A solid phase synthesis system and method capable of identifying materials

Abstract

This invention relates to the fields of biochemical engineering and pharmaceutical technology, specifically a solid-phase synthesis system and method for identifying materials. The system comprises a monomer delivery unit, a low-flow-rate reagent delivery unit, a high-flow-rate reagent delivery unit, an analytical monitoring device, a mixing and draining valve assembly, a common flow path, a reactor, and a circulating draining switching valve assembly. The monomer delivery unit and the low-flow-rate reagent delivery unit have the same internal piping volume. The mixing and draining valve assembly has a first inlet, a second inlet, a third inlet, a first outlet, and a second outlet. The analytical monitoring device performs spectral analysis on the materials before they enter the reactor; if the results do not meet preset values, the system shuts down or pauses. The circulating draining switching valve assembly can switch between waste discharge and circulation states. This invention achieves real-time online identification and error-proof feeding of materials before they enter the reactor, enabling simultaneous mixing of different materials and direct transfer of processes across energy levels, thus improving the safety and reliability of the synthesis.

Description

Technical Field

[0001] This invention relates to the fields of biochemical and pharmaceutical technology, and in particular to a solid-phase synthesis system and method for identifying materials. Background Technology

[0002] The market application of nucleic acid drugs is expanding from the treatment of rare diseases to the management of chronic diseases, with the global market size continuing to grow. This places higher demands on the production capacity and product quality control capabilities of oligonucleotide solid-phase synthesis systems. Currently, commercially available large-scale oligonucleotide synthesis systems generally lack material identification capabilities. Nucleic acid sequences are composed of multiple monomers linked in a specific order, and nucleic acid monomers for different application scenarios often require different types of chemical modifications. This results in a wide variety of monomer materials actually used, with similar appearances and physicochemical properties, making material management quite difficult. During production, problems such as incorrect material preparation, incorrect pipeline connections, or valve operation errors often lead to the scrapping of entire batches of materials, resulting in significant economic losses.

[0003] The existing system has a large overall pipeline volume, and the internal volumes of different input channels are inconsistent. This increases solvent consumption, leading to excessive reagent consumption and higher production costs. Furthermore, the volume differences in the pipelines prevent multiple materials added simultaneously from reaching the mixing point synchronously, affecting the synthesis reaction efficiency and product quality. In addition, the inconsistent pipeline structure also complicates solution replacement and system evacuation.

[0004] Currently, nucleic acid synthesis systems on the market differ in hardware configuration and control platforms at the laboratory, pilot-scale, and production levels. The same synthesis method cannot be directly transferred between devices of different energy levels. When scaling up a process from laboratory scale to production scale, or vice versa, it is necessary to rely on human experience to correct process parameters. This correction process is prone to introducing errors, and the reference value between results obtained from devices of different scales is limited. Summary of the Invention

[0005] In response to the above situation and to overcome the shortcomings of existing solid-phase synthesis systems, this invention provides a solid-phase synthesis system and method capable of identifying materials. It also solves the technical challenges of material safety control, uniform flow path volume design, and direct scale-up and scaling-up of cross-platform processes. It is applicable to the solid-phase synthesis of nucleic acids and peptides.

[0006] The technical solution to the problem solved by this invention is as follows:

[0007] This invention provides a solid-phase synthesis system capable of identifying materials, comprising a monomer delivery unit, a low-flow-rate reagent delivery unit, a high-flow-rate reagent delivery unit, an analytical monitoring device, a mixing and draining valve assembly, a common flow path, a reactor, and a circulating draining switching valve assembly;

[0008] The single-unit conveying unit is used to convey single-unit materials and includes a first set of pumps; the low-flow-rate reagent conveying unit is used to convey low-flow-rate reagents and includes a second set of pumps; the high-flow-rate reagent conveying unit is used to convey high-flow-rate reagents and includes a third set of pumps; the internal pipeline volume of the single-unit conveying unit and the low-flow-rate reagent conveying unit is the same.

[0009] The mixed drain valve assembly is a combined valve assembly, having a first inlet, a second inlet, and a third inlet respectively connected to the single delivery unit, the low-flow-rate reagent delivery unit, and the high-flow-rate reagent delivery unit. The mixed drain valve assembly also has a first outlet and a second outlet. The first outlet is connected to a back pressure valve and is used to discharge gas or liquid from the system. The second outlet is connected to the common flow path.

[0010] The analysis and monitoring device is installed in at least one of the flow paths of the monomer delivery unit, the low-flow-rate reagent delivery unit, and the high-flow-rate reagent delivery unit, and is located before the material enters the reactor. It is used to perform spectral analysis on the material and compare it with preset parameters. When the comparison result does not meet the preset value, the system stops or pauses.

[0011] The common flow path is provided with the mixing drain valve group, the reactor switching valve group and the circulating drain switching valve group in sequence along the material flow direction; the reactor is connected to the reactor switching valve group, and the reactor switching valve group has the function of switching the material to react in the reactor or bypass the reactor;

[0012] The circulating drain switching valve group has a waste discharge state and a circulation state. In the waste discharge state, the solution is discharged out of the system. In the circulation state, the solution returns to the inlet of the third pump through the circulating drain switching valve group, and then re-enters the mixing drain valve group through the third pump for mixing, forming a circulation loop.

[0013] A second aspect of the present invention provides a method for solid-phase synthesis using the aforementioned solid-phase synthesis system capable of identifying materials, comprising the following steps:

[0014] (1) Use the analysis and monitoring device to perform spectral analysis on the monomeric materials, and / or low-flow-rate reagents, and / or high-flow-rate reagents input into the system and compare them with the preset parameters. If the comparison results are inconsistent, stop or pause the machine.

