Continuous production system of baloxvir dipivoxil intermediate

Abstract

The utility model provides a continuous production system of a baloxvir dipivoxil intermediate. The continuous production system comprises a weighing module, preparation modules, a reaction module and a detection module, wherein the weighing module is used for accurately weighing a solid or liquid reactant and supplying the solid or liquid reactant to the next preparation module; the preparation module is used for carrying out pretreatment of reaction, mixing several reactants according to a ratio in advance to form an intermediate reaction solution, and conveying the intermediate reaction solution to the reaction module; the main equipment of the reaction module is a micro-channel reactor capable of controlling the reaction temperature and is used for accurately and safely carrying out the main reaction of a compound; the detection module is used for detecting the pretreatment degree of reactants and the proceeding degree of the main reaction, so that the industrial production of the baloxvir dipivoxil intermediate is better completed. The continuous production system disclosed by the utility model is more cost-saving, higher in efficiency and capable of more effectively completing the industrial production of the baloxvir dipivoxil intermediate.

Description

Technical Field

[0001] The utility model relates to a continuous production system for baloxavir marboxil intermediates, belonging to the technical field of semi-automatic production. Background Technique

[0002] With the rapid development of modern society, the demand for various products is increasing. At the same time, while various industrial manufacturing industries are studying how to increase production, they are also improving product production efficiency and reducing the input of human resources. Especially pharmaceutical enterprises have relatively high requirements for the sterile environment during the industrial production process, precise control of the addition amount of production raw materials, and relatively high standards for protecting the personal safety of operators. Therefore, enterprises need to improve the operation level in all aspects as much as possible while ensuring that products meeting production standards are obtained.

[0003] In the process of producing pharmaceutical compounds such as oseltamivir, remdesivir, and baloxavir marboxil, it is necessary to strictly control the ratio between reactants, the stirring time and degree of reaction. For steps involving operations in a high-temperature environment, the reaction temperature also needs to be precisely controlled. However, in the above aspects of the existing production methods, operations such as feeding and proportioning reactants still largely rely on manual handling. On the one hand, the time cost and labor cost are relatively large. On the other hand, dust raw materials have a certain impact on the respiratory system of operators. Therefore, the utility model relates to a continuous production system for baloxavir marboxil intermediates that is more cost-saving and efficient. Content of the Utility Model

[0004] Aiming at the deficiencies of the existing technology, the purpose of the utility model is to provide a continuous production system for baloxavir marboxil intermediates to solve the problems raised in the above background technique.

[0005] In order to achieve the above purpose, the utility model is realized through the following technical solutions.

[0006] A continuous production system for baloxavir marboxil intermediates includes a preparation module, a reaction module, a detection module, and a controller. The preparation module includes a mixing container and a weighing feeder connected to the mixing container through a solenoid valve. The reaction module includes a microchannel reactor, and the feeding end of the microchannel reactor is connected to the weighing feeder. The detection module includes an on-line viscosity sensor and a high-performance liquid chromatograph. The on-line viscosity sensor is arranged inside the mixing container, and the high-performance liquid chromatograph is connected to the discharging end of the microchannel reactor. The controller is electrically connected to at least one of the preparation module, the reaction module, and the detection module.

[0007] Preferably, the number of the preparation modules is 1 to 5 sets, and the weighing feeders of each set of preparation modules are all connected to the feeding end of the microchannel reactor.

[0008] Preferably, it further includes a weighing module, which includes a powder bin and a liquid bin, a weighing and feeding machine connected to the powder bin, a liquid storage tank connected to the liquid bin, the weighing and feeding machine is connected to the mixing container, and the liquid storage tank is connected to the feeding end of the mixing container or the microchannel reactor.

[0009] Preferably, the powder bin and the weighing and feeding machine are connected by a screw conveyor, the weighing and feeding machine and the mixing container are connected by a vacuum transporter, and the liquid bin and the liquid storage tank are connected by a quantitative filling machine.

[0010] Preferably, the weighing module, the preparation module, the reaction module and the detection module are all electrically connected to the controller.

[0011] Advantages of the present utility model:

[0012] (1) The present utility model relates to a continuous production system for baloxavir marboxil intermediates. The continuous production system includes a weighing module and a preparation module. By presetting basic information in the controller, the weighing module is used for storing, transporting, weighing, proportioning, etc. of powder materials or liquid materials, and the preparation module is used for pretreatment operations such as mixing different materials and stirring evenly, reducing manual operations in related links. On the one hand, it saves labor costs and reduces time costs, and on the other hand, it reduces the excessive contact of operators with powder materials so as to damage their physical health.

