A constant temperature reaction device for purifying brigatinib

Abstract

The utility model discloses a kind of constant-temperature reaction devices for brigatinib purification, including box, the front and rear sides of the box are all open and set, the box is provided with liftable shelter frame, the shelter frame is used to shelter the opening of the side of box, chromatography column is provided in the box.The utility model through the mutual cooperation of box, shelter frame, chromatography column, constant-temperature sleeve, hose one, hose two, hydraulic cylinder, baffle, shunt pipe, temperature regulating shell, cannula, cooperation pipe, grommet, sealing ring, sensor, heater, stabilizing plate, side block, threaded rod, telescopic rod, controller, feeding pipe, plugging cover, air pump and rotating rod, ion exchange chromatography is used for constant-temperature purification and recrystallization to brigatinib, and, the front and rear of box are open and set, move on shelter frame, most structures in the box can be exposed, easy to overhaul, chromatography column is also easy to be disassembled from box, convenient to use.

Description

Technical Field

[0001] This utility model relates to the field of brigatinib purification technology, specifically to a constant temperature reaction device for brigatinib purification. Background Technology

[0002] Brigatinib is an ALK tyrosine kinase inhibitor developed by Takeda China, primarily targeting ALK-positive locally advanced or metastatic non-small cell lung cancer. During the production of brigatinib, purification is required. Currently, many drugs are purified using ion exchange chromatography. However, existing purification reactors have their processing mechanisms located inside a housing, and the housing lacks a large-area opening mechanism. This hinders the opening of the housing for large-area exposure, making maintenance difficult and inconvenient to use.

[0003] A search revealed a drug purification device with publication number CN219209123U, comprising: a purification chamber, a sealing cover, a sealing piston, and a filtering mechanism. The sealing cover is slidably mounted on the top of the purification chamber, and the sealing piston is slidably mounted inside the purification chamber, with the top of the sealing piston fixedly connected to the sealing cover. The filtering mechanism is disposed inside the purification chamber. The filtering mechanism includes two mounting blocks, four insert rods, two first moving blocks, two second moving blocks, two sets of connecting rods, and two filter plates. The two mounting blocks are respectively fixedly mounted on the inner walls of both sides of the purification chamber, and the four insert rods are respectively slidably mounted on the two mounting blocks. This technical solution also suffers from the aforementioned technical problems. Utility Model Content

[0004] The purpose of this invention is to provide a constant temperature reaction apparatus for the purification of brigatinib, so as to solve the problems mentioned in the background art.

[0005] To achieve the above objectives, this utility model provides the following technical solution: a constant temperature reaction device for purifying brigatinib, comprising a chamber, the front and rear sides of which are open, a liftable shielding frame is provided on the chamber to shield the openings on the sides of the chamber, a chromatography column is provided inside the chamber, the surface of the chromatography column is covered with a constant temperature sleeve, and a flexible tube is connected to the side of the constant temperature sleeve.

[0006] Optionally, a hydraulic cylinder is installed on the top of the housing, and the output shaft of the hydraulic cylinder is fixedly connected to the shield.

[0007] Optionally, a partition is fixedly connected to the inner wall of the chamber, and a branch pipe is installed between the partition and the inner wall of the chamber. A threaded pipe is fixedly connected to the bottom of the chromatography column, and the threaded pipe is threadedly connected to the branch pipe.

[0008] Optionally, the top of the chamber is provided with a temperature-regulating shell, the bottom of the temperature-regulating shell is fixedly connected to an insertion tube, the top of the chromatography column is fixedly connected to a matching tube, and the insertion tube is movably sleeved on the surface of the matching tube.

[0009] Optionally, a gasket is fixedly connected to the surface of the mating tube, and a sealing ring is fixedly connected to the surface of the mating tube, with the surface of the sealing ring in close contact with the inner wall of the insertion tube.

[0010] Optionally, a sensor is installed inside the temperature control housing, and a heater is fixedly installed on the side of the temperature control housing.

[0011] Optionally, a stabilizing plate is fixedly connected to the top of the housing, and a side block is fixedly connected to the side of the temperature regulating shell, with the top of the stabilizing plate penetrating through the side block.

[0012] Optionally, the side block is threadedly connected to a threaded rod, which is threadedly connected to the stabilizing plate.