[0015] (2) The monomeric materials, low-flow-rate reagents and high-flow-rate reagents that have passed the identification and meet the preset conditions are combined and mixed in the mixing and draining valve group;

[0016] (3) The mixed solution is fed into a common flow path and its temperature is controlled;

[0017] (4) The temperature-controlled solution enters the reactor switching valve group. Through the switching of the reactor switching valve group, the solution passes through the reactor for deprotection and activation coupling reaction, or bypasses the reactor.

[0018] (5) The solution after the reaction enters the circulating drain switching valve group. Through the switching of the circulating drain switching valve group, the solution is discharged out of the system or returned to the inlet of the third pump group and re-enters the mixing drain valve group for mixing. It then enters the reactor through the common flow path and the reactor switching valve group to form a self-circulating loop.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The solid-phase synthesis system for identifying materials provided by this invention includes an analytical monitoring device in the flow path of the monomer delivery unit, low-flow-rate reagent delivery unit, or high-flow-rate reagent delivery unit. The analytical monitoring device is located before the material enters the reactor and is used to perform spectral analysis on the material and compare it with preset parameters. When the comparison results are inconsistent, the system automatically stops or pauses. This effectively solves the problem in existing systems where it is difficult to accurately identify nucleic acid monomers manually due to their numerous types and similar appearance and physicochemical properties. It also eliminates the scrapping of entire batches of materials due to factors such as incorrect material preparation, incorrect pipeline connection, or valve not being opened, significantly reducing economic losses and production risks.

[0021] 2. The solid-phase synthesis system for identifiable materials provided by this invention employs a specially customized combined valve assembly as a mixing and draining valve assembly. Its first outlet is connected to a back pressure valve, which can quickly discharge gas or liquid from the system to achieve pipeline evacuation and solution replacement. Solutions from the three delivery units achieve uniform mixing through convection and collision within the valve assembly base of the mixing and draining valve assembly. Simultaneously, by optimizing the component layout and connecting pipe dimensions, the internal pipeline volume of the individual delivery unit and the low-flow-rate reagent delivery unit is made the same, ensuring that different materials arrive at the mixing point simultaneously. This design avoids the drawbacks of traditional systems, such as large pipeline volume, difficulty in evacuation, and the inability of materials to arrive at the mixing point simultaneously. Furthermore, three independent pumps correspond to the three delivery units respectively, and the individual flow path and reagent flow path are completely independent from the inlet end until they converge at the mixing and draining valve assembly, completely avoiding cross-contamination.

[0022] 3. The circulating discharge switching valve group of this invention has a waste discharge state and a circulation state: in the waste discharge state, the solution is discharged out of the system; in the circulation state, the solution returns to the third pump and re-enters the mixing discharge valve group and reactor, forming a circulation loop. This allows for flexible extension of the reaction time or improvement of coupling efficiency according to process requirements. Simultaneously, the system uses the same flow path topology, valve group configuration scheme, and control platform in the laboratory, pilot-scale, and production stages. The same synthesis method can be directly transferred between different energy level devices, realizing direct cross-platform scale-up and scaling-up of the process and avoiding process parameter adjustment deviations caused by platform inconsistencies. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of a solid-phase synthesis system for identifiable materials according to an embodiment of the present invention.

[0024] Figure 2 This is a schematic diagram of the structure of a mixing and draining valve assembly in one embodiment of the present invention.

[0025] Figure label:

[0026] V1: First valve group of individual inlet valves; V2: Second valve group of individual inlet valves; V3: Third valve group of individual inlet valves; V4: Low flow rate reagent inlet valve group; V5: High flow rate reagent inlet valve group; V6: Mixing drain valve group; V7: Temperature control valve group; V8: Reactor switching valve group; V9: Circulating drain switching valve group; SV1: Cleaning agent inlet valve of the first valve group; SV2: Cleaning agent inlet valve of the second valve group; SV3: Cleaning agent inlet valve of the low flow rate reagent inlet valve; SV4: Cleaning agent inlet valve of the high flow rate reagent inlet valve; FV1: First waste liquid outlet valve; FV2: Second waste liquid outlet valve; FV3: Third waste liquid outlet valve; FV4: Fourth waste liquid outlet valve; BP1: First back pressure valve; BP2: Second back pressure valve; P1: First pump group; P2: Second pump group; P3: Third pump group; FI-01: First Flow meter; FI-02: Second flow meter; FI-03: Third flow meter; AM-01: Analysis and monitoring device; PI-01: First pressure monitor; PI-02: Second pressure monitor; PI-03: Third pressure monitor; PI-04: Fourth pressure monitor; PI-05: Fifth pressure monitor; TI: Temperature monitor; CT: Conductivity monitor; UV: UV monitor; V6-base: Valve assembly base; V61: First pneumatic diaphragm valve; V62: Second pneumatic diaphragm valve; V63: Third pneumatic diaphragm valve; V64: Fourth pneumatic diaphragm valve; V62-a: Valve body; V62-b: Actuator; V62-c: Electrical position indicator; S1: First inlet; S2: Second inlet; S3: Third inlet; S4: First outlet; S5: Second outlet. Detailed Implementation

[0027] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

[0028] It should be understood that the structures, proportions, sizes, etc., illustrated in the accompanying drawings of this specification are merely for illustrative purposes to aid those skilled in the art and to facilitate understanding and reading. They are not intended to limit the implementation conditions of this invention and therefore have no substantial technical significance. Any modifications to the structure, changes in proportions, or adjustments to size, without affecting the effectiveness and objectives of this invention, should still fall within the scope of the technical content disclosed in this invention. Furthermore, the terms such as "upper," "lower," "left," "right," "middle," and "one" used in this specification are merely for clarity of description and are not intended to limit the scope of implementation of this invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of implementation of this invention.

[0029] The first aspect of this invention provides a solid-phase synthesis system capable of identifying materials, with reference to... Figure 1 It includes a single-unit delivery unit, a low-flow-rate reagent delivery unit, a high-flow-rate reagent delivery unit, an analysis and monitoring device AM-01, a mixing and draining valve group V6, a common flow path, a reactor, a reactor switching valve group V8, and a circulating draining switching valve group V9.