[0013] (2) The present utility model relates to a continuous production system for baloxavir marboxil intermediates. The continuous production system includes a reaction module, which uses a microchannel reactor as the main reaction container and can complete industrial production more safely and efficiently.

[0014] (3) The present utility model relates to a continuous production system for baloxavir marboxil intermediates. The continuous production system includes a detection module, which is used to detect the pretreatment degree of reactants and the progress of the main reaction, and better complete the industrial production of baloxavir marboxil intermediates.

[0015] (4) The present utility model relates to a continuous production system for baloxavir marboxil intermediates. The continuous production system may further include a controller, and some modules or all modules are selected to be electrically connected to the controller to achieve different degrees of automated production, appropriately liberating the labor force and improving the control accuracy of the reaction at the same time. Description of the Drawings

[0016] By reading the detailed description of the non-restrictive embodiments with reference to the following drawings, other features, purposes and advantages of the present utility model will become more obvious:

[0017] Figure 1 This is a schematic structural diagram of the continuous production system of the present utility model.

[0018] Figure 2 This is a schematic structural diagram of the continuous production system shown in Embodiment 1.

[0019] In the figure: 11 powder bin, 1101 first powder bin, 12 liquid bin, 1201 first liquid bin, 1202 second liquid bin, 1203 third liquid bin, 13 screw conveyor, 1301 first screw conveyor, 14 weighing feeder, 1401 first weighing feeder, 15 vacuum transporter, 1501 first vacuum transporter, 16 quantitative filling machine, 1601 first quantitative filling machine, 1602 second quantitative filling machine, 1603 third quantitative filling machine, 17 liquid storage tank, 1701 first liquid storage tank, 1702 second liquid storage tank, 1703 third liquid storage tank, 21 mixing container, 2101 first mixing container, 2102 second mixing container, 22 solenoid valve, 2201 first solenoid valve, 2202 second solenoid valve, 23 weighing feeder, 2301 first weighing feeder, 2302 second weighing feeder, 31 microchannel reactor, 41 on-line viscosity sensor, 4101 first line viscosity sensor, 4102 second on-line viscosity sensor, 42 high performance liquid chromatography. Specific embodiments

[0020] In order to make the technical means, creative features, achieved purposes and functions of the present utility model easy to understand, the present utility model will be further described below in conjunction with specific embodiments. Suitable products of equipment or sensors not described in detail in the specific embodiments can be purchased on the market.

[0021] As Figure 1 shown, a continuous production system for baloxavir marboxil intermediate includes a weighing module, a preparation module, a reaction module, a detection module and a controller: the weighing module is used to accurately weigh solid or liquid reactants and supply them to the next preparation module; the preparation module is used for pre-treatment of the reaction, mixing several reactants in advance according to the ratio to form an intermediate reaction solution, and at the same time accurately transporting it to the reaction module; the main equipment of the reaction module is a microchannel reactor that can control the reaction temperature, which is used to accurately and safely carry out the main reaction of the compound; the detection module is used to detect the pre-treatment degree of the reactants and the progress of the main reaction, so as to better complete the industrial production of baloxavir marboxil intermediate. The controller (not shown in the figure) can be selectively electrically connected to at least one of the preparation module, the reaction module and the detection module.

[0022] The weighing module includes a powder bin 11, a weighing and feeding machine 14 connected to the powder bin 11 through a screw conveyor 13, a vacuum transporter 15 connected to the weighing and feeding machine 14, a liquid bin 12, and a liquid storage tank 17 connected to the liquid bin 12 through a quantitative filling machine 16. Both ends of the vacuum transporter 15 are respectively connected to the weighing and feeding machine 14 and the mixing container 21, and the liquid storage tank 17 is connected to the feeding end of the mixing container 21 or the microchannel reactor 31. Among them, the powder bin 11, the screw conveyor 13, the weighing and feeding machine 14, and the vacuum transporter 15 are used in combination to quantitatively transport solid reactants or powdered reactants to the preparation module; the liquid bin 12, the quantitative filling machine 16, and the liquid storage tank 17 are used in combination to quantitatively transport liquid reactants to the preparation module.

[0023] The preparation module includes a mixing container 21 and a weighing feeder 23 connected to the mixing container 21 through a solenoid valve 22; the number of preparation modules is 1 to 5 sets.

