An apparatus for synthesizing candesartan intermediates

Abstract

The application relates to the technical field of candesartan intermediate synthesis, in particular to a device for synthesizing candesartan intermediate; the device comprises a micro-channel reactor, a tubular reactor and a continuous separator; the tubular reactor further comprises an outer tube and a mixer installed in the inner part of the outer tube; the mixer comprises a tube body and an SK core; the SK core is composed of a plurality of left and right twisted 180-degree spiral pieces; liquid inlets and liquid outlets are arranged on the surface of the outer tube; the SK core can be detachably connected, so that the user can separately detach the blocked SK core, clean or replace the blocked SK core, the expensive SK type static mixer does not need to be replaced as a whole, the equipment procurement cost is greatly reduced, the tubular reactor as a whole does not need to be complicatedly detached and reassembled, the downtime is obviously reduced, and the overall production efficiency of the synthesized candesartan intermediate is improved.

Description

Technical Field

[0001] This invention relates to the field of candesartan intermediate synthesis technology, specifically to an apparatus for synthesizing candesartan intermediates. Background Technology

[0002] Candesartan is an organic compound belonging to the angiotensin II receptor antagonist class. It is used to treat hypertension in humans and has the characteristics of significant efficacy and high safety. However, the prodrug of candesartan is candesartan cilexetil, which needs to be rapidly hydrolyzed in the patient's body into the active metabolite candesartan in order to exert its therapeutic effect. Methyl 2-amino-3-nitrobenzoate is a pharmaceutical intermediate for the synthesis of candesartan cilexetil.

[0003] Several existing technologies have also proposed methods for preparing methyl 2-amino-3-nitrobenzoate. For example, Chinese patent CN111253271A discloses a method for preparing methyl 2-amino-3-nitrobenzoate, which includes the following steps: first, phthalimide solution and sodium hypochlorite solution are pumped into a microreactor for mixing and reaction, and then reacted with water in a tubular reactor to obtain methyl anthranilate, which is then separated into a crude product; the crude methyl anthranilate, acetic anhydride solution, and fuming nitric acid are pumped into a microchannel reactor for mixing and reaction to obtain methyl N-nitrobenzoate, which is then separated into a crude product; the methyl N-nitrobenzoate solution, concentrated sulfuric acid, and water are pumped into a microchannel reactor for mixing and reaction to obtain crude methyl 2-amino-3-nitrobenzoate; the crude product is recrystallized in methanol to obtain the product methyl 2-amino-3-nitrobenzoate. This method has high yield, good safety, and is suitable for industrial production.

[0004] However, when using a tubular reactor, this technical solution is susceptible to side reactions between phthalimide and sodium hypochlorite due to temperature fluctuations or uneven distribution of sodium hypochlorite. These reactions can generate isomers such as aminobenzoic acid and m-aminobenzoic acid, which have low solubility and are prone to precipitation. This precipitation can lead to the accumulation of sediment in the gaps of the SK core components of the SK-type static mixer, one of the core components of the tubular reactor (the SK-type static mixer consists of a tube and an internal SK core component, which is made of spiral blades twisted 180° to the left and right and welded at 90° angles). This results in a reduction in the flow area. Since the SK core component is often fixed to the tube by welding (to prevent displacement of the SK core component due to material impact), it cannot be disassembled and cleaned separately after blockage. The entire SK-type static mixer must be replaced, which significantly increases the equipment purchase cost. In addition, replacing the SK-type static mixer requires shutting down the reactor and draining the liquid inside, which increases the downtime of the tubular reactor and reduces the overall production efficiency.

[0005] In view of this, in order to overcome the above-mentioned technical problems, the present invention proposes an apparatus for synthesizing candesartan intermediates, which solves the above-mentioned technical problems. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, this invention proposes an apparatus for synthesizing candesartan intermediates. By setting up a detachable connection for the SK core, this invention facilitates the user to disassemble and clean or replace clogged SK cores individually, eliminating the need to replace the entire expensive SK-type static mixer, thus significantly reducing equipment procurement costs. It also eliminates the need for complex disassembly and reassembly of the tubular reactor, significantly reducing downtime and thereby improving the overall production efficiency of synthesizing candesartan intermediates.

