A process for the preparation of a diphenylmethyl ester of a sulbactam acid

Abstract

The application relates to a preparation process of benzhydryl heptablin acid, which comprises the following steps: S1, ring-opening reaction: ring-opening dichloromethane is prepared; S2, chlorination reaction: wherein step 2.2, 0.3-0.5 parts of a hydrochloric acid solution with a concentration of 31% is slowly added into a reaction kettle two at a temperature less than 0 DEG C; a feeding pipe extending into the reaction kettle two is vertically slidably connected to the top of the reaction kettle two, a feeding tank for loading the hydrochloric acid solution with a concentration of 31% or the sodium nitrite solution with a concentration of 13-15% is fixedly arranged at the top of the feeding pipe, the feeding pipe and the feeding tank are in communication, threads are formed in the outer wall of the feeding pipe, and a driving mechanism for driving the vertical movement of the feeding pipe is connected to the top of the reaction kettle two; 3, condensation reaction: a condensate with certain humidity is prepared; and S4, double oxidation reaction. The application has the effects of reducing the volatilization of hydrochloric acid and not affecting the final conversion efficiency of benzhydryl heptablin acid.

Description

Technical Field

[0001] This invention relates to the field of organic polymer synthesis technology, and in particular to a preparation process of tazobactamic acid diphenylmethyl ester. Background Technology

[0002] β-lactam antibiotics have been around for over half a century. During this time, as bacteria have developed resistance to commonly used antibiotics, researchers have continuously developed more effective antibiotics that are more potent against resistant bacteria. Simultaneously, targeting the mechanism by which resistant bacteria produce β-lactamases that inactivate β-lactamases, β-lactamase inhibitors have been developed for use in combination with antibiotics. A typical example is tazobactam. Tazobactam is highly effective against various types of β-lactamases, even type I enzymes, and is 10 times more potent than subaculant. It is more stable than clavulanic acid and exhibits stronger inhibitory activity against various plasmid-mediated and chromosome-mediated β-lactamases than both clavulanic acid and subaculant. Satisfactory results have been achieved in in vitro and in vivo experiments when used in combination with ampicillin, amoxicillin, etc. It possesses advantages such as low toxicity, good stability, and strong enzyme-inhibiting activity. It was recognized as one of the most promising β-lactamase inhibitors at the 30th International Chemotherapy Conference.

[0003] The existing technology, as described in application publication number CN108164550A, involves the preparation process and application of tazobactam diphenylmethyl ester and tazobactam acid. The preparation route uses toluene, mercaptobenzothiazole, and debrominated compounds as starting materials, undergoing ring-opening, chlorination, condensation, and oxidation reactions to obtain tazobactam diphenylmethyl ester. After deprotection, tazobactam diphenylmethyl ester is converted to tazobactam acid. However, the preparation method in this scheme improves upon the existing iodination reaction by introducing a chlorination reaction, optimizing reaction quality, increasing product purity, and reducing the use of toxic, harmful, flammable, and explosive substances during the reaction, making the reaction more green and environmentally friendly. Furthermore, the product yield can reach 98%~99.92%, and the preparation cost is lower than that of the existing technology.

[0004] In recent years, the international demand for tazobactam has been increasing, and the market prospects are very broad. More and more laboratories and companies are beginning to research tazobactam. During the chlorination reaction, a 31% hydrochloric acid solution needs to be added dropwise into the reactor. Because concentrated hydrochloric acid is volatile, when it is added dropwise from the feed pipe at the top of the reactor to the liquid surface, it easily evaporates into small water droplets that adhere to the top of the stirred tank, thus affecting the conversion efficiency of tazobactam diphenylmethyl ester. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a preparation process for tazobactam diphenyl ester, which reduces hydrochloric acid volatilization without affecting the final conversion efficiency of tazobactam diphenyl ester.