[0024] The reaction module includes a microchannel reactor 31. Each weighing feeder 23 of the preparation module is numbered, and at the same time, different feeding ends of the microchannel reactor 31 are noted, and the weighing feeder 23 is sequentially connected to the feeding end of the microchannel reactor 31.

[0025] The detection module includes an on-line viscosity sensor 41 and a high-performance liquid chromatograph 42: The on-line viscosity sensor 41 is arranged inside the mixing container 21 to detect the progress of the pre-treatment of the reaction; the high-performance liquid chromatograph 42 is connected to the discharge end of the microchannel reactor 31; it is used to detect the reaction degree of the main reaction, measure the content of the target product, and further control the reaction end time.

[0026] The above-mentioned weighing module, preparation module, reaction module, and detection module can also be electrically connected to a controller (not shown in the figure) to achieve different levels of industrial automation production. The controller mentioned in this application can select a common PLC controller on the market. The PLC controller mostly uses a programmable memory to store operation instructions such as logical operations, sequential control, timing, counting, and arithmetic operations inside it, and through digital and analog inputs and outputs, it can control various types of production processes and is dedicated to industrial environments. The connection relationships of all devices connected to the PLC controller in this specific embodiment refer to the corresponding instruction manual; or only the weighing module can be selected for electrical connection to reduce the number of manual feeding times and reduce the adverse effects of powdered reactants on the respiratory tract of operators, etc. It can also only select the detection module for electrical connection according to actual operation needs to control the reaction progress in real time.

[0027] Example 1

[0028] As Figure 2As shown in the figure, this embodiment provides a continuous production system for baloxavir marboxil intermediates, including a weighing module, a preparation module, a reaction module, a detection module, and a controller.

[0029] The weighing module includes: (1) a first powder bin 1101, a first screw conveyor 1301, a first weighing feeder 1401, and a first vacuum transporter 1501 connected in sequence, which are used to store and transport the 3,4-difluorobenzoic acid powder raw material; (2) a first liquid bin 1201, a first metering filling machine 1601, and a first liquid storage tank 1701 connected in sequence, which are used to store and transport the tetrahydrofuran liquid raw material; (3) a second liquid bin 1202, a second metering filling machine 1602, and a second liquid storage tank 1702 connected in sequence, which are used to store and transport the n-butyllithium liquid raw material; (4) a third liquid bin 1203, a third metering filling machine 1603, and a third liquid storage tank 1703 directly connected to the microchannel reactor 31, which are used to store and transport the N,N-dimethylformamide liquid raw material; for the remaining reagents such as the tetrahydrofuran solution of diisopropylamine, quantitative weighing by the weighing module or manual addition can be selected according to the actual situation in production.

[0030] The preparation module includes: (1) a first mixing container 2101 and a first weighing feeder 2301 connected to the first mixing container 2101 through a first solenoid valve 2201, which are used to mix the 3,4-difluorobenzoic acid powder and the tetrahydrofuran solution, and at the same time, the first mixing container 2101 serves as a temporary storage device for the obtained first solution; (2) a second mixing container 2102 and a second weighing feeder 2302 connected to the second mixing container 2102 through a second solenoid valve 2202, which are used to stir the n-butyllithium and the tetrahydrofuran solution of diisopropylamine to obtain the second solution, that is, the tetrahydrofuran solution of lithium diisopropylamide.

[0031] The reaction module includes a microchannel reactor 31, and several feed ends of the microchannel reactor 31 are connected to the first weighing feeder 2301, the second weighing feeder 2302, and the third liquid storage tank 1703 in sequence. In this embodiment, the length of the microchannel of the microchannel reactor 31 is 25 m, and the equivalent diameter of the channel is 5 mm to ensure that the reaction can proceed fully.

[0032] The detection module includes a first on-line viscosity sensor 4101 and a second on-line viscosity sensor 4102 respectively fixed in the first mixing container 2101 and the second mixing container 2102, and a high performance liquid chromatograph 42 connected to the microchannel reactor 31.

[0033] The above-mentioned weighing module, preparation module, reaction module, and detection module are electrically connected to the controller according to the actual situation in production. In this embodiment, the controller selects a common PLC controller on the market to achieve different levels of industrial automation production.