[0007] The technical solution adopted by this invention to solve its technical problem is as follows: An apparatus for synthesizing candesartan intermediates, comprising a microchannel reactor, a tubular reactor, and a continuous separator; the tubular reactor further comprises an outer tube and a mixer installed inside the outer tube; the mixer comprises a tube body and an SK core; the SK core is composed of multiple spiral blades twisted 180° to the left and right; the outer tube surface is provided with an inlet and an outlet.

[0008] The pipe body is fitted with a No. 1 flange and a No. 2 flange at both ends; bolt holes are provided on the surfaces of both the No. 1 flange and the No. 2 flange; threaded holes corresponding to the bolt holes are provided at both ends of the outer pipe; the No. 1 flange is fixedly connected to the pipe body; the No. 2 flange is threadedly connected to the pipe body; a connecting block is fixedly connected to one end of the spiral blade; a locking block is fixedly connected to the other end; a locking groove that mates with the connecting block is provided at the end of the locking block away from the spiral blade; a locking unit is installed in the locking groove; the locking unit is used to connect two adjacent spiral blades.

[0009] A fixing unit is installed inside the tube; the fixing unit is used to fix the SK chip inside the tube.

[0010] Preferably, the fixing unit includes a fixing groove; the fixing groove is formed on the inner wall of the pipe body; a fixing block is slidably and sealingly connected in the fixing groove; a connecting groove is formed at the lower end of the fixing block; a positioning groove that cooperates with the fixing block is formed at the upper end of the locking block; a groove communicating with the fixing groove is formed on the surface of the first flange; a lead rod is threadedly connected to the groove.

[0011] Preferably, the outer tube surface has a through groove; an adjusting rod is rotatably connected in the through groove; the adjusting rod is connected to the groove wall of the through groove by an adjusting spring; and the upper end of the lead screw has a slot that cooperates with the adjusting rod.

[0012] Preferably, the tubular reactor is arranged in three rows, with at least two tubular reactors in each row, and adjacent tubular reactors connected in series. The three rows of tubular reactors are fixedly connected in series by U-shaped tubes.

[0013] Preferably, the cross-sectional shape of the connecting groove is set to an isosceles trapezoid.

[0014] Preferably, the clamping unit includes a clamping rod; a rectangular groove is formed on the upper wall of the clamping slot; the clamping rod is slidably and sealingly connected in the rectangular groove; the clamping rod and the bottom of the rectangular groove are connected by a support spring; and a square groove that mates with the clamping rod is formed on the surface of the connecting block.

[0015] Preferably, the lower end of the card block has a cylindrical groove communicating with the rectangular groove; a rotating rod is rotatably connected inside the cylindrical groove; a threaded cylinder is threadedly connected to one end of the rotating rod near the bottom of the cylindrical groove; the threaded cylinder is slidably connected inside the cylindrical groove.

[0016] A method for synthesizing a candesartan intermediate, applicable to the aforementioned apparatus for synthesizing a candesartan intermediate, comprising the following steps:

[0017] S1: Phthalimide solution with a concentration range of 1.8-4.0 mol / L and sodium hypochlorite solution with a concentration range of 5%-13% are pumped into a microchannel reactor for reaction. The reaction temperature is -5-15℃ and the reaction residence time is 20-40s. The reactant solution flows into the tubes of the first row of tubular reactors and flows out from the tubes of the third row of end tubular reactors.

[0018] S2: Before the raw material solution is conveyed to the first row of tubular reactors, the hot water temperature in the outer tube of the first row of tubular reactors is 60-70℃, the hot water temperature in the outer tube of the second row of tubular reactors is 75-85℃, and the hot water temperature in the outer tube of the third row of tubular reactors is 85-90℃.

[0019] S3: The reaction product flowing out from the end of the third tubular reactor is transported to the continuous separator to obtain crude methyl anthranilate, which is then prepared into a methyl anthranilate solution with a concentration range of 1.2-2.0 mol / L through a batching tank.

[0020] S4: Crude methyl anthranilate, acetic anhydride solution (3.6-4.8 mol / L), and fuming nitric acid are pumped into a microchannel reactor for mixing and reaction. The mixture is then conveyed to a continuous separator to separate crude methyl N-nitrobenzene. The crude methyl N-nitrobenzene is then prepared into a methyl N-nitrobenzene solution with a concentration range of 0.8-1.6 mol / L using a mixing tank.