[0006] The above-mentioned objective of this invention is achieved through the following technical solutions: A process for preparing tazobactam diphenylmethyl ester includes the following steps: S1: Ring-opening reaction: to prepare ring-opening dichloromethane; S2: Chlorination reaction Step 2.1: Transfer the ring-opening dichloromethane solution from Step 1.3 into Reactor 2, continue stirring and cooling until the ring-opening dichloromethane solution in Reactor 2 reaches 0-5℃; Step 2.2: Slowly add 0.3-0.5 parts of a 31% hydrochloric acid solution to reactor 2, with the addition temperature below 0℃; Step 2.3: Add 0.5-0.6 parts of a 13-15% sodium nitrite solution to reactor 2, controlling the dropping temperature at 5-10℃ and the dropping time at 85-100 minutes; The top of the second reactor is vertically slidably connected to a feed pipe extending into the second reactor. The top of the feed pipe is fixed with a feed tank for carrying a 31% hydrochloric acid solution or a 13-15% sodium nitrite solution. The feed pipe and the feed tank are connected. The outer wall of the feed pipe is threaded. The top of the second reactor is connected to a drive mechanism for driving the feed pipe to move vertically. S3: Condensation reaction: to obtain a condensate with a certain humidity; S4: Dioxide reaction: The condensate obtained by the condensation reaction is passed into a new reactor. Then, dichloromethane is added to the reactor and stirred. Then, 0.06-0.07 parts of potassium permanganate are added. Finally, 0.5-0.6 parts of ethyl acetate are added to the reactor to disperse the solid. After cooling to 0-5℃, the mixture is allowed to stand for 1 hour and then centrifuged. After washing with ethyl acetate, the mixture is dried to obtain the final product.

[0007] By adopting the above technical solution, when adding hydrochloric acid, the drive mechanism drives the feed pipe to move vertically to near the liquid surface inside the second reactor, and then adds hydrochloric acid to the feed tank. The hydrochloric acid in the feed tank drips into the feed pipe and finally falls into the second reactor through the feed pipe. The feed pipe can extend into the reactor, thereby reducing the distance between the feed pipe and the liquid surface, thus reducing the distance that hydrochloric acid needs to fall from the feed pipe to the liquid surface, reducing the volatilization of hydrochloric acid, and not affecting the final conversion efficiency of tazobactam diphenyl ester.

[0008] In a preferred embodiment, the present invention may be further configured such that: the driving mechanism includes a stepper motor fixed to the second part of the reactor, a main gear fixed on the output shaft of the stepper motor, the main gear meshing with a driven gear, the driven gear being rotatably connected to the top of the second part of the reactor, and a feed pipe passing through the driven gear and being threadedly connected to the driven gear.

[0009] By adopting the above technical solution, the stepper motor drives the main gear to rotate, and the main gear drives the driven gear to rotate, which in turn drives the feed pipe to move vertically, thus reducing the distance that hydrochloric acid falls from the feed pipe to the liquid surface.

[0010] In a preferred embodiment, the present invention may be further configured such that: a limiting groove is formed along the axial direction of the feed pipe, and a limiting block is fixedly provided on the second reactor and engaged in the limiting groove.

[0011] By adopting the above technical solution, when the stepper motor drives the feed tube to move vertically, the limiting block can restrict the circumferential movement of the feed tube, so that the feed tube can move vertically under the drive of the stepper motor.

[0012] In a preferred embodiment, the present invention may be further configured such that: a switch module for controlling a stepper motor is connected to the feed tube; the switch module includes a proximity switch fixed to the bottom of the feed tube, the proximity switch being used to control the stepper motor to stop.

[0013] By adopting the above technical solution, the stepper motor drives the feed pipe to move vertically. When the feed pipe approaches the liquid surface in the second reactor, the stepper motor is controlled to stop working, that is, the feed pipe stops moving downward to prevent the feed pipe from extending into the liquid surface. At the same time, the vertical movement distance of the feed pipe is controlled according to the height of the liquid surface, which can reduce the contact area of ​​hydrochloric acid in the feed pipe.

[0014] In a preferred embodiment, the present invention can be further configured as follows: the feed pipe includes an outer pipe, and an inner pipe concentrically arranged is fixed inside the outer pipe; a temperature control module is connected to the feed pipe; the temperature control module includes a sleeve fixed inside the outer pipe, the sleeve is fitted onto the inner pipe, a water supply jacket is formed between the sleeve and the inner pipe, an inlet pipe and an outlet pipe are fixed on the sleeve, a water tank is fixed on the reaction vessel, the inlet pipe and the outlet pipe extend out of the outer pipe and are fixedly connected to the water tank, a water pump is fixed on the inlet pipe, a cooling plate and a heating plate are fixed in the water tank, and a temperature sensor is provided in the water tank.

