Polypeptide solid-phase synthesis device

Abstract

The utility model provides a polypeptide solid-phase synthesis device. The polypeptide solid-phase synthesis device comprises at least two mutually independent circulating pipelines; a synthetic column is arranged on the first pipeline and the circulating pipeline; a first branch pipe; the second branch pipe is communicated with the liquid outlet end of the first pipeline; a second pipeline; a first switching valve; a third pipeline; the liquid outlet ends of the second switching valve, the second pipeline and the third pipeline are selectively communicated with the liquid inlet end of the first pipeline, and the liquid outlet end of the second branch pipe is selectively communicated with the third pipeline. According to the technical scheme, the problems that an existing polypeptide synthesizer can only complete synthesis of one peptide chain every time, and when synthesis of a plurality of peptide chains with different sequences needs to be completed at the same time, after synthesis of a single peptide chain is completed, a product needs to be taken out, a synthesis column needs to be cleaned, then filling is conducted again, and then synthesis of a next peptide chain can be conducted are solved. And the synthesis period is too long.

Description

TECHNICAL FIELD

[0001] The utility model relates to polypeptide synthesis device technical field, specifically, relate to a polypeptide solid phase synthesis device. BACKGROUND

[0002] Polypeptide is by multiple amino acids through the peptide bond connection and form a kind of compound. In recent years, with the development and maturity of polypeptide synthesis technology, polypeptide drug has become one of the hot spots of drug research and development, and it is widely used in the prevention, diagnosis and treatment of tumor, cardiovascular and cerebrovascular diseases, hepatitis, diabetes, AIDS and other diseases because of wide indications, high safety and significant efficacy, with broad development prospects. With the continuous expansion of the application range of polypeptide drugs in clinical and the listing of new products, the clinical treatment position of this kind of drugs is continuously improved, and many varieties are included in the international and domestic relevant disease treatment guidelines and expert consensus. With the rapid development of technology related to polypeptide synthesis (such as the generation of solid phase polypeptide synthesis technology), equipment and process, the cost of polypeptide drug research and development and production cost have been greatly reduced, and the development of polypeptide drugs has continued to heat up.

[0003] At present, in the polypeptide solid phase synthesis process, polypeptide synthesizer is often used for synthesis, however, the traditional polypeptide synthesizer can only complete the synthesis of one peptide chain at a time, when several different sequence peptide chains need to be synthesized at the same time, the product needs to be taken out after the synthesis of single peptide chain is completed, and the synthesis column needs to be cleaned before filling again to synthesize the next peptide chain, which leads to long synthesis cycle. UTILITY MODEL CONTENT

[0004] The main purpose of the utility model is to provide a polypeptide solid phase synthesis device, which can solve the problem that the existing polypeptide synthesizer can only complete the synthesis of one peptide chain at a time, when several different sequence peptide chains need to be synthesized at the same time, the product needs to be taken out after the synthesis of single peptide chain is completed, and the synthesis column needs to be cleaned before filling again to synthesize the next peptide chain, which leads to long synthesis cycle.

[0005] In order to achieve the above object, the utility model provides a polypeptide solid phase synthesis device, include: at least two independent circulation pipeline, be provided with synthesis column on circulation pipeline, first pipeline, first branch pipe, the liquid outlet end of first branch pipe can select at least one of at least two circulation pipeline intercommunication, second branch pipe, with the liquid outlet end of first pipeline intercommunication, the liquid outlet end of each circulation pipeline can select second branch pipe intercommunication, second pipeline, be provided with first delivery pump on second pipeline, first switch valve, set up in the liquid inlet end of second pipeline, first switch valve has first export and at least two first import with first export optional intercommunication, the liquid inlet end of second pipeline can select first export intercommunication, third pipeline, be provided with second delivery pump on third pipeline, second switch valve, set up in the liquid inlet end of third pipeline, second switch valve has second export and at least two second import with second export optional intercommunication, the liquid inlet end of third pipeline can select second export intercommunication, the liquid outlet end of second pipeline and third pipeline can select the liquid inlet end of first pipeline intercommunication, the liquid outlet end of second branch pipe can select third pipeline intercommunication.

[0006] Further, the polypeptide solid phase synthesis device further comprises a third switch valve and a fourth switch valve, the circulation pipeline comprises a main pipeline and a third branch pipe, the liquid inlet end of the main pipeline is selectively communicated with the liquid outlet end of the first branch pipe through the third switch valve, the liquid outlet end of the main pipeline is selectively communicated with the second branch pipe through the fourth switch valve, one end of the third branch pipe is communicated with the main pipeline and forms a first node A with the main pipeline, the other end of the third branch pipe is communicated with the main pipeline and forms a second node B with the main pipeline, the synthesis column is arranged on the main pipeline, the synthesis column is located between the first node A and the second node B, and a third delivery pump is arranged on the third branch pipe.

[0007] Further, the synthesis column comprises a shell and a piston rod, the first end of the piston rod extends into the inner cavity of the shell, the piston rod is movably arranged along the extension direction of the shell relative to the shell, the first end of the piston rod is provided with a piston, and the outer circumferential surface of the piston is sealingly matched with the inner wall surface of the shell.