[0021] S5: Pump N-nitrobenzoate solution and sulfuric acid solution with a concentration of 65%-98% into a microchannel reactor, mix and react to obtain crude 2-amino-3-nitrobenzoate; finally, recrystallize the crude 2-amino-3-nitrobenzoate from methanol to obtain the product 2-amino-3-nitrobenzoate.

[0022] The beneficial effects of this invention are as follows:

[0023] 1. This invention features a detachable connection for the SK core component, allowing users to easily disassemble and clean or replace clogged SK core components without replacing the entire expensive SK-type static mixer. This significantly reduces equipment procurement costs and eliminates the need for complex disassembly and reassembly of the tubular reactor, thereby significantly reducing downtime and improving the overall production efficiency of synthesizing candesartan intermediates.

[0024] 2. This invention uses multiple detachably connected spiral blades to form the SK chip, allowing for effective connection of the SK chips within each row of tubular reactors. After the SK chip is separated from the tube, the user can pull one end of the SK chip, causing it to move synchronously with the connected SK chips within the row of tubular reactors. This allows the SK chip in the row of tubular reactors to be pulled out from the outermost end of the tubular reactor, significantly reducing the difficulty and efficiency of SK chip disassembly. This, in turn, reduces downtime of the tubular reactors and improves overall production efficiency. Furthermore, the user can quickly replace SK chips with different structural parameters (such as adjusting the spiral blade angle) according to changes in raw material characteristics and reaction conditions, thereby optimizing the mixing effect of the raw material solution. Attached Figure Description

[0025] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0026] Figure 1 This is a perspective view of the tubular reactor used in this invention;

[0027] Figure 2 This is a schematic diagram of the tubular reactor used in this invention;

[0028] Figure 3 yes Figure 2 Enlarged view of point A in the middle;

[0029] Figure 4 yes Figure 2 Enlarged view of point B in the middle;

[0030] Figure 5 This is a partial cross-sectional view of the tubular reactor used in this invention;

[0031] Figure 6This is a schematic diagram of the connection of the spiral plates used in this invention;

[0032] Figure 7 This is a flowchart of the method of the present invention.

[0033] In the diagram: 1. Outer tube; 11. Inlet; 12. Outlet; 13. Threaded hole; 14. Through groove; 141. Adjusting rod; 142. Adjusting spring; 15. U-shaped tube; 2. Mixer; 21. Tube body; 211. No. 1 flange; 212. No. 2 flange; 213. Bolt hole; 214. Fixing groove; 215. Fixing block; 216. Connecting groove; 22. SK core component; 221. Spiral blade; 23. Connecting block; 231. Square groove; 24. Locking block; 241. Locking groove; 242. Positioning groove; 25. Groove; 251. Lead screw; 252. Slotted groove; 26. Rectangular groove; 261. Locking rod; 262. Support spring; 27. Columnar groove; 271. Rotating rod; 272. Threaded cylinder. Detailed Implementation

[0034] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0035] like Figures 1 to 7 As shown, the apparatus for synthesizing candesartan intermediates according to the present invention includes a microchannel reactor, a tubular reactor, and a continuous separator; the tubular reactor further includes an outer tube 1 and a mixer 2 installed inside the outer tube 1; the mixer 2 includes a tube body 21 and an SK core 22; the SK core 22 is composed of multiple helical blades 221 twisted 180° to the left and right; the outer tube 1 has an inlet 11 and an outlet 12 on its surface;

[0036] The pipe body 21 is fitted with a first flange 211 and a second flange 212 at both ends, respectively; bolt holes 213 are provided on the surfaces of both the first flange 211 and the second flange 212; threaded holes 13 corresponding to the bolt holes 213 are provided at both ends of the outer pipe 1; the first flange 211 is fixedly connected to the pipe body 21; the second flange 212 is threadedly connected to the pipe body 21; a connecting block 23 is fixedly connected to one end of the spiral blade 221; a locking block 24 is fixedly connected to the other end; a locking groove 241 that mates with the connecting block 23 is provided at the end of the locking block 24 away from the spiral blade 221; a locking unit is installed in the locking groove 241; the locking unit is used to connect two adjacent spiral blades 221.

[0037] A fixing unit is installed inside the tube body 21; the fixing unit is used to fix the SK chip inside the tube body 21.

