Full-continuous chemical synthesis device and method for (E)-2-oxopentenedioic acid dimethyl ester

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a full-continuous chemical synthesis device and method for (E)-2-oxopentenedioic acid dimethyl ester. A multi-step continuous reaction system is adopted, a feeding pump, a mixer, a fixed bed reactor, a coil reactor, a back pressure valve, a liquid-liquid separator and a solvent recovery device are sequentially connected, the full-continuous chemical synthesis device for (E)-2-oxopentenedioic acid dimethyl ester is provided according to a linear synthesis method, and continuous manufacturing is achieved. The full-continuous chemical synthesis device for (E)-2-oxopentenedioic acid dimethyl ester can stably produce products with consistent quality, is high in integration degree, small in occupied area for production and high in unit productivity, can adjust the yield according to requirements, and avoids the amplification effect of a kettle type process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a fully continuous chemical synthesis apparatus and method for (E)-2-oxopentenedioic acid dimethyl ester. Background Technology

[0002] Dimethyl (E)-2-oxopentenedioic acid is an important organic synthesis intermediate with wide applications in chemical synthesis. Its structure, as shown in Formula (I), combines a ketone carbonyl group, an ester group, and a carbon-carbon double bond, enabling it to participate in various types of chemical reactions. Dimethyl (E)-2-oxopentenedioic acid can easily form a ring with various aromatic amines in one step, thus proving valuable in the preparation of several biologically significant quinoline derivatives. In its initial application, dimethyl (E)-2-oxopentenedioic acid was used in a one-pot synthesis of pyrroloquinoline quinone (PQQ), an oxidase cofactor, from ethyl 6-amino-5-methoxyindole-2-carboxylate.

[0003] ; Chinese patent CN104557921 A and international patents WO2006102642 A1 and WO2012170378 A1 disclose a synthetic route using α-ketoglutaric acid as a starting material, which is obtained through esterification, bromination, and elimination reactions. This process uses inexpensive and readily available raw materials and has a high yield, but the esterification reaction requires at least 2 equivalents of thionyl chloride, posing significant safety risks, and the generated acidic waste gas is difficult to treat. Indian patent IN201741000952 A uses sulfuric acid-catalyzed esterification, which, although inexpensive, is highly corrosive, requires complex post-treatment, poses significant environmental hazards, and cannot be recycled. Furthermore, the synthetic methods disclosed in the above patents require each reaction to be carried out independently, resulting in long reaction times and low space-time efficiency. Summary of the Invention

[0004] In view of the problems existing in the prior art, the purpose of this invention is to provide a fully continuous chemical synthesis apparatus and method for (E)-2-oxoprenoidic acid dimethyl ester with high production efficiency, good and stable product quality, and low emissions of waste.

[0005] The fully continuous chemical synthesis apparatus and method for (E)-2-oxopentenedioic acid dimethyl ester provided by this invention replaces the liquid acid catalyst in the esterification reaction with a solid acid catalyst, resulting in high catalytic efficiency and recyclability. Under long-term operation, this helps reduce costs and effectively avoids the drawbacks of liquid acid catalysts, such as strong corrosiveness, significant safety hazards, cumbersome post-processing, and substantial environmental harm, thus significantly improving the inherent safety of the process. Through multi-step continuous production, the space-time efficiency is greatly improved.

