron pipe, sixteenth inch polytetrafluoroethylene pipe; the inner diameter of the microchannel reactor is 0.5 mm to 15 mm; preferably, the inner diameter is 0.5 mm to 5 mm, and further preferably, the inner diameter is 4.8 mm or 1.6 mm. The reaction device is selected from a three-necked flask or a receiving bottle.

[0110] Pressure supply: back pressure valve or gas cylinder or double injection pump The heating module comprises a stirrer.

[0111] The three-step synthesis flow chart of oxyquinoline acid is shown in Figure 3 and described in detail as follows: Phase A: N-ethyl piperamine; Phase B: diethyl ethoxymethylene malonate; Phase C: acetic anhydride; Phase D: concentrated sulfuric acid Phase A of N-ethyl piperamine in the feeding device and Phase B of diethyl ethoxymethylene malonate in the feeding device are pumped into the first microchannel reactor through the first double injection pump, and the first reaction liquid is obtained after sufficient reaction; The first reaction liquid obtained in the above step and Phase C of acetic anhydride in the feeding device are mixed in the T-type mixer through the second double injection pump, and then flow into the first reaction device (for example, a three-necked flask). Phase D of concentrated sulfuric acid in the feeding device is pumped into the first reaction device (for example, a three-necked flask) through the third double injection pump. After the four phases are mixed uniformly, they are pumped into the second reaction module of the second microchannel reactor through the second pumping module of the second microchannel reactor for reaction, and the second reaction liquid is obtained after the reaction is completed; The second reaction liquid obtained in the above step is pumped into the second reaction device (for example, a receiving bottle) containing water through the fourth double injection pump, and the product oxyquinoline acid is obtained after heat preservation.

[0112] Preferably, the flow rate of N-ethyl piperamine is 0.2 mL / min to 2 mL / min, and preferably 0.24 mL / min. Preferably, the flow rate of diethyl ethoxymethylene malonate is 0.2 mL / min to 2 mL / min, and preferably 0.4 mL / min.

[0113] Preferably, the molar ratio of N-ethyl-3,4-methylenedioxyaniline to diethyl ethoxymethylene malonate is 1: (1.05 to 1.5), and preferably 1:1.2.

[0114] Preferably, the retention time of the first microchannel reactor is 5 min to 20 min, and preferably 14 min.

[0115] Preferably, the temperature of the first micro-channel reactor is 90°C-130°C, preferably 110°C.

[0116] Preferably, the pressure of the first micro-channel reactor is 0.5 MPa-2 MPa; preferably 0.5 MPa-1.5 MPa, preferably 0.8 MPa.

[0117] Further, the flow rate of the first reaction solution is 0.04 mL / min-4 mL / min, preferably 0.287 mL / min.

[0118] Preferably, the flow rate of acetic anhydride is 0.1 mL / min-0.5 mL / min, preferably 0.287 mL / min. Preferably, the flow rate of concentrated sulfuric acid is 0.06 mL / min-0.2 mL / min, preferably 0.085 mL / min, and the concentrated sulfuric acid refers to sulfuric acid with a mass fraction of 98%.

[0119] Preferably, the pump-in flow rate of the second reaction solution (i.e., the four-phase mixed solution) is 0.2 mL / min-2 mL / min, preferably 1 mL / min.

[0120] Preferably, the temperature of the second micro-channel reactor is 70°C-150°C, preferably 150°C.

[0121] Preferably, the residence time of the second micro-channel reactor is 3 min-10 min, preferably 5 min.

[0122] Preferably, the pressure of the second micro-channel reactor is 0.5 MPa-1.5 MPa, preferably 0.8 MPa.

[0123] Preferably, the volume of the water is 1-5 times, preferably 2-4 times, preferably 2 times, the volume of the second reaction solution.

[0124] Preferably, the temperature of the second reaction device is 60°C-100°C, preferably 100°C.

[0125] Preferably, the heat preservation time of the second reaction device is 2-8 h or 3 h-8 h, preferably 6 h.