[0038] In one embodiment of the present invention, the fixing unit includes a fixing groove 214; the fixing groove 214 is formed on the inner wall of the pipe body 21; a fixing block 215 is slidably and sealingly connected in the fixing groove 214; a connecting groove 216 is formed at the lower end of the fixing block 215; a positioning groove 242 that cooperates with the fixing block 215 is formed at the upper end of the locking block 24; a groove 25 that communicates with the fixing groove 214 is formed on the surface of the first flange 211; and a lead rod 251 is threadedly connected to the groove 25.

[0039] In one embodiment of the present invention, a through groove 14 is provided on the surface of the outer tube 1; an adjusting rod 141 is rotatably connected in the through groove 14; the adjusting rod 141 is connected to the groove wall of the through groove 14 by an adjusting spring 142; and a slot 252 is provided at the upper end of the lead screw 251 to cooperate with the adjusting rod 141.

[0040] In one embodiment of the present invention, the tubular reactor is arranged in three rows, with at least two tubular reactors in each row, and two adjacent tubular reactors connected in series. The three rows of tubular reactors are fixedly connected in series by U-shaped tubes 15.

[0041] In one embodiment of the present invention, the cross-sectional shape of the connecting groove 216 is set as an isosceles trapezoid.

[0042] During operation, when used in a tubular reactor, temperature fluctuations or uneven distribution of sodium hypochlorite can cause phthalimide to react with sodium hypochlorite to produce isomers such as aminobenzoic acid and m-aminobenzoic acid. These substances have low solubility and are prone to precipitation. This precipitation can lead to the accumulation of sediment in the gaps of the SK core 22 of the SK-type static mixer 2, one of the core components of the tubular reactor (the SK-type static mixer 2 consists of a tube body 21 and an internal SK core 22, which is made of spiral blades 221 twisted 180° to the left and right and welded at 90° angles). This reduces the flow area. Since the SK core 22 is mostly fixed to the tube body 21 by welding (to prevent the SK core 22 from shifting due to material impact), it cannot be disassembled and cleaned separately after blockage. The entire SK-type static mixer 2 must be replaced, which significantly increases the equipment purchase cost. In addition, replacing the SK-type static mixer 2 requires shutting down and draining the liquid in the tubular reactor, thereby reducing the downtime of the tubular reactor and improving the overall production efficiency.

[0043] In response, this invention provides a detachable connection for the SK core 22, which allows users to easily remove and clean or replace the clogged SK core 22 without replacing the entire expensive SK-type static mixer 2, thus significantly reducing equipment purchase costs. It also eliminates the need for complex disassembly and reassembly of the tubular reactor, significantly reducing downtime and thereby improving the overall production efficiency of synthesizing candesartan intermediates.

[0044] Initially, phthalimide solution and sodium hypochlorite solution are stored separately in storage tanks. The concentration of phthalimide solution in the storage tanks ranges from 1.8 to 4.0 mol / L, and the concentration of sodium hypochlorite solution ranges from 5% to 13%. The phthalimide solution and sodium hypochlorite solution are pumped into a microchannel reactor at a ratio of 1:1.2-1.5. The reaction temperature is -5 to 15℃, and the reaction residence time is 20 to 40 s. After the reaction, the raw material solution is transferred to a tubular reactor, where the reaction temperature is 55℃ to 90℃, and the reaction residence time is 180 to 300 s. After the reaction is completed, the solution is passed through a continuous separator (such as a disc separator). A pale yellow oily substance, namely crude methyl anthranilate, was obtained by separation. The crude methyl anthranilate was then prepared into a methyl anthranilate solution with a concentration range of 1.2-2.0 mol / L using a mixing tank. Subsequently, the crude methyl anthranilate, acetic anhydride solution (3.6-4.8 mol / L), and fuming nitric acid were pumped into a microchannel reactor for mixing and reaction to obtain methyl N-nitrobenzene. After separation by a continuous separator, the crude product was obtained. The methyl N-nitrobenzene solution, concentrated sulfuric acid, and water were pumped into the microchannel reactor for mixing and reaction to obtain the crude product. The crude product was recrystallized in methanol to obtain the product methyl 2-amino-3-nitrobenzene.