[0015] By adopting the above technical solution, hydrochloric acid is added to the second reactor or a temperature sensor is used to detect the water temperature in the water tank. The operation of the cooling or heating element is controlled according to the temperature of the raw materials entering the second reactor through the feed pipe as needed. When hydrochloric acid is fed, it needs to be fed at a low temperature, so the cooling element is controlled to cool down the hydrochloric acid. When sodium nitrite solution is fed, the heating element is controlled to heat the solution appropriately, thereby ensuring that the raw materials entering the reactor meet the required requirements.

[0016] In a preferred embodiment, the present invention can be further configured as follows: a dripping mechanism is provided on the top of the feed tank, and an air inlet is provided on the top of the feed tank; the dripping mechanism includes a clamping plate fixed to the top of the feed tank, a groove is formed between the clamping plate and the feed tank, an air inlet cylinder is fixed to the top of the clamping plate, a baffle is provided to the top of the air inlet cylinder, the baffle is rotatably connected to the top of the feed tank, and a drive assembly for driving the baffle to reciprocate is fixed to the top of the feed tank.

[0017] By adopting the above technical solution, the drive component drives the baffle to reciprocate, so that the gas enters the feed tank intermittently, and the solution in the feed tank drips into the inner tube drop by drop, thereby achieving the drop-by-drop feeding of hydrochloric acid solution or sodium nitrite solution.

[0018] In a preferred embodiment, the present invention may be further configured such that: the drive assembly includes a drive motor fixed to the top of the feed tank, a transmission wheel fixed to the output shaft of the drive motor, a connecting rod hinged to the transmission wheel, the connecting rod being hinged at an eccentric position of the transmission wheel, and the end of the connecting rod away from the transmission wheel being hinged to a baffle.

[0019] By adopting the above technical solution, the rotation of the drive motor can drive the baffle to reciprocate at the top of the air inlet cylinder, allowing the gas gap to enter the air inlet cylinder. In addition, by adjusting the speed of the drive motor, the reciprocating time of the baffle can be adjusted, thereby controlling the amount of air entering the feed tank, and thus controlling the speed of material dripping.

[0020] In a preferred embodiment, the present invention can be further configured such that a partition is slidably connected inside the card plate, and the partition has multiple vent holes of different diameters.

[0021] By adopting the above technical solution, the air vents and air inlets of different diameters can be connected by adjusting the position of the baffle, thereby controlling the amount of gas entering the feed tank each time, and thus controlling the amount of material dripping.

[0022] The present invention includes at least one of the following beneficial technical effects: 1. A feed pipe extending into the reactor is vertically slidably connected to the top of the reactor. The top of the feed pipe is fixed with a feed tank for carrying a 31% hydrochloric acid solution or a 13-15% sodium nitrite solution. The feed pipe and the feed tank are connected. The outer wall of the feed pipe is threaded. The top of the reactor is connected to a drive mechanism for driving the feed pipe to move vertically. The hydrochloric acid in the feed tank drips into the feed pipe and eventually falls into the reactor. The feed pipe can extend into the reactor, thereby reducing the distance between the feed pipe and the liquid surface, thus reducing the distance between the hydrochloric acid and the liquid surface, reducing the volatilization of hydrochloric acid, and not affecting the final conversion efficiency of tazobactam diphenyl ester. 2. A switch module for controlling a stepper motor is connected to the feed pipe. The switch module includes a proximity switch fixed at the bottom of the feed pipe. The proximity switch is used to control the stop of the stepper motor. The stepper motor drives the feed pipe to move vertically. When the feed pipe approaches the liquid surface in the reactor, the stepper motor is controlled to stop working, that is, the feed pipe stops moving downward to prevent the feed pipe from extending into the liquid surface. At the same time, the vertical movement distance of the feed pipe is controlled according to the height of the liquid surface, which can reduce the contact area of ​​hydrochloric acid in the feed pipe. 3. A partition plate is slidably connected inside the plate. The partition plate has multiple vent holes of different diameters. By adjusting the position of the partition plate, the vent holes of different diameters are connected to the air inlet, which can control the amount of gas entering the feed tank each time, and thus control the amount of material dripping. Attached Figure Description