[0006] In this invention, the chemical synthesis of (E)-2-oxoprenoidic acid dimethyl ester involves the following raw materials: α-ketoglutaric acid, bromine source, triethylamine, and hydrochloric acid; α-ketoglutaric acid is dissolved in methanol and is designated as the first material; the bromine source is dissolved in dichloromethane and is designated as the second material, wherein the bromine source includes, but is not limited to, bromine, NBS, dibromohydantoin, cuprous bromide, and copper bromide, preferably, the bromine source is bromine; triethylamine is designated as the third material; and an aqueous solution of hydrochloric acid is designated as the fourth material; the chemical synthesis of (E)-2-oxoprenoidic acid dimethyl ester involves reactions including esterification, bromination, elimination, and quenching. Correspondingly, the fully continuous chemical synthesis apparatus for (E)-2-oxopentenedioic acid dimethyl ester provided by this invention comprises 7 feed pumps, 3 mixers, 4 reactors, 2 back pressure valves, 1 solvent recovery device, 1 liquid-liquid separator, and 3 storage tanks connected sequentially according to the (E)-2-oxopentenedioic acid dimethyl ester synthesis route, forming a fully continuous chemical synthesis apparatus matching the (E)-2-oxopentenedioic acid dimethyl ester synthesis route; wherein: The first pump is used to transport the prepared first material through the pipeline to the first reactor, which is used for esterification reaction; the first reactor is connected to the first back pressure valve; the reaction liquid flowing out of the first reactor flows through the first back pressure valve, which is used to regulate the reaction pressure in the first reactor, suppress gas generation that affects residence time, and ensure that the reaction fluid flows smoothly in the reactor. The first back pressure valve is connected to the solvent recovery device via a pipeline, and the effluent from the first back pressure valve directly enters the solvent recovery device through the pipeline. The solvent recovery device is equipped with an upper outlet and a lower outlet. The upper outlet is connected to a first storage tank, which is used to store the recovered solvent. The lower outlet is connected to a second storage tank, which is used to store the esterification reaction products. The esterification reaction products in the second storage tank are transported to the first mixer by a second pump, and the second material is transported to the first mixer by a third pump. The first mixer is connected to the second reactor via a pipeline, and the materials in the first mixer are fully mixed and then directly enter the second reactor through the pipeline. The bromination reaction takes place in the second reactor. The reaction liquid flowing out of the second reactor flows through the second back pressure valve and directly enters the second mixer; the fourth pump inputs the third material into the second mixer, and the fifth pump delivers water to the second mixer. After the three are fully mixed in the second mixer, they enter the third reactor through pipelines, where the elimination reaction takes place. The reaction liquid flowing out of the third reactor is fully mixed with the fourth material delivered by the sixth pump in the third mixer and then directly enters the fourth reactor, where the quenching reaction takes place. The quenched liquid directly enters the first liquid-liquid separator, where the organic phase and the aqueous phase separate into layers. The first liquid-liquid separator is equipped with an upper outlet and a lower outlet. The upper outlet is connected to a third storage tank, which is used to store wastewater. The lower outlet is connected to a seventh pump to output the liquid. After recovering the solvent, the target product (E)-2-oxoprenoidic acid dimethyl ester is obtained.

[0007] Preferably: In this invention, the first pump, the second pump, the third pump, the fourth pump, the fifth pump, the sixth pump, and the seventh pump are all plunger pumps or peristaltic pumps for conveying solutions.

[0008] In this invention, the first and third mixers are Y-type or T-type mixers, and the second mixer is a cross-type mixer. The materials used are one or a combination of several of the following: glass, polytetrafluoroethylene, stainless steel, Hastelloy, tantalum, and zirconium.

[0009] In this invention, the first reactor is a fixed-bed reactor, the main body of which is a cylindrical reaction chamber filled with a solid acid catalyst. A heat exchange fluid jacket can be added to the outer layer of the chamber for heat exchange. The diameter is 1-20 cm, the length is 20-200 cm, and the applicable throughput is 1-5000 mL / min. The material is one of glass, polytetrafluoroethylene, stainless steel, Hastelloy, tantalum, and zirconium. The solid acid includes, but is not limited to, acidic macroporous resins, zeolites, heteropoly acids and their salts, acidic metal oxides, and supported liquid acids. Preferably, the solid acid is a silica-supported solid sulfuric acid catalyst.

[0010] In this invention, the second, third, and fourth reactors are coil-type reactors. The main body is a tubular cavity that serves as a fluid channel. The diameter of the fluid channel is 100 μm-20 mm, and the length is 1-1000 m. The material is one or a combination of polytetrafluoroethylene, stainless steel, Hastelloy, tantalum, and zirconium.

[0011] In this invention, the solvent recovery device consists of a rotary evaporator, a cooling circulation device, and a pressure reducing device. The main body of the evaporator is a cylindrical jacketed bottle. The outer jacket is connected to a circulating oil bath to heat the system, the inner jacket stores the reaction liquid, and the middle is a central shaft with a stirring paddle. The central shaft is driven by a motor to rotate and perform stirring. The circulating cooling device is used to condense solvent vapor and recover the solvent, and the pressure reducing device is used to reduce the system pressure to improve the solvent recovery efficiency.