[0045] Assembly of the tubular reactor: The user needs to first connect the outer tube 1 to the tube body 21. Specifically, rotate the second flange 212 so that the second flange 212 at one end of the tube body 21 rotates spirally and separates from the tube body 21. Then, insert the end of the tube body 21 that is detached from the second flange 212 into the outer tube 1 until the end of the tube body 21 that is detached from the second flange 212 extends out of the outer tube 1. Then tighten the second flange 212 onto the end of the tube body 21 that extends out of the outer tube 1. At this time, the fixing groove 214 at the upper end of the first flange 211 is located below the through groove 14. At this time, the tube body 21 and the outer tube 1 are in a sliding sealing connection. Then rotate the tube body 21 so that the first flange 211 and the second flange 212 are in a sliding sealing connection. The bolt holes 213 on the surface of tube 212 are aligned with the threaded holes 13 at both ends of the outer tube 1. Bolts are then threaded through the bolt holes 213 and connected to the threaded holes 13, allowing the tube body 21 to be fixed to the outer tube 1 via flange 211 and flange 212. At this point, the fixing groove 214 is aligned with the through groove 14. After connecting the tube body 21 to the outer tube 1, the SK chip is inserted into the tube body 21, so that the locking block 24 on one side of the leftmost spiral plate 221 of the SK chip is directly below the fixing groove 214. At this point, the positioning groove 242 at the upper end of the locking block 24 is aligned with the fixing groove 214. The user pushes the adjusting rod 141, causing the adjusting rod 141 to... The adjusting spring 142 is pressed into the through groove 14, causing the end of the adjusting rod 141 near the lead screw 251 to pass through the through groove 14 and enter the groove 25. Since the lower end of the adjusting rod 141 engages with the slot 252, the lower end of the adjusting rod 141 is inserted into the slot 252. Because the adjusting rod 141 is rotatably connected to the adjusting spring 142, rotating the adjusting rod 141 will not cause the adjusting spring 142 to rotate, and the adjusting spring 142 will not obstruct the rotation of the adjusting rod 141 within the through groove 14. This allows the rotating adjusting rod 141 to push the lead screw 251 to rotate through the groove wall of the slot 252, thus allowing the rotating lead screw... 251 can spirally enter the groove 25. Since the groove 25 is filled with hydraulic oil, the hydraulic oil in the groove 25 will enter the fixing groove 214 communicating with the groove 25, causing the fixing block 215 in the fixing groove 214 to extend out of the fixing groove 214, and causing the locking block 24 below the fixing block 215 to insert into the connecting groove 216, until the fixing block 215 is inserted into the positioning groove 242 at the upper end of the locking block 24, so that the fixing block 215 and the locking block 24 are engaged through the connecting groove 216 and the positioning groove 242, thereby allowing the locking block 24 to be fixedly connected to the tube body 21 through the fixing block 215; at this time, the connection between the SK core 22 and the tube body 21 is completed.

[0046] Since the SK core 22 is manually pushed into the tube body 21 by the operator, human error can affect the accuracy of the connection between the upper slot 241 of the locking block 24 and the lower connecting slot 216 of the fixing block 215. Therefore, by setting the connecting slot 216 to an isosceles trapezoid, the opening of the end of the connecting slot 216 away from the bottom of the fixing slot 214 is larger. This ensures that during the descent of the fixing block 215, the locking block 24 can be inserted into the connecting slot 216 through the larger opening end. This ensures that the locking block 24 can be inserted into the connecting slot 216 during the insertion process. The locking block 24 is limited by the wall of the connecting groove 216, so that the locking block 24 rotates appropriately under the obstruction of the wall of the connecting groove 216, so as to ensure that the positioning groove 242 at the upper end of the locking block 24 is aligned with the bottom of the connecting groove 216. This facilitates the precise engagement between the fixing block 215 and the locking block 24 through the connecting groove 216 and the positioning groove 242, eliminating the need for repeated calibration by the operator. This shortens the connection time between the SK core 22 and the tube body 21, improves the replacement efficiency of the SK core 22, and thus reduces the downtime of the tubular reactor and improves the overall production efficiency.