[0013] Compared with the prior art, the beneficial effects of this utility model are as follows: This invention utilizes the coordinated operation of a housing, a shielding frame, a chromatography column, a constant temperature sleeve, a first hose, a second hose, a hydraulic cylinder, a partition, a branch pipe, a temperature regulating shell, an insert pipe, a mating pipe, a gasket, a sealing ring, a sensor, a heater, a stabilizing plate, a side block, a threaded rod, a telescopic rod, a controller, a feeding pipe, a sealing cap, a venting pump, and a rotating rod to perform isothermal purification and recrystallization of brigatinib using ion exchange chromatography. Furthermore, the housing is designed with open front and rear sections, allowing most of the internal structure to be exposed by moving the shielding frame, facilitating maintenance. The chromatography column is also easily disassembled from the housing, making it convenient to use. Attached Figure Description

[0014] Figure 1 This is a three-dimensional structural schematic diagram of the front view of this utility model; Figure 2 Compared with the present invention Figure 1 A three-dimensional structural diagram from another perspective; Figure 3 This is a three-dimensional structural diagram of the concealed shielding frame of this utility model from a first-person perspective; Figure 4 This is a three-dimensional structural diagram of the hidden shielding frame of this utility model from a second perspective; Figure 5 This is a first-view three-dimensional structural diagram of the chromatography column, branch pipe and temperature control shell of this utility model. Figure 6 This is a two-dimensional structural diagram of the chromatography column, branch pipe and temperature control shell of this utility model from a second perspective. Figure 7 This is a three-dimensional sectional view of a portion of the structure of this utility model; Figure 8 This is a three-dimensional structural diagram of the fitting pipe and the electrically controlled valve of this utility model; Figure 9 This is a three-dimensional sectional view of the thermostatic sleeve, hose one, and hose two of this utility model.

[0015] In the diagram: 1. Box body, 2. Baffle frame, 3. Chromatography column, 4. Constant temperature jacket, 5. Hope 1, 6. Hope 2, 7. Hydraulic cylinder, 8. Partition plate, 9. Branch pipe, 10. Temperature control shell, 11. Insert tube, 12. Matching pipe, 13. Gasket, 14. Sealing ring, 15. Sensor, 16. Heater, 17. Stabilizing plate, 18. Side block, 19. Threaded rod, 20. Telescopic rod, 21. Controller, 22. Feeding pipe, 23. Sealing cap, 24. Air pump, 25. Fan, 27. Heating plate, 28. Crystallization box, 29. Threaded pipe, 30. Rotating rod. Detailed Implementation

[0016] The technical solutions of the present utility model will be clearly and completely described below with reference to the accompanying drawings of the embodiments. Obviously, the described embodiments are only some embodiments of the present utility model, and not all embodiments. Based on the embodiments of the present utility model, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the protection scope of the present utility model.

[0017] Please see Figure 1-9A constant-temperature reaction apparatus for purifying brigatinib includes a chamber 1 with openings at both the front and back. A partition 8 is fixedly connected to the inner wall of the chamber 1, dividing the chamber 1 into two independent cavities. A hydraulic cylinder 7 providing linear driving force is installed on the top of the chamber 1. A shielding frame 2 is fixedly connected to the output shaft of the hydraulic cylinder 7, which is used to shield the openings at the front and back of the chamber 1. Two telescopic rods 20 are fixedly connected to the top of the inner wall of the shielding frame 2. The telescopic rods 20 can be extended or shortened, and their bottom ends are fixedly connected to the top of the inner wall of the chamber 1. The telescopic rods 20 limit the shielding frame. 2. The movement is a linear variable-pitch motion perpendicular to the housing 1. A branch pipe 9 is installed between the partition 8 and the inner wall of the housing 1. A chromatography column 3 for purifying brigatinib solution is installed above the branch pipe 9. The chromatography column 3 uses ion exchange chromatography to purify brigatinib, which is existing technology. Its internal structure is also existing technology and will not be described in detail here. A threaded pipe 29 is fixedly connected to the bottom of the chromatography column 3. The threaded pipe 29 is threaded to the branch pipe 9. One of the two outlets of the branch pipe 9 goes out of the housing 1, and the other goes through the partition 8 and out of the housing. The outlet of column 1 is used to discharge the equilibrium buffer and gradient wash solution, while the outlet through column 1 is used to discharge the purified brigatinib solution. A fitting tube 12 is fixedly connected to the top of column 3. Both fitting tube 12 and branch tube 9 are equipped with electrically controlled valves, which are opened and closed by a conventional electrically controlled switch. This technical solution requires the use of a basic electrically controlled switch, which is existing technology and will not be described in detail here. A thermostatic sleeve 4 is fitted over the surface of column 3. The top and bottom of the left side of the thermostatic sleeve 4 are fixedly connected to flexible tube 5 and flexible tube 6, respectively. The ends of flexible tube 5 and flexible tube 6 extend out of the chamber. The two are movably connected to the chamber 1. Pulling the two near the side of the constant temperature sleeve 4 allows their ends to enter the chamber 1. The constant temperature sleeve 4 is a hollow sleeve. The second hose 6 is used to introduce liquid at the required temperature into the constant temperature sleeve 4, and the first hose 5 is used to discharge the liquid. The first hose 5, the second hose 6, and the constant temperature sleeve 4 form a liquid circulation path. The temperature of the chromatography column 3 and its internal structure is controlled by water bath heating. The temperature control is precise. In order to discharge the water vapor evaporated in the chamber 1, a fan 25 is fixedly installed on the right side of the chamber 1. The pipe connected to the exhaust end of the fan 25 extends into the interior of the chamber.