[0030] The unit conveying unit is used to convey unit materials and includes a first pump group P1. The first pump group P1 is a sanitary-grade positive displacement infusion pump used to deliver the unit materials to the mixing and draining valve group V6 at a precise flow rate. The outlet end of the first pump group P1 is equipped with a first flow meter FI-01 and a first pressure monitor PI-01, which are used to monitor the conveying flow rate and pressure of the unit materials in real time, respectively.

[0031] In some embodiments of the present invention, reference is made to Figure 1The individual conveying unit further includes a first valve group V1 and a second valve group V2 of individual inlet valves arranged in parallel. Both the first valve group V1 and the second valve group V2 are multi-channel pneumatic diaphragm switching valves, with their inlet ends used to connect to multiple individual storage tanks. The outlet ends of both the first valve group V1 and the second valve group V2 are connected to the inlet end of a third valve group V3 of individual inlet valves. The outlet end of the third valve group V3 is connected to the inlet of the analysis and monitoring device AM-01, and the outlet of the analysis and monitoring device AM-01 is connected to the inlet of the first pump group P1. With the above-mentioned parallel structure of two-stage valves, when a specific type of single material needs to be transported, the control system first controls the third valve group V3 of the single material inlet valve to switch to connect to the first or second channel, and then controls the corresponding first valve group V1 or second valve group V2 of the single material inlet valve to switch to the inlet channel where the single material is located. The single material can then be drawn by the first pump P1 through the corresponding valve group and then through the third valve group V3 of the single material inlet valve and transported to the analysis and monitoring device AM-01 for material identification.

[0032] In some embodiments of the present invention, the first valve group V1 and the second valve group V2 of the monomer inlet valve are both 10-way selector valves. Each 10-way selector valve has 10 inlet channels and 1 outlet, which can be connected to different types of nucleic acid monomer solutions respectively. The washing port is located at the front end of all inlet channels and is used to connect the washing solvent. The two valve groups are connected in parallel to realize the access capability of multiple different monomers, which fully meets the synthesis requirements of complex nucleic acid sequences.

[0033] The low-flow-rate reagent delivery unit, comprising a second pump P2, is used to deliver low-flow-rate reagents. Pump P2 is a sanitary-grade volumetric infusion pump used to deliver low-flow-rate reagents (such as capping reagents, activating reagents, etc.) at a low flow rate to the mixing and draining valve assembly V6. The outlet of pump P2 is equipped with a second flow meter FI-02 and a second pressure monitor PI-02, used to monitor the flow rate and pressure of the low-flow-rate reagents in real time. The low-flow-rate reagent inlet valve assembly V4 is a multi-channel pneumatic diaphragm switch valve, whose inlet end selectively connects to multiple low-flow-rate reagent storage tanks, and whose outlet end connects to the inlet of pump P2.

[0034] The high-flow-rate reagent delivery unit, comprising a third pump P3, is used to deliver high-flow-rate reagents. Pump P3 is a sanitary-grade volumetric infusion pump used to deliver high-flow-rate reagents (such as washing solvents and deprotection reagents) at a high flow rate to the mixing and draining valve assembly V6. A third pressure monitor PI-03 is installed at the outlet of pump P3 to monitor the delivery pressure of the high-flow-rate reagents in real time. The high-flow-rate reagent inlet valve assembly V5 is a multi-channel pneumatic diaphragm switch valve. Its inlet is selectively connected to multiple high-flow-rate reagent storage tanks, and its outlet is connected to one inlet of the circulating draining switching valve assembly V9. The outlet of the circulating draining switching valve assembly V9 ​​is connected to the inlet of the third pump P3.

[0035] In some embodiments of the present invention, the internal pipeline volume of the monomer delivery unit and the low-flow-rate reagent delivery unit is the same. The internal volume of each component in both the monomer delivery unit and the low-flow-rate reagent delivery unit is calculated using 3D modeling, optimizing the placement of components and the dimensions of connecting pipes to ensure that the flow path volumes of both are identical. This ensures that when monomer materials and low-flow-rate reagents are added simultaneously, they can reach the mixing and draining valve assembly synchronously, improving reaction efficiency. Furthermore, during solution displacement, the two flow paths can use the same displacement volume, eliminating the need to set different displacement parameters, thereby simplifying the process and improving efficiency.

[0036] The analytical monitoring device AM-01 is installed in at least one of the flow paths of the monomer delivery unit, the low-flow-rate reagent delivery unit, and the high-flow-rate reagent delivery unit, and is located before the material enters the reactor. It is used to perform spectral analysis on the material and compare it with preset parameters. When the comparison result does not meet the preset value, the system stops or pauses.

[0037] In some embodiments of the present invention, reference is made to Figure 1 The analytical monitoring device AM-01 is located between the outlet end of the third valve group V3 of the monomer inlet valve and the inlet end of the first pump P1, and is used for real-time online identification of monomer materials. In other embodiments of the present invention, the analytical monitoring device AM-01 may also be located at the front or rear end of the second pump P2, and / or at the front or rear end of the third pump P3, for material identification of low-flow-rate reagents and / or high-flow-rate reagents. The material identification location can be flexibly configured according to actual needs.

[0038] In some embodiments of the present invention, the analytical monitoring device AM-01 is one or more of an infrared spectrometer, a Raman spectrometer, or an ultraviolet-visible spectrometer. The analytical monitoring device AM-01 performs real-time online spectral scanning of the material, acquires spectral characteristic peaks or absorbance data, and compares it with preset standard parameters. If the comparison results are consistent, the material is allowed to enter subsequent processes; if the comparison results do not meet the preset values, the system immediately stops or pauses and issues an alarm signal to prevent incorrect material from entering the reactor.