[0047] When the SK core 22 needs to be disassembled and cleaned due to blockage, the user only needs to push the adjusting rod 141 into the groove 25, so that the adjusting rod 141 is connected to the lead screw 251. Rotating the adjusting rod 141 in the opposite direction causes the lead screw 251 to rotate in the opposite direction, so that the lead screw 251 rotates away from the fixing block 215. At this time, the hydraulic oil in the fixing groove 214 flows back into the groove 25, so that the fixing block 215 enters the fixing groove 214 under the suction of negative pressure. At this time, the SK core 22 is no longer connected to the tube body 21 through the fixing block 215. The user can directly pull the SK core 22 out of the tube body 21, so that the user can directly replace or clean the SK core 22 without the need for complex disassembly and reassembly of the entire tubular reactor, which significantly reduces downtime and improves the overall production efficiency of synthesizing candesartan intermediates.

[0048] Before the raw material solution is delivered to the tubular reactor, the user delivers hot water at 60-90°C into the outer tube 1 through the inlet 11, allowing the hot water to flow between the outer tube 1 and the tube body 21. After the raw material solution is delivered into the tubular reactor, the SK core 22 inside the tube body 21 will fully mix the two mixed raw material solutions delivered into the tubular reactor. When the hot water heats the raw material solution inside the tube body 21 through the outer wall of the tube body 21, the fully mixed raw material solution can react rapidly and generate methyl anthranilate.

[0049] Because the tubular reactors are arranged in three rows from top to bottom, with at least two tubular reactors in each row, and two tubular reactors connected in series, and the three rows of tubular reactors connected in series via U-shaped tubes 15, initially, the raw material solution is introduced through the tubular reactor in the first row above. At this time, the hot water temperature in the inlet 11 of the tubular reactor in the first row above is set at 60-70℃, the hot water temperature in the inlet 11 of the tubular reactor in the second row is set at 75-85℃, and the hot water temperature in the inlet 11 of the tubular reactor in the third row is set at 85-90℃. This is because the high temperature conditions of the tubular reactors can be regarded as a necessary temperature-changing step in the esterification and hydrolysis reactions, and this temperature range corresponds to the requirements of the Hoffmann degradation reaction and the esterification reaction (for example, when using N-chlorophthalimide as raw material, it is necessary to react below 0℃ first, and then raise the temperature to 50-80℃ to complete the conversion). Matching the 90℃ range, the temperature is increased to promote amide bond breaking and esterification dissociation, ensuring the formation efficiency of methyl anthranilate: that is, in the early stage of the reaction, the low temperature needs to be controlled in the microchannel reactor (-5-15℃) to prevent sodium hypochlorite decomposition, while in the later stage, a high temperature environment of 60-90℃ needs to be maintained in the tubular reactor to achieve amide bond breaking and esterification reaction. Therefore, the gradient temperature scheme of three-row series tubular reactors can precisely control the reaction process. Specifically, in the first row of tubular reactors, the raw material solution initiates the reaction at a lower temperature (e.g., 60-70℃), in the second row of tubular reactors, the raw material solution promotes the main reaction at a medium temperature (e.g., 75-85℃), and in the third row of tubular reactors, the raw material solution completes the conversion or decomposes the by-products at a higher temperature (e.g., 85-90℃), thereby maintaining a specific reaction stage and gradually promoting the reaction to ensure the formation efficiency of methyl anthranilate.

[0050] In one embodiment of the present invention, the clamping unit includes a clamping rod 261; a rectangular groove 26 is provided on the upper wall of the clamping groove 241; the clamping rod 261 is slidably and sealingly connected in the rectangular groove 26; the clamping rod 261 and the bottom of the rectangular groove 26 are connected by a support spring 262; and a square groove 231 that cooperates with the clamping rod 261 is provided on the surface of the connecting block 23.

[0051] In one embodiment of the present invention, the lower end of the card block 24 is provided with a cylindrical groove 27 communicating with the rectangular groove 26; a rotating rod 271 is rotatably connected in the cylindrical groove 27; a threaded cylinder 272 is threadedly connected to one end of the rotating rod 271 near the bottom of the cylindrical groove 27; the threaded cylinder 272 is slidably connected in the cylindrical groove 27.

[0052] During operation, since there are three rows of tubular reactors, with at least two in each row, the outer tube 1 between the two tubular reactors in each row is fixed. Therefore, after rotating the two adjusting rods 141 inside the two tubular reactors in each row to separate the SK chip from the tube body 21, the SK chip needs to be pulled out from the two connected tube bodies 21 from both ends of the two connected tubular reactors. If there are three or more tubular reactors in each row, the user can only use tools to push the SK chip located in the middle out of the tube body 21, which greatly increases the difficulty of disassembling the SK chip and reduces the efficiency of disassembling the SK chip.