[0008] Further, the polypeptide solid phase synthesis device further comprises a pre-activation circulation pipeline, the liquid inlet end of the pre-activation circulation pipeline is selectively communicated with the second pipeline and the third pipeline, the liquid outlet end of the pre-activation circulation pipeline is selectively communicated with the liquid inlet end of the first pipeline, and a fourth delivery pump and a reactor are arranged on the pre-activation circulation pipeline.

[0009] Further, the polypeptide solid phase synthesis device further comprises at least one fourth pipeline, the liquid inlet end of the fourth pipeline is provided with a fifth switch valve, the fifth switch valve has a third outlet and at least two third inlets selectively communicated with the third outlet, the liquid inlet end of the fourth pipeline is selectively communicated with the third outlet, and the liquid outlet end of the fourth pipeline is selectively communicated with the second pipeline through the first switch valve.

[0010] Further, the polypeptide solid-phase synthesis device further comprises a sixth switch valve and a liquid discharge pipeline, and the liquid outlet end of the second branch pipe is selectively communicated with the third pipeline and the liquid discharge pipeline through the sixth switch valve.

[0011] Further, the third pipeline comprises a first pipe segment and a second pipe segment, and the liquid outlet end of the second branch pipe is selectively communicated with the first pipe segment and the second pipe segment through the sixth switch valve.

[0012] Further, the liquid outlet end of the liquid discharge pipeline is provided with a seventh switch valve, the seventh switch valve has a fourth inlet and at least two fourth outlets selectively communicated with the fourth inlet, and the liquid outlet end of the liquid discharge pipeline is selectively communicated with the fourth inlet.

[0013] Further, the polypeptide solid-phase synthesis device further comprises at least two conductivity detectors, the at least two conductivity detectors are one-to-one corresponding to the at least two circulating pipelines, and the conductivity detector is installed on the corresponding circulating pipeline; and / or the polypeptide solid-phase synthesis device further comprises at least two ultraviolet detection devices, the at least two ultraviolet detection devices are one-to-one corresponding to the at least two circulating pipelines, and the ultraviolet detection device is installed on the corresponding circulating pipeline.

[0014] Further, the polypeptide solid-phase synthesis device further comprises a fifth pipeline and an eighth switch valve, the fourth switch valve has a fifth outlet and at least two fifth inlets selectively communicated with the fifth outlet, the at least two main pipelines are one-to-one corresponding to the at least two fifth outlets, the liquid outlet end of the main pipeline is selectively communicated with the corresponding fifth outlet, one end of the fifth pipeline is selectively communicated with the fifth outlet, and the other end of the fifth pipeline is selectively communicated with the second branch pipe through the eighth switch valve.

[0015] Applying the technical solution of this utility model, the first switching valve has a first outlet and at least two first inlets selectively connected to the first outlet. The configuration of at least two first inlets allows the introduction of at least two different reagents. These reagents can then be delivered to the first pipeline via a second pipeline using a first delivery pump. Similarly, the configuration of at least two second inlets also enables the introduction of at least two different reagents. These reagents (e.g., deprotecting reagents, activators, and amino acids) can be delivered to the first pipeline via a third pipeline using a second delivery pump. The reagents in the first pipeline can then selectively enter the corresponding circulation pipeline for peptide chain synthesis. The configuration of at least two independent circulation pipelines allows the peptide solid-phase synthesis device of this application to simultaneously synthesize multiple peptide chains. It allows the synthesis reactions of different peptide chains to proceed independently in their respective circulation pipelines, eliminating the need for cleaning and reloading after the previous peptide chain synthesis is completed. This significantly improves the peptide chain synthesis efficiency and significantly reduces the peptide chain synthesis cycle. Simultaneously, it enables the production of more peptide chains with different or identical sequences in a single synthesis process, which can be widely applied in the field of peptide drug development, promoting the research and innovation of peptide drugs.

[0016] Existing peptide solid-phase synthesizers have the following drawbacks: they mostly use semi-automatic batch synthesizers, the synthesis process is batch synthesis, which is time-consuming and labor-intensive, and mostly requires manual intervention, resulting in low synthesis efficiency; the pipeline design is unreasonable, and reagents in the pipeline are easily cross-contaminated, affecting the quality of synthesis; there is a lack of online monitoring instruments, so the synthesis progress cannot be judged in real time, and sampling and monitoring from the batch are time-consuming and labor-intensive; the synthesis process is intermittent and discontinuous, requiring a lot of manual intervention, lacking process detection, and is time-consuming and labor-intensive.

[0017] The polypeptide solid-phase synthesis apparatus of this application has the following advantages:

[0018] 1) By setting up multiple delivery pumps and multiple switching valves, it is possible to achieve simultaneous synthesis in at least two circulation channels, which can save manpower, improve synthesis efficiency, and shorten the research and development cycle;

[0019] 2) By movably setting the piston rod relative to the shell along the extension direction of the shell, the volume of the reaction space of the synthesis column can be dynamically adjusted as the volume of the resin increases, thereby changing the size of the reaction space of the synthesis column, ensuring that the reagents fully contact the resin, reducing waste, ensuring the purity of the synthesized peptides, and improving the synthesis efficiency.