[0039] In this embodiment, reference Figure 2 The mixing and draining valve assembly V6 is a combined valve assembly with an integrated structure, including a valve assembly base V6-base and four pneumatic diaphragm valves mounted on it (namely, a first pneumatic diaphragm valve V61, a second pneumatic diaphragm valve V62, a third pneumatic diaphragm valve V63, and a fourth pneumatic diaphragm valve V64). The first inlet S1, the second inlet S2, the third inlet S3, the first outlet S4, and the second outlet S5 are located on the valve assembly base V6-base. The valve assembly base V6-base has internal flow channels connecting each pneumatic diaphragm valve to each inlet and outlet. Each pneumatic diaphragm valve is respectively located in its corresponding flow channel to control the opening and closing of each flow channel. Furthermore, the four pneumatic diaphragm valves have the same structure. Taking the second pneumatic diaphragm valve V62 as an example, each pneumatic diaphragm valve includes a valve body V62-a, a drive actuator V62-b disposed on the valve body V62-a, and an electrical position indicator V62-c disposed on the top of the drive actuator V62-b. The valve body V62-a is selectively connected to various interfaces on the valve assembly base V6-base through internal flow channels to control the opening and closing of the flow path. Specifically, the valve base V6-base has a main flow channel and a first branch channel and a second branch channel connected to the main flow channel, respectively. The third inlet S3 is directly connected to the beginning of the main flow channel. The first inlet S1 is connected to the first branch channel and is connected to the main flow channel via the first pneumatic diaphragm valve V61. The second inlet S2 is connected to the second branch channel and is connected to the main flow channel via the second pneumatic diaphragm valve V62. The end of the main flow channel is divided into two outlet channels, one of which is connected to the first outlet S4 via the third pneumatic diaphragm valve V63, and the other is connected to the second outlet S5 via the fourth pneumatic diaphragm valve V64. During the synthesis process, monomer materials and low-flow-rate reagents are injected into the main flow channel by opening the first pneumatic diaphragm valve V61 and the second pneumatic diaphragm valve V62, respectively, and merge and mix with the high-flow-rate reagent from the third inlet S3 within the main flow channel. The above flow channel design eliminates internal dead volume and prevents material residue.

[0040] In some embodiments of the present invention, the first valve group V1, the second valve group V2, the third valve group V3, the low-flow-rate reagent inlet valve group V4, the high-flow-rate reagent inlet valve group V5, the temperature control valve group V7, the reactor switching valve group V8, and the circulating drainage switching valve group V9 are all multi-channel pneumatic diaphragm switching valve groups. Each pneumatic diaphragm switching valve group includes a valve body, a drive actuator mounted on the valve body, and an electrical position indicator mounted on top of the drive actuator. The system also includes a control system electrically connected to the drive actuators of each pneumatic diaphragm switching valve group, used to switch the corresponding valve group by controlling the action of each drive actuator; the electrical position indicator is used to provide real-time feedback on the valve core position to ensure that the on / off state of each flow path is accurate and controllable.

[0041] The first inlet S1 is connected to the outlet of the first pump P1 in the monomer delivery unit, the second inlet S2 is connected to the outlet of the second pump P2 in the low-flow-rate reagent delivery unit, and the third inlet S3 is connected to the outlet of the third pump P3 in the high-flow-rate reagent delivery unit. The first outlet S4 is connected to the first back pressure valve BP1 via a pipeline, used to discharge gas or liquid from the system, achieving pipeline evacuation or solution replacement. The second outlet S5 is connected to the upstream end of the common flow path. When the system undergoes a synthesis reaction, the monomer material, low-flow-rate reagent, and high-flow-rate reagent enter the valve base V6-base of the mixing and draining valve group V6 from the three inlets respectively, achieving rapid and uniform mixing through convection and collision within the valve base V6-base.

[0042] The first outlet S4 of the mixing drain valve group V6 has a dual function: firstly, it is a venting function. When the system starts up or the material is changed, the mixing drain valve group V6 switches to venting mode, and the first outlet S4 opens. The solution from the individual conveying unit, the low-flow-rate reagent conveying unit, and the high-flow-rate reagent conveying unit is quickly discharged through the first outlet S4 to vent the air or gas-liquid mixture in the pump chamber and save solvent consumption. Secondly, it is a displacement function. When the system needs to increase the solution displacement volume (i.e., to fully clean the common flow path), the mixing drain valve group V6 switches to buffer mode. The solution from the individual conveying unit and / or the low-flow-rate reagent conveying unit passes through the common flow path (i.e., through the flow path of the temperature control valve group V7, the reactor switching valve group V8, and the circulating drain switching valve group V9) and is discharged from the system through the waste outlet of the circulating drain switching valve group V9 to increase the solution displacement volume and ensure that there is no residual material from the previous batch in the common flow path.

[0043] Along the material flow direction, the common flow path is provided with a mixing and draining valve group V6, a temperature control valve group V7, a reactor switching valve group V8, and a circulating draining switching valve group V9 in sequence.

[0044] The second outlet S5 of the mixing drain valve assembly V6 is connected to the inlet of the third flow meter FI-03, which is used to monitor the solution flow rate in the common flow path in real time. The outlet of the third flow meter FI-03 is connected to the inlet of the temperature control valve assembly V7. The temperature control valve assembly V7 is connected to a sanitary heat exchanger for temperature control of the solution in the common flow path, ensuring the solution reaches the required reaction temperature. The outlet of the temperature control valve assembly V7 is connected to the fourth pressure monitor PI-04 and the temperature monitor TI. The fourth pressure monitor PI-04 and the temperature monitor TI are installed in parallel on the fourth flow cell, respectively used to monitor the pressure and temperature of the solution in the common flow path in real time.