[0012] In this invention, the liquid-liquid separator is designed based on the principle of gravity sedimentation. The main body of the liquid-liquid separator is a cylindrical cavity. The lower end of the cavity is provided with an inlet for the material to be separated and an outlet for the lower heavy phase, while the upper end of the cavity is provided with an outlet for the upper light phase. The inner diameter of the separator is 1-20 cm, the height is 1-200 cm, and the material is one or a combination of several of the following: glass, polytetrafluoroethylene, stainless steel, Hastelloy, tantalum, and zirconium.

[0013] In this invention, the first back pressure valve 1 and the second back pressure valve 2 are made of polytetrafluoroethylene, stainless steel or Hastelloy, the size of the connecting pipe is 1.6 mm-10 mm, and the pressure condition range is 0.1-10.0 MPa.

[0014] This invention also provides a fully continuous chemical synthesis method for dimethyl (E)-2-oxopentenedioic acid based on the aforementioned device, comprising: The first reactor is a fixed-bed reactor, the main body of which is a cylindrical reaction chamber filled with a solid acid catalyst. The reaction temperature in the first reactor 1 is controlled at 50-150℃, and the reaction time is controlled at 30-90 minutes; The reaction temperature in the second reactor 2 is controlled at 30-100℃, and the reaction time is controlled at 10-30 minutes; The reaction temperature in the third reactor 3 is controlled at 0-30℃, and the reaction time is controlled at 10-30 minutes; The reaction temperature in the fourth reactor 4 is controlled at 0-30℃, and the reaction time is 3-10 minutes.

[0015] The pressure of the first back pressure valve is controlled to be 0.5-2.0 MPa; The pressure of the second back pressure valve is controlled to be 1.0-5.0 MPa.

[0016] The flow rate of the first material conveyed by the first pump is controlled to be 0.5-2.0 mL / min; Control the flow rate of the reaction solution delivered by the second pump to be 0.2-0.8 mL / min; The flow rate of the second material delivered by the third pump is controlled to be 1.0-4.0 mL / min; The flow rate of the third material delivered by the fourth pump is controlled to be 0.3-1.2 mL / min; Control the flow rate of water delivered by the fifth pump to 0.15-0.6 mL / min; The flow rate of the fourth substance delivered by the sixth pump is controlled to be 1.0-4.0 mL / min; Control the flow rate of the reaction solution delivered by the seventh pump to be 1.0-4.0 mL / min.

[0017] The concentration of the methanol solution of α-ketoglutaric acid (first material) is controlled to be 0.5-1.5 mol / L. The concentration of the dichloromethane solution (second material) containing the bromine source was controlled to be 1.5-2.0 mol / L. The concentration of the hydrochloric acid aqueous solution (fourth material) is controlled at 5-10%.

[0018] The fully continuous chemical synthesis apparatus and method for (E)-2-oxopentenedioic acid dimethyl ester provided by this invention features a small liquid hold-up volume, rapid material mixing rate, and high mass and heat transfer efficiency, effectively improving reaction selectivity and safety. In traditional batch reactions, insufficient temperature control precision, long reaction cycles, and a tendency to initiate side reactions leading to decreased product selectivity and yield are common problems. Furthermore, deviations from the set reaction parameters can easily generate toxic and harmful substances, affecting batch product quality. The continuous flow synthesis method provided by this invention offers highly efficient mass and heat transfer characteristics, providing a foundation for precise control of reaction parameters, thereby improving reaction selectivity and product yield. The system also exhibits rapid response to parameter changes, laying a technical foundation for process automation. Attached Figure Description

[0019] Figure 1 The flowchart shows the apparatus for the fully continuous chemical synthesis of (E)-2-oxopentenedioic acid dimethyl ester. Detailed Implementation

[0020] To illustrate the technical content, structural features, objectives, and effects of the technical solution in detail, the following description, in conjunction with specific embodiments and accompanying drawings, provides further explanation. This embodiment is implemented based on the technical solution of this invention, providing detailed implementation methods and specific operating procedures; however, the scope of protection of this invention is not limited to the following embodiments.

