High-throughput screening drug synthesis condition automation device and method thereof

Abstract

The application provides a high-throughput screening drug synthesis condition automation device and a method thereof, which comprises a central robot and a drug synthesis line arranged at the periphery of the central robot, a first feeding device, a second feeding device and a feeding and discharging device are arranged on a container access station; a code assigning and scanning device is arranged on a container identification station; a solid filling device is arranged on a solid filling station; a first pipetting device and a solution filling device are arranged on a liquid filling station; an air-adding lock cover device and a reaction testing device are arranged on an encapsulation reaction station; a multi-accessory supply device is arranged on an accessory supply station; and a second pipetting device is arranged on a dilution and sampling station. The application can realize automatic weighing, sampling and sampling, solves the defects of repeated and time-consuming screening of drug synthesis reaction conditions in the prior art, and greatly improves the integration, efficiency and accuracy of drug synthesis condition screening.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a high-throughput screening drug synthesis condition automation device and method thereof. BACKGROUND

[0002] High-throughput screening (HTS) technology refers to a technical system based on experimental methods at the molecular and cellular levels, using microplates as experimental tool carriers, using automatic operation systems to perform test processes, using sensitive and rapid detection instruments to collect experimental result data, using computers to analyze and process experimental data, detecting millions of samples at the same time, and supporting operation with the corresponding database. It has the characteristics of micro, rapid, sensitive and accurate. In short, a large amount of information can be obtained through one experiment, and valuable information can be found. Most of the current high-throughput screening devices are used for drug screening, and high-throughput screening devices are not publicly used in the drug synthesis stage.

[0003] In the drug synthesis stage, multiple reaction steps are involved, each reaction step involves screening solvents, reagents, reactants, catalysts, and corresponding operations involve weighing, sampling, reaction, sampling, etc.

[0004] Screening suitable reaction conditions and optimizing reaction conditions mainly aim to select reaction conditions with lower cost. These steps are simple, repetitive and time-consuming. The high-precision and high-efficiency sampling and reaction work is completed by replacing manual work with robots. The system completes complex multi-group experiment full-process control and all process data collection through logical control, and the data structure helps to improve the efficiency of screening reaction conditions and realize high-throughput screening.

[0005] Therefore, there is an urgent need for an automated device with high precision, suitable for liquid-solid compounds and multiple reaction vessels to further improve the efficiency of drug synthesis condition screening. SUMMARY

[0006] In order to achieve the above application purpose, the present application provides a high-throughput screening drug synthesis condition automation device and method thereof, which can realize automatic weighing, sampling and sampling, solve the defects of repeated and time-consuming screening of drug synthesis reaction conditions in the prior art, and greatly improve the integration, efficiency and accuracy of drug synthesis condition screening.

[0007] In order to solve the above technical problems, the application provides a high-throughput screening drug synthesis condition automation device high-throughput screening chemical drug synthesis automatic operation system, which comprises a central robot and a chemical drug synthesis line arranged at the periphery of the central robot, the central robot is used for transferring one of a reaction container, a reagent container and a sample injection container, and the chemical drug synthesis line comprises a container access station, a container identification station, a solid loading station, a liquid filling station, a reaction sealing station, a component supply station and a dilution sampling station.

[0008] The container access station is provided with a first feeding device, a second feeding device and a feeding and discharging device, the first feeding device is used for supplying the reaction container, the second feeding device is used for supplying the reagent container, and the feeding and discharging device is used for supplying or recovering the sample injection container.

[0009] The container identification station is provided with a coding and scanning device, which is used for giving information to one of the reaction container, the reagent container and the sample injection container and collecting the information.

[0010] The solid loading station is provided with a solid loading device, which is used for adding solid to the reaction container.

[0011] The liquid filling station is provided with a first pipetting device and a solution filling device, the first pipetting device is used for adding the reagent in the reagent container to the reaction container, and the solution filling device is used for simultaneously adding solution to multiple reaction containers.

[0012] The reaction sealing station is provided with a gas-filled lock cover device and a reaction test device, the gas-filled lock cover device is used for filling inert gas into the reaction container and closing the cover of the reaction container, and the reaction test device is used for magnetically stirring and heating oscillation of the liquid in the reaction container.

[0013] The component supply station is provided with a multi-component supply device, which is used for supplying the magnetic stirring bar of the reaction test device, the cover of the reaction container and the cover of the sample injection container.

[0014] The dilution sampling station is provided with a second pipetting device, which is used for adding the reaction liquid in the reaction container and the reagent in the reagent container to the sample injection container to dilute the reaction liquid to a preset concentration.

[0015] Preferably, the solid loading device comprises a weighing table for real-time weighing of the reaction container, a rotary disc rotatably arranged above the weighing table, and a plurality of feeding heads arranged in a circular array at the edge of the rotary disc with the center line of the rotary disc as the center.