[0045] The outlet of temperature control valve group V7 is connected to the inlet of reactor switching valve group V8. Reactor switching valve group V8 is a multi-channel pneumatic diaphragm switching valve group connected to a reactor. The reactor is filled with a carrier for solid-phase synthesis. Reactor switching valve group V8 has a switching function that allows materials to react in the reactor or bypass the reactor. Specifically, reactor switching valve group V8 has a common end, a first branch end, and a second branch end. The common end is connected to the second outlet S5 of the mixing drain valve group V6. The first branch end is connected to the inlet of the reactor. The second branch end is connected to a bypass pipeline. The outlet of the bypass pipeline merges with the outlet of the reactor and then connects to the inlet of the circulating drain switching valve group V9. When a synthesis reaction is required, reactor switching valve group V8 introduces the solution into the reactor, where the solution contacts and reacts with the solid-phase synthesis carrier filled in the reactor. When rapid replacement of the solution system is required, reactor switching valve group V8 switches the solution to the bypass pipeline, bypassing the reactor, to quickly complete pipeline cleaning or solution replacement.

[0046] The outlet of reactor switching valve group V8 is connected to the fifth pressure monitor PI-05, which is installed on the fifth flow cell and used to monitor the solution pressure at the reactor outlet in real time. The outlet of the fifth pressure monitor PI-05 is connected to the inlet of the UV monitor UV, which is used to monitor the ultraviolet absorption value of the solution after the reaction in real time. The outlet of the UV monitor UV is connected to the inlet of the circulating drain switching valve group V9. The conductivity monitor CT is installed in parallel with the fifth pressure monitor PI-05 on the fifth flow cell, located at the reactor outlet, and is used to monitor the change in conductivity of the solution after the reaction in real time.

[0047] The circulating drain switching valve group V9 is a multi-channel pneumatic diaphragm switching valve group with two operating modes: waste discharge and circulation. In waste discharge mode, the solution is discharged from the system through the waste discharge outlet of the circulating drain switching valve group V9, which is connected to the second back pressure valve BP2. In circulation mode, the solution returns to the inlet of the third pump P3 through the circulation outlet of the circulating drain switching valve group V9, and then re-enters the mixing drain valve group V6 for mixing. Finally, it enters the reactor through the reactor switching valve group V8, forming a self-circulating loop.

[0048] In some embodiments of the present invention, each inlet end of the system is further provided with a cleaning agent inlet valve. Specifically, the monomer delivery unit also includes a first valve group cleaning agent inlet valve SV1 located at the front end of the first valve group V1 of the monomer inlet valve and a second valve group cleaning agent inlet valve SV2 located at the front end of the second valve group V2 of the monomer inlet valve, respectively used to introduce cleaning solvent into the flow paths corresponding to the first valve group V1 and the second valve group V2 of the monomer inlet valve. The low-flow-rate reagent delivery unit includes a low-flow-rate reagent inlet valve cleaning agent inlet valve SV3 located at the front end of the low-flow-rate reagent inlet valve group V4, used to introduce cleaning solvent into the low-flow-rate reagent flow path. The high-flow-rate reagent delivery unit includes a high-flow-rate reagent inlet valve cleaning agent inlet valve SV4 located at the front end of the high-flow-rate reagent inlet valve group V5, used to introduce cleaning solvent into the high-flow-rate reagent flow path. By controlling each cleaning agent inlet valve, each delivery unit can be independently cleaned before the start of each synthesis batch or when changing the type of material, effectively avoiding cross-contamination between different batches or different materials.

[0049] In some embodiments of the present invention, the system further includes a first waste liquid outlet valve FV1, a second waste liquid outlet valve FV2, a third waste liquid outlet valve FV3, and a fourth waste liquid outlet valve FV4. The waste liquid outlet valves are all pneumatic diaphragm switch T-type valves, which are composed of two or more common channels connected in series and connected to the waste outlet of the circulating discharge switching valve group V9 for switching the waste liquid discharge channel. The number of valves can be increased according to the type of waste liquid to achieve classified discharge of waste liquid.

[0050] In some embodiments of the present invention, the system further includes a flow meter, a pressure monitor, and a temperature monitor. The flow meter is disposed at the outlet end of at least one of the first group of pumps P1, the second group of pumps P2, and the third group of pumps P3, and is used to monitor the real-time flow rate. The pressure monitor and the temperature monitor are disposed on a common flow path and are used to monitor the system pressure and temperature. Specifically, the first flow meter FI-01 is disposed at the outlet end of the first group of pumps P1, the second flow meter FI-02 is disposed at the outlet end of the second group of pumps P2, and the third flow meter FI-03 is disposed on the common flow path and located between the mixing drain valve group V6 and the temperature control valve group V7. The first pressure monitor PI-01 is located at the outlet of the first pump group P1, the second pressure monitor PI-02 is located at the outlet of the second pump group P2, the third pressure monitor PI-03 is located at the outlet of the third pump group P3, the fourth pressure monitor PI-04 and the temperature monitor TI are located on the common flow path and between the temperature control valve group V7 and the reactor switching valve group V8, and the fifth pressure monitor PI-05 is located on the common flow path and between the reactor switching valve group V8 and the UV monitor UV.

[0051] In some embodiments of the present invention, the system further includes a UV monitor (UV) and a conductivity monitor (CT). The UV monitor and the conductivity monitor (CT) are disposed on a common flow path and located between the reactor and the circulating drain switching valve group V9. The UV monitor is used to monitor the ultraviolet absorbance of the solution after the reaction in real time, and the conductivity monitor (CT) is used to monitor the change in conductivity of the solution after the reaction in real time. The combined use of the UV monitor (UV) and the conductivity monitor (CT) allows for real-time monitoring of both parameters of the synthesis process, providing multi-dimensional data support for process monitoring and synthesis efficiency evaluation.