[0018] A temperature-regulating shell 10 is provided on the top of the housing 1. A tube 11 is fixedly connected to the bottom of the temperature-regulating shell 10. The bottom end of the tube 11 is inserted into the interior of the housing 1 and is movably fitted onto the surface of the mating tube 12. In order to seal the gap between the tube 11 and the mating tube 12, a sealing ring 14 is fixedly bonded to the surface of the mating tube 12. The upper outer edge of the sealing ring 14 is beveled. The purpose of this setting is to make it easier for the tube 11 to fit onto the surface of the sealing ring 14 when it moves downward. The outermost diameter of the sealing ring 14 is slightly larger than the inner diameter of the tube 11. So when the tube 11 is fitted onto the surface of the mating tube 12, the sealing ring 14 is in a compressed state. The sealing ring 14 is made of rubber. The compressed sealing ring 14 can achieve a good sealing effect. In addition, a gasket 13 is fixedly connected to the surface of the mating tube 12. The top of the gasket 13 is in contact with the bottom of the tube 11.

[0019] A sensor 15, specifically a temperature sensor, is installed at the bottom of the inner wall of the temperature-regulating housing 10. A heater 16 is fixedly installed on the side of the inner wall of the temperature-regulating housing 10. A feeding pipe 22 is fixedly connected to the top of the temperature-regulating housing 10, and a sealing cap 23 is closed on the feeding pipe 22. The sensor 15 is used to monitor the temperature of the liquid added into the temperature-regulating housing 10. When the heater 16 operates, it changes the temperature of the liquid added into the temperature-regulating housing 10. The heater 16, in conjunction with the sensor 15, can control the temperature of the liquid inside the temperature-regulating housing 10 and... The liquid requiring the specified temperature is introduced into column 3. In order to enable the temperature control shell 10 to have the function of pressurizing the liquid and to avoid negative pressure in the temperature control shell 10, an air pump 24 is installed on the side of the temperature control shell 10. The air pump 24 can introduce air into the temperature control shell 10, so that the pressure inside the temperature control shell 10 increases. This can provide air pressure to push the liquid into the chromatography column 3. However, if there is no need for pressurizing the liquid, the air pump 24 can introduce a small amount of air into the temperature control shell 10 to avoid negative pressure in the temperature control shell 10.

[0020] A stabilizing plate 17 is fixedly connected to the top of the housing 1, and a side block 18 is fixedly connected to the side of the temperature regulating shell 10. The side block 18 is movably fitted onto the surface of the stabilizing plate 17. A threaded rod 19 is threadedly connected to the side of the side block 18. The threaded rod 19 is threadedly connected to the stabilizing plate 17, thus locking the relative position of the stabilizing plate 17 and the side block 18. A rotating rod 30 is fixedly connected to one end of the threaded rod 19 outside the side block 18. The rotating rod 30 is designed to facilitate manual rotation of the threaded rod 19 by the operator.

[0021] To recover the purified brigatinib solution and to evaporate and crystallize it, a heating plate 27 is installed on the right side of the bottom of the inner wall of the chamber 1. A crystallization box 28 is placed on top of the heating plate 27. The crystallization box 28 is located directly below the outlet of the branch pipe 9 that passes through the partition 8. The brigatinib solution discharged through the branch pipe 9 will enter the crystallization box 28. When the heating plate 27 is working, the brigatinib solution in the crystallization box 28 can be evaporated and recrystallized. A handle is also fixedly connected to the side of the crystallization box 28. A slot is opened in the chamber 1 corresponding to the position of the crystallization box 28. The slot is designed so that the staff can take out the crystallization box 28 from the chamber 1.

[0022] To further automate the temperature control and operation of this device, a controller 21 is fixedly installed on the top of the housing 1. The controller 21 is specifically a PLC controller, model Siemens S7-1200. The controller 21 is electrically connected to the hydraulic cylinder 7, controlling its operation and shutdown. The controller 21 is also electrically connected to the air pump 24, the heater 16, and the sensor 15. The sensor 15 monitors the temperature and transmits an electrical signal to the controller 21, which then controls the operation and shutdown of the heater 16. The controller 21 is also electrically connected to the fan 25 and the heating plate 27. The controller 21 is designed to control the operation and shutdown of the electrically driven equipment. It has basic setting functions; once set, the controller 21 can control the operation and shutdown of the aforementioned electrically driven equipment. The setting of the controller 21 is based on existing technology.