[0020] 3) This application optimizes existing peptide synthesis equipment that is too bulky and unsuitable for research and development experiments. Based on the overall layout, the pipelines through which materials need to pass and where residues are generated are optimized and shortened, reducing dead volume and material residues, while further minimizing the risk of cross-contamination.

[0021] 4) This application optimizes the existing peptide synthesis equipment to address the problem that mechanical stirring can easily damage the product. The peptide solid-phase synthesis device of this application can realize the circulation of reagents in the circulation pipeline through the circulation pipeline and the third delivery pump in the circulation pipeline, thereby replacing the stirring device. This can reduce the shear force of mechanical stirring on the resin, thereby reducing the risk of product damage and improving the yield. At the same time, it can fully mix the materials and save material and labor costs.

[0022] 5) This application can monitor part of the synthesis process in real time by setting up a pressure sensor, a temperature sensor, a conductivity meter, an ultraviolet detection device and a bubble sensor;

[0023] 6) By adopting a reasonable pipeline layout and equipped with multiple delivery pumps and multiple switching valves, it is possible to achieve the simultaneous synthesis of multiple peptide chains;

[0024] 7) The setup of at least two independent circulation pipelines enables the polypeptide solid-phase synthesis apparatus of this application to synthesize multiple peptide chains simultaneously, allowing the synthesis reactions of different peptide chains to proceed independently in their respective circulation pipelines without waiting for the cleaning and reloading process after the synthesis of the previous peptide chain is completed. This maximizes the continuity of synthesis, reduces the operation time between each process and between processes, and greatly improves production efficiency.

[0025] 8) It adopts a reasonable pipeline layout and has a relatively simple overall structure with a small dead volume, which can reduce material residue and the risk of cross-contamination between materials. At the same time, it can save materials and achieve multiple circulation modes without manual switching, saving costs and improving synthesis efficiency.

[0026] In summary, the polypeptide solid-phase synthesis apparatus of this application has a simple structure, reasonable pipeline layout, small dead volume and saves materials. It can simultaneously synthesize peptide chains with multiple different peptide sequences, save manpower, effectively improve synthesis efficiency and shorten the synthesis cycle. Compared with traditional synthesis kettles, which are equipped with mechanical stirring devices to ensure sufficient reaction, this application can achieve self-circulation, so as to fully mix the materials, save materials and eliminate the risk of product damage caused by mechanical stirring. It can also be easily converted from laboratory scale to industrial production scale. Attached Figure Description

[0027] The accompanying drawings, which form part of this specification, are used to provide a further understanding of this utility model. The illustrative embodiments and descriptions of this utility model are used to explain this utility model and do not constitute an undue limitation thereof. In the drawings:

[0028] Figure 1 A schematic diagram of the structure of a polypeptide solid-phase synthesis apparatus according to an embodiment of the present invention is shown.

[0029] The above figures include the following reference numerals:

[0030] 10. Circulation pipeline; 11. Main pipeline; 111. Synthesis column; 12. Third branch pipeline; 121. Third transfer pump; 20. First pipeline; 30. First branch pipeline; 40. Second branch pipeline; 50. Second pipeline; 51. First switching valve; 60. Third pipeline; 61. Second switching valve; 62. First pipe section; 63. Second pipe section; 70. Third switching valve; 80. Fourth switching valve; 90. Pre-activation circulation pipeline; 91. Fourth transfer pump; 92. Reactor; 100. Fourth pipeline; 101. Fifth switching valve; 200. Sixth switching valve; 300. Drainage pipeline; 400. Seventh switching valve; 500. Conductivity meter; 600. Ultraviolet detection device; 700. First transfer pump; 800. Second transfer pump; 900. Fifth pipeline; 901. Eighth switching valve; 902. Ninth switching valve; 903. Sixth pipeline. Detailed Implementation

[0031] It should be noted that, where there is no conflict, the embodiments and features in the embodiments of this utility model can be combined with each other. The present utility model will now be described in detail with reference to the accompanying drawings and embodiments.

[0032] like Figure 1 As shown, this utility model provides a polypeptide solid-phase synthesis apparatus, which includes: at least two independent circulation pipelines 10, with a synthesis column 111 disposed on each circulation pipeline; a first pipeline 20; a first branch pipe 30 connected to the liquid outlet of the first pipeline 20, the liquid outlet of the first branch pipe 30 being selectively connected to at least one of the at least two circulation pipelines 10; a second branch pipe 40, with the liquid outlet of each circulation pipeline 10 selectively connected to the second branch pipe 40; a second pipeline 50, with a first delivery pump 700 disposed on the second pipeline 50; and a first switching valve 51 disposed at the liquid inlet of the second pipeline 50. 51 has a first outlet and at least two first inlets selectively connected to the first outlet; the inlet end of the second pipeline 50 is selectively connected to the first outlet; a third pipeline 60 is provided with a second transfer pump 800; a second switching valve 61 is provided at the inlet end of the third pipeline 60, the second switching valve 61 has a second outlet and at least two second inlets selectively connected to the second outlet; the inlet end of the third pipeline 60 is selectively connected to the second outlet; the outlet ends of both the second pipeline 50 and the third pipeline 60 are selectively connected to the inlet end of the first pipeline 20; and the outlet end of the second branch pipe 40 is selectively connected to the third pipeline 60.