[0052] In some embodiments of the present invention, the system further includes a first flow reservoir, a second flow reservoir, and a third flow reservoir. The first flow reservoir is located at the outlet end of the first group of pumps P1, the second flow reservoir is located at the outlet end of the second group of pumps P2, and the third flow reservoir is located at the outlet end of the third group of pumps P3. Each flow reservoir is sanitary designed to provide a mounting base for the pressure monitor and flow meter, ensuring the accuracy of pressure and flow monitoring.

[0053] Each flow meter, pressure monitor, temperature monitor (TI), UV monitor (UV), and conductivity monitor (CT) is connected to the control system for transmitting monitoring data to the control system in real time.

[0054] In some embodiments of the present invention, the system further includes an inert gas supply unit. The individual storage tank, the low-flow-rate reagent storage tank, and the high-flow-rate reagent storage tank are all equipped with gas-sealed interfaces. The inert gas supply unit is connected to each of the gas-sealed interfaces via pipelines to provide positive-pressure inert gas to each storage tank, thereby maintaining the stability of the liquid transport and preventing the formation of a vacuum within the storage tank.

[0055] In some embodiments of the present invention, the first outlet S4 of the mixing drain valve group V6 is connected to a first back pressure valve BP1, and the waste outlet of the circulating drain switching valve group V9 is connected to a second back pressure valve BP2. Both back pressure valves are sanitary-grade designs, used to provide a stable back pressure for the system, ensuring uniform distribution of the solution in the reactor, and simultaneously balancing the impact of the inert gas seal pressure in the storage tank on the pump metering accuracy.

[0056] In some embodiments of the present invention, the system further includes a control unit, which is communicatively connected to the analysis and monitoring device, the first group of pumps, the second group of pumps, and the third group of pumps; the control unit receives the spectral analysis results and compares them with preset parameters, and when the results do not meet the preset values, the control unit controls each pump to stop operating so that the system is shut down or paused.

[0057] A second aspect of the present invention provides a method for solid-phase synthesis using the aforementioned identifiable material solid-phase system, comprising the following steps:

[0058] (1) Use the analysis and monitoring device to perform spectral analysis on the monomeric materials, and / or low-flow-rate reagents, and / or high-flow-rate reagents input into the system and compare them with the preset parameters. If the comparison results are inconsistent, stop or pause the machine.

[0059] (2) The monomeric materials, low-flow-rate reagents and high-flow-rate reagents that have passed the identification and meet the preset conditions are combined and mixed in the mixing and draining valve group;

[0060] (3) The mixed solution is fed into a common flow path and its temperature is controlled;

[0061] (4) The temperature-controlled solution enters the reactor switching valve group. By switching the reactor switching valve group, the solution can selectively pass through the reactor for deprotection and activation coupling reactions, or bypass the reactor.

[0062] (5) The solution after the reaction enters the circulating drain switching valve group. Through the switching of the circulating drain switching valve group, the solution is selectively discharged out of the system or returned to the inlet of the third pump group and re-enters the mixing drain valve group for mixing. Then, it enters the reactor through the reactor switching valve group to form a self-circulating loop.

[0063] refer to Figure 1The workflow of the solid-phase system for identifying materials described in this invention includes steps such as material identification, cleaning and pre-filling, deprotection, activation and coupling, sealing and oxidation, cyclic synthesis and back pressure balancing.

[0064] (1) Material identification

[0065] After system startup, the AM-01 analytical monitoring device first performs spectral analysis on the input monomer materials, low-flow-rate reagents, and high-flow-rate reagents, comparing the results with preset parameters. Taking monomer materials as an example, the monomer materials enter through either the first valve group V1 or the second valve group V2 of the monomer inlet valve, then flow through the third valve group V3 of the monomer inlet valve, before entering the AM-01 analytical monitoring device. The AM-01 performs real-time online spectral scanning on the materials, acquiring spectral characteristic peaks or absorbance data, and comparing them with the system's preset standard parameters. If the comparison results are consistent, the materials are allowed to proceed to subsequent processes; if the comparison results do not meet the preset values, the system immediately stops or pauses and issues an alarm signal. If the low-flow-rate reagents and / or high-flow-rate reagents are also equipped with the AM-01 analytical monitoring device, they must also undergo identification and confirmation before entering the mixing drain valve group V6.

[0066] (2) Cleaning and prefilling

[0067] Before synthesis begins, the circulating drain switching valve group V9 is switched to the waste discharge state. The control system controls the first group pump P1, the second group pump P2, and the third group pump P3 to switch to their respective solvent storage tanks to extract cleaning solvent. The three solvents enter the mixing drain valve group V6 through their respective delivery units. After merging in the valve chamber, they enter the common flow path through the second outlet S5 of the mixing drain valve group V6, flow through the third flow meter FI-03, the temperature control valve group V7, the reactor switching valve group V8 (at this time, the reactor switching valve group V8 is switched to the bypass pipeline and does not pass through the reactor), the circulating drain switching valve group V9 (waste discharge state), and the UV monitor UV, before being discharged from the system through the waste discharge outlet of the circulating drain switching valve group V9.

[0068] During pre-filling, switch the reactor switching valve group V8 to the reactor passage, and discharge the cleaning solvent after passing through the reactor to fully wet the solid synthesis carrier in the reactor.

[0069] (3) Deprotection

[0070] The circulating drain switching valve group V9 remains in the waste discharge state. Only the third pump group P3 operates, delivering the deprotection reagent. The deprotection reagent enters the mixing drain valve group V6 through the flow path of the high-flow-rate reagent delivery unit, and then enters the reactor through the common flow path and reactor switching valve group V8, where it reacts with the protecting groups on the solid support to remove the protecting groups. After the reaction, the waste liquid is discharged from the system through the circulating drain switching valve group V9 (waste discharge state).

[0071] (4) Activation and Coupling

[0072] The first pump group P1 delivers the monomer solution, while the second pump group P2 and / or the third pump group P3 deliver the activating reagent. After the monomer solution and the activating reagent are uniformly mixed through convection and collision in the valve chamber of the mixing and draining valve group V6, they enter the reactor through the common flow path and the reactor switching valve group V8, where they undergo a coupling reaction with the active groups on the deprotected solid support.