[0126] The following describes specific examples: Preparation Example 1: Preparation of nitro-piperine ring in continuous flow The pepper ring and dilute nitric acid (mass fraction of 22%) were injected into the reaction system by double injection pump, the flow rate was 1 mL / min and 10 mL / min respectively, the two phases were mixed in the T-type mixer, entered the micro-channel reactor (which contained the reaction coil with ultrasonic, the inner diameter was 0.5-15 mm), the frequency of ultrasonic vibration was 80 kHZ, the reaction temperature was set to 55 ℃, the retention time was 6 min, and the effluent was collected by a collection bottle. The collected reaction liquid was neutralized with NaOH aqueous solution, the neutralization pH was 7-8, the reaction liquid was suction filtered, and the filter cake was washed with water, and then placed in a blast drying oven and dried at 80 ℃ for 8 h to obtain a yellow solid powder. Yield: 95%, space-time yield 95 g / h, purity 99.5%.

[0127] Structure detection: 1 H NMR (500 MHz, DMSO-d6) data as follows (δ [ppm]): 7.88 (dd, 1H), 7.73 (d, 1H), 7.12 (d, 1H), 6.26 (s, 2H).

[0128] Preparation Example 2: One-pot preparation of N-ethyl pepperamine from nitro pepper ring 500 mg of nitro pepper ring was dissolved in 50 mL of acetonitrile, and 0.25 mL of acetaldehyde was added. 5% Pt / C catalyst 1.7 g (catalyst was metered into the fixed bed reaction module of the micro-channel reactor connected with high-pressure hydrogen generator for 48 h of continuous reaction) was added. The flow rate of the reaction liquid was 0.5 mL / min, the temperature was set to 40 ℃, the hydrogen flow rate was 20 mL / min, the back pressure valve pressure was 1.7 MPa, and the retention time was 6 min. Yield: 84%, purity 99%, space-time yield: 0.26 g / h.

[0129] Preparation Example 3: Three-step sequential synthesis of oxolinic acid A phase: N-ethyl pepperamine; B phase: ethoxymethylidene malonic acid diethyl ester; C phase: acetic anhydride; D phase: concentrated sulfuric acid A phase and B phase were pumped into the sixteenth iron coil by double injection pump at a flow rate of 0.24 mL / min and 0.4 mL / min respectively, the reaction temperature was set to 110 ℃, the reaction time was 14 min, and the back pressure valve pressure was 0.8 MPa. The molar ratio of N-ethyl pepperamine and ethoxymethyl methyl ester was 1:1.2, and after sufficient reaction, the reaction liquid was obtained; The reaction solution obtained in the above step and phase C were mixed at a flow rate of 0.287 mL / min in a T-type mixer, flowed into a three-necked flask, phase D was pumped into the three-necked flask by a double injection pump at a flow rate of 0.085 mL / min, after the four phases were mixed uniformly, they were pumped into a 1 / 16 polytetrafluoroethylene coil at a flow rate of 1 mL / min, reaction was carried out, a gas back pressure device was applied at the rear end of the receiving bottle, the pressure was 0.8 MPa, the retention volume was 5 mL, the retention time was 5 min, and the temperature was 150°C. Water was added into the receiving bottle in an amount of 2 times the volume of the receiving solution. After the reaction was completed, the obtained reaction solution was kept at 100°C for 6 h, then filtration was carried out, the filter cake was washed with water and ethanol, the filter cake was dried in a blast drying oven at 80°C for 6 h, and a white solid was obtained. Yield: 88%, purity: 99.4%, and space-time yield: 23.2 g / h.

[0130] Structure detection: 1 H NMR (500 MHz, DMSO-d6) data are as follows (δ [ppm]): 15.70 (s, 1H), 8.93 (s, 1H), 7.67 (s, 2H), 6.31 (s, 2H), 4.56 (q, 2H), 1.39 (t, 3H).