[0033] In this embodiment, the first pipeline 20 refers to Figure 1 In the section of pipe from point C to point D, the first branch pipe 30 refers to...Figure 1 The section of pipe from point D to point P, the second branch pipe 40 refers to... Figure 1 The section of pipe from point P to point E, the second pipe 50 refers to... Figure 1 The section of pipe from point M to point N, and the third section 60 refers to the section of pipe from point H to point L.

[0034] The first switching valve 51 has a first outlet and at least two first inlets selectively connected to the first outlet. The configuration of at least two first inlets allows at least two different reagents to be introduced. The reagents can then be delivered to the first pipeline 20 via the second pipeline 50 through the first delivery pump 700. Similarly, the configuration of at least two second inlets also enables the introduction of at least two different reagents. The reagents (e.g., deprotection reagents, activators, and amino acids) can be delivered to the first pipeline 20 via the third pipeline 60 through the second delivery pump 800. Then, the reagents in the first pipeline 20 can be selectively entered into the corresponding circulation pipeline 10 for peptide chain synthesis. The configuration of at least two independent circulation lines 10 enables the polypeptide solid-phase synthesis apparatus of this application to synthesize multiple peptide chains simultaneously. This allows the synthesis reactions of different peptide chains to proceed independently in their respective circulation lines 10, eliminating the need to wait for the cleaning and reloading process after the synthesis of the previous peptide chain. This significantly improves the synthesis efficiency of peptide chains and significantly reduces the synthesis cycle time. At the same time, it enables the production of more peptide chains with different or identical sequences in a single synthesis process. This apparatus can be widely applied in the field of polypeptide drug development, promoting the research and innovation of polypeptide drugs.

[0035] The liquid outlet of the second branch pipe 40 can be selectively connected to the third pipe 60. When the liquid outlet of the second branch pipe 40 is connected to the third pipe 60, the liquid in the second branch pipe 40 can return to the circulation pipe 10 after passing through the third pipe 60, the first pipe 20, and the first branch pipe 30.

[0036] like Figure 1 As shown, in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes a third switching valve 70 and a fourth switching valve 80. The circulation pipeline 10 includes a main pipeline 11 and a third branch pipeline 12. The inlet end of the main pipeline 11 is selectively connected to the outlet end of the first branch pipeline 30 through the third switching valve 70. The outlet end of the main pipeline 11 is selectively connected to the second branch pipeline 40 through the fourth switching valve 80. One end of the third branch pipeline 12 is connected to the main pipeline 11 and forms a first node A with the main pipeline 11. The other end of the third branch pipeline 12 is connected to the main pipeline 11 and forms a second node B with the main pipeline 11. The synthesis column 111 is disposed on the main pipeline 11 and is located between the first node A and the second node B. A third delivery pump 121 is disposed on the third branch pipeline 12.

[0037] In this embodiment, the outlet of the second branch pipe 40 can be connected to a collection device or other equipment. The main pipeline 11 and the third branch pipe 12 are connected. With the third delivery pump 121, the reagent can circulate between the main pipeline 11 and the third branch pipe 12, allowing the reaction reagent to flow through the synthesis column 111 multiple times, ensuring sufficient contact between the reagent and the carrier in the synthesis column, thus improving reaction efficiency. The third switching valve 70 allows the reagent in the first branch pipe 30 to enter the corresponding main pipeline 11 as needed. The fourth switching valve 80 ensures that the outlet of the main pipeline 11 is not connected to the second branch pipe 40 during the reaction, allowing the reagent to circulate only within the circulation pipeline 10. After the reaction, the fourth switching valve 80 connects the outlet of the main pipeline 11 to the second branch pipe 40, allowing the reacted liquid to be discharged through the second branch pipe 40 for collection, storage, or subsequent processing of the generated peptide chains.

[0038] Traditional synthesis reactors are equipped with mechanical stirrers to ensure complete reaction, which increases synthesis costs and the risk of product damage from mechanical stirring. The peptide solid-phase synthesis apparatus of this application, through a circulation pipeline 10 and a third delivery pump 121 on the circulation pipeline 10, can circulate reagents within the circulation pipeline 10, replacing the stirring device. This reduces the shear force exerted on the resin by mechanical stirring, thereby reducing the risk of product damage and increasing yield.

[0039] like Figure 1 As shown, in one embodiment of the present invention, the synthesis column 111 includes a housing and a piston rod. The first end of the piston rod extends into the inner cavity of the housing. The piston rod is movably disposed relative to the housing along the extension direction of the housing. A piston is disposed at the first end of the piston rod, and the outer peripheral surface of the piston is sealed to the inner wall surface of the housing.