[0023] The controller 21 is electrically connected to the aforementioned electrically controlled switch used to control the electrically controlled valve.

[0024] In use, first add equilibration buffer to the temperature-controlled chamber 10. Sensor 15 monitors the temperature, and heater 16 operates to bring the equilibration buffer to the required temperature. When the liquid temperature in the temperature-controlled chamber 10 reaches the required temperature, controller 21 controls the opening of the electrically controlled valve on the coupling tube 12 via an electronic switch, allowing the liquid to enter the chromatography column 3. The electrically controlled valve on the branch tube 9 is open on the left and closed on the right, thus discharging the equilibration buffer from the chamber 1. Then, add brigatinib solution to the temperature-controlled chamber 10, and similarly control the temperature. Here, the electrically controlled valve on the branch tube 9 is closed on the left and open on the right. The brigatinib solution purified by the chromatography column 3 enters the crystallization box 28. Finally, heating plate 27 operates to recrystallize the brigatinib solution. Subsequently, gradient washing can be performed on the chromatography column 3. The elution and regeneration rinsing are existing technologies in ion exchange chromatography, so they will not be described in detail. However, for both gradient elution and regeneration rinsing, the left-side electrically controlled valve on the branch pipe 9 is opened and the right-side valve is closed. Both the eluent and the regeneration rinsing solution are discharged from the chamber 1. The controller 21 is controlled, and the hydraulic cylinder 7 works. The hydraulic cylinder 7 will drive the shielding frame 2 to move upward, thus exposing the front and rear openings of the chamber 1 for easy maintenance. By rotating the rotating rod 30, the threaded rod 19 will be rotated, and the threaded rod 19 will disengage from the stabilizing plate 17, causing the temperature control shell 10 to move upward. The insertion tube 11 will disengage from the surface of the mating tube 12. Pulling the first hose 5 and the second hose 6 will allow them to enter the chamber 1. Then, the chromatography column 3 is rotated, which will drive the threaded tube 29 to rotate. The threaded tube 29 will disengage from the branch pipe 9, allowing the chromatography column 3 to be removed from the chamber 1.

[0025] Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A constant-temperature reaction apparatus for the purification of brigatinib, comprising a chamber (1), characterized in that: The front and rear sides of the box (1) are open. The box (1) is equipped with a liftable shield (2) to block the opening of the side of the box (1). The box (1) is equipped with a chromatography column (3). The surface of the chromatography column (3) is covered with a constant temperature sleeve (4). The side of the constant temperature sleeve (4) is connected to a flexible tube (5,6).

2. The isothermal reaction apparatus for purifying brigatinib according to claim 1, characterized in that: A hydraulic cylinder (7) is installed on the top of the housing (1), and the output shaft of the top of the hydraulic cylinder (7) is fixedly connected to the shield (2).

3. The isothermal reaction apparatus for purifying brigatinib according to claim 2, characterized in that: A partition (8) is fixedly connected to the inner wall of the box (1), and a branch pipe (9) is installed between the partition (8) and the inner wall of the box (1). A threaded pipe (29) is fixedly connected to the bottom of the chromatography column (3), and the threaded pipe (29) is threadedly connected to the branch pipe (9).

4. The isothermal reaction apparatus for purifying brigatinib according to claim 3, characterized in that: The top of the box (1) is provided with a temperature control shell (10), the bottom of the temperature control shell (10) is fixedly connected to an insertion tube (11), the top of the chromatography column (3) is fixedly connected to a matching tube (12), and the insertion tube (11) is movably sleeved on the surface of the matching tube (12).

5. The isothermal reaction apparatus for purifying brigatinib according to claim 4, characterized in that: A gasket (13) is fixedly connected to the surface of the fitting tube (12), and a sealing ring (14) is fixedly connected to the surface of the fitting tube (12). The surface of the sealing ring (14) is in close contact with the inner wall of the insertion tube (11).

6. The isothermal reaction apparatus for purifying brigatinib according to claim 5, characterized in that: A sensor (15) is installed inside the temperature control shell (10), and a heater (16) is fixedly installed on the side of the temperature control shell (10).

7. The isothermal reaction apparatus for purifying brigatinib according to claim 6, characterized in that: A stabilizing plate (17) is fixedly connected to the top of the housing (1), and a side block (18) is fixedly connected to the side of the temperature regulating shell (10). The top of the stabilizing plate (17) passes through the side block (18).

8. The isothermal reaction apparatus for purifying brigatinib according to claim 7, characterized in that: The side block (18) is threadedly connected to a threaded rod (19), which is threadedly connected to the stabilizing plate (17).

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