[0023] Figure 1 This is a structural schematic diagram of an embodiment; Figure 2 This is a cross-sectional view of an embodiment; Figure 3 yes Figure 1 Enlarged view of part A; Figure 4 This is a structural diagram of the feed pipe, temperature control module, and feed tank 13; Figure 5 This is a cross-sectional view of the feed pipe, temperature control module, and feed tank 13; Figure 6 yes Figure 5 Enlarged view of part B; Figure 7 This is a schematic diagram of the structure of the feed tank 13; Figure 8 This is a cross-sectional view of the feed tank 13.

[0024] In the diagram, 1. Reactor II; 11. Feed pipe; 111. Limiting groove; 112. Outer pipe; 113. Inner pipe; 12. Drive mechanism; 121. Positioning plate; 1211. Limiting block; 122. Stepper motor; 123. Main gear; 124. Driven gear; 13. Feed tank; 131. Feed pipe; 132. Air inlet; 133. Plug; 2. Switch module; 21. Proximity switch; 3. Temperature control module; 31. Sleeve; 32. Water inlet pipe; 33. Water outlet pipe; 34. Water pump; 35. Water tank; 36. Temperature sensor; 4. Drip mechanism; 41. Card plate; 411. Card slot; 42. Baffle; 43. Air inlet cylinder; 44. Drive assembly; 441. Drive motor; 442. Transmission wheel; 443. Connecting rod; 45. Partition plate; 454. Vent hole. Detailed Implementation

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

[0026] The present invention discloses a preparation process for tazobactam diphenyl ester, comprising the following steps: S1: Ring-opening reaction: preparation of ring-opening dichloromethane Step 1.1: Add 3.0-3.5 parts toluene, 0.2-0.4 parts debrominated compound and 0.1-0.2 parts MBT to reactor one, and heat to 70-75℃ and react for 80-100 minutes; Step 1.2: After the reaction is complete, cool down to 58-75℃; Step 1.3: Concentrate the product from Step 1.2 under reduced pressure to dryness, add 2.3-2.5 parts of dichloromethane and stir until completely dissolved to obtain a clear liquid, thus obtaining a dichloromethane solution of the ring-opening compound.

[0027] S2: Chlorination reaction Step 2.1: Transfer the ring-opening dichloromethane solution from Step 1.3 into Reactor 21 and continue stirring while cooling until the ring-opening dichloromethane solution in Reactor 21 reaches 0-5℃; Step 2.2: Slowly add 0.3-0.5 parts of a 31% hydrochloric acid solution to reactor 21 at a temperature below 0°C. Step 2.3: Add 0.5-0.6 parts of a 13-15% sodium nitrite solution to reactor 21, controlling the dropping temperature at 5-10℃ and the dropping time at 85-100 minutes; Reference Figure 1 The top of the second reactor 1 is provided with a feed pipe 11, which extends into the second reactor 1. The top of the feed pipe 11 is fixed with a feed tank 13, and the feed pipe 11 and the feed tank 13 are connected. The feed tank 13 is used to carry a 31% hydrochloric acid solution or a 13-15% sodium nitrite solution. The outer wall of the feed pipe 11 is threaded. The top of the second reactor 1 is connected to a drive mechanism 12 for driving the feed pipe 11 to move vertically.

[0028] See Figure 2 and Figure 3The drive mechanism 12 includes a positioning plate 121 fixed to the top of the second reactor 1. A stepper motor 122 is fixed on the positioning plate 121. A main gear 123 is fixed on the output shaft of the stepper motor 122. A driven gear 124 meshes with the main gear 123. The driven gear 124 is rotatably connected to the top of the second reactor 1. The feed pipe 11 passes through the driven gear 124 and is threadedly connected to the driven gear 124. A limiting groove 111 is opened along the axial direction of the feed pipe 11. A limiting block 1211 is fixed on the positioning plate 121 and is engaged in the limiting groove 111. The limiting block 1211 can restrict the circumferential movement of the feed pipe 11, so that the feed pipe 11 moves vertically under the drive of the stepper motor 122.