[0040] In this embodiment, solid-phase synthesis of peptides involves covalently linking the carboxyl group of the terminal amino acid of the desired peptide chain to an insoluble solid support via a dehydration condensation reaction. Then, starting with the amino group of this amino acid, amino acids are linked one by one until the entire peptide chain is synthesized. As amino acids are linked, the volume of the resin gradually increases. A reaction space is formed between the piston and the bottom wall of the shell. Reagents are introduced into this reaction space. In solid-phase peptide synthesis, the volume of the resin gradually increases with the number of amino acids. Traditional synthesis columns cannot adapt to this change, potentially leading to excessive reagent extrusion from the reaction system and waste. However, the piston rod of this application is movable along the extension direction of the shell, allowing the volume of the reaction space in the synthesis column to be dynamically adjusted as the resin volume increases. This changes the size of the reaction space, ensuring sufficient reagent contact with the resin, reducing waste, guaranteeing the purity of the synthesized peptide, and improving synthesis efficiency.

[0041] It should be noted that the piston rod can be moved along the extension direction of the shell using existing equipment (e.g., motors, cylinders, etc.), or its position can be manually adjusted. The size of the reaction space in the synthesis column can be adjusted during the synthesis process using software programs and monitors to reduce reagent waste and save costs.

[0042] like Figure 1 As shown, in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes a pre-activation circulation pipeline 90. The inlet end of the pre-activation circulation pipeline 90 can be selectively connected to the second pipeline 50 and the third pipeline 60, and the outlet end of the pre-activation circulation pipeline 90 can be selectively connected to the inlet end of the first pipeline 20. A fourth delivery pump 91 and a reactor are provided on the pre-activation circulation pipeline 90.

[0043] In this embodiment, the reactor 92 allows for a pre-activation reaction before the amino acids reach the synthesis column, ensuring that the amino acids are highly activated before coupling with the peptide chains on the solid support, thus significantly increasing the reaction rate and efficiency. The fourth delivery pump 91 allows the activator and amino acids to circulate within the pre-activation circulation pipeline 90, passing through the reactor 92 multiple times to ensure effective activation.

[0044] In one embodiment, reactor 92 can be a tank or a container capable of holding reaction reagents. The outer periphery of reactor 92 is provided with a jacket of the prior art for adjusting the temperature and ensuring the smooth progress of the reaction.

[0045] like Figure 1 As shown, in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes at least one fourth pipeline 100. The inlet end of the fourth pipeline 100 is provided with a fifth switching valve 101. The fifth switching valve 101 has a third outlet and at least two third inlets that can be selectively connected to the third outlet. The inlet end of the fourth pipeline 100 is selectively connected to the third outlet, and the outlet end of the fourth pipeline 100 is selectively connected to the second pipeline 50 through a first switching valve 51.

[0046] In this embodiment, the fifth switching valve 101 has at least two third inlets, which can be connected to at least two different reagent tanks or reagent supply devices at the same time. The setting of at least two third inlets allows at least two different reagents to be added to the second pipeline 50 through the fourth pipeline 100. With the above setting, the number of different reagents that can be added to the polypeptide solid-phase synthesis device of this application can be further increased.

[0047] like Figure 1As shown, in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes a sixth switching valve 200 and a drain pipe 300. The outlet end of the second branch pipe 40 is selectively connected to the third pipe 60 and the drain pipe 300 through the sixth switching valve 200.

[0048] In this embodiment, the drain pipe 300 refers to Figure 1 The section of pipeline from point J to point K. The sixth switching valve 200 allows the liquid in the second branch pipe 40 to be directed to the third pipe 60 for further recycling, or to the drain pipe 300 for discharge. When the outlet end of the second branch pipe 40 is connected to the third pipe 60 through the sixth switching valve 200, the inlet end of the third pipe 60 is not connected to the second outlet. At this time, the liquid in the second branch pipe 40 can be recirculated into the circulation pipe 10.

[0049] like Figure 1 As shown, in one embodiment of the present invention, the third pipeline 60 includes a first pipeline segment 62 and a second pipeline segment 63, and the liquid outlet end of the second branch pipe 40 is selectively connected to the first pipeline segment 62 and the second pipeline segment 63 through a sixth switching valve 200.

[0050] In this embodiment, the first pipe segment 62 refers to Figure 1 The section of pipe from point F to point G, the second pipe segment 63 refers to... Figure 1 The section of pipe from point H to point L. When it is necessary for the liquid in the second branch pipe 40 to return to the circulation pipe 10 for circulation, the outlet end of the second branch pipe 40 is connected to the second pipe section 63 through the sixth switching valve 200. At this time, the liquid in the second branch pipe 40 can return to the circulation pipe 10 for circulation after passing through the second pipe section 63, the first pipe 20, and the first branch pipe 30 in sequence.

[0051] like Figure 1 As shown, in one embodiment of the present invention, a seventh switching valve 400 is provided at the outlet end of the drain pipe 300. The seventh switching valve 400 has a fourth inlet and at least two fourth outlets that can be selectively connected to the fourth inlet. The outlet end of the drain pipe 300 is selectively connected to the fourth inlet to collect waste liquid in categories, which can be recycled and reused.

[0052] In this embodiment, the provision of at least two fourth outlets means that different waste liquids generated during the synthesis process can be directed to different waste liquid collection containers or treatment systems. This helps to manage waste liquids more precisely, prevents mutual interference between waste liquids of different properties, and facilitates subsequent waste liquid treatment or recycling.