[0016] Preferably, the center robot comprises a fixed base and a mechanical arm rotatably arranged on the fixed base; and the accessory feeding station is further provided with a quick-change gripper device, and a plurality of clamps are arranged in the quick-change gripper device, each of the clamps is detachably installed on the mechanical arm and is used for grabbing a container.

[0017] Preferably, the packaging reaction station is further provided with a bottle cap temporary storage table for placing a cover of the reaction container.

[0018] Preferably, the dilution sampling station is further provided with a container cooling table for cooling the reaction container after the reaction is completed.

[0019] Preferably, the chemical synthesis line further comprises a container waste station, and the container waste station is provided with a recovery tank.

[0020] Preferably, the first pipetting device comprises a first pipetting carrying table, and the first pipetting carrying table is provided with a reaction container placing rack, a reagent container placing rack and a first pipetting mechanism.

[0021] Preferably, the second pipetting device comprises a second pipetting carrying table, and the second pipetting carrying table is provided with a reaction container placing disc, a reagent container placing disc, a sample container placing disc and a second pipetting mechanism.

[0022] Preferably, the solution filling device comprises a large-capacity liquid storage tank, a filling main machine in pipeline communication with the large-capacity liquid storage tank, a filling arm horizontally swingably arranged on the filling main machine and a plurality of filling heads arranged on the filling arm.

[0023] Preferably, a plurality of pipette nozzle loading racks are arranged at intervals on the chemical synthesis line, and the pipette nozzle on the pipette nozzle loading rack is adapted to one of the first pipetting device, the solution filling device and the second pipetting device.

[0024] The application further provides a method for using the high-throughput screening drug synthesis condition automation device, comprising the following steps:

[0025] The process of the reaction container comprises:

[0026] S1, the reaction container is transferred from the first feeding device to the code assignment and scanning device by the center robot, and then is coded and scanned;

[0027] S2, the reaction container is transferred from the code assignment and scanning device to the solid filling device by the center robot, and then is filled with solid;

[0028] S3, the reaction container is transferred from the solid filling device to the first pipetting device by the center robot, and then is added with reagent;

[0029] S4, the reaction container is transferred from the first pipetting device to the solution filling device by the central robot, and then filled with solution;

[0030] S5, the reaction container is transferred from the solution filling device to the gas filling and sealing device by the central robot, and then sealed by gas filling;

[0031] S6, the reaction container is transferred from the gas filling and sealing device to the reaction testing device by the central robot, and then reacted;

[0032] S7, the reaction container is transferred from the reaction testing device to the second pipetting device by the central robot, and then opened by the central robot and provided with reaction liquid to the sample container;

[0033] S8, the reaction container is discarded;

[0034] The process of the reagent container comprises:

[0035] S1, part of the reagent container is transferred from the second feeding device to the first pipetting device by the central robot, and the other part of the reagent container is transferred from the second feeding device to the second pipetting device by the central robot;

[0036] S2, the reagent container is discarded;

[0037] The process of the sample container comprises:

[0038] S1, the sample container is transferred from the feeding and discharging device to the second pipetting device by the central robot, and then added with reaction liquid and reagent, and the sampling precision of the reaction liquid and the reagent is microliter;

[0039] S2, the sample container is transferred from the second pipetting device to the feeding and discharging device by the central robot.

[0040] The high-throughput screening drug synthesis condition automation device and method of the present application have the following beneficial effects: the drug synthesis line is arranged at the periphery of the central robot, the drug synthesis line comprises a container access station, a container identification station, a solid loading station, a liquid filling station, a sealing reaction station, a spare part supply station, and a dilution sampling station, so that the central robot can transfer one of the reaction container, the reagent container and the sample container to any station and complete the corresponding action, replacing manual work to complete high-precision and high-efficiency feeding, reaction and sampling, thereby reducing the workload of manual work and ensuring the consistency, continuity and safety and reliability of high-throughput screening drug synthesis. The container access station is provided with a first feeding device, a second feeding device and a feeding and discharging device. The first feeding device comprises a transfer carrying mechanism, which transfers the reaction container from the feeding position to the discharging position by a carrier. After the central robot takes all the reaction containers on the carrier, the transfer carrying mechanism transfers the empty carrier to the discharging position. The second feeding device is used to supply the reagent container, and the feeding and discharging device is used to supply or recover the sample container. The container identification station is provided with a coding and scanning device, which gives or collects actual data information and experimental process. The coding and scanning device can realize data connection in the form of digital tags or two-dimensional codes, achieve the structuring, correlation and traceability of experimental data, and reduce human errors caused by manual experiments and avoid the problems of incorrect and missed filling caused by manual filling of experimental data. The solid loading station is provided with a solid loading device. After the empty reaction container is coded and scanned, the central robot transfers the reaction container to the solid loading device, and then the solid loading device loads the solid into the reaction container. The solid can be in powder or granular form, and the solid loading device measures the weight of the reaction container in real time to ensure the accuracy of the amount of solid added. The liquid filling station is provided with a first pipetting device and a solution filling device. After the reaction container is loaded with solid, the central robot transfers the reaction container loaded with solid to the first pipetting device, and after the reagent container is coded and scanned, the central robot transfers the reagent container to the first pipetting device. At this time, the first pipetting device adds the reagent in the reagent container to the reaction container. Then, the central robot transfers the reaction container loaded with solid and reagent to the solution filling device, and the solution filling device adds solution to multiple reaction containers at the same time, thereby greatly improving the filling efficiency. The spare part supply station is provided with a multi-spare part supply device. Before the reaction container is sealed, the multi-spare part supply device needs to put a magnetic stirrer into the reaction container to prepare for subsequent magnetic stirring. The sealing reaction station is provided with an air-locked cover device and a reaction test device. After the reaction container is loaded with solid, reagent, solution and magnetic stirrer, the air-locked cover device not only needs to fill inert gas such as nitrogen into the reaction container, but also needs to use the cover supplied by the multi-spare part supply device to seal the reaction container.Subsequently, the central robot transfers the capped reaction container to the reaction test device, and then the reaction test device simultaneously performs magnetic stirring and heating oscillation on the liquid in multiple reaction containers. The second pipetting device is arranged on the dilution sampling station, and after the reaction container in which the reaction has been completed is cooled, the central robot transfers the reaction container to the second pipetting device, and the central robot also transfers the reagent container and the sample container to the second pipetting device, and then the second pipetting device adds the reaction liquid in the reaction container and the reagent in the reagent container into the sample container to dilute the reaction liquid to a preset concentration. Finally, the central robot caps the sample container using the cap supplied by the multi-component feeding device, and transfers the capped sample container to the feeding and discharging device.