[0053] To address this, the present invention addresses the issue by configuring the SK chip as a detachable connection of multiple spiral plates 221. This allows the SK chips within each row of tubular reactors to be effectively connected. After the SK chip is separated from the tube 21, the user can pull one end of the SK chip, causing it to move synchronously with the connected SK chips within the row of tubular reactors. This allows the SK chip within the row of tubular reactors to be pulled out from one end of the outermost tubular reactor, significantly reducing the difficulty of disassembling the SK chip, improving the disassembly efficiency, thereby reducing downtime of the tubular reactors and improving overall production efficiency.

[0054] Because SK chips are pre-assembled before leaving the factory, the two spiral blades 221, twisted 180° to the left and right, are crossed at 90°, so that the connecting block 23 of the left spiral blade 221 (the spiral blade 221 twisted 180° to the left) is aligned with the locking block 24 of the right spiral blade 221 (the spiral blade 221 twisted 180° to the right). As the two spiral blades 221 move closer to each other, the connecting block 23 of the left spiral blade 221 is inserted into the locking slot 241 of the right spiral blade 221. In the initial state, the locking rod 261 is pushed and squeezed by the hydraulic oil. The support spring 262 is located inside the rectangular groove 26. At this time, the threaded cylinder 272 is close to the bottom of the cylindrical groove 27. When it is necessary to connect the two spiral blades 221, simply rotate the rotating rod 271, causing relative rotation between the rotating rod 271 and the threaded cylinder 272. Since the threaded cylinder 272 is slidably connected inside the cylindrical groove 27, it slides continuously away from the bottom of the cylindrical groove 27 under the helical push of the rotating rod 271. This increases the space inside the cylindrical groove 27, allowing the locking rod 261 to be pushed by the restoring force of the support spring 262. The rectangular groove 26 extends downwards, causing the hydraulic oil inside the rectangular groove 26 to flow into the cylindrical groove 27 under negative pressure. This allows the locking rod 261 extending from the rectangular groove 26 to insert into the square groove 231 on the surface of the connecting block 23, thus fixing the connecting block 23 and the locking block 24 together through the locking rod 261. Similarly, when connecting two adjacent tubular reactors, first rotate the adjusting rod 141 inside one of the tubular reactors to separate the SK chip inside the tubular reactor from the tube body 21. Then connect the SK chip to the adjacent SK chip, and then connect the connected SK chip to the tube body 21 of the tubular reactor. Finally, connect the outer tubes 1 of the two tubular reactors. When cleaning the SK chip, the user can pull one end of the SK chip to pull the SK chip out from the outermost end of the tubular reactor. In addition, the user can also quickly replace the SK core 22 with different structural parameters (such as adjusting the angle of the spiral blade 221) according to the characteristics of the raw materials and changes in the reaction conditions, thereby optimizing the mixing effect of the raw material solution.

[0055] In addition, the SK chip is designed to be detachably connected by multiple spiral blades 221. This means that when the SK chip needs to be replaced due to wear in a certain part, only the worn spiral blade 221 needs to be quickly removed and replaced, without replacing the entire SK chip. This greatly reduces the purchase cost of the SK chip and lowers the equipment maintenance cost.

[0056] A method for synthesizing a candesartan intermediate, applicable to the aforementioned apparatus for synthesizing a candesartan intermediate, comprising the following steps:

[0057] S1: A phthalimide solution with a concentration range of 1.8-4.0 mol / L and a sodium hypochlorite solution with a concentration range of 5%-13% are pumped into a microchannel reactor for reaction. The reaction temperature is -5-15℃, and the reaction residence time is 20-40s. The reactant solution flows into the tube 21 of the first row of tubular reactors and flows out from the tube 21 of the third row of end tubular reactors.

[0058] S2: Before the raw material solution is conveyed to the first row of tubular reactors, the hot water temperature in the outer tube 1 of the first row of tubular reactors is 60-70℃, the hot water temperature in the outer tube 1 of the second row of tubular reactors is 75-85℃, and the hot water temperature in the outer tube 1 of the third row of tubular reactors is 85-90℃.