[0053] like Figure 1As shown in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes at least two conductivity meters 500, each corresponding to one of at least two circulation pipelines 10, and the conductivity meters 500 are installed on the corresponding circulation pipelines 10. The polypeptide solid-phase synthesis apparatus also includes at least two ultraviolet (UV) detection devices 600, each corresponding to one of the at least two circulation pipelines 10, and the UV detection devices 600 are installed on the corresponding circulation pipelines 10.

[0054] In this embodiment, conductivity is an indicator of the ability of ions to conduct electricity in a solution, directly reflecting the ionic strength of the solution. During peptide synthesis, changes in conductivity can reflect changes in the properties of the reaction medium in real time, such as the concentration of the activator and the degree of deprotection reaction. During the synthesis process, the conductivity detector 500 can detect the conductivity signal in the synthesis process online.

[0055] The UV detection device 600 is used for online detection of UV absorption during the synthesis process. By setting up the conductivity meter 500 and the UV detection device 600, the progress of some reactions can be judged online, guiding the correction of the synthesis process to ensure product purity.

[0056] It should be noted that the conductivity meter 500 and the ultraviolet detection device 600 adopt existing technology, and their specific structures will not be described in detail here.

[0057] like Figure 1 As shown, in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes a fifth pipeline 900 and an eighth switching valve 901. The fourth switching valve 80 has a fifth outlet and at least two fifth inlets that can be selectively connected to the fifth outlet. At least two main pipelines 11 are configured to correspond one-to-one with at least two fifth outlets. The liquid outlet end of the main pipeline 11 is selectively connected to the corresponding fifth outlet. One end of the fifth pipeline 900 is selectively connected to the fifth outlet, and the other end of the fifth pipeline 900 is selectively connected to the second branch pipe 40 through the eighth switching valve 901.

[0058] With the above settings, the circulation pipe 10 and the second branch pipe 40 can be selectively connected.

[0059] like Figure 1 As shown, in one embodiment of the present invention, the polypeptide solid-phase synthesis apparatus further includes a ninth switching valve 902, and the second pipeline 50 and the third pipeline 60 are selectively connected to the pre-activated circulation pipeline 90 and the first pipeline 20 through the ninth switching valve 902.

[0060] In one embodiment of this utility model, the first switching valve 51, the second switching valve 61, the third switching valve 70, the fourth switching valve 80, the fifth switching valve 101, the sixth switching valve 200, the seventh switching valve 400, the eighth switching valve 901, and the ninth switching valve 902 are all multi-port valves. The operation of each switching valve can be controlled by the rotation of an actuator motor driver, which drives the rotor fixed at the shaft end to rotate, switching to the channel on the required valve head, thereby controlling the on / off state of the pipeline connected to the individual switching valve.

[0061] like Figure 1 As shown, in one embodiment of this utility model, the polypeptide solid-phase synthesis apparatus further includes a sixth pipeline 903, which refers to... ​ In the section of pipeline from point D to point Q, the inlet end of the sixth pipeline 903 is connected to the outlet end of the first pipeline 20, and the outlet end of the sixth pipeline 903 can be selectively connected to the inlet end of the first pipeline 20. The outlet end of the second branch pipeline 40 can be selectively connected to the drain pipeline 300 through the sixth switching valve 200.

[0062] If impurities are present in the second pipeline 50, the first transfer pump 700, and the second transfer pump 800, or if the pre-activation reaction through the reactor 92 fails, in order to prevent the waste liquid containing impurities from entering the circulation pipeline 10 and contaminating the reaction solution, the waste liquid can be discharged sequentially through the first pipeline 20, the sixth pipeline 903, the second branch pipe 40, and the drain pipeline 300.

[0063] In one embodiment of this invention, the polypeptide solid-phase synthesis apparatus further includes a deprotection cycle, an amino acid activation cycle, and an amino acid coupling cycle. During the deprotection cycle, the deprotecting reagent enters through the second switching valve 61, passes through the first pipe section 62 and the sixth switching valve 200, and is then transported by the second delivery pump 800 to the ninth switching valve 902. It then passes through the first pipe 20 and the first branch pipe 30 to reach the third switching valve 70. The third switching valve 70 then selects the corresponding circulation pipe 10, and the reagent enters the corresponding synthesis column 111. At this time, the third delivery pump 121 is activated for circulation, ensuring sufficient contact between the deprotecting reagent and the carrier in the synthesis column. During the amino acid activation cycle, the amino acid and activator are combined through the first delivery pump 700 and the second delivery pump 800, pass through the ninth switching valve 902, and enter the pre-activation circulation pipe 90. Then, the fourth delivery pump 91 is activated for circulation, ensuring sufficient contact between the amino acid and the activator, thus activating the amino acid. During the amino acid coupling cycle, after the amino acid is fully activated, it enters the synthesis column 111 on the corresponding circulation pipeline 10, and then the third delivery pump 121 is turned on for circulation, so that the activated amino acid can fully contact the carrier.