[0041] Therefore, the high-throughput screening drug synthesis condition automation device and the method thereof can screen drug synthesis reaction conditions, realize full-process operations such as weighing, sampling, reaction, sampling, and the like of multiple control experiments in an automated manner, complete high-precision and high-efficiency work by replacing manual work with the central robot 1, complete full-process control of complex multiple experiments, collection of all process data, and structuring of data by a logic control program, accurately quantitatively record and integrate the operation process by corresponding devices, and strictly execute an experimental process according to a preset process, so that experimental results are quickly extracted, thereby greatly improving the integration, efficiency, and accuracy of high-throughput screening chemical drug synthesis operations. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 A perspective view of the high-throughput screening drug synthesis condition automation device of the present application is shown;

[0043] Figure 2 A perspective view of the quick-change gripper device is shown;

[0044] Figure 3 A perspective view of the solid filling device is shown;

[0045] Figure 4 A top view of the high-throughput screening drug synthesis condition automation device of the present application is shown;

[0046] Figure 5 A top view of the central robot and the multi-component feeding device is shown;

[0047] Figure 6 A top view of the first feeding device, the second feeding device, and the feeding and discharging device is shown;

[0048] Figure 7 A top view of the code assignment and scanning device is shown;

[0049] Figure 8 A top view of the first pipetting device is shown;

[0050] Figure 9 Figure 1 shows a top view of a solution filling device;

[0051] Figure 10 Figure 2 shows a top view of a gas filling lock cap device, a reaction test device and a bottle cap temporary storage table;

[0052] Figure 11 Figure 3 shows a top view of a second pipetting device and a container cooling table;

[0053] Figure 12 Figure 4 shows a method flow chart using a high-throughput screening drug synthesis condition automation device.

[0054] Element number explanation

[0055] 1 central robot

[0056] 11 fixed seat

[0057] 12 mechanical arm

[0058] 13 claw

[0059] 2 chemical synthesis line

[0060] 21 container in-out station

[0061] 211 first feeding device

[0062] 212 second feeding device

[0063] 213 feeding and discharging device

[0064] 22 container identification station

[0065] 221 code assignment and scanning device

[0066] 23 solid filling station

[0067] 231 solid filling device

[0068] 231a weighing table

[0069] 231b rotary disc

[0070] 231c feeding head

[0071] 24 liquid filling station

[0072] 241 first pipetting device

[0073] 241a first pipetting support table

[0074] 241b reaction container placing rack

[0075] 241c reagent container placing rack

[0076] 241d first pipetting mechanism

[0077] 242 solution filling device

[0078] 242a large-capacity liquid storage tank

[0079] 242b liquid filling main machine

[0080] 242c filling arm

[0081] 242d filling head

[0082] 25 packaging reaction station

[0083] 251 gas filling lock cover device

[0084] 252 reaction test device

[0085] 253 bottle cap temporary storage table

[0086] 26 accessory supply station

[0087] 261 multi-accessory supply device

[0088] 262 quick-change gripper device

[0089] 27 dilution sampling station

[0090] 271 second pipetting device

[0091] 271a second pipetting carrier table

[0092] 271b reaction vessel rest tray

[0093] 271c reagent vessel rest tray

[0094] 271d sample introduction vessel rest tray

[0095] 271e second pipetting mechanism

[0096] 272 vessel cooling table

[0097] 28 vessel waste station

[0098] 281 recovery tank

[0099] 3 reaction vessel

[0100] 4 reagent vessel

[0101] 5 sample introduction vessel

[0102] 6 pipette tip loading rack DETAILED DESCRIPTION

[0103] The present application will be described in detail by specific embodiments, and other advantages and effects of the present application can be easily understood by those skilled in the art from the contents disclosed in the specification.