[0073] Depending on the reaction requirements, the following two modes can be selected:

[0074] 1) Drainage mode: After the coupling reaction is completed, the circulating drainage switching valve group V9 remains in the waste discharge state, and the reaction liquid is discharged out of the system through the waste discharge outlet of the circulating drainage switching valve group V9.

[0075] 2) Circulation Mode: When it is necessary to extend the reaction time or improve the coupling efficiency, switch the circulation drain switching valve group V9 to circulation mode. The reaction liquid flows out from the circulation outlet of the circulation drain switching valve group V9, returns to the inlet of the third pump P3 through the pipeline, and re-enters the mixing drain valve group V6 for mixing through the third pump P3. Then, it enters the reactor through the common flow path and the reactor switching valve group V8, and the cycle repeats until the coupling reaction achieves the expected effect. Then, switch the circulation drain switching valve group V9 to waste discharge mode to discharge the reaction liquid.

[0076] (5) Sealing and oxidation

[0077] The circulating drain switching valve group V9 remains in the waste discharge state. The corresponding infusion pumps (either the second group pump P2 or the third group pump P3, depending on the reagent flow rate requirements) sequentially deliver the blocking reagent and the oxidizing reagent. The blocking reagent is used to block uncoupled active sites, and the oxidizing reagent is used to oxidize phosphite bonds to stable phosphate ester bonds. After the reagents are mixed in the mixing drain valve group V6, they enter the reactor through the common flow path and the reactor switching valve group V8 to complete the blocking and oxidation reactions. The reaction solution is then discharged through the waste discharge flow path.

[0078] (6) Cyclic synthesis

[0079] Repeat the above steps of deprotection, activation and coupling, blocking and oxidation, and sequentially insert the next monomer according to the preset nucleic acid or peptide sequence until the synthesis of the entire sequence is completed.

[0080] Back pressure balancing explanation: Throughout the synthesis process, the first back pressure valve BP1, connected to the first outlet S4 of the mixing drain valve group V6, and the second liquid adjustable back pressure valve, connected to the waste outlet of the circulating drain switching valve group V9, provide stable back pressure for the system. The opening pressure of the two back pressure valves is pre-adjusted to match the inert gas sealing pressure in each storage tank. This ensures that when the pump delivers liquid, the back pressure at the pump outlet is balanced by the downstream back pressure valve, thereby offsetting the influence of the inert gas sealing pressure in the storage tank on the pump's metering accuracy and guaranteeing the pump's delivery accuracy and liquid supply stability.

[0081] Description of the switching states of the circulating discharge switching valve group: In the waste discharge state, the circulating discharge switching valve group V9 connects the common flow path to the waste discharge outlet, and the reaction liquid or waste liquid is discharged out of the system through the waste discharge outlet. In the circulation state, the circulating discharge switching valve group V9 connects the common flow path to the inlet of the third pump group P3, and the reaction liquid returns to the inlet of the third pump group P3. After entering the mixing discharge valve group V6 again through the third pump group P3 for mixing, it enters the reactor through the common flow path and the reactor switching valve group V8, forming a self-circulating loop. This allows the reaction liquid to come into contact with the solid carrier in the reactor multiple times, reducing material waste.

[0082] Description of the first outlet venting and replacement function of the mixing drain valve assembly: When the system starts up or the material is changed, the mixing drain valve assembly V6 switches to venting mode, and the first outlet S4 opens. Gas or gas-liquid mixtures from the solutions of the three conveying units are discharged through the first outlet S4 under system pressure, thus venting the pipeline. When the system needs to increase the solution replacement volume, the mixing drain valve assembly V6 switches to buffer mode. The solution from the individual conveying unit and / or the low-flow-rate reagent conveying unit is discharged from the system through the waste outlet of the circulating drain switching valve assembly V9 ​​after passing through the common flow path, thereby increasing the solution replacement volume and ensuring that there is no residual material from the previous batch in the common flow path.

[0083] Based on the above working principle, this invention utilizes an analytical monitoring device to achieve real-time online identification and error prevention of materials before they enter the reactor, utilizes a mixing and draining valve group to achieve rapid mixing, emptying, and replacement of the three solutions, and utilizes a circulating draining switching valve group to achieve flexible control of the self-circulation and waste discharge of the reaction solution. At the same time, it ensures that the internal pipeline volume of the monomer conveying unit and the low-flow-rate reagent conveying unit is the same, ensuring that different materials arrive at the mixing point simultaneously, improving reaction efficiency, and effectively solving the technical problems of existing solid-phase synthesis systems in terms of material safety control, flow path volume consistency, and process scale-up and scaling-up.