[0064] In one embodiment of this utility model, the first switching valve 51, the second switching valve 61, the third switching valve 70, the fourth switching valve 80, the fifth switching valve 101, the sixth switching valve 200, the seventh switching valve 400, the eighth switching valve 901, and the ninth switching valve 902 in this application can be electric valves or pneumatic valves. The first delivery pump 700, the second delivery pump 800, the third delivery pump 121, and the fourth delivery pump 91 can be electric or pneumatic diaphragm pumps, plunger pumps, mechanical pumps, magnetic pumps, etc.

[0065] It should be noted that the switching valve of this application can achieve selective connection of more circulation pipelines 10 by increasing the valve position, and can increase the number of delivery pumps and switching valves to meet the material feeding requirements; the pipeline connection can adopt threaded or ferrule, chuck, flange connection, etc.

[0066] In one embodiment, the first switching valve 51 has 20 first inlets, the fifth switching valve 101 has 20 third inlets, and the second switching valve 61 has 10 second inlets.

[0067] Example 1

[0068] The polypeptide solid-phase synthesis apparatus of this application was used for testing. The synthesized amino acid sequence in this test was H-Gly-Lys-Val-Phe-Ser-Cys-OH. The specific testing process was as follows: 1) Equipment debugging: pre-feeding to confirm that the equipment can operate normally; 2) Pre-preparation: material preparation and column packing; 3) Synthesis: polypeptide synthesis was carried out by automatic feeding according to the predetermined synthesis sequence (deprotection, washing, activation, washing, synthesis, washing, end-capping, washing, coupling each amino acid in this order until the predetermined length of the target chain is reached); 4) Cutting: the complete polypeptide chain was peeled off from the carrier.

[0069] The above are the general steps for testing using the polypeptide solid-phase synthesis apparatus of this application. After cleavage, post-processing and purity testing are also required. According to the test results, the purities of the polypeptide chains synthesized using the polypeptide solid-phase synthesis apparatus of this application are 78.82%, 85.61%, 81.63%, 89.33%, 87.77%, and 93.13%, respectively, all meeting the research and development requirements. Improved synthesis efficiency: Synthesizing six target hexapeptides took 64.2 hours, while using existing equipment, synthesizing a single target hexapeptide takes 33.6 hours, and synthesizing six requires 201.6 hours, representing an efficiency improvement of more than two times.

[0070] From the above description, it can be seen that the above embodiments of this utility model achieve the following technical effects: The first switching valve has a first outlet and at least two first inlets selectively connected to the first outlet. The setting of at least two first inlets allows at least two different reagents to be introduced. Then, the reagents can be transported to the first pipeline via a second pipeline through a first delivery pump. Similarly, the setting of at least two second inlets can also enable the introduction of at least two different reagents. The reagents (e.g., deprotection reagents, activators, and amino acids, etc.) can be transported to the first pipeline via a third pipeline through a second delivery pump. Then, the reagents in the first pipeline can be selectively entered into the corresponding circulation pipeline for peptide chain synthesis. The setting of at least two independent circulation pipelines allows the peptide solid-phase synthesis device of this application to synthesize multiple peptide chains simultaneously, allowing the synthesis reactions of different peptide chains to be carried out independently in their respective circulation pipelines, without waiting for the cleaning and reloading process after the synthesis of the previous peptide chain is completed, thereby significantly improving the peptide chain synthesis efficiency and significantly reducing the peptide chain synthesis cycle. At the same time, it enables the production of more peptide chains with different or the same sequences in a single synthesis process, which can be widely used in the field of peptide drug development and promote the research and innovation of peptide drugs.

[0071] Obviously, the embodiments described above are only some embodiments of this utility model, and not all embodiments. Based on the embodiments of this utility model, all other embodiments obtained by those skilled in the art without creative effort should fall within the protection scope of this utility model.

[0072] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments according to this application. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0073] The above description is merely a preferred embodiment of this utility model and is not intended to limit the utility model. Various modifications and variations can be made to this utility model by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this utility model should be included within the protection scope of this utility model.

Claims

1. A polypeptide solid phase synthesis apparatus, characterized by, The polypeptide solid-phase synthesis device comprises: at least two independent circulation pipelines (10) provided with a synthesis column (111); a first pipeline (20); a first branch pipeline (30) in communication with a liquid outlet end of the first pipeline (20), and a liquid outlet end of the first branch pipeline (30) being selectively in communication with at least one of the at least two circulation pipelines (10); a second branch pipeline (40) in selective communication with a liquid outlet end of each of the circulation pipelines (10); a second pipeline (50) provided with a first delivery pump (700); a first switch valve (51) arranged at a liquid inlet end of the second pipeline (50), the first switch valve (51) having a first outlet and at least two first inlets in selective communication with the first outlet, and the liquid inlet end of the second pipeline (50) being selectively in communication with the first outlet; a third pipeline (60) provided with a second delivery pump (800); a second switch valve (61) arranged at a liquid inlet end of the third pipeline (60), the second switch valve (61) having a second outlet and at least two second inlets in selective communication with the second outlet, and the liquid inlet end of the third pipeline (60) being selectively in communication with the second outlet, and liquid outlet ends of the second pipeline (50) and the third pipeline (60) being selectively in communication with a liquid inlet end of the first pipeline (20), and a liquid outlet end of the second branch pipeline (40) being selectively in communication with the third pipeline (60).