[0104] It should be understood that the structures, proportions, sizes, etc. shown in the drawings attached to the specification are only used to illustrate the contents disclosed in the specification for those skilled in the art to understand and read, and are not used to limit the conditions that the present application can be implemented, so they do not have technical significance. Any modification of the structure, change of the proportional relationship or adjustment of the size, without affecting the effects and purposes that the present application can produce, should still fall within the scope of the technical content disclosed by the present application. At the same time, the terms such as "upper", "lower", "left", "right", "middle" and "one" used in the specification are only for the convenience of clear description, and are not used to limit the scope of the present application, and the change or adjustment of the relative relationship, without substantially changing the technical content, is also considered as the scope of the present application.

[0105] As shown in Figures 1 to 11 , the present application provides an automatic device for high-throughput screening of drug synthesis conditions, comprising: a central robot 1 and a chemical drug synthesis line 2 arranged at the periphery of the central robot 1, the central robot 1 being used to transfer one of a reaction container 3, a reagent container 4 and a sample container 5, the reaction container 3, the reagent container 4 and the sample container 5 can be bottle-shaped or tank-shaped, the chemical drug synthesis line 2 comprising a container in-out station 21, a container identification station 22, a solid loading station 23, a liquid filling station 24, an encapsulation reaction station 25, a accessory supply station 26 and a dilution sampling station 27;

[0106] Specifically referring to Figure 6 , the container in-out station 21 is arranged with a first feeding device 211, a second feeding device 212 and a feeding and discharging device 213, the first feeding device 211 being used to supply the reaction container 3, the second feeding device 212 being used to supply the reagent container 4, and the feeding and discharging device 213 being used to supply or recover the sample container 5;

[0107] Specifically referring to Figure 7 , the container identification station 22 is arranged with a coding and scanning device 221, the coding and scanning device 221 being used to give information to and collect information from one of the reaction container 3, the reagent container 4 and the sample container 5;

[0108] Specifically referring to Figure 3 , the solid loading station 23 is arranged with a solid loading device 231, the solid loading device 231 being used to add solid to the reaction container 3;

[0109] Specifically referring to Figure 8 and Figure 9The liquid filling station 24 is provided with a first pipetting device 241 for adding reagent in the reagent container 4 to the reaction container 3 and a solution filling device 242 for simultaneously adding solution to multiple reaction containers 3.

[0110] Specifically referring to Figure 10 The packaging reaction station 25 is provided with a gas filling and sealing device 251 for filling inert gas into the reaction container 3 and sealing the cover of the reaction container 3 and a reaction testing device 252 for magnetically stirring and heating the liquid in the reaction container 3.

[0111] Specifically referring to Figure 5 The accessory supply station 26 is provided with a multi-accessory supply device 261 for supplying the magnetic stirring rod of the reaction testing device 252, the cover of the reaction container 3 and the cover of the sample container 5.

[0112] Specifically referring to Figure 11 The dilution and sampling station 27 is provided with a second pipetting device 271 for adding the reaction liquid in the reaction container 3 and the reagent in the reagent container 4 to the sample container 5 to dilute the reaction liquid to a preset concentration.