[0084] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A solid-phase synthesis system capable of identifying materials, characterized in that, It includes a single-unit delivery unit, a low-flow-rate reagent delivery unit, a high-flow-rate reagent delivery unit, an analytical monitoring device (AM-01), a mixing drain valve assembly (V6), a common flow path, a reactor, and a circulating drain switching valve assembly (V9). The single-unit conveying unit is used to convey single-unit materials and includes a first set of pumps (P1); the low-flow-rate reagent conveying unit is used to convey low-flow-rate reagents and includes a second set of pumps (P2); the high-flow-rate reagent conveying unit is used to convey high-flow-rate reagents and includes a third set of pumps (P3); the internal pipeline volume of the single-unit conveying unit and the low-flow-rate reagent conveying unit is the same. The mixed drain valve assembly (V6) is a combined valve assembly with a first inlet, a second inlet, and a third inlet that are respectively connected to the single delivery unit, the low-flow-rate reagent delivery unit, and the high-flow-rate reagent delivery unit. The mixed drain valve assembly (V6) also has a first outlet and a second outlet. The first outlet is connected to a first back pressure valve (BP1) and is used to discharge gas or liquid in the system. The second outlet is connected to the common flow path. The analytical monitoring device (AM-01) is installed in at least one of the flow paths of the monomer delivery unit, the low-flow-rate reagent delivery unit, and the high-flow-rate reagent delivery unit, and is located before the material enters the reactor. It is used to perform spectral analysis on the material and compare it with preset parameters. When the comparison result does not meet the preset value, the system stops or pauses. Along the flow direction of the common flow path, the mixing drain valve group (V6), the reactor switching valve group (V8), and the circulating drain switching valve group (V9) are arranged in sequence; the reactor is connected to the reactor switching valve group (V8), and the reactor switching valve group (V8) has the function of switching the material to react in the reactor or bypass the reactor; The circulating drain switching valve group (V9) has a waste discharge state and a circulation state. In the waste discharge state, the solution is discharged outside the system. In the circulation state, the solution returns to the inlet of the third pump (P3) through the circulating drain switching valve group (V9) and re-enters the mixing drain valve group (V6) through the third pump (P3) for mixing, forming a circulation loop.

2. The solid-phase synthesis system for identifying materials according to claim 1, characterized in that, The single-unit delivery unit includes a first valve group (V1) and a second valve group (V2) of single-unit inlet valves arranged in parallel. The outlet ends of the first valve group (V1) and the second valve group (V2) of single-unit inlet valves are both connected to the inlet end of the third valve group (V3) of single-unit inlet valves. The outlet end of the third valve group (V3) of single-unit inlet valves is connected to the analysis and monitoring device (AM-01).

3. The solid-phase synthesis system for identifying materials according to claim 1, characterized in that, In the low-flow-rate reagent delivery unit, the analytical monitoring device (AM-01) is provided at the front or rear end of the second set of pumps (P2).

4. The solid-phase synthesis system for identifying materials according to claim 1, characterized in that, In the high-flow-rate reagent delivery unit, the analytical monitoring device (AM-01) is provided at the front or rear end of the third pump (P3).

5. The solid-phase synthesis system for identifying materials according to claim 1, characterized in that, The analytical monitoring device is one or more of the following: infrared spectrometer, Raman spectrometer, and ultraviolet-visible spectrometer.

6. The solid-phase synthesis system for identifiable materials according to claim 1, characterized in that, The mixing and draining valve assembly (V6) is an integrated structure, including a valve assembly base (V6-base) and multiple pneumatic diaphragm valves mounted on the valve assembly base; the first inlet (S1), the second inlet (S2), the third inlet (S3), the first outlet (S4), and the second outlet (S5) are located on the valve assembly base (V6-base). The valve assembly base (V6-base) has a flow channel inside that connects each of the pneumatic diaphragm valves with each inlet and each outlet. Each of the pneumatic diaphragm valves is respectively located in the corresponding flow channel to control the opening and closing of each flow channel.

7. The solid-phase synthesis system for identifiable materials according to claim 2, characterized in that, The single-unit delivery unit further includes a first valve group cleaning agent inlet valve (SV1) located at the front end of the first valve group (V1) of the single-unit inlet valve and a second valve group cleaning agent inlet valve (SV2) located at the front end of the second valve group (V2) of the single-unit inlet valve; the low-flow-rate reagent delivery unit includes a low-flow-rate reagent inlet valve cleaning agent inlet valve (SV3) located at the front end of the low-flow-rate reagent inlet valve group (V4); the high-flow-rate reagent delivery unit includes a high-flow-rate reagent inlet valve cleaning agent inlet valve (SV4) located at the front end of the high-flow-rate reagent inlet valve group (V5).

8. The solid-phase synthesis system for identifying materials according to claim 1, characterized in that, The common flow path is also provided with a temperature control valve group (V7) and a heat exchanger. The temperature control valve group (V7) is located between the mixing and draining valve group (V6) and the reactor switching valve group (V8). The heat exchanger is connected to the temperature control valve group (V7).

9. The solid-phase synthesis system for identifiable materials according to claim 1, characterized in that, It also includes a flow meter and / or a pressure monitor and / or a temperature monitor, wherein the flow meter is disposed at the outlet end of at least one of the first group of pumps, the second group of pumps and the third group of pumps, for monitoring real-time flow; and the pressure monitor and / or temperature monitor is disposed on the common flow path for monitoring system pressure and temperature; And / or, also includes a UV monitor (UV) and / or a conductivity monitor (CT), the UV monitor (UV) and / or the conductivity monitor (CT) being disposed on the common flow path and located between the reactor and the circulating discharge switching valve assembly (V9); And / or, the waste outlet of the circulating drainage switching valve group (V9) is connected to a second back pressure valve (BP2).

10. A method for solid-phase synthesis using the solid-phase synthesis system for identifiable materials as described in any one of claims 1 to 9, characterized in that, Includes the following steps: (1) Use the analysis and monitoring device to perform spectral analysis on the monomeric materials, and / or low-flow-rate reagents, and / or high-flow-rate reagents input into the system and compare them with the preset parameters. If the comparison results are inconsistent, stop or pause the machine. (2) The monomeric materials, low-flow-rate reagents and high-flow-rate reagents that have passed the identification and meet the preset conditions are combined and mixed in the mixing and draining valve group; (3) The mixed solution is fed into a common flow path and its temperature is controlled; (4) The temperature-controlled solution enters the reactor switching valve group. Through the switching of the reactor switching valve group, the solution passes through the reactor for deprotection and activation coupling reaction, or bypasses the reactor. (5) The solution after the reaction enters the circulating drain switching valve group. Through the switching of the circulating drain switching valve group, the solution is discharged out of the system or returned to the inlet of the third pump group and re-enters the mixing drain valve group for mixing. It then enters the reactor through the common flow path and the reactor switching valve group to form a self-circulating loop.

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