[0034] In summary, the working principle and operation process of the present utility model are as follows: First, input the required reactants and corresponding dosages into the PLC controller, start the corresponding equipment in the weighing module, and control a quantitative amount of reactants to enter the corresponding mixing container 21; Secondly, preset the reaction standard of the preparation module, start the mixing container 21 and the on-line viscosity sensor 41, and stir the reactants in real time for pretreatment. The on-line viscosity sensor 41 transmits the parameter information of the reaction solution back to the PLC controller, and the PLC controller judges whether the pretreatment meets the standard. If it does not meet the standard, continue to stir. If it reaches the preset standard, proceed to the next step; Thirdly, set parameters such as the reaction sequence, reaction flow rate, and reaction ratio of the main reaction in the microchannel reactor 31 through the PLC controller, start the high-performance liquid chromatograph 42 in the reaction module and the detection module in sequence, control the solenoid valves 22 and the weighing feeders 23 corresponding to each mixing container in the preparation module, and convey the pretreated reaction solution into the microchannel reactor 31 for reaction, and use the high-performance liquid chromatograph 42 to detect the progress of the reaction. The high-performance liquid chromatograph 42 transmits the detection data back to the PLC controller, and the PLC controller makes a judgment to determine whether the entire reaction is completed, and finally obtains the product, realizing the continuous production of baloxavir marboxil intermediate.

[0035] The specific reactions involved are as follows: First, mix 3,4-difluorobenzoic acid stored in the first powder silo 1101 and tetrahydrofuran stored in the first liquid silo 1201 in a certain proportional relationship to obtain a first solution and temporarily store it in the first mixing container 2101; Mix n-butyllithium stored in the second liquid silo 1202 and a tetrahydrofuran solution of a certain amount of diisopropylamine to obtain a second solution, a tetrahydrofuran solution of diisopropylaminolithium, and store it in the second mixing container 2102 for standby; The N,N-dimethylformamide liquid stored in the third liquid silo 1203 is directly used as the third solution for standby. Secondly, at a temperature of about -10°C to -20°C, inject the first solution and the second solution into the microchannel reactor 31 at a flow rate close to 1.0 g / min at the same time for full reaction to obtain an intermediate reaction solution, and then inject the third solution into the microchannel reactor 31 at a speed of 0.1 g / min, and fully react with the intermediate reaction solution for about 20 min. After being detected by the high-performance liquid chromatograph 42 to confirm that the reaction is over, a continuous reaction solution containing baloxavir marboxil intermediate is obtained, realizing the industrial continuous production of baloxavir marboxil intermediate.

[0036] The foregoing has shown and described the basic principles, main features and advantages of the present utility model. For those skilled in the art, it is obvious that the present utility model is not limited to the details of the above-described exemplary embodiments, and without departing from the spirit or basic characteristics of the present utility model, the present utility model can be implemented in other specific forms. Therefore, in any regard, the embodiments should be regarded as exemplary and non-limiting. The scope of the present utility model is defined by the appended claims rather than the above description. Therefore, it is intended to embrace all changes that fall within the meaning and scope of the equivalent elements of the claims in the present utility model.

[0037] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment only contains an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A continuous production system for a baloxavir intermediate, characterized in that: It includes preparation module, reaction module, detection module and controller. The preparation module comprises a mixing container (21), and a weighing feeder (23) connected to the mixing container (21) via a solenoid valve (22); The reaction module comprises a microchannel reactor (31), and a feed end of the microchannel reactor (31) is connected to the weighing feeder (23); The detection module comprises an online viscosity sensor (41) and a high performance liquid chromatograph (42), wherein the online viscosity sensor (41) is arranged inside the mixing container (21), and the high performance liquid chromatograph (42) is connected to the discharge end of the microchannel reactor (31); The controller is electrically connected to at least one of the preparation module, the reaction module, and the detection module.

2. The continuous production system according to claim 1, characterized in that: The number of the preparation modules is 1 to 5 sets, and the weighing feeder (23) of each set of preparation modules is connected to the feed end of the microchannel reactor (31).

3. The continuous production system according to claim 1, characterized in that: The device further comprises a weighing module, wherein the weighing module comprises a powder silo (11) and a liquid silo (12), a weighing feeder (14) connected to the powder silo (11), a liquid storage tank (17) connected to the liquid silo (12), the weighing feeder (14) connected to the mixing container (21), and the liquid storage tank (17) connected to the mixing container (21) or the feeding end of the microchannel reactor (31).

4. The continuous production system according to claim 3, characterized in that: The powder silo (11) and the weighing feeder (14) are connected via a screw conveyor (13), the weighing feeder (14) and the mixing container (21) are connected via a vacuum conveyor (15), and the liquid silo (12) and the liquid storage tank (17) are connected via a quantitative filling machine (16).

5. The continuous production system according to claim 3 or 4, characterized in that: The weighing module, the preparation module, the reaction module and the detection module are all electrically connected to the controller.

Images