[0113] In the application, the chemical synthesis line 2 is arranged at the periphery of the central robot 1, and the chemical synthesis line 2 comprises a container in-out station 21, a container identification station 22, a solid loading station 23, a liquid filling station 24, an encapsulation reaction station 25, a component supply station 26, and a dilution sampling station 27, so that the central robot 1 can transfer one of the reaction container 3, the reagent container 4 and the sample container 5 to any station and complete the corresponding action, instead of manually completing the high-precision and high-efficiency feeding, reaction and sampling, thereby reducing the workload of manual work and ensuring the consistency, continuity and safety and reliability of high-throughput screening of chemical synthesis. The first feeding device 211, the second feeding device 212 and the feeding and discharging device 213 are arranged on the container in-out station 21, the first feeding device 211 comprises a transfer carrying mechanism, which transfers the reaction container 3 from the feeding position to the sampling position through the carrier, and the reaction container 3 can be a 20ml reaction bottle with the cap opened, and after the central robot 1 takes all the reaction containers 3 on the carrier, the transfer carrying mechanism transfers the empty carrier to the discharging position. The second feeding device 212 is used for supplying the reagent container 4, which can be a 50ml reagent bottle with the cap opened, and the feeding and discharging device 213 is used for supplying or recycling the sample container 5, which can be a 2ml sampling bottle with the cap opened. The code assigning and scanning device 221 is arranged on the container identification station 22, which assigns or collects actual data information and experimental process, and the code assigning and scanning device 221 can realize data connection in the form of digital label or two-dimensional code, so as to realize the structuring, correlation and traceability of experimental data, reduce human errors caused by manual experiments, and avoid the problems of wrong filling and missing filling caused by manual filling of experimental data. The solid filling device 231 is arranged on the solid loading station 23, after the empty reaction container 3 is coded and scanned, the central robot 1 transfers the reaction container 3 to the solid filling device 231, and then the solid filling device 231 fills the solid into the reaction container 3, which can be in powder or granular form, and the solid filling device 231 measures the weight of the reaction container 3 in real time to ensure the accuracy of the amount of solid added. The first pipetting device 241 and the solution filling device 242 are arranged on the liquid filling station 24, after the reaction container 3 is added with solid, the central robot 1 transfers the reaction container 3 filled with solid to the first pipetting device 241, and after the reagent container 4 is coded and scanned, the central robot 1 transfers the reagent container 4 to the first pipetting device 241, at this time, the first pipetting device 241 adds the reagent in the reagent container 4 to the reaction container 3. Then, the central robot 1 transfers the reaction container 3 filled with solid and reagent to the solution filling device 242, and the solution filling device 242 simultaneously adds solution to multiple reaction containers 3, thereby greatly improving the filling efficiency.The multi-accessory supplying device 261 is arranged on the accessory supplying station 26, and before the reaction container 3 is capped, the multi-accessory supplying device 261 needs to put the magnetic stirrer into the reaction container 3 to prepare for the subsequent magnetic stirring. The gas filling and capping device 251 and the reaction testing device 252 are arranged on the reaction processing station 25, and after the reaction container 3 is added with the solid, the reagent, the solution and the magnetic stirrer, the gas filling and capping device 251 not only needs to fill the non-reactive gas such as nitrogen into the reaction container 3, but also needs to cap the reaction container 3 using the cap supplied by the multi-accessory supplying device 261. Then, the capped reaction container 3 is transferred to the reaction testing device 252 by the central robot 1, and then the reaction testing device 252 simultaneously performs the magnetic stirring and the heating oscillation on the liquid in the plurality of reaction containers 3. The second pipetting device 271 is arranged on the dilution and sampling station 27, and after the reaction container 3 in which the reaction is completed is cooled, the reaction container 3 is transferred to the second pipetting device 271 by the central robot 1, and the reagent container 4 and the sample container 5 are also transferred to the second pipetting device 271 by the central robot 1, and then the second pipetting device 271 adds the reaction liquid in the reaction container 3 and the reagent in the reagent container 4 into the sample container 5 to dilute the reaction liquid to a preset concentration. Finally, the sample container 5 is capped by the central robot 1 using the cap supplied by the multi-accessory supplying device 261, and the capped sample container 5 is transferred to the feeding and discharging device 213.

[0114] The method of the high-throughput screening drug synthesis condition automation device includes the following steps:

[0115] The process of the reaction container 3 includes the following steps:

[0116] S1, the reaction container 3 is transferred from the first feeding device 211 to the code assigning and scanning device 221 by the central robot 1, and then is coded and scanned;

[0117] S2, the reaction container 3 is transferred from the code assigning and scanning device 221 to the solid filling device 231 by the central robot 1, and then is filled with the solid;

[0118] S3, the reaction container 3 is transferred from the solid filling device 231 to the first pipetting device 241 by the central robot 1, and then is added with the reagent;

[0119] S4, the reaction container 3 is transferred from the first pipetting device 241 to the solution filling device 242 by the central robot 1, and then is filled with the solution;

[0120] S5, the reaction container 3 is transferred from the solution filling device 242 to the gas filling and capping device 251 by the central robot 1, and then is filled with the gas and capped;

[0121] S6, the reaction container 3 is transferred from the gas filling lock cover device 251 to the reaction test device 252 by the central robot 1, and then the reaction is carried out;

[0122] S7, the reaction container 3 is transferred from the reaction test device 252 to the second liquid transfer device 271 by the central robot 1, and then the reaction liquid is provided to the sample container 5 by the central robot 1.

[0123] S8, the reaction container 3 is discarded.

[0124] Before step S5 is performed, the reaction container 3 is transferred to the multi-component supply device 261 by the central robot 1, and a magnetic stirrer is added.

[0125] The process of the reagent container 4 includes:

[0126] S1, part of the reagent container 4 is transferred from the second feeding device 212 to the first liquid transfer device 241 by the central robot 1, and the other part of the reagent container 4 is transferred from the second feeding device 212 to the second liquid transfer device 271 by the central robot 1;

[0127] S2, the reagent container 4 is discarded.

[0128] The process of the sample container 5 includes:

[0129] S1, the sample container 5 is transferred from the feeding and discharging device 213 to the second liquid transfer device 271 by the central robot 1, and then the reaction liquid and the reagent are added, and the sampling precision of the reaction liquid and the reagent is microliter;

[0130] S2, the sample container 5 is transferred from the second liquid transfer device 271 to the feeding and discharging device 213 by the central robot 1.