[0021] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. Example 1

[0022] The prepared feed 1 (a methanol solution of α-ketoglutaric acid, 1.37 M) was pumped to reactor 1 (a fixed-bed reactor, made of stainless steel, with an inner diameter of 10 mm and a volume of 25 mL, filled with silica-supported sulfuric acid HND-580) via pump 1 (0.5 mL / min). Esterification was carried out at 80°C for 50 min. A back pressure valve 1 was installed at the outlet of reactor 1 to adjust the back pressure to 0.5 MPa. Its function was to regulate the reaction pressure in reactor 1, suppress solvent vaporization which could affect the reaction residence time, and ensure stable flow of the reaction fluid within the reactor. The effluent from back pressure valve 1 went directly into a solvent recovery device, where the methanol solvent was recovered at 80°C and 170 mbar and stored in tank 1. The lower outlet of the solvent recovery device was connected to tank 2 to store the esterification reaction products. Pump 2 (0.2 mL / min) delivers the esterification product and feed 2 (bromine in dichloromethane solution, 1.56 M) delivered by pump 3 (1.0 mL / min) to T-mixer 1 (PTFE material, inner diameter 1.6 mm). After thorough mixing, the mixture enters reactor 2 (coil reactor, PTFE material, inner diameter 1.6 mm, volume 23 mL), where the bromination reaction is carried out at 50°C for a residence time of 19 min. A back pressure valve 2 is installed at the outlet of reactor 2 to adjust the back pressure to 1.0 MPa. Its function is to regulate the reaction pressure in reactor 2, suppress solvent vaporization which affects the reaction residence time, and ensure a stable flow of the reaction fluid within the reactor. The effluent from back pressure valve 2 directly enters cross-shaped mixer 2 (PTFE material, inner diameter 1.6 mm). Simultaneously, pump 4 (0.3 mL / min) feeds material 3 (triethylamine) and water supplied by pump 5 (0.15 mL / min) into mixer 2. After thorough mixing, the mixture enters reactor 3 (coil reactor, PTFE material, inner diameter 4 mm, volume 33 mL) for elimination reaction at 20°C with a retention time of 20 min. The outlet of reactor 3 is directly connected to T-type mixer 3 (Hastelloy alloy material, inner diameter 4 mm), where it mixes with material 4 (5% hydrochloric acid aqueous solution) supplied by pump 6 (1.0 mL / min) and then enters reactor 4 (coil reactor, PTFE material, inner diameter 4 mm, volume 20 mL) for quenching at 20°C with a retention time of 7.5 min. Reactor 4 is directly connected to liquid-liquid separator 1 (glass, 20 mm inner diameter, 30 cm length) at its outlet. In separator 1, the organic and aqueous phases separate into layers. Separator 1 has an upper outlet and a lower outlet. The upper outlet is connected to tank 3 to store the separated upper wastewater. The lower outlet is connected to pump 7, which pumps the lower liquid (1.0 mL / min) to output the product (E)-2-oxopentenedioic acid dimethyl ester after recovering the solvent dichloromethane. This is a yellow solid with a purity greater than 99% and a yield of 97%. Example 2