2. The polypeptide solid-phase synthesis apparatus according to claim 1, characterized by The polypeptide solid-phase synthesis device further comprises a third switch valve (70) and a fourth switch valve (80), the circulation pipeline (10) comprises a main pipeline (11) and a third branch pipeline (12), a liquid inlet end of the main pipeline (11) is selectively in communication with a liquid outlet end of the first branch pipeline (30) through the third switch valve (70), a liquid outlet end of the main pipeline (11) is selectively in communication with the second branch pipeline (40) through the fourth switch valve (80), one end of the third branch pipeline (12) is in communication with the main pipeline (11) and forms a first node A with the main pipeline (11), the other end of the third branch pipeline (12) is in communication with the main pipeline (11) and forms a second node B with the main pipeline (11), the synthesis column (111) is arranged on the main pipeline (11), the synthesis column (111) is located between the first node A and the second node B, and a third delivery pump (121) is arranged on the third branch pipeline (12).

3. The polypeptide solid-phase synthesis apparatus according to claim 2, wherein The synthesis column (111) comprises a shell and a piston rod, a first end of the piston rod extends into an inner cavity of the shell, the piston rod is movably arranged relative to the shell along an extension direction of the shell, a first end of the piston rod is provided with a piston, and an outer circumferential surface of the piston is in sealing cooperation with an inner wall surface of the shell.

4. The polypeptide solid-phase synthesis apparatus according to any one of claims 1 to 3, characterized by The polypeptide solid-phase synthesis device further comprises a pre-activation circulation pipeline (90), a liquid inlet end of the pre-activation circulation pipeline (90) is selectively communicated with the second pipeline (50) and the third pipeline (60), a liquid outlet end of the pre-activation circulation pipeline (90) is selectively communicated with the liquid inlet end of the first pipeline (20), and a fourth delivery pump (91) and a reactor (92) are arranged on the pre-activation circulation pipeline (90).

5. The polypeptide solid-phase synthesis apparatus according to any one of claims 1 to 3, characterized by The polypeptide solid-phase synthesis device further comprises at least one fourth pipeline (100), a fifth switch valve (101) is arranged at a liquid inlet end of the fourth pipeline (100), the fifth switch valve (101) has a third outlet and at least two third inlets selectively communicated with the third outlet, the liquid inlet end of the fourth pipeline (100) is selectively communicated with the third outlet, and a liquid outlet end of the fourth pipeline (100) is selectively communicated with the second pipeline (50) through the first switch valve (51).

6. The polypeptide solid-phase synthesis apparatus according to any one of claims 1 to 3, characterized by The polypeptide solid-phase synthesis device further comprises a sixth switch valve (200) and a liquid discharge pipeline (300), and the liquid outlet end of the second branch pipeline (40) is selectively communicated with the third pipeline (60) and the liquid discharge pipeline (300) through the sixth switch valve (200).

7. The polypeptide solid-phase synthesis apparatus according to claim 6, wherein The third pipeline (60) comprises a first pipe section (62) and a second pipe section (63), and the liquid outlet end of the second branch pipeline (40) is selectively communicated with the first pipe section (62) and the second pipe section (63) through the sixth switch valve (200).

8. The polypeptide solid-phase synthesis apparatus according to claim 6, wherein A liquid outlet end of the liquid discharge pipeline (300) is provided with a seventh switch valve (400), the seventh switch valve (400) has a fourth inlet and at least two fourth outlets selectively communicated with the fourth inlet, and the liquid outlet end of the liquid discharge pipeline (300) is selectively communicated with the fourth inlet.

9. The polypeptide solid-phase synthesis apparatus according to any one of claims 1 to 3, characterized by The polypeptide solid-phase synthesis device further comprises at least two conductivity detectors (500), at least two conductivity detectors (500) are arranged in one-to-one correspondence with at least two circulation pipelines (10), and the conductivity detector (500) is installed on the corresponding circulation pipeline (10); and / or the polypeptide solid-phase synthesis device further comprises at least two ultraviolet detection devices (600), at least two ultraviolet detection devices (600) are arranged in one-to-one correspondence with at least two circulation pipelines (10), and the ultraviolet detection device (600) is installed on the corresponding circulation pipeline (10).

10. The polypeptide solid-phase synthesis apparatus according to claim 2 or 3, characterized by The polypeptide solid-phase synthesis device further comprises a fifth pipeline (900) and an eighth switch valve (901). The fourth switch valve (80) has a fifth outlet and at least two fifth inlets in selective communication with the fifth outlet. At least two of the main pipelines (11) are arranged in one-to-one correspondence with the at least two fifth outlets. The liquid outlet end of the main pipeline (11) is in selective communication with the corresponding fifth outlet. One end of the fifth pipeline (900) is in selective communication with the fifth outlet. The other end of the fifth pipeline (900) is in selective communication with the second branch pipeline (40) through the eighth switch valve (901).

Images