[0131] Therefore, the high-throughput screening drug synthesis condition automatic device and the method thereof can screen drug synthesis reaction conditions, realize full-process operations such as weighing, sampling, reaction, and sampling of multiple groups of control experiments in an automatic manner, complete high-precision and high-efficiency work by replacing manual work with the central robot 1, complete full-process control of complex multiple experiments, collection of all process data, and structuring of data by a logic control program, accurately quantitatively record and integrate the operation process by corresponding devices, and strictly execute the experimental process according to the preset process, so that the experimental results can be quickly extracted, and the integration, efficiency, and accuracy of high-throughput screening chemical drug synthesis operations are greatly improved.

[0132] In order to accurately add the solid by the solid filling device 231, the solid filling device 231 includes a weighing table 231a for weighing the reaction container 3 in real time, a rotary disc 231b rotatably arranged above the weighing table 231a, and a plurality of feeding heads 231c arranged in a circular array at the edge of the rotary disc 231b with the center line of the rotary disc 231b as the center line. Specifically, the feeding head 231c can be driven by a servo motor to feed the powder through a screw rod, so as to control the supply amount of the solid; the weight of the reaction container 3 is weighed in real time by the weighing table 231a, so as to realize accurate weighing, and the accuracy can be milligrams; different feeding heads 231c can store different solids, and different solids can be switched and added by rotating the rotary disc 231b.

[0133] In order to make the center robot 1 grasp containers and covers of different shapes and sizes, the center robot 1 includes a fixed seat 11 and a mechanical arm 12 rotatably arranged on the fixed seat 11; the accessory feeding station 26 is further provided with a quick-change gripper device 262, and a plurality of clamps 13 are placed in the quick-change gripper device 262, each clamp 13 being detachably installed on the mechanical arm 12 and being used for grasping a container.

[0134] In order to make the cover processing of the reaction container 3 more efficient, the packaging reaction station 25 is further provided with a cap temporary storage table 253 for placing the cover of the reaction container 3, and the cover on the cap temporary storage table 253 is supplied by the multi-accessory feeding device 261.

[0135] In order to facilitate the cooling of the reaction container 3, the dilution and sampling station 27 is further provided with a container cooling table 272 for cooling the reaction container 3 after the reaction is completed.

[0136] As shown in Figure 4 In order to recycle the used reaction container 3 and reagent container 4, the chemical synthesis line 2 further includes a container waste station 28, and the container waste station 28 is provided with a recycling tank 281.

[0137] In order to realize the liquid adding function, the first pipetting device 241 includes a first pipetting carrying table 241a, and the first pipetting carrying table 241a is provided with a reaction container placing rack 241b, a reagent container placing rack 241c, and a first pipetting mechanism 241d. The accuracy of the first pipetting mechanism 241d can be 0.01 milliliter.

[0138] In order to realize the function of diluting the reaction liquid, the second pipetting device 271 includes a second pipetting support table 271a, which is provided with a reaction container rest tray 271b, a reagent container rest tray 271c, a sample container rest tray 271d, and a second pipetting mechanism 271e. The accuracy of the second pipetting mechanism 271e can be 0.01 milliliter.

[0139] In order to realize multi-channel rapid solution adding, the solution filling device 242 includes a large-capacity liquid storage tank 242a, a liquid filling main machine 242b in pipeline communication with the large-capacity liquid storage tank 242a, a filling arm 242c horizontally oscillatingly arranged on the liquid filling main machine 242b, and a plurality of filling heads 242d arranged on the filling arm 242c. The liquid filling main machine 242b can be used for large-dose liquid adding by means of a syringe pump; the filling arm 242c serves to drive the filling heads 242d, and the plurality of filling heads 242d arranged on the suspended part of the filling arm 242c can realize multi-channel rapid liquid adding, and the accuracy can be milliliter.

[0140] As shown in Figure 1 In order to avoid cross contamination in the pipetting process, a plurality of pipette nozzle loading racks 6 are arranged on the chemical synthesis line 2, and the pipette nozzles on the pipette nozzle loading racks 6 are adapted to one of the first pipetting device 241, the solution filling device 242, and the second pipetting device 271.

[0141] The reaction test device 252 can realize temperature change by oil bath method, ensure controllable stability of the temperature of the reaction container 3, and control the uniformity of the liquid by magnetic stirring; the reaction test device 252 can realize partition control of different control groups in parallel experiments, and realize precise regulation and control of the reaction containers 3 of different control groups by different reaction conditions, different stirring speeds, and temperature control.