[0029] See Figure 2 and Figure 4 A switch module 2 for controlling a stepper motor 122 is connected to the feed pipe 11. The switch module 2 includes a proximity switch 21 fixed at the bottom of the feed pipe 11. The proximity switch 21 is used to control the stop of the stepper motor 122. The stepper motor 122 drives the feed pipe 11 to move vertically. When the feed pipe 11 approaches the liquid surface in the reactor 21, the stepper motor 122 is controlled to stop working, that is, the feed pipe 11 stops moving downward to prevent the feed pipe 11 from extending into the liquid surface. At the same time, the vertical movement distance of the feed pipe 11 is controlled according to the height of the liquid surface, which can reduce the contact area of ​​hydrochloric acid in the feed pipe 11.

[0030] See Figure 5 and Figure 6 The feed pipe 11 includes an outer pipe 112 with threads inside. An inner pipe 113, concentrically arranged, is fixed inside the outer pipe 112. A temperature control module 3 is connected to the feed pipe 11. The temperature control module 3 includes a sleeve 31 fixed inside the outer pipe 112, which is fitted onto the inner pipe 113. A jacket for water supply is formed between the sleeve 31 and the inner pipe. An inlet pipe 32 and an outlet pipe 33 are fixed to the sleeve 31. A water tank 35 is fixed to the reactor 2 (see previous section). Figure 5 The inlet pipe 32 and outlet pipe 33 extend out to the outer pipe 112 and are fixedly connected to the water tank 35. A water pump 34 is fixedly mounted on the inlet pipe 32. Cooling and heating elements are fixedly mounted in the water tank 35. A temperature sensor 36 is installed in the water tank 35. The temperature sensor 36 detects the water temperature in the water tank 35 and controls the operation of the cooling or heating elements based on the temperature of the raw materials entering the reactor 2 1 through the feed pipe 11 as needed, thereby ensuring that the raw materials entering the reactor meet the required requirements.

[0031] See Figure 7 and Figure 8 The top of the feed tank 13 is fixedly provided with a feed pipe 131 that communicates with the inside of the feed tank 13. A plug 133 is inserted into the top of the feed pipe 131. A dripping mechanism 4 is provided on the top of the feed tank 13. (See back) Figure 1The feed tank 13 has an air inlet 132 at its top. The dripping mechanism 4 includes a clamping plate 41 fixed to the top of the feed tank 13, forming a groove 411 between the clamping plate 41 and the feed tank 13. An air inlet cylinder 43 is fixed to the top of the clamping plate 41, and a baffle plate 42 is provided at the top of the air inlet cylinder 43. The baffle plate 42 is rotatably connected to the top of the feed tank 13. A drive assembly 4412 is fixed to the top of the feed tank 13 to drive the baffle plate 42 to reciprocate. The drive assembly 4412 drives the baffle plate 42 to reciprocate, so that gas enters the feed tank 13 intermittently, and the solution in the feed tank 13 drips into the inner tube 113 drop by drop, thereby achieving the drop-by-drop feeding of hydrochloric acid solution or sodium nitrite solution. The drive assembly 4412 includes a drive motor 441 fixed to the top of the feed tank 13. The output shaft of the drive motor 441 is fixed with a transmission wheel 442. A connecting rod 443 is hinged to the transmission wheel 442. The connecting rod 443 is hinged at an eccentric position of the transmission wheel 442. The end of the connecting rod 443 away from the transmission wheel 442 is hinged to a baffle 42. When the drive motor 441 rotates, it can drive the baffle 42 to reciprocate at the top of the air inlet cylinder 43, so that the gas gap enters the air inlet cylinder 43. In addition, by adjusting the speed of the drive motor 441, the reciprocating time of the baffle 42 can be adjusted, thereby controlling the amount of air entering the feed tank 13, and thus controlling the speed of material dripping.

[0032] See Figure 8 A partition plate 45 is slidably connected inside the card plate 41. The partition plate 45 has multiple vent holes 454 with different diameters. By adjusting the position of the partition plate 45, the vent holes 454 with different diameters can be connected to the air inlet, which can control the amount of gas entering the feed tank 13 each time, and thus control the amount of material dripping.