[0131] The method of the present application has been described by preferred embodiments, and the related personnel can obviously make changes or appropriate changes and combinations to the method and application described herein within the content, spirit and scope of the present application to realize and apply the present application technology. Those skilled in the art can refer to the content herein to appropriately improve the process parameters. It is particularly pointed out that all similar replacements and changes are obvious to those skilled in the art, and they are considered to be included in the present application.

Claims

1. A method for synthesizing oxiquinac acid using a microchannel reactor, characterized by, The application comprises the following steps: N-ethyl piperamine and diethyl ethoxymethylene malonate are pumped into a first micro-channel reactor for mixing and reaction to obtain a first reaction liquid; The first reaction liquid and acetic anhydride are pumped into a T-shaped mixer for mixing, and then the reaction mixture is pumped into a first reaction device and concentrated sulfuric acid at the same time, and then the mixture is pumped into a second micro-channel reactor for complete reaction to obtain a second reaction liquid; The second reaction liquid is directly pumped into a second reaction device containing water for heat preservation reaction, and then post-treatment is performed to obtain oxolinic acid.

2. The method of claim 1, wherein, The flow rate of N-ethyl piperamine is 0.2 mL / min to 2 mL / min; and / or the flow rate of diethyl ethoxymethylene malonate is 0.2 mL / min to 2 mL / min; and / or the molar ratio of N-ethyl piperamine to diethyl ethoxymethylene malonate is 1:(1.05 to 1.5); and / or the retention time of the mixing and reaction in the first micro-channel reactor is 5 min to 20 min; and / or the temperature of the mixing and reaction in the first micro-channel reactor is 90 °C to 130 °C; and / or the pressure of the back pressure valve of the mixing and reaction in the first micro-channel reactor is 0.5 MPa to 2 MPa.

3. The method of claim 1, wherein, The molar ratio of N-ethyl piperamine: acetic anhydride: H2SO4 is 1:(1.5 to 2.5):(0.75 to 1.5); and / or the flow rate of the first reaction liquid is 0.04 mL / min to 4 mL / min; and / or the flow rate of acetic anhydride is 0.1 mL / min to 0.5 mL / min; and / or the flow rate of concentrated sulfuric acid is 0.06 mL / min to 0.2 mL / min; and / or the temperature of the reaction in the second micro-channel reactor is 70 °C to 150 °C, and / or the retention time of the reaction in the second micro-channel reactor is 3 min to 10 min, and / or the pressure of the reaction in the second micro-channel reactor is 0.5 MPa to 1.5 MPa.

4. The method of claim 1, wherein, The flow rate of the second reaction liquid is 0.2 mL / min to 2 mL / min, and / or the volume of water is 1 to 5 times the volume of the second reaction liquid, and / or the temperature of the heat preservation is 60 °C to 100 °C, and / or the time of the heat preservation is 2 h to 8 h; Further preferably, after the heat preservation reaction is completed, the post-treatment process is as follows: filtration, rinsing with water and ethanol to obtain a filter cake, drying the filter cake to obtain a solid; Further preferably, the first micro-channel reactor, the T-shaped mixer and the second micro-channel reactor can be connected or not connected with each other in any combination.

5. A method for synthesizing N-ethyl piperamine using a microchannel reactor, characterized by, The application comprises the following steps: Nitro piperazine and acetaldehyde are mixed in an organic solvent to obtain a mixture, the mixture is preheated, and then the mixture and hydrogen are respectively transported into a fixed bed reaction module of a third micro-channel reactor for mixing and reaction in the presence of a catalyst to obtain N-ethyl piperamine.