[0142] As shown in Figure 11 As a specific embodiment of the method, the empty 2mL sample bottle, the empty 20mL reaction bottle, and the 50mL reagent bottle already filled with reagents used in the reaction are prepared and arranged in the container in-out station 21 by automatic or manual operation. The pipette nozzles are prepared and arranged in the pipette nozzle loading rack 6 by automatic or manual operation. The caps of the 20mL reaction bottle and the 2mL sample bottle are prepared and arranged in the accessory supply station 26 by automatic or manual operation. The solid compound used in the reaction is prepared and loaded into the filling head 231c of the solid filling device 231. The solvent is prepared and poured into the large-capacity liquid storage tank 242a of the solution filling device 242.

[0143] According to the reagent configuration requirement of the reaction, the first kind of claw 13 for grabbing 20 mL reaction bottle or 50 mL reagent bottle is installed on the mechanical arm 12 of the central robot 1, the 20 mL reaction bottle is grabbed and transferred to the container identification station 22, and after the identification is filled, it is placed in the solid loading station 23, and after the weighing, it is placed on the first pipetting device 241; the central robot 1 grabs the 50 mL reagent bottle and places it on the first pipetting device 241, and the first pipetting device 241 adds the reagent in the 50 mL reagent bottle to the 20 mL reaction bottle. The 20 mL reaction bottle after adding the reagent is transferred to the accessory supply station 26, and a magnetic stirrer is added. The 20 mL reaction bottle is transferred to the solution filling device 242, and the pump of the solution filling device 242 adds the solvent in the large-capacity liquid tank 242a to the 20 mL reaction bottle according to the preset filling amount, and the 20 mL reaction bottle is transferred to the gas lock cover device 251 for nitrogen filling and locking, and the central robot 1 transfers the 20 mL reaction bottle after locking to the reaction test device 252, and a plurality of 20 mL reaction bottles are placed in the reaction test device 252 for oscillation and heating. After the reaction is completed, the central robot 1 transfers a group of 20 mL reaction bottles to the container cooling table 272 for cooling, and after cooling, it is transferred to the second pipetting device 271, and the central robot 1 also transfers the 50 mL reagent bottle to the second pipetting device 271.

[0144] At this time, the central robot 1 needs to replace the second kind of claw 13 to clamp the 2 mL sample bottle to the second pipetting device 271, the second pipetting device 271 transfers the solution in the 20 mL reaction bottle to the 2 mL sample bottle, and the reagent in the 50 mL reagent bottle is transferred to the 2 mL sample bottle for dilution. After dilution, the central robot 1 transfers the 2 mL sample bottle to the accessory supply station 26 for capping, and finally to the temporary storage.

[0145] The third kind of claw 13 is also placed in the above-mentioned quick-change gripper device 262, which is used to grab the above-mentioned pipetting nozzle and transfer it to the first pipetting device 241, the second pipetting device 271 and the solution filling device 242, so as to supply the pipetting nozzle at each device.

[0146] In summary, the high-throughput screening drug synthesis condition automatic device and method thereof can screen drug synthesis reaction conditions, realize full-process operations such as weighing, sampling, reaction, sampling and the like of multiple groups of control experiments in an automatic manner, complete high-precision and high-efficiency work by replacing manual work with the central robot 1, complete full-process control of complex multiple experiments, collection of all process data and data structuring by a logic control program, accurately quantitatively record and integrate operations through corresponding devices, real-time monitoring, strictly execute experimental processes according to preset processes, quickly extract experimental results, and greatly improve the integration, efficiency and accuracy of high-throughput screening chemical drug synthesis operations. Therefore, the present application effectively overcomes various shortcomings in the prior art and has high industrial utilization value.

[0147] The above embodiments only exemplarily illustrate the principles and effects of the present application, and are not used to limit the present application. Any person skilled in the art can modify or change the above embodiments without departing from the spirit and scope of the present application. Therefore, all equivalent modifications or changes completed by those skilled in the art without departing from the spirit and technical thought disclosed by the present application should be covered by the claims of the present application.

Claims

1. An automated device for high-throughput screening of drug synthesis conditions, characterized in that, Comprising: A central robot (1) and a chemical synthesis line (2) arranged around the central robot (1). The central robot (1) is used to transfer one of a reaction vessel (3), a reagent container (4), and a sampling container (5). The chemical synthesis line (2) includes a container inlet / outlet station (21), a container identification station (22), a solid addition station (23), a liquid filling station (24), a sealing and reaction station (25), a fitting supply station (26), and a dilution and sampling station (27). A first loading device (211), a second loading device (212), and a loading / unloading device (213) are arranged at the container inlet / outlet station (21). The first loading device (211) is used to supply the reaction vessel (3), the second loading device (212) is used to supply the reagent container (4), and the loading / unloading device (213) is used to supply or recover the sampling container (5). An encoding and scanning device (221) is arranged at the container identification station (22). The encoding and scanning device (221) is used to assign information to and collect information from one of the reaction vessel (3), the reagent container (4), and the sampling container (5). A solid addition device (231) is arranged at the solid addition station (23). The solid addition device (231) is used to add solids to the reaction vessel (3). A first pipetting device (241) and a solution filling device (242) are arranged at the liquid filling station (24). The first pipetting device (241) is used to add the reagent in the reagent container (4) to the reaction vessel (3), and the solution filling device (242) is used to add the solution to multiple reaction vessels (3) simultaneously. An airtight lid device (251) and a reaction test device (252) are arranged at the sealing and reaction station (25). The airtight lid device (251) is used to fill the reaction vessel (3) with an inert gas and close the lid of the reaction vessel (3). The reaction test device (252) is used to magnetically stir and heat and oscillate the liquid in the reaction vessel (3). A multi-fitting supply device (261) is arranged at the fitting supply station (26). The multi-fitting supply device (261) is used to supply the magnetic stirrer of the reaction test device (252), the lid of the reaction vessel (3), and the lid of the sampling container (5). A second pipetting device (271) is arranged at the dilution and sampling station (27). The second pipetting device (271) is used to add the reaction liquid in the reaction vessel (3) and the reagent in the reagent container (4) to the sampling container (5) together to dilute the reaction liquid to a preset concentration.

2. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The solid addition device (231) includes a weighing platform (231a) for weighing the reaction vessel (3) in real time, a rotary disk (231b) rotatably arranged above the weighing platform (231a), and a plurality of feeding heads (231c) arranged in a circular array along the circumference of the rotary disk (231b) with the center line of the rotary disk (231b) as the center line.

3. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The central robot (1) includes a fixed base (11) and a robotic arm (12) that is rotatably mounted on the fixed base (11); the accessory supply station (26) is also equipped with a quick-change gripper device (262), which contains a variety of grippers (13), each of which can be detachably mounted on the robotic arm (12) and used to grip a container.

4. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The encapsulation reaction station (25) is also equipped with a bottle cap storage platform (253), which is used to place the caps of the reaction vessel (3).

5. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The dilution sampling station (27) is also equipped with a container cooling platform (272), which is used to cool the reaction vessel (3) after the reaction is completed.

6. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The chemical drug synthesis line (2) also includes a container waste station (28), on which a recycling tank (281) is arranged.

7. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The first pipetting device (241) includes a first pipetting stage (241a), on which a reaction container rack (241b), a reagent container rack (241c), and a first pipetting mechanism (241d) are provided.

8. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The second pipetting device (271) includes a second pipetting stage (271a), on which a reaction container shelf (271b), a reagent container shelf (271c), an injection container shelf (271d), and a second pipetting mechanism (271e) are provided.

9. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: The solution filling device (242) includes a large-capacity storage tank (242a), a filling host (242b) connected to the large-capacity storage tank (242a) by a pipeline, a filling arm (242c) horizontally swinging on the filling host (242b), and a plurality of filling heads (242d) on the filling arm (242c).

10. The automated device for high-throughput screening drug synthesis conditions according to claim 1, characterized in that: Multiple pipette tip racks (6) are arranged at intervals on the chemical drug synthesis line (2). The pipette tips on the pipette tip racks (6) are adapted to one of the first pipetting device (241), the solution filling device (242), and the second pipetting device (271).

11. A method using the automated apparatus for high-throughput screening of drug synthesis conditions as described in any one of claims 1 to 10, characterized in that, Includes the following steps: The process of the reaction vessel (3) includes: S1, the reaction vessel (3) is transferred from the first feeding device (211) to the coding and scanning device (221) by the central robot (1), and then coded and scanned; S2, the reaction vessel (3) is transferred by the central robot (1) from the coding and scanning device (221) to the solid dispensing device (231), and then solids are added; S3, the reaction vessel (3) is transferred by the central robot (1) from the solid dispensing device (231) to the first pipetting device (241), where reagents are then added; S4, the reaction vessel (3) is transferred from the first pipetting device (241) to the solution filling device (242) by the central robot (1), and then filled with solution; S5, the reaction vessel (3) is transferred by the central robot (1) from the solution filling device (242) to the gas-filling and capping device (251), and then gas-filled and capped; S6, the reaction vessel (3) is transferred from the gas filling and locking device (251) to the reaction test device (252) by the central robot (1), and then the reaction is carried out; S7, the reaction vessel (3) is transferred from the reaction test device (252) to the second pipette device (271) by the central robot (1), and then the central robot (1) opens the cap and provides the reaction solution to the injection container (5); S8, reaction vessel (3) is discarded; The process for the reagent container (4) includes: S1, a portion of the reagent containers (4) are transferred from the second feeding device (212) to the first pipetting device (241) by the central robot (1), and another portion of the reagent containers (4) are transferred from the second feeding device (212) to the second pipetting device (271) by the central robot (1); S2, reagent container (4) is discarded; The process of the injection container (5) includes: S1, the sample container (5) is transferred from the loading and unloading device (213) to the second pipetting device (271) by the central robot (1), and then the reaction solution and reagents are added. The sampling accuracy of the reaction solution and reagents is microliters. S2, the sample container (5) is transferred by the central robot (1) from the second pipetting device (271) to the loading and unloading device (213).

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