[0033] Step 2.4: Connect the reaction vessel B to the substances inside and keep it at 5-10℃ for 10-12 hours to end the reaction; Step 2.5: After centrifugation and filtration, the filtrate is transferred to another reaction vessel C and allowed to stand for separation. The aqueous layer is extracted with dichloromethane. After combining the organic layers, the liquid is washed repeatedly with water, sodium bicarbonate aqueous solution, and purified water in sequence. Step 2.6: Transfer the washed organic layer into reaction vessel D, distill under reduced pressure until dry, add 1.4-1.5 parts of acetone to obtain a chloride acetone solution for later use; S3: Condensation reaction: to obtain a condensate with a certain moisture content. The product obtained from the chlorination reaction was added to another reaction vessel and stirred. Then, 0.4-0.5 parts of purified water and 0.08-0.10 parts of 1,2,3-triazole were added, and the temperature was controlled at 25-30℃ while stirring. Then, 1.3-1.6 parts of dichloromethane were added, and finally, 0.3-0.4 parts of ethyl acetate were added and stirred for 2.0 hours until crystallization. After stirring, the mixture was centrifuged, and the stirring temperature was controlled at 25℃. After centrifugation, the mixture was dried to obtain a condensate with a certain moisture content.

[0034] S4: Dioxide reaction: The condensate obtained by the condensation reaction is passed into a new reactor. Then, dichloromethane is added to the reactor and stirred. Then, 0.06-0.07 parts of potassium permanganate are added. Finally, 0.5-0.6 parts of ethyl acetate are added to the reactor to disperse the solid. After cooling to 0-5℃, the mixture is allowed to stand for 1 hour and then centrifuged. After washing with ethyl acetate, the mixture is dried to obtain the final product.

[0035] The implementation principle of this embodiment is as follows: When adding hydrochloric acid solution, firstly, the stepper motor 122 drives the feeding pipe to move vertically. When the proximity switch 21 at the bottom of the feeding pipe moves close to the liquid surface in the second reactor 1, the stepper motor 122 is controlled to stop working. Then, the hydrochloric acid solution is added to the feed tank 13. The speed of the drive motor 441 in the feed tank 13 is adjusted so that the drive motor 441 drives the baffle 42 to reciprocate, so that air intermittently enters the feed tank 13, and the hydrochloric acid in the feed tank 13 drips into the feeding pipe and enters the second reactor 1 through the feeding pipe. At the same time, the temperature sensor 36 controls the temperature of the water in the water tank 35. When the water temperature is too high, the cooling plate is controlled to cool down. When the temperature is too low, the heating plate is controlled to heat up, so as to ensure that the hydrochloric acid entering the second reactor 1 reaches the required feeding temperature.