[0059] S3: The reaction product flowing out from the end of the third tubular reactor is transported to the continuous separator to obtain crude methyl anthranilate, which is then prepared into a methyl anthranilate solution with a concentration range of 1.2-2.0 mol / L through a batching tank.

[0060] S4: Crude methyl anthranilate, acetic anhydride solution (3.6-4.8 mol / L), and fuming nitric acid are pumped into a microchannel reactor for mixing and reaction. The mixture is then conveyed to a continuous separator to separate crude methyl N-nitrobenzene. The crude methyl N-nitrobenzene is then prepared into a methyl N-nitrobenzene solution with a concentration range of 0.8-1.6 mol / L using a mixing tank.

[0061] S5: Pump N-nitrobenzoate solution and sulfuric acid solution with a concentration of 65%-98% into a microchannel reactor, mix and react to obtain crude 2-amino-3-nitrobenzoate; finally, recrystallize the crude 2-amino-3-nitrobenzoate from methanol to obtain the product 2-amino-3-nitrobenzoate.

[0062] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. An apparatus for synthesizing candesartan intermediates, comprising a microchannel reactor, a tubular reactor, and a continuous separator; the tubular reactor further comprising an outer tube (1) and a mixer (2) installed inside the outer tube (1); the mixer (2) comprising a tube body (21) and an SK core (22); the SK core (22) being composed of a plurality of helical blades (221) twisted 180° to the left and right; the outer tube (1) having an inlet (11) and an outlet (12) on its surface, characterized in that: The pipe body (21) is fitted with a No. 1 flange (211) and a No. 2 flange (212) at both ends respectively; bolt holes (213) are provided on the surface of both the No. 1 flange (211) and the No. 2 flange (212); threaded holes (13) corresponding to the bolt holes (213) are provided at both ends of the outer pipe (1); the No. 1 flange (211) is fixedly connected to the pipe body (21); the No. 2 flange (212) is threadedly connected to the pipe body (21); the spiral blade (221) One end is fixedly connected to a connecting block (23); the other end is fixedly connected to a locking block (24); the locking block (24) has a slot (241) that cooperates with the connecting block (23) at the end away from the spiral blade (221); a locking unit is installed in the slot (241); the locking unit is used to connect two adjacent spiral blades (221); a fixing unit is installed in the tube body (21); the fixing unit is used to fix the SK chip in the tube body (21); The fixing unit includes a fixing groove (214); the fixing groove (214) is formed on the inner wall of the pipe body (21); a fixing block (215) is slidably and sealingly connected in the fixing groove (214); a connecting groove (216) is formed at the lower end of the fixing block (215); a positioning groove (242) is formed at the upper end of the locking block (24) to cooperate with the fixing block (215); a groove (25) is formed on the surface of the first flange (211) to communicate with the fixing groove (214); a screw rod (251) is threadedly connected to the groove (25); The outer tube (1) has a through groove (14) on its surface; an adjusting rod (141) is rotatably connected inside the through groove (14); the adjusting rod (141) is connected to the groove wall of the through groove (14) by an adjusting spring (142); the upper end of the lead screw (251) has a slot (252) that cooperates with the adjusting rod (141); The clamping unit includes a clamping rod (261); a rectangular groove (26) is provided on the upper wall of the clamping groove (241); the clamping rod (261) is slidably and sealingly connected in the rectangular groove (26); the clamping rod (261) and the bottom of the rectangular groove (26) are connected by a support spring (262); the surface of the connecting block (23) is provided with a square groove (231) that cooperates with the clamping rod (261); The lower end of the card block (24) is provided with a cylindrical groove (27) that communicates with the rectangular groove (26); a rotating rod (271) is rotatably connected in the cylindrical groove (27); a threaded cylinder (272) is threadedly connected to one end of the rotating rod (271) near the bottom of the cylindrical groove (27); the threaded cylinder (272) is slidably connected in the cylindrical groove (27).

2. The apparatus for synthesizing a candesartan intermediate according to claim 1, characterized in that: The tubular reactor is arranged in three rows, with at least two tubular reactors in each row. Two adjacent tubular reactors are connected in series, and the three rows of tubular reactors are fixedly connected in series by U-shaped tubes (15).

3. The apparatus for synthesizing a candesartan intermediate according to claim 2, characterized in that: The cross-sectional shape of the connecting groove (216) is set as an isosceles trapezoid.

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