[0023] The prepared feed 1 (a methanol solution of α-ketoglutaric acid, 1.37 M) is pumped to reactor 1 (a fixed-bed reactor, made of stainless steel, with an inner diameter of 10 mm and a volume of 35 mL, filled with silica-supported sulfuric acid HND-580) via pump 1 (1 mL / min). Esterification is carried out at 80°C for 35 min. A back pressure valve 1 is installed at the outlet of reactor 1 to adjust the back pressure to 0.5 MPa. Its function is to regulate the reaction pressure in reactor 1, suppress solvent vaporization which affects the reaction residence time, and ensure stable flow of the reaction fluid within the reactor. The effluent from back pressure valve 1 directly enters a solvent recovery device, where the methanol solvent is recovered at 80°C and 170 mbar and stored in tank 1. The lower outlet of the solvent recovery device is connected to tank 2 to store the esterification reaction products. Pump 2 (0.4 mL / min) delivers the esterification product and the feed 2 (bromine in dichloromethane solution, 1.56 M) delivered by pump 3 (2.0 mL / min) to T-mixer 1 (PTFE material, inner diameter 1.6 mm). After thorough mixing, the mixture enters reactor 2 (coil reactor, PTFE material, inner diameter 1.6 mm, volume 23 mL), where the bromination reaction is carried out at 50°C for a residence time of 10 min. A back pressure valve 2 is installed at the outlet of reactor 2 to adjust the back pressure to 1.0 MPa. Its function is to regulate the reaction pressure in reactor 2, suppress solvent vaporization from affecting the reaction residence time, and ensure a stable flow of the reaction fluid within the reactor. The effluent from back pressure valve 2 directly enters cross-shaped mixer 2 (PTFE material, inner diameter 1.6 mm). Simultaneously, pump 4 (0.6 mL / min) feeds material 3 (triethylamine) and water supplied by pump 5 (0.3 mL / min) into mixer 2. After thorough mixing, the mixture enters reactor 3 (coil reactor, PTFE material, inner diameter 4 mm, volume 33 mL) for elimination reaction at 20°C with a retention time of 10 min. The outlet of reactor 3 is directly connected to T-type mixer 3 (Hastelloy alloy material, inner diameter 4 mm), where it mixes with material 4 (10% hydrochloric acid aqueous solution) supplied by pump 6 (2.0 mL / min) and then enters reactor 4 (coil reactor, PTFE material, inner diameter 4 mm, volume 20 mL) for quenching at 20°C with a retention time of 3.8 min. Reactor 4 is directly connected to liquid-liquid separator 1 (glass, 20 mm inner diameter, 30 cm length) at its outlet. In separator 1, the organic and aqueous phases separate into layers. Separator 1 has an upper outlet and a lower outlet. The upper outlet is connected to tank 3 to store the separated upper wastewater. The lower outlet is connected to pump 7 (2.0 mL / min) to pump out the lower liquid. After recovering the solvent dichloromethane, the product (E)-2-oxopentenedioic acid dimethyl ester is obtained. It is a yellow solid with a purity greater than 99% and a yield of 96%. Example 3

[0024] The prepared feed 1 (a methanol solution of α-ketoglutaric acid, 1.37 M) is pumped by pump 1 (1 mL / min) to reactor 1 (a fixed-bed reactor, made of stainless steel, with an inner diameter of 10 mm and a volume of 35 mL, filled with a macroporous network solid acid catalyst (Amberlyst 15), and the esterification reaction is carried out at 100 °C for a residence time of 35 min. A back pressure valve 1 is installed at the outlet of reactor 1 to adjust the back pressure to 0.5 MPa. Its function is to regulate the reaction pressure in reactor 1, suppress solvent vaporization from affecting the reaction residence time, and ensure stable flow of the reaction fluid within the reactor. The effluent from back pressure valve 1 directly enters the solvent recovery device, where the methanol solvent is recovered at 80 °C and 170 mbar and stored in tank 1. The lower outlet of the solvent recovery device is connected to tank 2 to store the esterification reaction products. Pump 2 (0.4 mL / min) pumps the esterification products along with feed 2 (a dichloromethane solution of bromine, 1.56 M) delivered by pump 3 (2.0 mL / min). M) is fed to T-type mixer 1 (PTFE material, inner diameter 1.6 mm), and after thorough mixing, it enters reactor 2 (coil reactor, PTFE material, inner diameter 1.6 mm, volume 23 mL), where the bromination reaction is carried out at 50°C for 10 min. A back pressure valve 2 is installed at the outlet of reactor 2 to adjust the back pressure to 1.0 MPa. Its function is to regulate the reaction pressure in reactor 2, suppress solvent vaporization from affecting the reaction residence time, and ensure stable flow of the reaction fluid within the reactor. The effluent from back pressure valve 2 directly enters cross-type mixer 2 (PTFE material, inner diameter 1.6 mm), while pump 4 (0.6 mL / min) feeds material 3 (triethylamine) and water from pump 5 (0.3 mL / min) into mixer 2. After thorough mixing, it enters reactor 3 (coil reactor, PTFE material, inner diameter 4 mm, volume 33 mL), where the elimination reaction is carried out at 20°C for 10 min. The outlet of reactor 3 is directly connected to T-type mixer 3 (Hastelloy alloy material, inner diameter 4 mm). After being mixed with material 4 (10% hydrochloric acid aqueous solution) delivered by pump 6 (2.0 mL / min), the mixture enters reactor 4 (coil reactor, PTFE material, inner diameter 4 mm, volume 20 mL), where it is quenched at 20℃ for 3.8 min. The outlet of reactor 4 is directly connected to liquid-liquid separator 1 (glass material, inner diameter 20 mm, length 30 cm). In separator 1, the organic phase and aqueous phase are separated into layers. Separator 1 has an upper outlet and a lower outlet. The upper outlet is connected to tank 3 to store the separated upper wastewater. The lower outlet is connected to pump 7, which outputs the lower liquid at 2.0 mL / min. After recovering the solvent dichloromethane, the product (E)-2-oxoprene dimethyl ester is obtained. It is a yellow solid with a purity greater than 99% and a yield of 97%.