[0036] The embodiments described herein are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, all equivalent changes made in accordance with the structure, shape, and principle of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A preparation process for tazobactam diphenylmethyl ester, characterized in that: S1: Ring-opening reaction: to prepare the ring-opening compound dichloromethane; Step 1.1: Add 3.0-3.5 parts toluene, 0.2-0.4 parts debrominated compound and 0.1-0.2 parts MBT to reactor one, and heat to 70-75℃ and react for 80-100 minutes; Step 1.2: After the reaction is complete, cool down to 58-75℃; Step 1.3: Concentrate the product from Step 1.2 to dryness under reduced pressure, add 2.3-2.5 parts of dichloromethane and stir until completely dissolved to obtain a clear liquid, thus obtaining a dichloromethane solution of the ring-opening compound; S2: Chlorination reaction Step 2.1: Transfer the ring-opening dichloromethane solution from Step 1.3 into reactor 2 (1) and continue stirring while cooling until the ring-opening dichloromethane solution in reactor 2 (1) reaches 0-5℃; Step 2.2: Slowly add 0.3-0.5 parts of 31% hydrochloric acid solution to reactor 2 (1) at a temperature below 0℃; Step 2.3: Add 0.5-0.6 parts of sodium nitrite solution with a concentration of 13-15% to the reaction vessel (1), control the dropping temperature at 5-10℃ and the dropping time at 85-100 minutes; The top of the second reactor (1) is vertically slidably connected to a feed pipe (11) extending into the second reactor (1). The top of the feed pipe (11) is fixed with a feed tank (13) for carrying a 31% hydrochloric acid solution or a 13-15% sodium nitrite solution. The feed pipe (11) and the feed tank (13) are connected internally. The outer wall of the feed pipe (11) is threaded, and the top of the reactor (1) is connected to a drive mechanism (12) for driving the feed pipe (11) to move vertically. The top of the feed tank (13) is provided with a dripping mechanism (4), and the top of the feed tank (13) is provided with an air inlet (132); The dripping mechanism (4) includes a clamping plate (41) fixed to the top of the feed tank (13), a groove (411) is formed between the clamping plate (41) and the feed tank (13), an air inlet cylinder (43) is fixed to the top of the clamping plate (41), a baffle (42) is provided on the top of the air inlet cylinder (43), the baffle (42) is rotatably connected to the top of the feed tank (13), and a drive assembly (44) for driving the baffle (42) to reciprocate is fixed to the top of the feed tank (13); a partition plate (45) is slidably connected inside the clamping plate (41), and multiple ventilation holes (454) with different diameters are opened on the partition plate (45); The drive assembly (44) includes a drive motor (441) fixed to the top of the feed tank (13), and a transmission wheel (442) is fixed to the output shaft of the drive motor (441). A connecting rod (443) is hinged on the transmission wheel (442). The connecting rod (443) is hinged at the eccentric position of the transmission wheel (442). The end of the connecting rod (443) away from the transmission wheel (442) is hinged to the baffle (42). The feed pipe (11) includes an outer pipe (112), and an inner pipe (113) is fixedly installed inside the outer pipe (112); A temperature control module (3) is connected to the feed pipe (11); The temperature control module (3) includes a sleeve (31) fixed inside the outer tube (112). The sleeve (31) is fitted onto the inner tube (113), and a water supply jacket is formed between the sleeve (31) and the inner tube. An inlet pipe (32) and an outlet pipe (33) are fixed on the sleeve (31). A water tank (35) is fixed on the reaction vessel (1). The inlet pipe (32) and the outlet pipe (33) extend out of the outer tube (112) and are fixedly connected to the water tank (35). On the inlet pipe (32), a water pump (34) is fixedly installed, and a cooling plate and a heating plate are fixedly installed in the water tank (35). A temperature sensor (36) is installed in the water tank (35). The drive assembly (44) drives the baffle (42) to reciprocate, so that the gas enters the feed tank (13) intermittently, and the solution in the feed tank (13) drips into the inner tube (113) drop by drop, thereby achieving the feeding of hydrochloric acid solution or sodium nitrite solution drop by drop. S3: Condensation reaction: to obtain a condensate with a certain humidity; S4: Dioxide reaction: The condensate obtained from the condensation reaction is passed into a new reactor, then dichloromethane is added to the reactor and stirred, then 0.06-0.07 parts of potassium permanganate are added, and finally 0.5-0.6 parts of ethyl acetate are added to the reactor to disperse the solid. After cooling to 0-5℃, it is allowed to stand for 1 hour and then centrifuged. After washing with ethyl acetate, it is dried to obtain the final product.

2. The preparation process of tazobactam diphenylmethyl ester according to claim 1, characterized in that: The drive mechanism (12) includes a stepper motor (122) fixed to the second reactor (1). A main gear (123) is fixed on the output shaft of the stepper motor (122). The main gear (123) meshes with a driven gear (124). The driven gear (124) is rotatably connected to the top of the second reactor (1). The feed pipe (11) passes through the driven gear (124) and is threadedly connected to the driven gear (124).

3. The preparation process of tazobactam diphenylmethyl ester according to claim 1, characterized in that: The feed pipe (11) has a limiting groove (111) along its axial direction, and the reactor (1) is fixed with a limiting block (1211) that is engaged in the limiting groove (111).

4. The preparation process of tazobactam diphenylmethyl ester according to claim 1, characterized in that: The feed pipe (11) is connected to a switch module (2) for controlling the stepper motor (122); the switch module (2) includes a proximity switch (21) fixed at the bottom of the feed pipe (11), and the proximity switch (21) is used to control the stop of the stepper motor (122).

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