6. The method of claim 5, wherein, The concentration of nitro-piperonyl ring in the organic solvent is 0.02 mol / L to 1 mol / L; and / or the concentration of acetaldehyde in the organic solvent is 0.05 mol / L to 0.6 mol / L; and / or the organic solvent is at least one selected from ethanol, acetonitrile or toluene; and / or the molar ratio of nitro-piperonyl ring and acetaldehyde is 1:(1.2 to 2.5); and / or The catalyst is at least one selected from palladium-carbon or Pt / C; and / or The preheating temperature is 30 ℃ to 50 ℃; and / or The pumping speed of the mixed solution is 0.1 mL / min to 1 mL / min; and / or The flow rate of hydrogen is 10 mL / min to 40 mL / min; and / or The temperature of the mixed reaction is 30 ℃ to 50 ℃; and / or The residence time of the mixed reaction is 1 min to 10 min; and / or The pressure of the mixed reaction is 0.5 MPa to 2 MPa; and / or The catalyst is placed in a fixed bed reaction module.

7. A method for synthesizing nitroveratryl ring using a microchannel reactor, characterized by, Comprising: Pumping the piperonyl ring and dilute nitric acid into the fourth micro-channel reactor for mixed reaction, and obtaining the product after post-treatment; And / or The reaction temperature is 40 ℃ to 70 ℃; and / or The molar ratio of the piperonyl ring to the dilute nitric acid, in terms of the content of nitric acid in the dilute nitric acid, is 1:(2 to 5); and / or The reaction time is 3 min to 15 min; and / or The feeding speed of the piperonyl ring is 0.5 mL / min to 1.5 mL / min; and / or The feeding speed of the dilute nitric acid is 5 mL / min to 15 mL / min; and / or The mass concentration of the dilute nitric acid is 15% to 30%; and / or The mixed reaction is carried out under ultrasonic condition; and / or The frequency of the ultrasonic vibration is 10 kHZ to 100 Khz.

8. A method for synthesizing oxiquinac acid using a microchannel reactor, characterized by, Comprising: Step one: synthesizing the nitro-piperonyl ring according to the method of claim 7; Step two: synthesizing the N-ethyl piperonylamine according to the method of any one of claims 5 to 6; Step three: synthesizing the oxiquinac acid according to the method of any one of claims 1 to 4.

9. A system for synthesizing oxfendazole by the method of any one of claims 1 to 4 and 8, characterized by, Comprising a condensation reaction unit, a ring-closing reaction unit and an ester hydrolysis reaction unit, wherein, The condensation reaction unit comprises an N-ethyl piperonylamine feeding device, a diethyl ethoxymethylene malonate feeding device, a first double injection pump and a first micro-channel reactor; the N-ethyl piperonylamine feeding device and the diethyl ethoxymethylene malonate feeding device are connected with the first double injection pump, and the first double injection pump is connected with the first micro-channel reactor; the first micro-channel reactor comprises a first pumping module, a first mixing module and a first reaction module connected in sequence, and a first pressure adjusting module; the first reaction module is composed of a plurality of reaction module units connected in series; The cyclization reaction unit comprises an acetic anhydride feeding device, a second double injection pump, a T-shaped mixer, a first reaction device, a concentrated sulfuric acid feeding device, a third double injection pump and a second micro-channel reactor; the second micro-channel reactor comprises a second pumping module and a second reaction module connected in sequence; the second reaction module is connected in series by a plurality of reaction module units; the acetic anhydride feeding device and the reaction module of the condensation reaction unit are connected with the second double injection pump; the second double injection pump is connected with the T-shaped mixer and the first reaction device in sequence, the concentrated sulfuric acid feeding device is connected with the first reaction device through the third double injection pump; the first reaction device is connected with the second pumping module of the second micro-channel reactor; The ester hydrolysis reaction unit comprises a second reaction device, and the second reaction module of the second micro-channel reactor is connected with the second reaction device through the third double injection pump.

10. The system of claim 9, wherein, The system further comprises a nitro reduction-reduction amination reaction unit and / or a nitro reaction unit; The condensation reaction unit, the cyclization reaction unit and the ester hydrolysis reaction unit are connected in sequence or exist independently. The nitro reduction-reduction amination reaction unit and the condensation reaction unit are connected in sequence or exist independently. The nitro reaction unit, the nitro reduction-reduction amination reaction unit, the condensation reaction unit, the cyclization reaction unit and the ester hydrolysis reaction unit are connected in sequence or exist independently.

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