Claims

1. A fully continuous chemical synthesis apparatus for (E)-2-oxopentenedioic acid dimethyl ester, wherein, The chemical synthesis of (E)-2-oxoprenoidic acid dimethyl ester involves the following raw materials: α-ketoglutaric acid, bromine source, triethylamine, and hydrochloric acid; α-ketoglutaric acid is dissolved in methanol and is referred to as the first material. A bromine source dissolved in dichloromethane is designated as the second material, wherein the bromine source is selected from bromine, NBS, dibromohydantoin, cuprous bromide, and copper bromide; triethylamine is designated as the third material, and an aqueous solution of hydrochloric acid is designated as the fourth material; the chemical synthesis of dimethyl (E)-2-oxopentenedioic acid involves reactions including esterification, bromination, elimination, and quenching; characterized in that... The fully continuous chemical synthesis apparatus consists of 7 feed pumps, 3 mixers, 4 reactors, 2 back pressure valves, 1 solvent recovery device, 1 liquid-liquid separator, and 3 storage tanks connected sequentially according to the (E)-2-oxoprenic acid dimethyl ester synthesis route; wherein: The first pump is used to transport the first material through the pipeline to the first reactor, which is used to carry out the esterification reaction; the first reactor is connected to the first back pressure valve; the reaction liquid flowing out of the first reactor flows through the first back pressure valve, which is used to regulate the reaction pressure in the first reactor, suppress gas generation that affects the residence time, and ensure that the reaction fluid flows smoothly in the reactor. The first back pressure valve is connected to the solvent recovery device via a pipeline, and the effluent from the first back pressure valve directly enters the solvent recovery device through the pipeline. The solvent recovery device is equipped with an upper outlet and a lower outlet. The upper outlet is connected to a first storage tank, which is used to store the recovered solvent. The lower outlet is connected to a second storage tank, which is used to store the esterification reaction products. The esterification reaction products in the second storage tank are transported to the first mixer by a second pump. The second material is transported to the first mixer by a third pump. The first mixer is connected to the second reactor via a pipeline, and the materials in the first mixer are fully mixed and then directly enter the second reactor through the pipeline. The bromination reaction takes place in the second reactor. The reaction liquid flowing out of the second reactor flows through the second back pressure valve and directly enters the second mixer; the fourth pump inputs the third material into the second mixer, and the fifth pump delivers water to the second mixer. After the three are fully mixed in the second mixer, they enter the third reactor through pipelines, where the elimination reaction takes place. The reaction liquid flowing out of the third reactor is fully mixed with the fourth material delivered by the sixth pump in the third mixer and then directly enters the fourth reactor, where the quenching reaction takes place. The quenched liquid directly enters the first liquid-liquid separator, where the organic phase and the aqueous phase separate into layers. The first liquid-liquid separator is equipped with an upper outlet and a lower outlet. The upper outlet is connected to a third storage tank, which is used to store wastewater. The lower outlet is connected to a seventh pump to output the liquid. After recovering the solvent, the target product (E)-2-oxoprenoidic acid dimethyl ester is obtained.

2. The fully continuous chemical synthesis apparatus according to claim 1, characterized in that: The first pump, the second pump, the third pump, the fourth pump, the fifth pump, the sixth pump, and the seventh pump are all plunger pumps or peristaltic pumps for transporting solutions; The first and third mixers are Y-type or T-type mixers, and the second mixer is a cross-type mixer; The first reactor is a fixed-bed reactor; the second, third, and fourth reactors are coil reactors. The connecting pipes of the first back pressure valve and the second back pressure valve have a size of 1.6 mm-10 mm and a pressure range of 0.1-10.0 MPa.

3. The fully continuous chemical synthesis apparatus according to claim 2, characterized in that: The first reactor has a cylindrical reaction chamber as its main body, filled with a solid acid catalyst. A heat exchange fluid jacket is added to the outer layer of the chamber for heat exchange. The diameter is 1-20 cm, the length is 20-200 cm, and the throughput is 1-5000 mL / min. The solid acid is an acidic macroporous resin, zeolite, heteropoly acid and its salts, acidic metal oxides, and supported liquid acid. The second, third, and fourth reactors are mainly tubular cavities that serve as fluid channels with a diameter of 100μm-20 mm and a length of 1-1000 m.

4. The fully continuous chemical synthesis apparatus according to claim 2, characterized in that: The solvent recovery device consists of a rotary evaporator, a cooling circulation device, and a pressure reducing device. The main body of the evaporator is a cylindrical jacketed bottle. The outer jacket is connected to a circulating oil bath to heat the system, and the inner jacket stores the reaction liquid. The middle part is a central shaft with a stirring paddle, which is driven by a motor to rotate and perform stirring. The circulating cooling device is used to condense solvent vapor and recover solvent. The pressure reducing device is used to reduce the system pressure and improve the solvent recovery efficiency.

5. The fully continuous chemical synthesis apparatus according to claim 2, characterized in that, The liquid-liquid separator is designed based on the principle of gravity sedimentation. The main body of the liquid-liquid separator is a cylindrical cavity. The lower end of the cavity is provided with an inlet for the material to be separated and an outlet for the lower heavy phase, while the upper end of the cavity is provided with an outlet for the upper light phase. The inner diameter of the separator is 1-20 cm and the height is 1-200 cm.

6. A method for the fully continuous chemical synthesis of dimethyl (E)-2-oxopentenedioic acid based on the fully continuous chemical synthesis apparatus according to any one of claims 1-5, characterized in that: The reaction temperature in the first reactor 1 is controlled at 50-150℃, and the reaction time is controlled at 30-90 minutes; The reaction temperature in the second reactor 2 is controlled at 30-100℃, and the reaction time is controlled at 10-30 minutes; The reaction temperature in the third reactor 3 is controlled at 0-30℃, and the reaction time is controlled at 10-30 minutes; The reaction temperature in the fourth reactor 4 is controlled at 0-30℃, and the reaction time is controlled at 3-10 minutes; The pressure of the first back pressure valve is controlled to be 0.5-2.0 MPa; The pressure of the second back pressure valve is controlled to be 1.0-5.0 MPa.

7. The fully continuous chemical synthesis method according to claim 6, characterized in that: The flow rate of the first material conveyed by the first pump is controlled to be 0.5-2.0 mL / min; Control the flow rate of the reaction solution delivered by the second pump to be 0.2-0.8 mL / min; The flow rate of the second material delivered by the third pump is controlled to be 1.0-4.0 mL / min; The flow rate of the third material delivered by the fourth pump is controlled to be 0.3-1.2 mL / min; Control the flow rate of water delivered by the fifth pump to 0.15-0.6 mL / min; The flow rate of the fourth substance delivered by the sixth pump is controlled to be 1.0-4.0 mL / min; Control the flow rate of the reaction solution delivered by the seventh pump to be 1.0-4.0 mL / min.

8. The fully continuous chemical synthesis method according to claim 7, characterized in that: The concentration of the methanol solution of α-ketoglutaric acid, i.e., the first material, is controlled to be 0.5-1.5 mol / L. The concentration of the dichloromethane solution (the second material) used as the bromine source was controlled to be 1.5-2.0 mol / L. The concentration of the hydrochloric acid aqueous solution, i.e., the fourth material, is controlled to be 5-10%.

Images